Key changes made to update the May 24, 2010, version o f the guidelines are summarized below. Throughout the revised guidelines, significant updates are highlighted and discussed. R ecom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal H IV Transmission in the United States i R ecom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal H IV Transmission in the United States iii Recom m endations for Use o f Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health a n d Interventions to Reduce Perinatal HIV Transmission in the United States vii Public comments A 2-week public comment period follows release of the updated guidelines on the AIDSinfo Web site. The Panel reviews comments received to determine whether additional revisions to the guidelines are indicated. The public may also submit comments to the Panel at any time at#
- This section and Table 3 include updates on recent results from international clinical trials, includ ing HPTN 046 in breastfeeding infants, which demonstrated that extending infant nevirapine pro phylaxis from 6 weeks to 6 months improved efficacy in reducing postnatal infections, and NICHD-HPTN 040/PACTG 1043 in formula-feeding infants, which demonstrated that when moth ers have not received antepartum antiretroviral (ARV) drugs, combination infant ARV prophylaxis reduces intrapartum transmission more than the standard 6-week infant zidovudine regimen.
- Preconception Care and Table 4

# (Drug Interactions Between H orm onal Contraceptives and A n tiretroviral A gents) :
- This section includes a new subsection on Reproductive Options for HIV Concordant and Serodiscordant Couples. The subsection includes discussion of HPTN 052 trial in discordant cou ples, which demonstrated that initiating antiretroviral therapy (ART) in infected individuals with CD4 cell counts from 350 to 550 cells/mm3 reduced the risk o f transmission to seronegative part ners. The subsection also includes discussion on trials of pre-exposure ARV prophylaxis.
- The section includes a new Table (Table 4) on drug interactions between hormonal contracep tives and ARV drugs. - Table 5 on ARV drugs in pregnancy has been revised to include drug formulation and dosing in formation in addition to pregnancy-related pharmacokinetic and toxicity data and recommenda tions for use in pregnancy. Table 5 also includes the newly approved drug rilpivirine.
- There is expanded discussion on treatment recommendations for adults and postpartum discon tinuation o f ARV drug regimens.
- Tenofovir has moved from a nucleoside reverse transcriptase inhibitor (NRTI) for Use in Spe cial Considerations to an Alternative NRTI choice; it is the Preferred NRTI choice for women who are co-infected with HIV and hepatitis B virus.
- Indinavir and nelfinavir have moved from Alternative protease inhibitor (PI) choices to PIs to Use in Special Circumstances.
- HIV-Infected Pregnant W om en W ho H ave N ever R eceived Antiretroviral Drugs (Antiretroviral N aive): This section includes expanded discussion o f new data suggesting early and sustained control of HIV viral replication is associated with decreased transmission in women who have undetectable viral load at delivery-data which favors initiation o f ARV drugs as early in pregnancy as possible for all women.
- HIV /H epatitis B C oinfection: The Panel now recommends combination ARV drug regimens in cluding anti-hepatitis B drugs for all HIV-infected pregnant women with hepatitis B virus (HBV) co infection:
- All pregnant women with HIV/HBV coinfection should receive a combination ARV drug regi men, including a dual nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide analogue re verse transcriptase inhibitor (NtRTI) backbone with two drugs active against both HIV and HBV (AII). Tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI/NtRTI backbone of a combination antepartum ARV regimen in HIV/HBV-coinfected pregnant women (AI).
- A cute H IV Infection: This is a new section discussing diagnosis and management o f acute HIV-1 infection in pregnancy.
- HIV-2 Infection and Pregnancy: This is a new section discussing diagnosis and management of HIV-2 infection in pregnancy.
- Com bination Antiretroviral Drugs and Pregnancy O utcom e: Data from several new studies on preterm delivery and combination ARV drug regimens are reviewed in this section. The Panel notes the following:
- Clinicians should be aware o f a possible small increased risk o f preterm birth in pregnant women receiving PI-based combination ARV regimens; however, given the clear benefits of such regimens for both the wom en's health and the prevention o f mother-to-child transmission, PIs should not be withheld for fear o f altering pregnancy outcome (A II).
- Intrapartum Antiretroviral T herapy/Prophylaxis: Based on the results o f the NICHD-HPTN 040/P1043 clinical trial, the Panel's no longer recommends intrapartum single-dose nevirapine for HIV-infected women in labor who have not received antepartum drugs. In this circumstance, the Panel recommends the following:
- Intravenous zidovudine is recommended for HIV-infected women in labor who have not re ceived antepartum ARV drugs, and infant combination ARV prophylaxis is recommended for 6 weeks (see Infant Antiretroviral Prophylaxis) (A II).
- Postpartum C are: This section includes expanded discussion o f considerations regarding stopping ARVs postpartum, including discussion o f results o f HPTN 052 and o f the importance o f counseling on safer sex practices and contraception during the postpartum period.
- Infant Antiretroviral Prophylaxis and - The Panel now recommends that twice daily dosing can be used for the 6-week zidovudine prophylaxis regimen in full-term infants.
- The recommended dose o f zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg body weight orally twice daily for the first 6 weeks o f life, begin ning as soon after birth as possible and preferably within 6-12 hours o f delivery.
- The design and results o f the NICHD-HPTN 040/PACTG 1043 clinical trial in formula-fed in fants are discussed. The trial demonstrated that when mothers have not received antepartum ARV drugs, combination infant ARV prophylaxis reduces intrapartum transmission more than the standard 6-week infant zidovudine regimen. Based on these data, the Panel's recommenda tion is now:
- Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen, started as soon after birth as possible (AI). A randomized, controlled trial has shown that a 2-drug regimen of zidovudine given for 6 weeks combined with three doses o f nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) is as effective as but less toxic than a 3-drug regimen o f zidovudine, nelfinavir and lamivudine. The 2drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States. (see General Considerations for Choice o f Infant Prophylaxis and Table 9) (A I).
- Table 9 includes the dosing for the 2-drug regimen used in the NICHD-HPTN 040/PACTG 1043 trial.
- A new subsection is included on management o f breastfeeding infants o f mothers first diag nosed with HIV infection during the postpartum period. , develops these guidelines. The guidelines provide health care providers with information for discussion with HIV-infected pregnant women to enable the patient/provider team to make informed decisions regarding the use o f ARV drugs during pregnancy and use o f scheduled cesarean delivery to reduce perinatal transmission o f HIV. The recommendations in the guidelines are accompanied by discussion o f various circumstances that commonly occur in clinical practice and the factors influencing treatment considerations. The Panel recognizes that strategies to pre vent perinatal transmission and concepts related to management o f HIV disease in pregnant women are rapidly evolving and will consider new evidence and adjust recommendations accordingly. The updated guidelines are available from the AID Sinfo Web site ().
Health care providers considering the use o f ARV agents for HIV-infected women during pregnancy must take into account two separate but related issues:
1. antiretroviral treatment (ART) o f maternal HIV infection; and 2.
ARV chemoprophylaxis to reduce the risk o f perinatal transmission o f HIV.
The benefits o f ARV drugs for a pregnant woman must be weighed against the risks o f adverse events to the woman, fetus, and newborn. Combination drug regimens are considered the standard o f care both for treatment o f HIV infection and for prevention o f perinatal transmission o f HIV2, 6. After provider coun seling and discussion on ARV drug use during pregnancy, a pregnant w om an's informed choice on whether to take ARV drugs either for her treatment or for prevention o f mother-to-child transmission or to follow other medical recommendations intended to reduce perinatal transmission o f HIV should be re spected. Coercive and punitive policies are potentially counterproductive; they may undermine provider patient trust and could discourage women from seeking prenatal care and adopting health care behaviors that optimize fetal and neonatal well-being.
The current guidelines have been structured to reflect the management o f an individual mother-child pair and are organized into a brief discussion o f preconception care followed by principles for management o f the woman and her infant during the antepartum, intrapartum, and postpartum periods. Although peri natal transmission of HIV occurs worldwide, these recommendations have been developed for use in the United States. Alternative strategies may be appropriate in other countries. Policies and practices in other countries regarding the use o f ARV drugs for reduction o f perinatal transmission o f HIV may differ from the recommendations in these guidelines and will depend on local considerations, including avail ability and cost o f ARV drugs, accessibility o f facilities for safe intravenous infusions during labor, and local recommendations regarding breastfeeding by HIV-infected women.

# Guidelines Development Process

# Topic Comment
Goal of the guidelines Provide guidance to HIV care practitioners on the optimal use of antiretroviral (ARV) agents in pregnant women for treatment of HIV infection and for prevention of mother-to-child transmission of HIV in the United States.

# Panel members
The Panel is composed of approximately 30 voting members who have expertise in management of pregnant HIV-infected women (such as training in either obstetrics/gynecology or women's health) and interventions to prevent mother-to-child transmission (such as specialized training in pediatric HIV infection) as well as com munity representatives with knowledge of HIV infection in pregnant women and interventions to prevent mother-to-child transmission. The U.S. government representatives, appointed by their agencies, include at

# Financial
All members of the Panel submit a written financial disclosure annually reporting any association with man disclosures ufacturers of ARV drugs or diagnostics used for management of HIV infections. A list of the latest disclo sures is available on the AIDSinfo Web site ().

# Users of the guidelines
Providers of care to HIV-infected pregnant women and to HIV-exposed infants Funding source Office of AIDS Research (OAR), NIH

# Evidence collection
The recommendations in these guidelines are generally based on studies published in peer-reviewed jour nals. On some occasions, particularly when new information may affect patient safety, unpublished data presented at major conferences or prepared by the FDA and/or manufacturers as warnings to the public may be used as evidence to revise the guidelines.

# Recommenda tion grading
See Table 2 .

# Method of synthesizing data
Each section of the guidelines is assigned to a small group of Panel members with expertise in the area of in terest. The members synthesize the available data and propose recommendations to the entire Panel. The Panel discusses and votes on all proposals during monthly teleconferences. Proposals receiving endorsement from a consensus of members are included in the guidelines as official Panel recommendations.
Other guidelines These guidelines focus on HIV-infected pregnant women and their infants. Other guidelines outline the use of antiretroviral therapy (ART) in nonpregnant HIV-infected adults and adolescents, HIV-infected children, and people who experience occupational or nonoccupational exposure to HIV. The guidelines described are also available on the AIDSinfo Web site (). Preconception management for non pregnant women of reproductive age is briefly discussed in this document. However, for more detailed dis cussion on issues of treatment of nonpregnant adults, the Working Group defers to the designated expertise offered by Panels that have developed those guidelines.

# Update plan
The Panel meets monthly by teleconference to review data that may warrant modification of the guidelines.
Updates may be prompted by new drug approvals (or new indications, new dosing formulations, or changes in dosing frequency), new significant safety or efficacy data, or other information that may have a significant impact on the clinical care of patients. In the event of significant new data that may affect patient safety, the Panel may issue a warning announcement and accompanying recommendations on the AIDSinfo Web site until the guidelines can be updated with appropriate changes. Updated guidelines are available at the AIDSinfo Web site ().
Recommendations in these guidelines are based on scientific evidence and expert opinion. Each recom mended statement is rated with a letter of A , B , or C that represents the strength o f the recommendation and with a numeral I , II, or III, according to the quality of evidence.

# Basis for Recommendations
Strength of Recommendation Quality of Evidence for Recommendation

# Mechanisms of Action of Antiretroviral Prophylaxis in Reducing Perinatal Transmission of HIV (Updated September 14, 2011)
Panel's Recommendations
- Antiretroviral (ARV) drugs reduce perinatal transmission by several mechanisms, including lowering maternal antepar tum viral load and providing infant pre-and post-exposure prophylaxis. Therefore, combined antepartum, intrapartum, and infant ARV prophylaxis is recommended to prevent perinatal transmission of HIV (AI).
Zidovudine and other ARV drugs can reduce perinatal transmission through a number o f mechanisms. Antenatal drug administration decreases maternal viral load in blood and genital secretions, which is a particularly important mechanism of action in women with high viral loads. Even among women with HIV RNA levels <1,000 copies/mL, however, ARV drugs have been shown to reduce the risk o f trans mission1. In addition, the level o f HIV RNA at delivery and receipt o f antenatal ARV drugs are inde pendently associated with risk o f transmission, suggesting that reduction in viral load is not solely responsible for the efficacy o f ARV prophylaxis2-3.
Another mechanism o f protection is infant pre-exposure prophylaxis achieved by administering ARV drugs that cross the placenta from mothers to infants and produce adequate systemic drug levels in the infants. This mechanism o f protection likely is particularly important during passage through the birth canal, a time when infants receive intensive exposure to maternal genital-tract virus. Infant post-expo sure prophylaxis is achieved by administering drugs to infants after birth. This intervention provides protection from cell-free or cell-associated virus that may have entered the fetal/infant systemic circula tion through maternal-fetal transfusion associated with uterine contractions during labor or systemic dis semination o f virus swallowed during infant passage through the birth canal.
The efficacy o f ARV drugs in reducing perinatal transmission likely is multifactorial, and each o f the mechanisms previously described may make a contribution. The importance o f the pre-and post-expo sure components of prophylaxis in reducing perinatal transmission is demonstrated by the efficacy o f in terventions that involve administration o f ARVs only during labor and/or to the newborns, discussed in the next section4-10.
transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double blind, placebo-controlled trial. Lancet.

# Lessons from International Clinical Trials of Short-Course Antiretroviral Regimens for Prevention of Perinatal Transmission of HIV (Updated September 14, 2011)
Panel's Recommendations
- All pregnant women who require therapy for their own health should receive a combination antepartum antiretroviral (ARV) drug regimen containing at least three drugs for treatment, which will also reduce the risk of perinatal transmis sion (AI).
- Combination antepartum drug regimens are also recommended for prevention of perinatal transmission in women who
do not yet require therapy for their own health (AII).
- ARV prophylaxis is more effective when given for a longer than a shorter duration. Therefore, ARV drugs should be started as soon as possible in women who require treatment for their own health (AI), and without delay after the first trimester in women who do not require immediate initiation of therapy for their own health, although earlier initiation can be considered in these women as well (BIII) (see Recommendations for Use of Antiretroviral Drugs during Pregnancy).
- In the absence of antepartum administration of ARV drugs, ARV drugs should be administered intrapartum in combina tion with infant ARV prophylaxis to reduce the risk of perinatal transmission (see Intrapartum Care) (AI); if antepartum and intrapartum ARV drugs are not received, infant ARV prophylaxis should be provided (see Infant Antiretroviral Pro phylaxis) (AI).
- Adding single-dose intrapartum/newborn nevirapine to the standard antepartum combination ARV regimens used for prophylaxis or treatment in pregnant women in the United States is not recommended. This is because the drug does not appear to provide additional efficacy in reducing transmission and it may be associated with development of nevirapine resistance (AI).
- Breastfeeding is not recommended for HIV-infected women in the United States-including those receiving combination antiretroviral therapy (ART)-because safe, affordable, and feasible alternatives are available (AII).
A number o f simple regimens have been identified that are effective in reducing perinatal transmission in resource-limited countries (see Table 3) . Direct comparison o f results from trials o f these regimens are difficult because the studies involved diverse patient populations residing in different geographic loca tions, infected with various viral subtypes, and with different infant feeding practices. However, some general conclusions can be drawn from the results, which are relevant to understanding use o f ARV drugs for prevention o f perinatal transmission in both resource-limited and resource-rich countries. 30.6% at 15 months (30% efficacy).
- MTCT was 22.5% in ZDV arm vs.
30.2% in placebo arm in pooled analysis at 24 months (26% effi cacy).
- MTCT was 16.5% in ZDV arm vs.
26.1% in placebo arm at 3 months (37% efficacy).
- MTCT was 22.5% in ZDV arm vs. 30.2% in placebo arm in pooled analysis at 24 months (26% effi cacy).

# PETRA trial
South Africa, Tanzania, and Uganda6
Breastfeeding and for mula feeding   12.3% in sdNVP arm vs. 9.3% in ZDV + 3TC arm at 8 weeks (difference not statistically significant, P = 0.11).
 Short-short arm stopped at interim analysis (10.5%). MTCT was 6.5% in long-long arm vs. 4.7% in long short arm and 8.6% in short-long arm at 6 months (no statistical dif ference). In utero transmission was significantly higher with short vs. long maternal therapy regimens (5.1% vs. 1.6%).
77% of women received dual-or triple-combination ARV regimens during pregnancy.
 Trial stopped early due to very low MTCT in both arms: 1.4% in sdNVP arm vs. 1.6% in placebo arm (53% of MTCT was in utero).
 ZDV-alone arm was stopped due to higher MTCT than the NVP-NVP arm (6.3% vs. 1.1%). In arms in which the mother received sdNVP MTCT rate did not differ significantly between the infant receiving or not receiving sdNVP (2.0% vs. 2.8%).
 MTCT was 6.5% (95% CI, 3.9%-9.1%) at 6 weeks; MTCT for histor ical control group receiving short ZDV (98% breastfed) was 12.8%.  Formula feeding + ZDV (infant) 4 weeks + sdNVP infant only
- Initial design: In formula-feeding arm, MTCT at 1 month was 2.4% in maternal and infant sdNVP arm and 8.3% in placebo arm (P = 0.05). In breastfeeding + infant ZDV arm, MTCT at 1 month was 8.4% in sdNVP arm and 4.1% in placebo arm (difference not statistically significant).
- R e v is e d d e sig n : MTCT at 1 month was 4.3% in maternal + infant sdNVP arm and 3.7% in maternal placebo + infant sdNVP arm (no significant dif ference; no interaction with mode of infant feeding).
- MTCT at 7 months was 9.1% in breastfeeding + ZDV arm and 5.6% in formula-feeding arm; mortality at 7 months was 4.9% in breastfeeding + ZDV arm vs. 9.3% in formula-feeding arm; HIV-free survival at 18 months was 15.6% breastfeeding + ZDV arm vs. 14.2% formula-feeding arm. -MTCT at 6 weeks was 5.3% in sdNVP arm vs. 2.5% in extended NVP arm (risk ratio 0.54, P = 0.009).
-MTCT at 6 months was 9.0% in sdNVP arm vs. 6.9% in extended NVP arm (risk ratio 0.80, P = 0.16).
- HIV-free survival significantly lower in extended NVP arm at both 6 weeks and 6 months of age.

# PEPI-Malawi Trial Malawi19
Breastfeeding sdNVP + ZDV for 1 week (control) vs. two extended infant regimens (NVP or NVP/ZDV) for 14 weeks
No AP ARV Oral IP: sdNVP (if mother presents in time)
Infant sdNVP + ZDV for 1 week (control) vs. con trol + NVP for 14 weeks vs. control + NVP/ZDV for 14 weeks
- Postnatal infection in infants unin fected at birth:
-MTCT at age 6 weeks was 5.1% in control vs. 1.7% in extended NVP (67% efficacy) and 1.6% in ex tended NVP/ZDV arms (69% effi cacy).
-MTCT at age 9 months was 10.6% in control vs. 5.2% in extended NVP (51% efficacy) and 6.4% in ex tended NVP/ZDV arms (40% effi cacy).
- No significant difference in MTCT be tween the extended prophylaxis arms; however, more hematologic toxicity with NVP/ZDV.  A rm 2: Maternal ZDV/3TC for 1 week (no further postnatal prophylaxis); infant sdNVP + ZDV for 1 week (no further postnatal prophy laxis)
MITRA
- MTCT at birth was 1.8% with mater nal triple-drug prophylaxis Arm 1 and 2.5% with ZDV/sdNVP Arm 2, not significantly different. In women with CD4 cell counts 350-500 cells/mm3, MTCT at birth was 1.7% in both arms.
- MTCT at age 12 months was 5.4% with maternal triple-drug prophylaxis Arm 1 and 9.5% with ZDV/sdNVP (with no further postnatal prophy laxis after 1 week) Arm 2 (P = |0.029).

# Mma Bana Botswana24
Breastfeeding Maternal triple-drug prophylaxis (com pares 2 regimens) in women with CD4 cell counts >200 cells/mm3
A rm 1:
ZDV/3TC/ABC

# A rm 2:
ZDV/3TC/LPV/r -MTCT at age 28 weeks was 5.7% in control Arm 1; 2.9% in maternal triple-drug prophylaxis Arm 2 (P = 0.009 vs. control); 1.7% in infant NVP Arm 3 (P <0.001 vs. control).
- No significant difference between maternal triple-drug prophylaxis Arm 2 and infant NVP Arm 3 (P = 0.12). - In infants uninfected at age 6 weeks, the 6month infant HIV infection rate was 1.1% (0.3-1.8%) in the extended NVP Arm 1 and 2.4% (1.3-3.6%) in the placebo Arm 2 (P = 0.048).
- At infant randomization at age 6 weeks, 29% of mothers in each arm were receiving a triple-ARV regimen for treatment of HIV.
- For mothers receiving triple-ARV drugs at the time of randomization, in infants unin fected at age 6 weeks, the 6-month infant HIV infection rate was 0.2% and not statis tically different between extended NVP Arm 1 (0.5%) and placebo Arm 2 (0%).
- For mothers with CD4 cell counts >350 cells/mm3 who were not receiving triple ARV drugs, in infants uninfected at age 6 weeks, the 6-month infant HIV infection rate was 0.7% (0-1.5%) in the extended NVP Arm 1 and 2.8% (1.3 -4.4%) in the placebo Arm 2 (P = 0.014). Efficacy has been demonstrated for a number o f short-course ARV regimens, including those with zi dovudine alone; zidovudine plus lamivudine; single-dose nevirapine; and single-dose nevirapine com bined with either short-course zidovudine or zidovudine/lamivudine2, 4-9, 13-15. In general, combination regimens are more effective than single-drug regimens in reducing perinatal transmission. In addition, administration of ARV drugs during the antepartum, intrapartum, and postpartum periods is superior in preventing perinatal transmission than administration o f ARV drugs only during the antepartum and in trapartum periods or intrapartum and postpartum periods6, 12, 28. Use o f ARV drugs to prevent transmis sion is highly effective, even among HIV-infected women with advanced disease24, 29.
Almost all trials in resource-limited countries have included oral intrapartum prophylaxis, with varying durations o f maternal antenatal and/or infant (and sometimes maternal) postpartum prophylaxis. Perina tal transmission is reduced by regimens with antenatal components starting as late as 36 weeks' gestation and lacking an infant prophylaxis component2, 4-5. However, longer duration antenatal ARV prophylaxis (starting at 28 weeks' gestation) is more effective than shorter duration ARV prophylaxis (starting at 36 weeks' gestation), suggesting that a significant proportion o f in utero transmission occurs between 28 and 36 weeks' gestation9. Analyses from the European National Study o f HIV in Pregnancy and Child hood have shown that efficacy is increased with even longer duration antenatal ARV prophylaxis (start ing before 28 weeks' gestation), with each additional week o f a triple-drug regimen corresponding to a 10% reduction in risk o f transmission after adjustment for viral load, mode o f delivery, and sex o f the in fant30. More prolonged infant post-exposure prophylaxis does not appear to substitute for longer duration maternal ARV prophylaxis9.
No trials have directly compared the efficacy o f zidovudine plus single-dose nevirapine with a triple drug ARV regimen for prevention o f in utero transmission in women with higher CD4 cell counts. In African women with CD4 cell counts ranging from 200 to 500 cells/mm3, the Kesho Bora trial compared a triple-ARV drug prophylaxis regimen with zidovudine plus single-dose nevirapine prophylaxis, both started at 28 weeks' gestation or later. The women in the triple-drug arm continued the drugs until breastfeeding ceased, while those in the zidovudine/single-dose nevirapine arm did not receive postnatal prophylaxis. Although the rate o f postnatal transmission was significantly lower in the triple-drug arm than in the zidovudine/single-dose nevirapine arm without postnatal prophylaxis, the rates o f transmis sion at birth were similar in women randomized to a triple-drug regimen (1.8%) and women randomized to antepartum zidovudine/single-dose nevirapine (2.5%); for women with CD4 cell counts from 350 to 500 cells/mm3, the rate o f infection at birth was 1.7% in each arm23. However, the study was not pow ered to address equivalence between regimens in preventing in utero infection in women with higher CD4 cell counts and the drugs in both arms were administered antepartum for only 6 weeks.
Regimens that do not include maternal ARV prophylaxis during pregnancy have been evaluated because some women may lack antenatal care and present for prenatal care for the first time when they go into labor. Regimens that include only intrapartum and postpartum drug administration also have been shown to be effective in reducing perinatal transmission6-8. However, without continued infant post-exposure prophylaxis, intrapartum pre-exposure prophylaxis alone with nucleoside reverse transcriptase inhibitor (NRTI) drugs (zidovudine/lamivudine) is not effective in reducing transmission6. The SAINT trial demonstrated that the two proven effective intrapartum/postpartum regimens (zidovudine/lamivudine or single-dose intrapartum/newborn nevirapine) are similar in efficacy and safety8.
In some situations, it may be impossible to administer maternal antepartum and intrapartum therapy and only infant prophylaxis may be an option. In the absence o f maternal therapy, the standard infant pro phylaxis regimen o f 6 weeks o f zidovudine was effective in reducing HIV transmission compared with no prophylaxis, based on epidemiologic data in resource-rich countries31. In a South African study o f in-fants born to mothers who did not receive antenatal or intrapartum ARV drug regimens, overall perinatal transmission rates were not significantly different for administration o f single-dose infant nevirapine given within 24 hours of delivery compared with 6 weeks o f infant zidovudine therapy15. However, a trial in Malawi in breastfeeding infants demonstrated that adding 1 week o f zidovudine therapy to infant single-dose nevirapine reduced the risk of transmission by 36% compared with infant single-dose nevi rapine alone13. To define the optimal infant prophylaxis regimen in the absence o f maternal antepartum ARV drug administration in a formula-fed population o f infants, the NICHD-HPTN 040/P1043 (NCT00099359) multicountry (Argentina, Brazil, South Africa, and the United States) clinical trial en rolled 1,735 formula-fed infants born to HIV-infected mothers who did not receive ARV drugs during the current pregnancy prior to labor (if women presented early enough, intravenous intrapartum zidovu dine was given). The study compared three infant ARV regimens: standard 6 weeks o f zidovudine alone versus 6 weeks of zidovudine plus three doses o f nevirapine given in the first week o f life (first dose birth to 48 hours; second dose 48 hours after first dose; third dose 96 hours after second dose) versus 6 weeks o f zidovudine plus lamivudine and nelfinavir given from birth through age 2 weeks. The study, presented at the 2011 Conference on Retroviruses and Opportunistic Infections, demonstrated that the combination regimens reduced the risk of intrapartum transmission by approximately 50% compared with infant prophylaxis with zidovudine alone (see Table 3). Based on these data, combination ARV pro phylaxis is now recommended in the United States for infants whose mothers have not received antena tal ARV drugs (see Infant Antiretroviral Prophylaxis).
Several studies in formula-fed and breastfed populations in resource-limited countries have found that adding maternal/infant single-dose nevirapine to a maternal short-course zidovudine or zidovudine / lamivudine regimen increased efficacy compared with the short-course regimen alone11, 12, 16. Whether single-dose nevirapine provides any additional efficacy when combined with the standard recommended combination ARV prophylaxis regimens used in the United States was evaluated in PACTG 316, a clini cal trial conducted in the United States, Europe, Brazil, and the Bahamas. This study demonstrated that for nonbreastfeeding women in resource-rich countries, the addition o f single-dose nevirapine did not offer significant benefit in the setting o f combination ARV prophylaxis throughout pregnancy and very low viral load at the time o f delivery10. Thus, adding single-dose intrapartum nevirapine is generally not recommended for women in the United States who are receiving standard recommended antenatal ARV prophylaxis (see Intrapartum Care).
Breastfeeding by HIV-infected women (including those receiving ARV drugs) is not recommended in the United States where replacement feeding is affordable, feasible, acceptable, sustainable, and safe and the risk of infant mortality due to diarrheal and respiratory infections is low. A number of studies have evalu ated the use of maternal or infant ARV prophylaxis during breastfeeding to reduce postnatal transmission (see Table 3). Observational data and randomized clinical trials have demonstrated that infant prophylaxis (primarily using daily infant nevirapine) during breastfeeding significantly decreases the risk of postnatal transmission in breast milk and that maternal triple-drug prophylaxis during breastfeeding likewise de creases postnatal infection18-25. Maternal prophylaxis with triple-drug regimens may be less effective than infant prophylaxis if first started in the postpartum period or late in pregnancy, likely because it takes sev eral weeks to months before full viral suppression in breast milk is achieved25, 32. Importantly, although sig nificantly lowering the risk of postnatal infection, neither infant nor maternal postpartum ARV prophylaxis completely eliminates the risk of HIV transmission through breast milk. Therefore, breastfeeding is not recommended for HIV-infected women in the United States (including those receiving combination ARV drug regimens). Finally, both infant nevirapine prophylaxis and maternal triple-drug prophylaxis during breastfeeding may be associated with development of ARV drug resistance in infants who become infected despite prophylaxis33-36. Three studies have found multiclass drug resistance in breastfeeding infants who Mother-to-child transmission has been observed across the entire range o f plasma HIV RNA levels, in cluding in women with undetectable viral loads1-3. In PACTG 076, an HIV RNA threshold below which there was no risk o f transmission was not identified; zidovudine was effective in reducing transmission regardless of maternal HIV RNA copy number4-5.
HIV RNA levels correlate with risk o f transmission even in women treated with ARV agents6-9. Although the risk o f perinatal transmission in women with undetectable HIV RNA levels appears to be extremely low, transmission has been reported even among women with very low or undetectable levels o f mater nal HIV RNA10. Additionally, although HIV RNA may be an important risk factor for transmission, other factors also appear to play a role6, 9 11.
Although there is a general correlation between viral loads in plasma and in the genital tract, discor dance also has been reported, particularly between HIV proviral load in blood and genital secretions, es pecially in the presence o f other genital tract infections12-15. Penetration o f ARV drugs into the female genital tract has been shown to vary between drugs16-17. If exposure to HIV in the maternal genital tract during delivery is a risk factor for perinatal transmission, plasma HIV RNA levels may not always be an accurate indicator o f risk. Long-term changes in one body compartment with ARV drugs may or may not be associated with comparable changes in other compartments. Additional studies are needed to deter mine the effect o f ARV drugs on genital tract viral load and the association between such effects and the risk o f perinatal transmission o f HIV. In the short-course zidovudine trial in Thailand, plasma and cervicovaginal HIV RNA levels were reduced by zidovudine prophylaxis, and each independently correlated with perinatal transmission18.
Because transmission can occur even when HIV RNA copy numbers are low or undetectable, all HIV-in fected women should be counseled about and administered ARV drugs during pregnancy, regardless of their HIV RNA levels.
References: - Discuss childbearing intentions with all women of childbearing age on an ongoing basis throughout the course of their care (AIII).
- Include information about effective and appropriate contraceptive methods to reduce the likelihood of unintended preg nancy (AI).
- During preconception counseling include information on safer sexual practices and elimination of use of alcohol and illicit drugs, and smoking, which are important for the health of all women as well as for fetal/infant health, should pregnancy occur (AII).
- When evaluating HIV-infected women, include assessment of HIV disease status and need for antiretroviral therapy (ART) for their own health (AII).
- Choose an ART regimen for HIV-infected women of childbearing age based on consideration of effectiveness for treat ment of maternal disease, teratogenic potential of the drugs in the regimen should pregnancy occur, and possible ad verse outcomes for mother and fetus (AII).
The Centers for Disease Control and Prevention (CDC), the American College o f Obstetricians and Gy necologists, and other national organizations recommend offering all women o f childbearing age com prehensive family planning and the opportunity to receive preconception counseling and care as a component of routine primary medical care. The purpose o f preconception care is to improve the health o f each woman before conception by identifying risk factors for adverse maternal or fetal outcome, pro viding education and counseling targeted to the patient's individual needs, and treating or stabilizing medical conditions to optimize maternal and fetal outcomes1. Preconception care is not a single clinical visit but rather a process o f ongoing care and interventions integrated into primary care to address the needs o f women during the different stages o f reproductive life. Because more than h alf o f all pregnan cies in the United States are unintended2-5 it is important that comprehensive family planning and pre conception care be integrated into routine health visits. Providers should initiate and document a nonjudgmental conversation with all women o f reproductive age concerning their reproductive desires because women may be reluctant to bring this up themselves6. HIV care providers who routinely care for women of reproductive age play an important role in promoting preconception health and informed re productive decisions.
The fundamental principles of preconception counseling and care are outlined in the CDC Preconception Care Work Group's Recommendations to Improve Preconception Health and Health Care. In addition to the general components of preconception counseling and care that are appropriate for all women of repro ductive age, HIV-infected women have specific needs that should be addressed7-8. Because many women infected with HIV are aware of their HIV status prior to pregnancy, issues that impact pregnancy may be addressed before conception during their routine medical care for HIV disease. In addition to those out lined by the CDC Preconception Care Work Group9 the following components of preconception counsel ing and care are specifically recommended for HIV-infected women. Health care providers should: a. Discuss reproductive options, actively assess women's pregnancy intentions on an ongoing basis throughout the course o f care and, when appropriate, make referrals to experts in HIV and wom en's health, including experts in reproductive endocrinology and infertility when necessary10.
b. Offer all women effective and appropriate contraceptive methods to reduce the likelihood o f unin tended pregnancy. Providers should be aware o f potential interactions between ARV drugs and hor monal contraceptives that could lower contraceptive efficacy (see Table 4) .
c. Counsel on safe sexual practices that prevent HIV transmission to sexual partners, protect women from acquiring sexually transmitted infections (STIs), and reduce the potential to acquire more viru lent or resistant strains o f HIV.
d. Counsel on eliminating alcohol, illicit drug use, and cigarette smoking.
e. Educate and counsel women about risk factors for perinatal transmission o f HIV, strategies to reduce those risks, potential effects of HIV or treatment on pregnancy course and outcomes, and the recom mendation that HIV-infected women in the United States not breastfeed because o f the risk o f trans mission o f HIV and the availability o f safe and sustainable infant feeding alternatives.
f. When prescribing ART to women of childbearing age consider the regimen's effectiveness for treat ment o f HIV, an individual's hepatitis B disease status, the drugs' potential for teratogenicity should pregnancy occur, and possible adverse outcomes for mother and fetus11-13.
g. Use the preconception period in women who are contemplating pregnancy to adjust ARV regimens to exclude efavirenz or other drugs with teratogenic potential.
h. For women who are on ART for their own health and who want to get pregnant, make a primary treatment goal the attainment o f a stable, maximally suppressed maternal viral load prior to concep tion to decrease the risk o f mother-to-child transmission.
i. Evaluate and appropriately manage therapy-associated side effects such as hyperglycemia, anemia, and hepatoxicity that may adversely impact maternal-fetal health outcomes. j. Evaluate the need for appropriate prophylaxis or treatment for opportunistic infections (OIs), includ ing safety, tolerability, and potential toxicity o f specific agents when used in pregnancy.
k. Administer medical immunizations (e.g., influenza, pneumococcal, or hepatitis A and B vaccines) as indicated.
l. Encourage sexual partners to receive HIV testing and, if infected, counseling and appropriate HIV care.  Panel's Recommendations
- For serodiscordant couples who want to conceive, expert consultation is recommended so that approaches can be tai lored to specific needs, which may vary from couple to couple (AIII).
- Partners should be screened and treated for genital tract infections before attempting to conceive (AII).
- For an HIV-infected female with an HIV-uninfected male partner, the safest conception option is artificial insemination, in cluding the option of self-insemination with her partner's sperm during the peri-ovulatory period (AIII).
- For HIV-infected men with an HIV-uninfected female partner, the use of sperm preparation techniques coupled with either intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection should be considered if using donor sperm from an HIV-uninfected male for insemination is unacceptable (AII).
- In a serodiscordant couple who wishes to conceive, initiation of antiretroviral therapy (ART) for the HIV-infected partner is recommended if the infected partner has a CD4 count 550 cells/mm3, initiation of ART could be considered (BIII). If therapy is initiated, maximal viral suppression is recommended before conception is attempted (AIII).
- Data are insufficient at the current time to recommend peri-conception administration of antiretroviral (ARV) pre-expo sure prophylaxis for HIV-uninfected partners to reduce the risk of sexual transmission (AIII).
For serodiscordant couples who want to conceive, expert consultation is recommended so that ap proaches can be tailored to specific needs, which may vary from couple to couple.
Before attempting to conceive, both partners should be screened for genital tract infections. If any such infections are identified, they should be treated because genital tract inflammation is associated with genital tract shedding o f HIV1-2. Semen analysis is recommended for HIV-infected males before concep tion is attempted because HIV, and possibly ART, may be associated with a higher prevalence o f semen abnormalities such as low sperm count, low motility, higher rate o f abnormal forms, and low semen vol ume3-6. If such abnormalities are present, the uninfected female partner may be exposed unnecessarily and for prolonged periods to her partner's infectious genital fluids when the likelihood o f getting preg nant naturally is low or even nonexistent.
Observational studies have demonstrated a decreased rate o f transmission o f HIV among heterosexual serodiscordant couples in which the HIV-infected partner is receiving ART compared with couples in which the HIV-infected partner is not receiving ART7-9. HPTN 052 is a randomized clinical trial de signed to evaluate whether immediate versus delayed initiation o f ART by HIV-infected individuals with CD4 counts of 350-550 cells/mm3 could prevent sexual transmission o f HIV among serodiscordant cou ples. Preliminary data from this study showed that earlier initiation o f ART led to a significant reduction in transmission o f HIV to the uninfected partner10. O f 28 cases o f HIV infection documented to be genet ically linked to the infected partner, 27 occurred among the 877 couples in which the HIV-infected part ner delayed initiation o f ART until the CD4 count fell below 250 cells/mm3, whereas only 1 case o f HIV infection occurred among the 886 couples with an HIV-infected partner who began immediate ART; 17 o f the 27 transmissions in the delayed therapy group occurred in individuals with CD4 counts >350 cells/mm3. These are the first data from a randomized trial to demonstrate that provision o f treatment to infected persons can reduce the risk o f transmission to their uninfected sexual partners11. Based on the results from HPTN 052, initiation o f ART would be recommended for the infected partner in a serodis cordant couple who has a CD4 count o f 550 cells/mm3, initation o f therapy could be considered, although the benefit of ART in reducing sexual transmission from individuals with higher CD4 counts has not been determined. Before conception is attempted, maximal viral suppression is recommended if an in fected individual is on ART for his/her own health or does not require therapy but opts to start ART to prevent sexual transmission.
It is important to recognize that no single method (including treatment o f the infected partner) is fully protective against transmission o f HIV. Effective ART that decreases plasma viral load to undetectable levels is also associated with decrease in the concentration o f virus in genital secretions. However, dis cordance between plasma and genital viral loads has been reported, and individuals with an undetectable plasma viral load may have detectable genital tract virus12-13. Additionally, ARV drugs vary in their abil ity to penetrate the genital tract14. Thus, maximal viral suppression may not completely eliminate risk of heterosexual transmission.
Reducing the risk of perinatal transmission is another potential rationale for starting ART prior to con ception in HIV-infected women who do not yet need treatment for their own health. Data suggest that early and sustained control of HIV viral replication may be associated with decreasing residual risk of perinatal transmission15-16, but that does not completely eliminate the risk o f perinatal transmission16. In addition, there are mixed reports on the possible effects o f combination ARV drug regimens on prematu rity and low birth weight, with some but not all data suggesting that such outcomes may be more fre quent in women on ARV drugs at conception17-18 (see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants).
The implications of initiating therapy prior to conception solely for prevention o f sexual and/or perinatal transmission should be discussed with the patient. These issues include willingness and ability to com mit to potential lifelong therapy, the potential risks versus benefits o f stopping or continuing the regimen after conception in the male or postpartum in the female, and the need for strict adherence to achieve maximal viral suppression. Consultation with an expert in HIV care is strongly recommended.
For HIV-discordant couples in which the female is the HIV-infected partner, the safest form o f concep tion is artificial insemination, including the option to self-inseminate with the partner's sperm during the peri-ovulatory period. Condom use should be advised at all times.
For HIV-discordant couples in which the male is the HIV-infected partner, the use o f sperm preparation techniques coupled with either intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection has been reported to be effective in avoiding seroconversion in uninfected women and off spring in several studies19-20. The National Perinatal HIV Hotline (1-888-448-8765) is a resource for a list o f institutions offering reproductive services for HIV-serodiscordant couples. More data are needed to demonstrate the complete efficacy of these techniques, and couples should be cautioned about the po tential risk of transmission o f HIV to the uninfected partner and to their offspring20. Discordant couples who do not have access to assisted reproduction services and who still wish to try to conceive after com prehensive counseling should be advised that timed, peri-ovulatory unprotected intercourse after the in fected partner has achieved maximal viral suppression (with use o f condoms at all other times) may reduce but not completely eliminate the risk o f sexual transmission20. Should the uninfected woman be come pregnant, she should be regularly counseled regarding consistent condom use to decrease her risk o f sexual transmission of HIV and the possible risk o f perinatal transmission (see Monitoring o f HIV Uninfected Pregnant Women with a Partner Known to be HIV Infected).
Periconception pre-exposure prophylaxis may offer an additional option in the future to minimize risk of transmission of HIV within discordant couples. Pre-exposure prophylaxis is use o f ARV medications by an HIV-uninfected individual to maintain blood and genital drug levels sufficient to prevent acquisition o f HIV. An experimental 1% tenofovir gel used intravaginally both before and after sex reduced the inci dence o f HIV infection among women by up to 54% in a randomized, placebo-controlled trial conducted in South Africa21. This product is not available commercially, and additional trials are needed to confirm these findings. Five efficacy trials o f pre-exposure prophylaxis with oral ARV agents (primarily teno fovir alone) are currently under way22. In 1 study o f daily tenofovir/emtricitabine in HIV-seronegative men who have sex with men, there was a 44% reduction in the risk o f acquisition o f HIV compared with placebo23-24. However, the FEM-PrEP clinical trial, designed to study whether HIV-uninfected women at high risk o f being exposed to HIV can safely use a daily dose o f tenofovir/emtricitabine to prevent infec tion, was stopped early by its Data and Safety Monitoring Board (DSMB) because it was highly unlikely the study would be able to demonstrate the effectiveness o f tenofovir/emtricitabine in preventing HIV infection in the study population. The approximate rate o f new HIV infections among trial participants was 5 percent per year. A total o f 56 new HIV infections had occurred, with an equal number o f infec tions in participants assigned to tenofovir/emtricitabine and those assigned to a placebo pill25.
Several studies evaluating the efficacy o f pre-exposure prophylaxis among heterosexual discordant cou ples are ongoing but data are not yet available. Currently data are insufficient to recommend periconception administration o f pre-exposure prophylaxis to uninfected partners to reduce the risk o f sexual transmission. In addition, the use o f pre-exposure prophylaxis during pregnancy and lactation for HIVuninfected women with HIV-infected partners has not been studied and cannot be recommended at this time. If pre-exposure prophylaxis is proven safe and efficacious in ongoing trials, this approach may offer an option for safer attempts at conception. However, it will be important to have outcome studies that examine adverse events, including risk o f congenital abnormalities.

# M onitoring o f HIV-Uninfected Pregnant Women with Partners Known to B e H IV Infected
Clinicians increasingly may be faced with the situation in which an HIV-uninfected woman presents dur ing pregnancy and relates that she has an HIV-infected partner. As is recommended for all pregnant women, the woman should be notified that HIV screening is recommended and that she will receive an HIV test as part of the routine panel of prenatal tests unless she declines. In addition, she should receive a second HIV test during the third trimester, preferably before 36 weeks of gestation, as is recommended for high-risk women. Furthermore, if the pregnant woman presents in labor without results of third-trimester testing, she should be screened with a rapid HIV test on the labor and delivery unit. If at any time during pregnancy the clinician suspects that a pregnant woman may be in the "window" period of seroconversion (i.e., has signs or symptoms consistent with acute HIV infection), then a plasma HIV RNA test should be used in conjunction with an HIV antibody test. If the plasma HIV RNA is negative, it should be repeated in 2 weeks. All HIV-uninfected pregnant women with HIV-infected partners should always use condoms during sexual intercourse to prevent acquisition of HIV. Women should be counseled regarding the symp toms of acute retroviral syndrome (i.e., fever, pharyngitis, rash, myalgia, arthralgia, diarrhea, headache) and the importance of seeking medical care and testing if they experience such symptoms. - The known benefits and potential risks of ARV use during pregnancy should be discussed with all women (AIII).
- ARV drug-resistance studies should be performed before starting or modifying ARV drug regimens in women whose HIV RNA levels are above the threshold for resistance testing (e.g., >500 to 1,000 copies/mL) (see Antiretroviral Drug Resist ance and Resistance Testing in Pregnancy) (AI). When HIV is diagnosed late in pregnancy, ARV therapy or prophylaxis should be initiated pending results of resistance testing (BIII).
- In counseling patients, the importance of adherence to the ARV regimen should be emphasized (AII).
- Considerations regarding continuation of the ARV regimen for maternal therapeutic indications after delivery are the same as for nonpregnant individuals. The pros and cons of continuing versus discontinuing ARV drugs postpartum should be dis cussed with women so they can make educated decisions about postpartum ARV use before delivery (AIII). Such decisions should be made in consultation with the provider who will assume responsibility for the women's HIV care going forward after delivery.
- Coordination of services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs is essential to ensure that infected women adhere to their ARV drug regimens (AIII).
In addition to the standard antenatal assessments for all pregnant women, the initial evaluation o f an HIV-infected pregnant woman should include an assessment o f HIV disease status and recommendations for HIV-related medical care. This initial assessment should include the following:

# W ith E FV or N VP (PI-naive or PI-ex p e rie n ced patients):
LPV/r 500 mg/125 mg tablets BID (use a combination of two LPV/r 200 mg/50 mg tablets + one LPV/r 100 mg/25 mg tablet to make a total dose of LPV/r 500 mg/125 mg.) or LPV/r 533 mg/133 mg oral solution (6.5 mL) BID

# Tablets:
Take without regard to meals.

# Oral solution:
Take with food.

# Not used in p reg nancy:

# Tablets:
Take with food.

# C a p su le and oral solution:
Take with food if possible, which may improve tolerability.

# PI-experienced patients (o n ce -d a ily do sin g not reco m m end ed):
- (FPV 700 mg + RTV 100 mg) BID W ith EFV:
- (FPV 700 mg + RTV 100 mg) BID or - (FPV 1,400 mg + RTV 300 mg) once daily

# Tablet:
Take without regard to meals (if not boosted with RTV tablet).

# S u sp en sio n :
Take without food.

# FP V with R T V tablet:
Take with meals.

# T P V taken with RTV tablets:
Take with meals.

# T P V taken with R TV ca p s u le s or solution:
Take without regard to meals.  ARV drugs for prevention o f perinatal transmission o f HIV are recommended for all pregnant women, regardless of whether they have indications for ART for their own health. In general, guidelines for the use o f ART for the benefit of maternal health during pregnancy are the same as for women who are not pregnant, with some modifications, based on concerns about specific drugs and limited experience dur ing pregnancy with newer drugs. ARV prophylaxis is recommended for all pregnant women with HIV infection who do not require therapy, regardless o f viral load (see HIV-Infected Pregnant Women Not on Antiretroviral Therapy Who Require Antiretroviral Prophylaxis Solely to Prevent Perinatal Transmission o f HIV).
Decisions regarding initiation or modification of ARV drug regimens during pregnancy include considera tions regarding the benefits and risks of ARV drug use that are common to all HIV-infected adults in addi tion to considerations unique to pregnancy. In general, the ARV drug combinations now available are more convenient and better tolerated than regimens used previously, resulting in greater efficacy and improved adherence. During pregnancy maternal ARV toxicities must be considered, along with the potential impact of the ARV regimen on pregnancy outcome and on the fetuses and infants. Decisions about ARV drug regi mens are further complicated because only limited data exist on the long-term maternal consequences of use of the agents during pregnancy solely for prophylaxis of transmission. Similarly, only limited data are available on the long-term consequences to infants of in utero exposure to ARVs.
The known benefits and known and unknown risks o f ARV drug use during pregnancy should be consid ered and discussed with women (see Special Considerations Regarding the Use o f Antiretroviral Drugs by HIV-infected Pregnant Women and their Infants). Results from preclinical and animal studies and available clinical information about use of the various agents during pregnancy also should be discussed (see Supplement: Safety and Toxicity o f Individual Antireroviral Agents in Pregnancy) . Potential risks of these drugs should be placed into perspective by reviewing the substantial benefits o f ARV drugs for maternal health and in reducing the risk of transmission of HIV to infants. Counseling of pregnant women about ARV use should be noncoercive, and providers should help women make informed deci sions regarding use o f ARV drugs.
Discussions with women about initiation of ARV drug regimens should include information about: a. maternal risk of disease progression and the benefits and risks of initiation of therapy for maternal health;
b. benefit o f combination ARV regimens for preventing perinatal transmission o f HIV50; c. potential adverse effects o f ARV drugs for mothers, fetuses, and infants, including potential interac tions with other medications the women may already be receiving; d. the limited long-term outcome data for both women who temporarily use ARV drugs during preg nancy for prophylaxis o f transmission and infants who are exposed to ARVs in utero; and e. the possibility of development o f ARV resistance, including the need for strict adherence to the pre scribed drug regimen to avoid it.
Studies of zidovudine for the prevention o f perinatal transmission suggest that pre-exposure prophylaxis o f the infant from transplacental passage o f drug is an important component o f prevention. Thus, when selecting an ARV regimen for a pregnant woman, at least one nucleoside/nucleotide (NRTI) agent with high placental transfer should be included as a component o f the dual NRTI backbone (see Table 5)13, 18,
In women with plasma HIV RNA above the threshold for resistance testing (e.g., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting ARV drugs for maternal health or prophylaxis. When HIV is diagnosed late in pregnancy, however, ARV drugs should be initi ated pending results o f resistance testing (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy).
Counseling should emphasize the importance o f adherence to the ARV drug regimen. Support services, mental health services, and drug abuse treatment may be required, depending on women's individual cir cumstances. Coordination o f services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs is es sential to ensure that infected women adhere to their ARV drug regimens.
Providers should work with women to develop long-range plans regarding continuity o f medical care and decisions about treatment for their own health after giving birth. Considerations regarding continua tion of the ARV regimen for maternal therapeutic indications are the same following delivery as for non pregnant individuals. The impact on short-and long-term maternal health is unknown for postpartum discontinuation o f combination ARV drug regimens used solely to prevent perinatal transmission. This is particularly important because women may have multiple pregnancies resulting in episodic receipt of ARV drugs. No increase in disease progression has been seen so far, however, in studies o f pregnant women with relatively high CD4 counts who stop combination ARV drug regimens after delivery53-55.
The risks versus benefits o f stopping ARV drug regimens postpartum in women with high CD4 cell counts are being evaluated in the ongoing PROMISE study (clinical trial number NCT00955968).
Current adult treatment guidelines strongly recommend ART for all individuals with CD4 cell counts <350 cells/mm3 based on randomized, controlled clinical trial data demonstrating a clear benefit in re duction o f mortality and morbidity. Pregnant women with CD4 counts <350 cells/mm3 should begin on combination ART as soon as possible during pregnancy and be counseled about the need to continue therapy after delivery and the importance o f adherence to the regimen.
Based on observational cohort data, the adult treatment guidelines make a moderate-to-strong recom mendation for initiating lifelong ART in individuals with CD4 cell counts between 350 and 500 cells/mm3. Observational studies suggest a relative decrease in mortality (although the overall number of events was small) and possibly a decrease in complications such as cardiovascular events with initiation o f ART in this setting compared with waiting until CD4 cell counts drop below 350 cells/mm3 56-57. Preg nant women with CD4 cell counts between 350 and 500 cells/mm3 should be started on a combination ARV regimen during pregnancy to prevent perinatal transmission o f HIV and counseled about the cur rent treatment recommendations, the potential risks versus benefits o f stopping versus continuing the regimen after delivery, and the need for strict adherence if the regimen is continued postpartum.
For individuals with CD4 counts >500 cells/mm3, the adult guidelines note that some experts would rec ommend initiating lifelong therapy, while other experts would view this as optional, given that data are inconclusive on the clinical benefit o f starting treatment at higher CD4 cell counts (>500 cells/mm3). So far, no increased risk of disease progression has been shown in studies o f pregnant women with rela tively high CD4 counts who stop ARV drugs after delivery53-55. The potential benefits o f early therapy must be weighed against possible drug toxicity, cost, and the risk o f development o f viral resistance with suboptimal adherence, which may be more likely during the postpartum period58. Pregnant women with CD4 cell counts >500 cells/mm3 should be started on a combination ARV regimen during pregnancy to prevent perinatal transmission. They should be assessed for their willingness and ability to commit to ongoing continuous therapy and counseled about the current treatment guidelines, the benefits and risks o f therapy, that data on the clinical benefit o f starting lifelong treatment at CD4 cell counts >500 cells/mm3 are inconclusive, and the importance o f adherence if the regimen is continued postpartum.
In general, when drugs are discontinued postnatally, all drugs should be stopped simultaneously. How ever, as discussed later (see Stopping Antiretroviral Therapy during Pregnancy), in women receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, continuing the dual-NRTI back bone for a period of time after stopping the NNRTI is recommended to reduce the development of NNRTI resistance. An alternative strategy is to replace the NNRTI with a protease inhibitor (PI) drug while continuing the NRTI, then to discontinue all the drugs at the same time59. The optimal interval be tween stopping an NNRTI and stopping the other ARV drugs is unknown, but a minimum o f 7 days is recommended. Drug concentrations may be detectable for more than 3 weeks after efavirenz is stopped in patients receiving an efavirenz-based NNRTI regimen. Therefore, for patients receiving efavirenz, some experts recommend continuing the other ARV agents or substituting a PI plus two other agents for up to 30 days.

# The National Perinatal HIV Hotline (1-888-448-8765)
The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation to providers caring for HIV-infected women and their infants.

# Recommendations fo r Use o f Antiretroviral Drugs D uring Pregnancy
The Panel recommends that choice o f ARV drug regimens for HIV-infected pregnant women be based on the same principles used to choose regimens for nonpregnant individuals, unless there are compelling pregnancy-specific maternal or fetal safety issues associated with specific drugs. The Panel reviews clin ical trial data published in peer-reviewed journals and data prepared by manufacturers for Food and Drug Administration (FDA) review related to treatment o f HIV-infected adult women, both pregnant and nonpregnant. The durability, tolerability, and simplicity o f a medication regimen is particularly impor tant for preserving future options for women who will be stopping medications after delivery and women who meet standard criteria for initiation o f ART per adult guidelines and will continue the regi men after pregnancy. Regimen selection should be individualized and the following factors should be considered:
- comorbidities;
- patient adherence potential;
- convenience;
- potential adverse maternal drug effects;
- potential drug interactions with other medications;
- results o f genotypic resistance testing;
- pharmacokinetic (PK) changes in pregnancy; and
- potential teratogenic effects and other adverse effects on fetuses or newborns.
Information used by the Panel for recommending specific drugs or regimens for pregnant women in clude:
- Data from randomized prospective clinical trials that demonstrate durable viral suppression as well as immunologic and clinical improvement;
- Incidence rates and descriptions o f short-and long-term drug toxicity o f ARV regimens, with special attention to maternal toxicity and potential teratogenicity and fetal safety;
- Specific knowledge about drug tolerability and simplified dosing regimens;
- Known efficacy o f some drug regimens in reducing mother-to-child transmission o f HIV;
- PK data during the prenatal period. (The physiologic changes o f pregnancy have the potential to alter drug PKs. ARV dosing during pregnancy should be based on PK data from studies in pregnant women. Physiologic changes are not fixed throughout pregnancy but, rather, reflect a continuum of change as pregnancy progresses, with return to baseline at various rates in the postpartum period.); and
- Data from animal teratogenicity studies.
Categories o f ARV regimens include:
- Preferred: Drugs or drug combinations are designated as preferred for use in pregnant women when clinical trial data in adults have demonstrated optimal efficacy and durability with acceptable toxic ity and ease o f use; pregnancy-specific PK data are available to guide dosing; and no evidence o f ter atogenic effects or established association with teratogenic or clinically significant adverse outcomes for mothers, fetuses, or newborn are present.
- Alternative: Drugs or drug combinations are designated as alternatives for initial therapy in pregnant women when clinical trial data in adults show efficacy but any one or more of the following conditions apply: experience in pregnancy is limited; data are lacking on teratogenic effects on the fetus; or the drug or regimen is associated with dosing, formulation, administration, or interaction issues.
- Use in Special Circum stances: Drug or drug combinations in this category can be considered for use when intolerance or resistance prohibits use o f other drugs with fewer toxicity concerns or in women who have comorbidities or require concomitant medications that may limit drug choice, such as active tuberculosis requiring rifampin therapy.
- Not Recom m ended: Drugs and drug combinations listed in this category are not recommended for therapy in pregnant women because o f inferior virologic response, potentially serious maternal or fetal safety concerns, or pharmacologic antagonism.
- Insufficient D ata to Recom m end: The drugs and drug combinations in this category are approved for use in adults but lack pregnancy-specific PK or safety data, or such data are too limited to make a recommendation for use for pregnancy.
A combination ARV regimen with at least three agents is recommended for use in pregnancy for either treatment or prophylaxis. Recommendations for choice o f ARV drug regimen during pregnancy must be individualized according to a pregnant woman's specific ARV history and the presence o f comorbidities. Some women may become pregnant and present for obstetrical care while receiving ART for their own health. In these cases, the choice o f active drugs with known safety data in pregnancy may be more lim ited. In general, women who are already on a fully suppressive regimen should continue their regimens. Use of efavirenz, however, should be avoided in the first trimester.
Other HIV-infected women may not be receiving ART at the time they present for obstetrical care. Some women have never received ARV drugs, while others may have taken ARV drugs for treatment that was stopped or for prophylaxis to prevent perinatal transmission o f HIV in prior pregnancies or for pre-or post-exposure prophylaxis. Considerations for initiating therapy in pregnant women differ, depending upon whether ARV drugs are currently indicated for maternal health or solely for fetal protection. The following sections will provide detailed discussions o f recommendations based on maternal ARV history and whether there are maternal indications for therapy.
For ARV-naive women, a combination regimen including two NRTIs and either an NNRTI or a PI (gen erally with low-dose ritonavir) would be preferred. Tenofovir is a preferred NRTI for nonpregnant women. Data from the Antiretroviral Pregnancy Registry on 1,092 pregnancies with first-trimester exposure to tenofovir have shown no increase in overall birth defects compared with the general population4. Animal studies, however, have shown decreased fetal growth and reduction in fetal bone porosity, and studies in infected children on chronic tenofovir-based therapy have shown bone demineralization in some children. Therefore, tenofovir would be considered an alternative NRTI during pregnancy for ARV-naive women. For pregnant women with chronic hepati tis B infection, however, tenofovir in combination with emtricitabine or lamivudine would be the pre ferred NRTI backbone o f a combination ARV regimen. The combination o f stavudine/didanosine should not be used in pregnant women because fatal cases o f lactic acidosis and hepatic failure have been re ported in women who received this combination throughout pregnancy.
In addition to the two NRTIs, either an NNRTI or a PI would be preferred for combination regimens in ARV-naive pregnant women. Efavirenz, the preferred NNRTI for nonpregnant adults, is not recom mended for use in the first trimester because non-human primate data show risk o f anencephaly, micro ophthalmia, and cleft palate, and there are several concerning case reports o f neural tube defects and a single case o f anophthalmia with severe facial cleft in humans. Use o f efavirenz can be considered after the first trimester, based on clinical indication, but current data are limited in defining the safety o f this use. Nevirapine would be the preferred NNRTI for ARV-naive pregnant women with CD4 cell lympho cyte counts 250 cells/mm3 because o f an increased risk o f sympto matic and potentially fatal rash and hepatic toxicity (see Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants). Elevated transaminase levels at baseline also may increase the risk o f nevirapine toxicity66. Safety and PK data on etravirine and rilpivirine in pregnancy are insufficient to recommend use o f these NNRTI drugs in ARV-naive women.
Lopinavir/ritonavir is the preferred PI regimen for ARV-naive pregnant women, based on efficacy stud ies in adults and experience with use in pregnancy (see Table 5 for dosing considerations). Alternative PIs include ritonavir-boosted atazanavir or saquinavir, although experience is more limited with these regimens in pregnancy. Nelfinavir can be considered in special circumstances when used solely for pro phylaxis o f perinatal transmission in ARV-naive women for whom therapy would not otherwise be indi cated and who cannot tolerate alternative agents. PK data and extensive clinical experience do exist for nelfinavir in pregnancy, but the rate o f viral response to nelfinavir-based regimens was lower than lopinavir/ritonavir or efavirenz-based regimens in clinical trials o f initial therapy in nonpregnant adults. Indinavir can also be considered in special circumstances for women in whom preferred or alternative drugs cannot be used. Indinavir may be associated with renal stones and has a higher pill burden than many other PI drugs. Data on use in pregnancy are too limited to recommend routine use o f darunavir, fosamprenavir, and tipranavir in pregnant women, although they can be considered for women who are intolerant o f other agents.
Safety and PK data in pregnancy are insufficient to recommend use o f the entry inhibitors enfuvirtide and maraviroc and the integrase inhibitor raltegravir during pregnancy. Use o f these agents can be con sidered for women who have failed therapy with several other classes o f ARV drugs after consultation with HIV and obstetric specialists.
Although data are insufficient to support or refute the teratogenic risk o f ARV drugs when administered during the first trimester, information to date does not support major teratogenic effects for the majority o f such agents. (For further data, see .) However, certain drugs are o f more concern than others-for example, efavirenz should be avoided during the first trimester o f pregnancy (see Supplement: Safety and Toxicity o f Individual Antiretroviral Drugs in Pregnancy).
Table 5 provides recommendations for use o f specific ARV drugs in pregnancy and data on PKs and tox icity in pregnancy. Table 6 summarizes management recommendations for the mothers and infants in a variety o f clinical scenarios.

# Clinical Scenario Recommendations
Nonpregnant HIV-infected Initiate combination antiretroviral (ARV) drug therapy as per adult treatment guidelines. When women of childbearing po tential who have indications feasible, include one or more nucleoside reverse transcriptase inhibitors (NRTIs) with good placental passage as a component of the ARV regimen. for initiating antiretroviral therapy (ART)
- Avoid drugs with teratogenic potential (e.g., efavirenz) in women who are trying to conceive or are not using adequate contraception. Exclude pregnancy and ensure access to effective (contraception before starting treatment with efavirenz.

# HIV-infected women on com bination ARV drug therapy who become pregnant
Women:
- In general, in women who require treatment, ARV drugs should not be stopped during the first trimester or during pregnancy.
- Continue current combination ART, if successfully suppressing viremia; however, avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the preg nancy.
- Perform HIV ARV drug-resistance testing in women on therapy who have detectable viremia.
- Continue combination ART regimen during the intrapartum period (zidovudine given as con tinuous infusiona during labor while other ARV agents are continued orally) and postpartum.
- Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery.
Infants:
- Start zidovudine as soon as possible after birth and administer for 6 weeks.b HIV-infected pregnant women who are ARV naive and have indications for ART Women:
- Perform HIV ARV drug-resistance testing prior to initiating combination ARV drug therapy and repeat after initiating therapy if viral suppression is suboptimal.
- Initiate combination ARV regimen.
- Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the pregnancy.
- When feasible, include one or more NRTIs with good placental passage in the ARV regi men.
- Use nevirapine as a component of the ARV regimen only in women who have CD4 counts 250 cells/mm3 only if the benefit clearly outweighs the risk.
- In women who require initiation of therapy for their own health, initiate treatment as soon as possible, including in the first trimester.
- Continue the combination regimen during the intrapartum period (zidovudine given as con tinuous infusion3 during labor while other ARV agents are continued orally) and postpartum.
- Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery.
Infants:
-  - Perform HIV ARV drug-resistance testing prior to initiating combination ARV drug therapy and repeat after initiation of therapy if viral suppression is suboptimal.
- Prescribe combination ARV drug prophylaxis (i.e., at least 3 drugs) to prevent perinatal transmission.
- Delayed initiation of prophylaxis until after the first trimester of pregnancy can be consid ered in women who are receiving ARV drugs solely for prevention of perinatal transmis sion, but earlier initiation of prophylaxis may be more effective in reducing perinatal transmission of HIV.
- Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for mother (e.g., combination stavudine/didanosine) throughout the pregnancy.
- When feasible, use one or more NRTIs with good transplacental passage as a component of the ARV regimen.
- Use nevirapine as a component of therapy in women who have CD4 counts >250 cells/mm3 only if the benefit clearly outweighs the risk because of the drug's association with an increased risk of severe hepatic toxicity.
- Continue ARV prophylaxis regimen during the intrapartum period (zidovudine given as con tinuous infusiona during labor while other ARV agents are continued orally).
- Evaluate need for continuing the combination regimen postpartum. Following delivery, con siderations for continuation of the mother's ARV regimen are the same as for other nonpreg nant individuals (see General Principles Regarding Use of Antiretroviral Drugs in Pregnancy). If treatment is to be stopped and the regimen includes a drug with a long half life, such as a non-nucleoside reverse transcriptase inhibitor (NNRTI), consider stopping NRTIs at least 7 days after stopping NNRTI. (See Stopping Antiretroviral Therapy Drugs Dur ing Pregnancy and Prevention of Antiretroviral Drug Resistance.)
- Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery.
Infants:
 Start zidovudine as soon as possible after birth and administer for 6 weeks.1

# Clinical Scenario Recommendations
HIV-infected pregnant women who are ARV experi enced but not currently re ceiving ARV drugs Women:
- Obtain full ARV drug history, including prior resistance testing, and evaluate need for ART for maternal health.
- Test for HIV ARV drug resistance before re-initiating ARV prophylaxis or therapy and retest after initiating combination ARV regimen if viral suppression is suboptimal.
- Initiate a combination ARV regimen (e.g., at least 3 drugs), with regimen chosen based on results of resistance testing and history of prior therapy.
- In women who require initiation of therapy for their own health, initiate treatment as soon as possible, including in the first trimester.
- Delayed initiation of prophylaxis until after the first trimester of pregnancy can be consid ered in women who are receiving ARV drugs solely for prevention of perinatal transmis sion, but earlier initiation of prophylaxis may be more effective in reducing perinatal transmission of HIV.
- Avoid use of efavirenz or other potentially teratogenic drugs in the first trimester and drugs with known adverse potential for the mother (e.g., combination stavudine/didanosine) throughout the pregnancy.
- When feasible, include one or more NRTIs with good transplacental passage as a compo nent of the ARV regimen.
- Use nevirapine as a component of therapy in women who have CD4 counts >250 cells/mm3 only if the benefit clearly outweighs the risk because of the drug's association with an increased risk of severe hepatic toxicity.
- Continue the combination regimen during intrapartum period (zidovudine given as continu ous infusiona during labor while other ARV agents are continued orally).
- Evaluate need for continuing the combination regimen postpartum. Following delivery, con siderations for continuation of the mother's ARV regimen are the same as for other nonpreg nant adults (see General Principles Regarding Use of Antiretroviral Drugs in Pregnancy). If treatment is to be stopped and the regimen includes a drug with a long half-life, such as NNRTIs, consider stopping NRTIs at least 7 days after stopping NNRTIs. (See Stopping Anti retroviral Therapy and Prevention of Antiretroviral Drug Resistance.)
- Schedule cesarean delivery at 38 weeks of gestation if plasma HIV RNA remains >1,000 copies/mL near the time of delivery.
Infants:
- Start zidovudine as soon as possible after birth and administer for 6 weeks.b HIV-infected women who have received no ART before labor Women: Give zidovudine as continuous infusion1 during labor.
Infants: Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen started as close to the time of birth as possible. Zidovudineb given for 6 weeks combined with 3 doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) has been shown to be effective in a randomized controlled trial and less toxic than a 3-drug regimen with nelfinavir and laminvudine for 2 weeks and 6 weeks of zidovudine. The 2-drug regimen is pre ferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see Infant Antiretroviral Prophylaxis and Table 9).
- Evaluate need for initiation of maternal therapy postpartum.

# Clinical Scenario Recommendations
Infants born to HIV-infected women who have received no ART before or during labor
Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen started as close to the time of birth as possible. Zidovudineb given for 6 weeks combined with 3 doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) has been shown to be effective in a randomized controlled trial and less toxic than a 3-drug regimen with nelfinavir and laminvudine for 2 weeks and 6 weeks of zidovudine. The 2-drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see Infant Antiretroviral Prophylaxis and Table 9).
- Evaluate need for initiation of maternal therapy postpartum.
a Zidovudine continuous infusion: 2 mg/kg zidovudine intravenously over 1 hour, followed by continuous infusion of 1 mg/kg/hour until delivery.
b Zidovudine dosing for infants >35 weeks' gestation at birth is 4 mg/kg/dose orally twice daily; for infants 30 weeks of gestation at birth or at 4 weeks of age if <30 weeks' gestation at birth.
Centers for Disease Control and Prevention C. Guidelines for vaccinating pregnant women, Available at:  preg guide.pdf. Atlanta, GA, 2007.    5) (AI).
- For women who require immediate initiation of therapy for their own health, treatment should be started as soon as possible, including in the first trimester (AII). (Note that the use of efavirenz should be avoided during the first trimester.)
- A three-drug combination ARV regimen for prophylaxis of perinatal transmission also is recommended for HIV-infected pregnant women who do not require treatment for their own health (AII).
- Consideration can be given to delaying initiation of prophylaxis until after the first trimester (BIII) in women who are receiving ARV drugs solely for prevention of perinatal transmission, but earlier initiation of therapy may be more ef fective in reducing in utero transmission.
- ARV regimens should include a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone that includes one or more NRTIs with high levels of transplacental passage, if possible, to provide pre-exposure prophylaxis to the infant (AIII).
If HIV RNA is above the threshold for resistance testing (i.e., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting the ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy) (AI). If HIV is diagnosed late in pregnancy, the ARV drug regimen should be initiated pending results of re sistance testing (BIII).
- Nevirapine can be used as a component of the ARV drug regimen for pregnant women with CD4 cell counts 250 cells/mm3, however, nevirapine should be used only if the ben efit clearly outweighs the risk because the drug is associated with an increased risk of hepatic toxicity (AII).
Pregnant women with HIV infection should receive standard clinical, immunologic, and virologie evalu ation. Decisions about the need for initiation of therapy should be based on the standard guidelines for nonpregnant adults1.

# H IV-Infected Pregnant Women N ot on Antiretroviral Therapy and Who N eed Antiretroviral Treatment fo r Their Own Health
Any HIV-infected pregnant woman who meets standard criteria for initiation o f ART as per ARV guide lines in nonpregnant adults should receive potent combination ART, generally consisting o f NRTIs plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI), with continuation of therapy postpartum. Treatment should be started as soon as possible-including in the first trimesterfor women who require immediate initiation o f therapy for their own health because the potential benefit o f treatment for the mother outweighs potential risks to the fetus. The regimen generally should be cho sen from among those shown to be effective in nonpregnant adults, taking into account what is known about use o f the drugs during pregnancy and risk o f teratogenicity (see General Principles Regarding Use of Antiretroviral Drugs during Pregnancy)1.
A review o f a large database o f nevirapine studies indicated that women with CD4 counts >250 cells/mm3 have an increased risk o f developing symptomatic, often rash-associated, nevirapine-related hepatotoxicity that can be severe, life threatening, and in some cases fatal2-3. A more recent study involv ing 820 women in Kenya, Zambia, and Thailand, however, did not find an association between CD4 count and development o f hepatotoxicity4. Rash and liver toxicity were associated with elevated baseline liver transaminases but not with CD4 count; all deaths from hepatic toxicity occurred in women with CD4 counts 250 cells/mm3, nevirapine should be used as a component o f a combination regimen only when the benefit clearly outweighs the risk. If nevirapine is used, frequent and careful monitoring o f transaminase levels is required, particularly dur ing the first 18 weeks o f treatment (see Nevirapine and Hepatic/Rash Toxicity). Transaminase levels should be checked in women who develop a rash while receiving nevirapine. Nevirapine should be stopped immediately in women who develop signs or symptoms o f hepatitis.

# H IV-Infected Pregnant Women N ot on Antiretroviral Therapy Who Require Antiretroviral Prophylaxis Solely to Prevent Perinatal Transmission o f H IV
HIV-infected pregnant women should be counseled regarding the benefits o f ARV drugs for prevention o f perinatal transmission even when initiation o f ART for maternal health is not recommended or is con sidered optional on the basis o f current guidelines for treatment o f nonpregnant persons1. Although such women are at low risk o f clinical disease progression if ARV treatment is delayed, use o f an ARV regi men that successfully reduces plasma HIV RNA to undetectable levels substantially lowers the risk of perinatal transmission o f HIV and lessens the need for consideration o f elective cesarean delivery as an intervention to reduce risk o f transmission.
The fetus is most susceptible to the potential teratogenic effects o f drugs during the first trimester and the risks o f ARV drug exposure during that period are not fully known. Therefore, women in the first trimester of pregnancy who do not require immediate initiation o f therapy for their own health may con sider delaying initiation o f ARV drugs until after 12 weeks o f gestation. This decision should be care fully considered by the health care provider and the woman. Their discussion should encompass an assessment of the wom an's health status, the benefits and risks to her o f delaying initiation o f ARV drugs for several weeks, the fact that most perinatal transmission o f HIV events occur late in pregnancy or during delivery, and the possibility that early control o f viral replication may be important in prevent ing the smaller proportion o f earlier in utero transmission. In a recent French study, lack o f early and sustained control o f maternal viral load appeared strongly associated with residual perinatal transmission o f HIV5. That study evaluated risk factors for perinatal transmission in women with HIV RNA <500 copies/mL at the time of delivery; overall HIV transmission was 0.5%. Women who transmitted were less likely to have received ARV drugs at the time o f conception than were nontransmitters and were less likely to have HIV RNA <500 copies/mL at 14, 28, and 32 weeks o f gestation. Among women starting ARV drugs during pregnancy, the gestational age at initiation o f therapy did not differ between groups (30 weeks), but viral load decreased earlier in the nontransmitters. These data suggest that early and sus tained control o f HIV viral replication is associated with decreasing residual risk o f transmission and favor initiating ARV drugs as early in pregnancy as possible for all women.
ARV prophylaxis is recommended for all pregnant women with HIV infection, regardless o f viral load.
Although rates o f perinatal transmission are low in women with undetectable or low HIV RNA levels, there is no threshold below which lack o f transmission can be assured6-8. The mechanism by which ARV drugs reduce perinatal HIV transmission is multifactorial. Although lowering maternal antenatal viral load is an important component o f prevention in women with higher viral load, ARV prophylaxis is ef fective even in women with low viral load9-13. Additional mechanisms o f protection include pre-exposure prophylaxis and post-exposure prophylaxis o f the infant. With pre-exposure prophylaxis, passage o f the ARV drug across the placenta results in presence o f drug levels sufficient for inhibition o f viral replica tion in the fetus, particularly during the birth process when there is intensive viral exposure. With post exposure prophylaxis, ARV drugs are administered to the infant after birth. Transplacental passage is excellent with zidovudine but may be variable with many other ARV drugs (Table 4). Therefore, when ever possible, combination ARV drug regimens initiated during pregnancy should include zidovudine or another NRTI with high transplacental passage, such as lamivudine, emtricitabine, stavudine, tenofovir, or abacavir (see Table 5)14-17.
All pregnant women with HIV infection should be counseled about and offered combination ARV regi mens containing at least three drugs for prevention o f perinatal transmission o f HIV. In an analysis of perinatal transmission in 5,151 HIV-infected women between 2000 and 2006 in the United Kingdom and Ireland, the overall mother-to-child transmission rate was 1.2%. A transmission rate o f 0.8% was seen in women on ARV drugs for at least the last 14 days o f pregnancy, regardless o f the type o f ARV regimen or mode o f delivery18. Transmission rates were 0.7% for women receiving a triple-ARV drug regimen combined with a planned cesarean delivery or with planned vaginal delivery and 0.5% in 464 women who received single-drug prophylaxis with zidovudine combined with a planned cesarean delivery (as recommended in the British HIV Association guidelines for women with HIV RNA levels <10,000 copies/mL and wild-type virus who do not require treatment for their own health)19, not significantly dif ferent between groups. After adjustment for viral load, mode o f delivery, and sex o f the infant, longer duration o f use o f ARV drugs was associated with reduced transmission rates.
A combination regimen including two NRTIs and either an NNRTI or a PI (the latter with or without lowdose ritonavir) would be the preferred prophylactic regimen for ARV-naive women receiving drugs solely for prevention of transmission, as discussed in Recommendations for Use of Antiretroviral Drugs during Pregnancy. A study in Botswana compared a PI-based triple-drug regimen to a triple-NRTI (zidovudine/lamivudine/abacavir) combination regimen for prevention of transmission in breastfeeding women with CD4 counts >200 cells/mm3 20. Both regimens had similar rates of viral suppression by deliv ery (96% receiving the PI regimen and 93% receiving the triple-NRTI regimen had HIV RNA <400 copies/mL) and perinatal transmission (0.4% and 1.4%, respectively, not significantly different). Thus, for women who plan to discontinue prophylaxis following delivery, a triple-NRTI regimen also can be consid ered. If using abacavir, testing for HLA-B*5701, which identifies patients at risk of abacavir hypersensi tivity reactions21-22, should be performed and the results documented as negative before abacavir is started. Some women may wish to restrict fetal exposure to ARV drugs while reducing the risk o f HIV transmis sion to the infant. Use o f zidovudine alone during pregnancy for prophylaxis o f perinatal transmission is not optimal, but it could be an option for women with low viral loads (i.e., HIV RNA <1,000 copies/mL) on no ARV drugs. Time-limited administration o f zidovudine during the second and third trimesters of pregnancy is less likely to induce the development o f resistance in women with low viral loads than in those with higher viral loads. This lower rate o f resistance is likely because o f the low level o f viral replication and the short duration o f exposure23-24.
Following delivery, considerations regarding continuation o f the ARV regimen for treatment o f the mother are the same as for other nonpregnant adults (see General Principles for Use o f Antiretroviral Drugs during Pregnancy).

# HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Treatment (Updated September 14, 2011)
Panel's Recommendations
- In general, pregnant women receiving and tolerating an antiretroviral therapy (ART) regimen that is currently effective in suppressing viral replication should continue on the regimen; however, the use of efavirenz should be avoided in the first trimester (AIII).
- HIV antiretroviral (ARV) drug-resistance testing is recommended for pregnant women who have detectable viremia (e.g., >500-1,000 copies/mL) on therapy (see Failure of Viral Suppression) (AI).
- Pregnant women receiving and tolerating nevirapine-containing regimens who are virologically suppressed should con tinue the regimen, regardless of CD4 count (AIII).
In general, women who have been receiving antiretroviral treatment (ART) for their HIV infection should continue that treatment during pregnancy. Discontinuation of therapy could lead to an increase in viral load with possible decline in immune status and disease progression as well as adverse consequences for the fetus, including increased risk of HIV transmission. Continuation of therapy, therefore, is recom mended when pregnancy is identified in HIV-infected women receiving ART.
HIV-infected women receiving ART who present for care during the first trimester should be counseled re garding the benefits and potential risks of administration of ARVs during this period. Clinicians should re view the safety and risk/benefit profiles and reproductive considerations for the ARV agents used in the current HIV therapeutic regimen. The use of efavirenz should be avoided during the first trimester of preg nancy. If a first-trimester pregnancy is confirmed in a woman who is receiving efavirenz, an alternative ARV drug should be substituted when possible (see Monitoring of the Woman and Fetus during Pregnancy).
Resistance testing should be performed in women who are on therapy but in whom viral replication is not fully suppressed. The results can be used to select a new regimen with a greater likelihood of suppressing viral replication to undetectable levels. It should be noted that resistance assays vary depending on the HIV RNA level required to detect resistance mutations. Some assays require HIV RNA levels of >500-1,000 copies/mL; other assays can be performed on patients with lower viral loads.
Pregnant women for whom nevirapine-containing regimens are achieving viral suppression and who are tolerating therapy should continue that regimen, regardless of current CD4 count. Although hepatic toxic ity is a concern in women starting a nevirapine-containing regimen who have CD4 counts >250 cells/mm3, an increased risk of hepatic toxicity has not been seen in women receiving nevirapine-based therapy for whom the therapy has produced immune reconstitution.

# HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Treatment or Prophylaxis but Are Not Currently Receiving Any Antiretroviral Medications (Updated September 14, 2011)
Panel's Recommendations
- Obtain an accurate history of all prior antiretroviral (ARV) regimens used for treatment of HIV disease or prevention of transmission, including virologic efficacy, tolerance to the medications, results of prior resistance testing, and any adher ence issues (AIII).
- If HIV RNA is above the threshold for resistance testing (e.g., >500-1,000 copies/mL), ARV drug-resistance studies should be performed before starting an ARV drug regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy)

# (AIII).
In women who present late in pregnancy, therapy or prophylaxis should be initiated pending results of resistance test ing (BIII).
- Choose and initiate a combination ARV drug regimen based on results of resistance testing and prior history of antiretro viral therapy (ART) while avoiding drugs with teratogenic potential (efavirenz in the first trimester of pregnancy) or with known adverse potential for the mother (AII).
- Consult specialists in treatment of HIV infection about the choice of ART in women who previously received ARVs for their own health (AIII).
- Perform repeat ARV drug-resistance testing (AI), assess adherence, and consult with an HIV treatment specialist to guide changes in ARV drugs in women do not achieve virologic suppression on their ARV regimens (see Monitoring of the Woman and Fetus During Pregnancy).
During a previous pregnancy, HIV-infected women may have received ARV drugs solely for prevention of perinatal transmission. At any time in the past, they also may have discontinued ARVs given to them for treatment of their own disease. A small number of clinical trials or observational studies have generated information about how effective ART is in individuals who previously received ARV prophylaxis. The data are limited to outcomes with therapy containing nevirapine initiated after the use of peripartum sin gle-dose nevirapine1-5.
Initial reports suggested a diminished virologic and clinical response to nevirapine-based ART if therapy was initiated within 6 months o f intrapartum single-dose nevirapine exposure1-3. Subsequent reports have confirmed that a shorter interval between intrapartum single-dose nevirapine exposure and therapy initiation is associated with decreased efficacy o f therapy and suggested that the diminished response may persist 12-24 months following exposure4-5. In addition, the subsequent failure o f non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART after single-dose nevirapine has been associated with lower CD4 count and higher HIV-RNA plasma concentration at the time o f single-dose nevirapine expo sure, and genotypic resistance to nevirapine. Adding other ARVs to single-dose nevirapine (e.g., use of an ARV "tail") decreases rates o f nevirapine resistance6-7 (see Antiretroviral Drug Resistance and Resist ance Testing in Pregnancy), but the effect on clinical response to the subsequent initiation o f NNRTIbased ART is unknown.
There is concern that time-limited use o f ARV drugs during pregnancy for prophylaxis o f perinatal trans mission may lead to genotypic resistance and thus reduced efficacy o f the ARV drugs when used for treatment. Rates o f resistance appear to be low, based on standard genotyping, after prophylaxis for pre vention o f perinatal transmission with combination ARVs consisting o f zidovudine, lamivudine, and nevirapine8-9. However, particularly in women whose virus was inadequately suppressed during the pe riod o f prophylaxis, minority populations o f virus with resistance to nevirapine or lamivudine have been detected using sensitive allele-specific polymerase chain reaction (PCR) techniques9-11. Only limited data are available on the impact o f these resistance-conferring minority variants on prediction o f viro logic or clinical failure o f subsequent ART, and the PCR-based assays are not widely available. Both standard and sensitive genotyping techniques appear to show a low rate o f resistance to protease in hibitors (PIs) after pregnancy-limited use o f Pi-based combination ARV regimens for prophylaxis, but these results reflect assessments in only small numbers o f women11-12. However, to date, treatment fail ure has not been demonstrated with reinitiation o f combination ARV regimens (particularly those con taining the dual nucleoside reverse transcriptase inhibitor  backbone o f zidovudine and lamivudine) following prophylactic use in pregnancy for prevention o f transmission, although controlled observations are lacking.
Given the lack o f substantive data, it is reasonable to use results o f initial resistance testing, if available, to make preliminary decisions about ARV regimens in women whose only previous exposure to ARVs was during pregnancy for prophylaxis o f perinatal transmission. However, interpretation o f resistance testing following discontinuation o f ARV drugs can be complex because drug-resistance testing is most accurate if performed while an individual is taking the ARV regimen or within 4 weeks o f treatment dis continuation. In the absence o f selective drug pressure, resistant virus may revert to wild-type virus, and although detection o f drug-resistance mutations is informative for choosing a regimen, a negative find ing does not rule out the presence o f archived drug-resistant virus that could re-emerge once drugs are reinitiated. Therefore, when selecting a new regimen for use during the current pregnancy, all informa tion from the previous pregnancy-including regimens received, viral response, laboratory testing (in cluding HLA-B*5701 results), and any tolerance or adherence issues-as well as the results of resistance testing should be taken into consideration. If the woman presents late in pregnancy, therapy or prophylaxis should be initiated pending results o f resistance testing. Careful monitoring o f virologic re sponse to the chosen ARV regimen is important.
If the chosen regimen produces an insufficient viral response, decisions about switching regimens should be guided by repeat resistance testing and assessment o f medication adherence. These measures should be undertaken in consultation with an HIV treatment specialist.
Some women who receive ART for their own health choose to discontinue the drugs for a variety o f rea sons, and the length of time between treatment termination and pregnancy may vary. In these cases, careful clinical and laboratory assessments are necessary before therapy is reinitiated during pregnancy. The evaluations should include a review o f a woman's prior history o f virologic response and medica tion toxicity as well as her adherence to therapy. The appropriate choice o f ARV regimen to be initiated during pregnancy will vary according to a woman's history o f ART; the indication for stopping therapy; the effect o f prior therapy on clinical, virologic, and immunologic status; and the results o f past and cur rent testing for resistance and for HLA-B*5701. It may be possible, for example, to restart the same reg imen in women with a history o f prior ART associated with successful suppression o f viral load who then stopped all drugs simultaneously (or staggered discontinuation if NNRTI based) and who have no evidence of resistance. On the other hand, the selection o f an appropriate ARV regimen may be challeng ing even for health care providers experienced in HIV care in women with advanced HIV disease, a his tory o f extensive prior ART, or previous significant toxicity or nonadherence to ARV drugs. In such cases, restarting the prior regimen for a week or two before performing a resistance assay may yield more accurate results. In addition to obtaining genotypic resistance testing, it is strongly recommended that specialists in the treatment o f HIV infection be consulted early during the pregnancy about the choice o f suitable ART.
Special Situations -HIV/Hepatitis B Virus Coinfection (Updated September 14, 2011)
Panel's Recommendations
- Screening for hepatitis B virus (HBV) infection is recommended for all pregnant women who have not been screened during the current pregnancy (AII).
- The HBV vaccine series should be administered to pregnant women who screen negative for hepatitis B (i.e., hepatitis B surface antigen negative, hepatitis B core antibody negative, and hepatitis B surface antibody negative) (AII).
- Pregnant women with chronic HBV infection should be screened for antibodies to hepatitis A virus (HAV), and those who screen negative should receive the HAV vaccine series (AII).
- Interferon alfa and pegylated interferon alfa are not recommended during pregnancy (AIII).
- The management of HIV/HBV coinfection in pregnancy is complex and consultation with an expert in HIV and HBV is strongly recommended (AIII).
- All pregnant women with HIV/HBV coinfection should receive a combination antiretroviral (ARV) drug regimen, including a dual nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide analogue reverse transcriptase inhibitor (NtRTI) back bone with two drugs active against both HIV and HBV (AII). Tenofovir plus lamivudine or emtricitabine is the preferred dual NRTI/NtRTI backbone of a combination antepartum ARV regimen in HIV/HBV-coinfected pregnant women (AI).
- If ARV drugs are discontinued postpartum in women with HIV/HBV coinfection, frequent monitoring of liver function tests for potential exacerbation of HBV infection is recommended, with prompt reinitiation of treatment for both HIV and HBV if a flare is suspected (BIII).
- Pregnant women with HIV/HBV coinfection receiving ARV drugs should be counseled about the signs and symptoms of liver toxicity, and liver transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter (BIII).
- Within 12 hours of birth, infants born to women with HBV infection should receive hepatitis B immune globulin (HBIG) and the first dose of the HBV vaccine series. The second and third doses of vaccine should be administered at ages 1 and 6 months, respectively (AI). All HIV-infected pregnant women should be screened for hepatitis A, B, and C. The management of HIV/HBVcoinfection in pregnancy is complex and consultation with an expert in HIV and HBV infection is strongly recommended. HIV-infected women who are found to have chronic HBV infection on the basis of persistent hepatitis B surface antigenemia for at least 6 months and who are hepatitis A immunoglobulin G (IgG) negative should receive the HAV vaccine series because of the added risk of acute hepatitis A in persons with chronic viral hepatitis.
HIV-infected pregnant women who test negative for hepatitis B surface antibody and hepatitis B surface antigen should receive the HBV vaccine series. A positive test for hepatitis B core antibody alone can be a false-positive result, or it may signify past exposure with subsequent loss of hepatitis B surface antibody, or "occult" HBV infection, which can be confirmed by detection of HBV DNA3-4. The clinical significance of isolated hepatitis B core antibody is unknown5-6. Some experts recommend that HIV-infected persons with hepatitis B core antibody alone should be tested for HBV DNA before vaccination for HBV or before treat ment or prophylaxis with ARV drugs is initiated because of the risk of a paradoxical exacerbation of HBV and the occurrence of immune reconstitution inflammatory syndrome (IRIS)2.
An ARV regimen that includes drugs active against both HIV and HBV is recommended for all individuals with HIV/HBV coinfection who require HBV treatment or who are starting ARV drugs, including pregnant women. Initiation of an ARV regimen that does not include anti-HBV drugs may be associated with reacti vation of HBV and development of IRIS; IRIS-related flare of HBV activity during pregnancy can occur even among women with relatively high CD4 cell counts at the time of ARV initiation. In addition, use of ARV drugs with anti-HBV activity during pregnancy lowers HBV viremia, potentially increasing the effi cacy of neonatal HBIG and hepatitis B vaccine in prevention of perinatal transmission of HBV. High mater nal HBV DNA levels are strongly correlated with perinatal HBV transmission and with failures of HBV passive-active immunoprophylaxis7-9. Several small studies suggest that lamivudine or telbivudine may re duce the risk of perinatal transmission of HBV if given during the third trimester to HBV-infected, HIVseronegative women with high HBV DNA viremia10-13. Although a high HBV viral load clearly is important, it is, however, not the only factor predisposing to failure of prophylaxis14.
Because lamivudine, tenofovir, and emtricitabine have activity against both HIV and HBV, the recom mended dual-NRTI/NtRTI backbone for HIV/HBV-coinfected individuals, including pregnant women, is tenofovir/emtricitabine or tenofovir/lamivudine. Lamivudine has been extensively studied and is recom mended for use in pregnancy (Table 5). The Antiretroviral Pregnancy Registry includes reports on the out comes of 3,864 pregnancies that involved administration of lamivudine in the first trimester and there is no indication that the exposure was associated with an increased risk of birth defects15. Similarly, no increase in birth defects has been noted in 641 cases of first-trimester exposure to emtricitabine, which is an alterna tive NRTI for use in pregnancy (Table 5). Tenofovir is not teratogenic in animals, but reversible bone changes at high doses have been seen in multiple animal species. A total of 1,092 cases of first-trimester ex posure have been reported to the Antiretroviral Pregnancy Registry, with no increase in birth defects noted15. Although tenofovir is recommended as an alternative NtRTI during pregnancy for ARV-naive women, it is a preferred NtRTI in women with HIV/HBV coinfection (Table 5).
Several other antivirals with activity against HBV, including entecavir, adefovir, and telbivudine, have had minimal evaluation in pregnancy. Entecavir is associated with skeletal anomalies in rats and rabbits but only at doses high enough to cause toxicity to the mother. No data are available on use of entecavir and ade fovir in human pregnancy. Telbivudine was given to 95 HBV-positive, HIV-negative women during the third trimester and was well tolerated13. Each of these anti-HBV drugs should be administered only in addi tion to a fully suppressive regimen for HIV. Because these other anti-HBV drugs also have weak activity against HIV, they may select for anti-HIV drug resistance in the absence of a fully suppressive ARV regi men as well as potential cross resistance to other ARV drugs. (Entecavir, for example, can select for the M184V mutation, which confers HIV resistance to lamivudine and emtricitabine.) These drugs should be used during pregnancy only if the preferred drugs are not appropriate in specific cases. Cases of exposure during pregnancy to any of the ARV drugs and HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263; ).
Interferon alfa and pegylated interferon alfa are not recommended for use in pregnancy and should be used only if the potential benefits outweigh the potential risks. Although interferons are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of the direct antigrowth and antiproliferative effects of these agents16.
Following initiation of ARV drugs, an elevation in hepatic enzymes can occur in HIV/HBV-coinfected women-particularly those with low CD cell counts at the time of treatment initiation-as a result of an immune-mediated flare in HBV disease triggered by immune reconstitution with effective HIV therapy. HBV infection also can increase hepatotoxic risk of certain ARV drugs, specifically protease inhibitors (PIs) and nevirapine. Pregnant women with HIV/HBVcoinfection should be counseled about signs and symptoms of liver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter. If hepatic toxicity occurs, it may be necessary to consider substituting a less hepatotoxic regimen or, if clinical symptoms or significant elevations of transaminases occur, drugs may need to be temporarily discontinued. Differentiating between a flare in HBV disease due to immune reconstitu tion and drug toxicity often can be difficult, and consultation with an expert in HIV and HBV coinfection is strongly recommended. Because tenofovir has potential to cause renal toxicity, kidney function also should be monitored regularly in women receiving this drug, based on toxicity seen in nonpregnant adults. Panel's Recommendations
- Screening for hepatitis C virus (HCV) infection is recommended for all HIV-infected pregnant women who have not been screened during the current pregnancy (AIII).
- Interferon alfa and pegylated interferon alfa are not recommended and ribavirin is contraindicated during pregnancy (AIII).
- Recommendations for antiretroviral (ARV) drug use during pregnancy are the same for women who have chronic HCV as for those without HIV/HCV coinfection (BIII).
- Pregnant women with HIV/HCV coinfection receiving ARV drugs should be counseled about signs and symptoms of liver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and then every 3 months thereafter (BIII). Tn a majority o f studies. the incidence o f HCV transmission from mother to infant increases if the mother is coinfected with HTV. with transmission rates between 10% and 20%7-10. These higher transmis sion rates are likely related to an increase in HCV viremia and/or other HTV-related impact on HCV dis ease activity11. Special Situations -HIV-2 Infection and Pregnancy (Updated September 14, 2011)
Panel's Recommendations
- HIV-2 infection should be suspected in pregnant women who are from-or have partners from-countries in which the disease is endemic, who are HIV antibody positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeterminate results on HIV-1 Western blot and an HIV-1 RNA viral load at or below the limit of detec tion (BII).
- A regimen with two nucleoside reverse transcriptase inhibitors (NRTIs) and a boosted protease inhibitor (PI) currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have signifi cant clinical disease or CD4 counts <500 cells/mm3 (AIII).
- Based on available data on safety in pregnancy, zidovudine/lamivudine plus lopinavir/ritonavir would be preferred (AIII). Tenofovir plus lamivudine or emtricitabine plus lopinavir/ritonavir can be considered as an alternative (BIII).
- Optimal prophylactic regimens have not been defined for HIV-2-infected pregnant women who do not require treatment for their own health (i.e., CD4 counts >500 cells/mm3 and no significant clinical disease). Experts have recommended the following approaches:
- A boosted PI-based regimen (two NRTIs plus lopinavir/ritonavir) for prophylaxis, with the drugs stopped postpartum (BIII);
- Zidovudine prophylaxis alone during pregnancy and intrapartum (BIII).
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis (AIII).
- All infants born to HIV-2-infected mothers should receive the standard 6-week zidovudine prophylactic regimen (BIII).
- In the United States, breastfeeding is not recommended for infants of HIV-2-infected mothers (AIII).
HIV-2 infection is endemic in Angola; Mozambique; West African countries including Cape Verde, Ivory Coast, Gambia, Guinea-Bissau, Mali, Mauritania, Nigeria, Sierra Leone, Benin, Burkina Faso, Ghana, Guinea, Liberia, Niger, Nigeria, Sao Tome, Senegal, and Togo; and in parts o f India1-3. It also oc curs in countries such as France and Portugal, which have large numbers o f immigrants from these re gions4. HIV-2 is rare in the United States. HIV-2 infection should be suspected in pregnant women who are from-or who have partners from-countries in which the disease is endemic, who are HIV-1 anti body positive on an initial enzyme-linked immunoassay screening test, and who have repeatedly indeter minate results on HIV-1 Western blot and HIV-1 RNA viral loads at or below the limit o f detection5-6. This pattern o f HIV testing can also be seen in patients who have a false-positive HIV-1 test.
The majority of commercially available HIV screening tests can detect both HIV-1 and HIV-2 but cannot distinguish between the two viruses. The only Food and Drug Administration (FDA)-approved antibody test that distinguishes between HIV-1 and HIV-2 is the Bio-Rad Laboratories Multispot HIV-1/HIV-2 test.
If HIV-2 is suspected, infection can be confirmed using a supplemental test such as an HIV-2 immunoblot or HIV-2-specific Western blot. HIV-2 immunoblots are available through commercial labs; however, none is FDA approved for HIV-2 diagnosis. HIV-2-specific Western blots can be requested through state health departments. HIV-2 viral load assays currently are not commercially available in the United States. The National Perinatal HIV Hotline (1-888-448-8765) can provide a list of sites that perform these tests.
HIV-2 has a longer asymptomatic phase than HIV-1, with a slower progression to AIDS. The most com mon mode of HIV-2 transmission is through heterosexual sex. HIV-2 is less infectious than HIV-1, with a 5-fold lower rate o f sexual transmission and 20-to 30-fold lower rate o f vertical transmission3, 7-8. Sev eral studies confirm that rates o f mother-to-child transmission o f HIV-2 are low with and without inter ventions (0% -4%), which may be a result o f reduced plasma viral loads and less cervical viral shedding, compared with that seen in HIV-1-infected women9-12. HIV-2 also can be transmitted through breastfeed ing. HIV-2 infection does not protect against HIV-1 and dual infection, which carries the same prognosis as HIV-1 monoinfection, can occur.
Few data exist on which to base treatment decisions or strategies for prevention o f mother-to-child trans mission in patients infected with HIV-2. NNRTIs and enfuvirtide are not active against HIV-2 and should not be used for treatment or prophylaxis13-14. HIV-2 has variable sensitivity to protease inhibitors (PIs), with lopinavir, saquinavir, and darunavir having the most activity against the virus15. The integrase inhibitors raltegravir and elvitegravir also appear to be effective against HIV-23, 16-17.
The care of HIV-2-infected pregnant women has been based on expert opinion. A regimen with two NRTIs and a boosted PI currently is recommended for HIV-2-infected pregnant women who require treatment for their own health because they have significant clinical disease or CD4 counts <500 cells/mm318. Based on available data on safety in pregnancy, zidovudine/lamivudine plus lopinavir/ritonavir would be preferred.
Tenofovir plus lamivudine or emtricitabine plus lopinavir/ritonavir can be considered as an alternative19-20.
NNRTIs should not be used because they are not active against HIV-2. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen.
For HIV-2-infected pregnant women with CD4 counts >500 cells/mm3 and no significant clinical dis ease, who do not require treatment for their own health, some experts would use a boosted PI-based reg imen for prophylaxis and stop the drugs postpartum. Other experts would consider zidovudine prophylaxis alone during pregnancy and intrapartum10. Because HIV-2 has a significantly lower risk of mother-to-child transmission than does HIV-1, single-drug prophylaxis with zidovudine alone can be considered for prevention o f mother-to-child transmission. All infants born to mothers infected with HIV-2 should receive the standard 6-week zidovudine prophylactic regimen20. The possible risks and benefits o f antiretroviral (ARV) prophylaxis should be discussed with the mother.
Pregnant women who have HIV-1/HIV-2 coinfection should be treated according to the guidelines for HIV-1-monoinfected patients, making sure that the ARV regimen chosen is also appropriate for HIV-2.
Other than the standard obstetrical indications, no data exist regarding the role o f elective cesarean de livery in women who are infected with HIV-2. The risk to the infant from breastfeeding is lower for HIV-2 than for HIV-1, but breastfeeding should be avoided in the United States and other resource-rich countries where safe infant formula is readily available10.
Infants born to HIV-2-infected mothers should be tested for HIV-2 infection with HIV-2-specific virologic assays at time points similar to those used for HIV-1 testing21. - Repeat HIV antibody testing in the third trimester is recommended for pregnant women with initial negative HIV antibody tests who are known to be at risk of HIV, are receiving care in facilities that have an HIV incidence in pregnant women of at least 1 per 1,000 per year, are incarcerated, or reside in jurisdictions with elevated rates of HIV infection (see Revised
Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings) (AII).
- All pregnant women with acute or recent HIV infection should start a combination antiretroviral (ARV) drug regimen as soon as possible to prevent mother-to-child transmission, with the goal of suppressing plasma HIV RNA to below de tectable levels (AI).
- In women with acute HIV infection, baseline genotypic resistance testing should be performed simultaneously with initia tion of the ARV regimen, and the ARV regimen should be adjusted, if necessary, to optimize virologic response (AIII).  An estimated 40%-90% of patients with acute HIV infection will experience symptoms of acute retroviral syndrome, characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms4, 6-10. Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses and individuals with the condition also can be asymptomatic. When acute retroviral syndrome is suspected, a plasma HIV RNA test typically is used in conjunction with an HIV antibody test to diagnose acute infection. A low-positive HIV RNA level (100,000 copies/mL)4, 10. In individuals infected with non-B HIV-1 subtypes, however, HIV RNA levels may be lower, even with acute infection, because those subtypes may not amplify as well as subtype B. In that sit uation, consultation with an HIV treatment specialist is recommended. Confirmatory serologic testing should be performed within 3 months on patients whose acute HIV infection is diagnosed with virologic testing but who are antibody negative or whose antibody levels cannot be determined.
Acute HIV infection also can be detected by repeat HIV antibody testing later in pregnancy in women whose initial HIV antibody testing earlier in pregnancy was negative. A report from the Mother-Infant Rapid Intervention at Delivery (MIRIAD) study found that 6 (11%) o f 54 women whose HIV was iden tified with rapid HIV testing during labor had primary infection11. Repeat HIV testing in the third trimester is recommended for pregnant women known to be at risk o f HIV who receive care in facilities with an HIV incidence o f at least 1 case per 1,000 pregnant women per year, who are incarcerated, or who reside in jurisdictions with elevated HIV incidence (see Revised Recommendations for HIV Testing o f Adults, Adolescents, and Pregnant Women in Health-Care Settings) 12.
Whether treatment o f acute or recent HIV infection results in long-term virologic, immunologic, or clini cal benefit is unknown, and in nonpregnant adults, therapy currently is considered optional13. In preg nant or breastfeeding women, however, acute or recent HIV infection is associated with a high risk of perinatal transmission o f HIV. All HIV-infected pregnant women with acute or recent infection should start a combination ARV regimen as soon as possible, with the goal o f preventing perinatal transmission by optimal suppression o f plasma HIV RNA below detectable levels. Data from the United States and Europe demonstrate that in 6% -16% o f patients, transmitted virus may be resistant to at least one ARV drug14-16. Therefore, baseline genotypic resistance testing should be performed to guide selection or ad justment of an optimal ARV drug regimen. If results o f resistance testing or the source virus's resistance pattern are known, that information should be used to guide selection o f the drug regimen, but initiation o f the ARV regimen should not be delayed. Because clinically significant resistance to PIs is less com mon than resistance to NNRTIs in ARV-naive persons, a PI-based ARV drug regimen generally should be initiated. Choice o f regimen should be based on recommendations for use o f ARV drugs in pregnancy (see Table 5). Following delivery, considerations regarding continuation o f the ARV regimen for treat ment are the same for the mother as for other nonpregnant individuals.
When acute HIV infection is diagnosed during pregnancy, and particularly if it is documented in late preg nancy, cesarean delivery is more likely to be necessary because there may be insufficient time to fully sup press the patient's viral load. In nursing mothers in whom seroconversion is suspected, breastfeeding should be interrupted and it should not resume if infection is definitively confirmed (see Breastfeeding In fants of Mothers Diagnosed with HIV Infection in Infant Antiretroviral Prophylaxis). In such a situation, consultation with a pediatric HIV specialist regarding appropriate infant management is recommended.
All women who are pregnant or breastfeeding should be counseled about prevention o f HIV acquisition.
Several studies suggest that pregnancy may be a time o f increased risk o f transmission o f HIV17-19, even when controlling for sexual risk behaviors17. It is hypothesized that the heightened risk may be attributa ble to hormonal changes that affect the genital tract mucosa or immune responses17. Although no reliable data on HIV serodiscordance rates in the United States exist, data on women from sub-Saharan Africa show that women in serodiscordant relationships may be particularly vulnerable to acquisition o f HIV20. HIV testing o f the sexual partners o f pregnant women should be encouraged. The importance o f using condoms should be reinforced in pregnant women who may be at risk o f acquisition o f HIV, including those whose partners are HIV-infected.
Special Situations -Stopping Antiretroviral Drugs during Pregnancy (Updated September 14, 2011)

# Panel's Recommendations
HIV-infected women receiving antiretroviral treatment (ART) who present for care during the first trimester should con tinue treatment during pregnancy (AII). Women who present in the first trimester on an efavirenz-containing regimen should continue on therapy without interruption but, when possible, an alternative antiretroviral (ARV) drug should be substituted for efavirenz (AIII).
- If an ARV drug regimen is stopped acutely for severe or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses that preclude oral intake, all ARV drugs should be stopped and reinitiated at the same time (AIII).
- If an ARV drug regimen is being stopped electively and the patient is receiving a non-nucleoside reverse transcriptase in hibitor (NNRTI) drug, consideration should be given to either: (1) stopping the NNRTI first and continuing the other ARV drugs for a period of time; or (2) switching from an NNRTI to a protease inhibitor (PI) before interruption and continuing the PI with the other ARV drugs for a period of time before electively stopping. The optimal interval between stopping an NNRTI and the other ARV drugs is unknown; at least 7 days is recommended. Given the potential for prolonged de tectable efavirenz concentrations for more than 3 weeks in patients receiving efavirenz-based therapy, some experts rec ommend continuing the other ARV agents or substituting a PI plus two other agents for up to 30 days (CIII).
- If nevirapine is stopped and more than 2 weeks have passed before restarting therapy, nevirapine should be restarted with the 2-week dose escalation period (AII).
Discontinuation of ARV drug regimens during pregnancy may be indicated in some situations, including serious drug-related toxicity, pregnancy-induced hyperemesis unresponsive to antiemetics, acute illnesses or planned surgeries that preclude oral intake, lack of available medication, or at patients' request.
HIV-infected women receiving ART who present for care during the first trimester o f pregnancy should continue treatment during pregnancy. Discontinuation of therapy could lead to an increase in viral load with possible decline in immune status and disease progression as well as adverse consequences for the fetus, including increased risk of transmission of HIV. A recent analysis from a prospective cohort of 937 HIV-infected mother-child pairs found that interruption of ART during pregnancy, including interruption in the first and third trimesters, was independently associated with perinatal transmission. In the first trimester, the median time at interruption was 6 weeks' gestation and length of time without therapy was 8 weeks (interquartile range , 7-11 weeks); in the third trimester, the median time at interruption was 32 weeks and length of time without therapy was 6 weeks (IQR, 2-9 weeks). Although the perinatal trans mission rate for the entire cohort was only 1.3%, transmission occurred in 4.9% (95% confidence interval , 1.9%-13.2%, adjusted odds ratio  10.33, P = .005) with first-trimester interruption and 18.2% (95% CI, 4.5%-72.7%, AOR 46.96, P = .002) with third-trimester interruption1. Although the use of efavirenz should be avoided during the first trimester, therapy should not be interrupted in women taking the drug who present in the first trimester but, rather, an alternative ARV should be substituted, if possible.
Continuation of all drugs during the intrapartum period generally is recommended. Women who are hav ing elective cesarean delivery can take oral medications before the procedure and restart drugs following surgery. Because most drugs are given once or twice daily, it is likely that no doses would be missed or that at most the postpartum dose would be given a few hours late.
When short-term drug interruption is indicated, in most cases, all ARV drugs should be stopped and rein troduced at the same time. This can be problematic with drugs that have a long half-life. However, in con-ditions such as serious or life-threatening toxicity, severe pregnancy-induced hyperemesis unresponsive to antiemetics, or other acute illnesses precluding oral intake, the clinician has no choice but to stop all ther apy at the same time. In the rare case in which a woman has limited oral intake but that does not meet food requirements for certain ARV agents, decisions about the ARV regimen administered during the intra partum period should be made on an individual basis and in consultation with an HIV treatment expert.
NNRTI drugs such as nevirapine and efavirenz have very long half-lives and can be detected for 21 days or longer after discontinuation; efavirenz has a longer half-life than nevirapine2-6. Because other drugs in the ARV regimen have shorter half-lives and are cleared more rapidly, only detectable NNRTI drug levels persist, resulting in subtherapeutic drug levels that can increase the risk of selection of NNRTI-resistant mutations. In addition, certain genetic polymorphisms, which may be more common among racial/ethnic groups such as African Americans and Hispanics, may have potential to result in a slower rate of clear ance4, 6. To prevent prolonged exposure to a single drug, some experts recommend stopping the NNRTI first and continuing the other ARV drugs for a period of time3. However, the optimal interval between stopping an NNRTI and the other ARV drugs is unknown; detectable levels of NNRTIs may be present from less than 1 week to more than 3 weeks after discontinuation, with the longer duration primarily ob served with efavirenz6. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual nucleoside reverse transcriptase inhibitors (NRTIs) for a period of time. In a post-study analysis of the patients who interrupted therapy in the SMART trial, patients who were switched from an NNRTIto a PI-based regimen before interruption had a lower rate of NNRTI-resistant mutation after interruption and a greater chance of HIV RNA resuppression after restarting therapy than those who stopped all the drugs simultaneously or stopped the NNRTI before the dual-NRTIs7.
The optimal duration for continuing either dual nucleosides or the substituted PI-based regimen after stop ping the NNRTI is unknown, but a minimum of 7 days is recommended based on studies to reduce resist ance following single-dose nevirapine8-9.
A pharmacokinetic (PK) study of nevirapine elimination in African adults following cessation of steadystate nevirapine-containing regimens found that nevirapine concentrations were estimated to have fallen below 20 ng/mL in 3 of 19 (16%) and 14 of 19 (74%) subjects by 7 and 14 days, respectively, after the cessation of dosing10. Elimination half-life was 39 hours in these subjects, considerably shorter than that observed after peripartum exposure to single doses of nevirapine (average 55-60 hours), likely related to induction of nevirapine metabolism with chronic nevirapine exposure2, 11-12. Because efavirenz concentra tions have potential to be detectable for more than 3 weeks, some experts suggest that if efavirenz-based therapy is stopped, the dual NRTIs or PI may need to be continued for up to 30 days. Further research is needed to assess appropriate strategies for stopping NNRTI-containing combination regimens.
Another consideration is reintroduction of nevirapine if it is temporarily stopped for some reason and sub sequently restarted. A 2-week, half-dose escalation currently is recommended in patients who are started on nevirapine. Dose escalation is necessary because nevirapine induces its own metabolism by inducing cytochrome P450 3A4 (CYP3A4) liver metabolic enzymes; thus, initial administration of the full thera peutic dose will result in elevated drug levels until metabolic enzyme induction has occurred. In cases where nevirapine has been discontinued for more than 2 weeks, another 2-week dose escalation is recom mended when it is reintroduced.
Special Situations -Failure of Viral Suppression (Updated September 14, 2011)

# Panel's Recommendations
- If an ultrasensitive HIV RNA assay indicates failure of viral suppression to below detectable levels after an adequate pe riod of treatment:
- Assess resistance and adherence (AII).
- Consult an HIV treatment expert (AIII).
- Scheduled cesarean delivery is recommended for HIV-infected pregnant women who have HIV RNA levels >1,000 copies/mL near the time of delivery (AII).
A three-pronged approach is indicated for management o f women on ARV regimens who have subopti mal suppression o f HIV RNA (i.e., detectable virus at any time during pregnancy using ultrasensitive as says). They should be: 1) evaluated for resistant virus (if plasma HIV RNA is >500-1,000 copies/mL); 2) assessed for adherence, incorrect dosing, or potential problems with absorption (e.g., with nausea/vomiting or lack o f attention to food requirements); and 3) consideration should be given to modifying the ARV regimen. Experts in the care of ARV-experienced adults should be consulted, partic ularly if a change in drug regimen is necessary. Hospitalization may be considered for directly observed drug administration, adherence education, and treatment o f comorbidities such as nausea and vomiting.
HIV RNA levels should be assessed 2-4 weeks after an ARV drug regimen is initiated or changed to pro vide an initial assessment of effectiveness1. Baseline HIV RNA levels have been shown to affect the time to response in both pregnant and nonpregnant individuals2. Most patients with an adequate viral response at 24 weeks have had at least a one log10 copies/mL HIV RNA decrease within 1 -4 weeks after starting therapy1. Treatment-naive individuals should have HIV RNA <400 copies/mL after 24 weeks of treatment and <50 copies/mL after 48 weeks of treatment.
Because maternal antenatal viral load correlates with risk o f perinatal transmission o f HIV, suppression o f HIV RNA to undetectable levels should be achieved as rapidly as possible. Scheduled cesarean deliv ery is recommended for HIV-infected pregnant women who have HIV RNA levels >1,000 copies/mL near the time o f delivery (see Transmission and Mode o f Delivery) .
Monitoring of the Woman and Fetus During Pregnancy (Updated September 14, 2011)

# Panel's Recommendations
- CD4 cell count should be monitored at the initial antenatal visit (AI) and at least every 3 months during pregnancy (BIII).
Monitoring of CD4 count may be performed every 6 months in patients on antiretroviral treatment (ART) for more than 2-3 years who are adherent to therapy, clinically stable, and have sustained viral suppression (BIII).
- Plasma HIV RNA levels should be monitored at the initial visit (AI); 2-4 weeks after initiating (or changing) antiretroviral (ARV) drug regimens (BI); monthly until RNA levels are undetectable (BIII); and then at least every 3 months during pregnancy (BIII). HIV RNA levels also should be assessed at approximately 34-36 weeks' gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery) (AIII).
- Genotypic ARV drug-resistance testing should be performed at baseline in all HIV-infected pregnant women with HIV RNA levels >500-1,000 copies/mL, whether they are ARV-naive or currently on therapy (AIII). Repeat testing is indicated following initiation of an ARV regimen in women who have suboptimal viral suppression or who have persistant viral re bound to detectable levels after prior viral suppression on an ARV regimen (AII).
- Monitoring for complications of ARV drugs during pregnancy should be based on what is known about the adverse ef fects of the drugs a woman is receiving (AIII).
- First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide timing of the procedure (see Transmission and Mode of Delivery) (AII).
- Given the limited data on the effect of combination ARV drugs on the fetus, most experts would recommend secondtrimester ultrasound to assess fetal anatomy for women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz (BIII).
- In women on effective combination ARV regimens, no perinatal transmissions have been reported after amniocentesis, but a small risk of transmission cannot be ruled out. If amniocentesis is indicated in HIV-infected women, it should be done only after initiation of an effective combination ARV drug regimen and, if possible, when HIV RNA levels are unde tectable (BIII). In women with detectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered.
In HIV-infected pregnant women CD4 cell count should be monitored at the initial visit and at least every 3 months during pregnancy, similar to recommendations in nonpregnant adults. Monitoring of CD4 counts may be performed every 6 months in patients on ART for more than 2-3 years who are adherent to ther apy, clinically stable, and have sustained viral suppression. Viral load should be monitored in HIV-infected pregnant women at the initial visit, 2-4 weeks after initiating or changing ARV regimens, monthly until undetectable, and at least every 3 months thereafter. If adherence is a concern, more frequent monitoring is recommended because of the potential increased risk of perinatal HIV infection associated with detectable HIV viremia during pregnancy. More frequent monitoring of viral load is recommended in pregnant versus nonpregnant individuals because of the urgency to lower viral load as rapidly as possible to reduce the risk of perinatal transmission. Therefore, there is a need to identify pregnant women in whom the decline in viral load is slower than expected. Adult ARV guidelines note that patients should have a decrease in plasma HIV RNA level by at least one log10 copies/mL within 1 month after initiation of potent therapy1. Viral suppression generally is achieved in 16-24 weeks in ARV-naive treatment-adherent individuals who do not harbor resistance mutations to the drugs they are receiving but, in rare cases, it may take longer.
Viral load also should be assessed at approximately 34-36 weeks' gestation to inform decisions about mode of delivery (see Transmission and Mode of Delivery).
Because o f physiologic changes such as hemodilution that are associated with pregnancy, CD4 percent age may be more stable than absolute CD4 count during pregnancy2-5. Nevertheless, most clinicians still rely on absolute CD4 count to evaluate immune status during pregnancy because parameters for initiat ing therapy are based on those values.
ARV drug-resistance testing should be performed in HIV-infected pregnant women before initiation of ARV drugs if HIV RNA levels are above the threshold for resistance testing (e.g., >500-1,000 copies/mL). Testing should also be performed in women with suboptimal viral suppression while receiv ing an ARV regimen or who have persistant viral rebound to detectable levels after prior viral suppres sion on an ARV regimen (see Antiretroviral Drug Resistance and Resistance Testing in Pregnancy). Drug-resistance testing in the setting o f virologic failure should be performed while patients are receiv ing ARV drugs or within 4 weeks after discontinuation o f drugs. Genotypic testing is preferable to phe notypic testing because it costs less, has a faster turnaround time, and is more sensitive for detection of mixtures o f wild-type and resistant virus.
Monitoring for potential complications of ARV drugs during pregnancy should be based on what is known about the adverse effects o f the drugs the woman is receiving. For example, routine hematologic monitoring is recommended for women receiving zidovudine-containing regimens. Liver function should be monitored in all women receiving ARV drugs. Hepatic dysfunction has been observed in pregnant women on protease inhibitors (PIs), and hepatic steatosis and lactic acidosis in pregnancy have been re lated to nucleoside reverse transcriptase inhibitor (NRTI) use. Women with CD4 counts >250 cells/mm3 are thought to be at particular risk o f developing symptomatic, rash-associated, nevirapine-associated hepatotoxicity within the first 18 weeks after initiation o f therapy. Data from a 2010 study, however, suggest that abnormal liver transaminase levels at baseline may be more predictive o f risk than CD4 cell count6. Transaminase levels should be monitored more frequently and carefully in pregnant women initiating therapy with nevirapine, and they should also be watched for clinical symptoms o f potential hepatotoxicity (see Nevirapine and Hepatic/Rash Toxicity). The drug can be used cautiously with careful monitoring in women with mildly abnormal liver function tests at the time of ARV drug initiation.
First-trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide potential timing because such deliveries for prevention o f perinatal transmission of HIV should be performed at 38 weeks' gestation (see Transmission and Mode o f Delivery)7-8. In patients who are not seen until later in gestation, second-trimester ultrasound can be used for both anatomical scanning and determination of gestational age.
Because less is known about the effect o f combination ARV drug regimens on the fetus during preg nancy, some experts consider more intensive fetal assessment for mothers receiving such therapy. Most experts would recommend second-trimester assessment o f fetal anatomy with ultrasound in women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz. Furthermore, in addition to standard clinical monitoring, some experts would also recommend ultrasound assessment o f fetal growth and well-being during the third trimester in woman who are re ceiving a combination drug regimen for which there is limited experience with use in pregnancy. The need for additional assessments such as non-stress testing should be determined based on ultrasound findings, any maternal comorbidities, and standard obstetrical indications.
Although data are still somewhat limited, the risk o f transmission does not appear to be increased with amniocentesis or other invasive diagnostic procedures in women receiving effective combination ARV drug regimens resulting in viral suppression. This is in contrast to the pre-combination drug regimen era, during which invasive procedures such as amniocentesis and chorionic villus sampling (CVS) were as sociated with a two-to fourfold increased risk o f perinatal transmission o f HIV9-11. In an evaluation of transmission rates o f HIV over time among women with or without amniocentesis, the transmission rate among women undergoing the procedure from 1984 to 1996 (pre-combination drug era) was 30% (3 of 10) compared with 16.2% (40 o f 247) in those who did not have amniocentesis12. In contrast, no trans missions were noted among 18 women undergoing amniocentesis between 1997 and 2000 who received suppressive combination ARV drug regimens12.
In an Italian multicenter study that included deliveries between 1997 and 2003, 3.3% (2 o f 60) o f infants were HIV infected after early invasive diagnostic procedures (CVS, amniocentesis, or cordocentesis) during pregnancy, compared with 1.7% (12 o f 712) o f infants born to women without invasive proce dures (P = 0.30)13. No transmissions occurred among 45 women on combination ARV drug regimens during the procedure. One mother o f an infected infant had not been diagnosed as HIV infected at the time o f amniocentesis and was not receiving ARV prophylaxis; the newborn's virologic test at birth was negative. The mother o f a second infected infant had been receiving zidovudine prophylaxis for 3 weeks and had an HIV RNA level o f 10,000 copies/mL at the time o f the procedure; the preterm infant had a positive virologic test at birth. In 2 other single-center series, no transmissions occurred in 6 and 9 live born infants after amniocentesis in HIV-infected pregnant women on combination ARV drug regimens14" 15. In the largest series to date, no transmissions were seen among 81 women receiving effective combination ARV drug regimens at the time o f amniocentesis16.
Thus, among 159 cases reported to date of amniocentesis or other invasive diagnostic procedures among women on effective combination ARV drug regimens, no transmissions have occurred, but a small in crease in risk cannot be ruled out. HIV-infected women who have indications for invasive testing in pregnancy, such as abnormal ultrasound or aneuploidy screening, should be counseled about the poten tial risk o f transmission o f HIV along with other risks o f the procedure and allowed to make an informed decision about testing. Some experts consider CVS and cordocentesis too risky to offer to HIV-infected women and they recommend limiting invasive procedures to amniocentesis14, but existing data on trans mission risk associated with these procedures are limited. At a minimum, HIV-infected pregnant women should receive an effective combination ARV drug regimen prior to undergoing any invasive prenatal testing and ideally have an undetectable HIV RNA level at the time o f the procedure. In women with de tectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered. These procedures should be done under continuous ultrasound guidance and, if possible, the placenta should be avoided.  ARV drug recommendations for pregnant women infected with HIV have been based on the concept that drugs o f known benefit to women should not be withheld during pregnancy unless there are known ad verse effects on the mother, fetus, or infant and unless these adverse effects outweigh the benefits to the woman1. Pregnancy should not preclude the use o f optimal drug regimens. The decision to use any ARV drug during pregnancy should be made by the woman after discussing with her health care provider the known and potential benefits and risks to her and her fetus.
Although clinical data on ARV drugs in pregnant women are more limited than in nonpregnant individu als, sufficient data exist on which to base recommendations related to drug choice for some o f the avail able ARV drugs. Physiologic changes that occur during pregnancy can affect the kinetics o f drug absorption, distribution, biotransformation, and elimination, thereby also affecting requirements for drug dosing and potentially altering the susceptibility o f the pregnant woman to drug toxicity1-2. During pregnancy, gastrointestinal transit time becomes prolonged; body water and fat increase throughout gestation and are accompanied by increases in cardiac output, ventilation, and liver and renal blood flow; plasma protein concentrations decrease; renal sodium reabsorption increases; and changes occur in metabolic enzyme pathways in the liver. Placental transport of drugs, compartmentalization o f drugs in the embryo/fetus and placenta, bio transformation o f drugs by the fetus and placenta, and elimination o f drugs by the fetus also can affect drug pharmacokinetics (PKs) in the pregnant woman.
Currently available data on the PKs of antiretroviral (ARV) agents in pregnancy are summarized in Table 5. In general, the PKs of nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are similar in pregnant and nonpregnant women, although protease in hibitor (PI) PKs are more variable, particularly in later pregnancy. The current data suggest that in many women, exposure to lopinavir/ritonavir, atazanavir, and nelfinavir is decreased during the second and/or third trimester (see Table 5). The need for a dose adjustment depends on the PI, the treatment experience of a particular patient, and use (if any) of concomitant medications with potential for interaction3-10. Teratogenicity (Updated September 14, 2011)
Panel's Recommendations
- All cases of antiretroviral (ARV) drug exposure during pregnancy should be reported to the Antiretroviral Pregnancy Reg istry (see details at ) (AIII).
- Efavirenz should not be used in the first trimester and nonpregnant women receiving efavirenz should be counseled to avoid pregnancy (AIII).
The potential harm to the fetus from maternal ingestion o f a specific drug depends not only on the drug itself but also on the dose ingested; the gestational age o f the fetus at exposure; the duration o f exposure; the interaction with other agents to which the fetus is exposed; and, to an unknown extent, the genetic makeup o f mother and fetus.
Information regarding the safety of drugs in pregnancy is derived from animal toxicity data, anecdotal ex perience, registry data, and clinical trials. Data are limited for antiretroviral (ARV) drugs, particularly when used in combination therapy. Drug choice should be individualized and must be based on discussion with the woman and available data from preclinical and clinical testing of the individual drugs. Preclinical data include results of in vitro and animal in vivo screening tests for carcinogenicity, clastogenicity/mutagenicity, and reproductive and teratogenic effects. However, the predictive value of such tests for adverse effects in humans is unknown. For example, of approximately 1,200 known animal teratogens, only about 30 are known to be teratogenic in humans1. Limited data exist regarding placental passage, long-term ani mal carcinogenicity, and animal teratogenicity for the Food and Drug Administration (FDA)-approved ARV drugs. Concerns have been raised about the risk of several ARV agents.
In cynomolgus monkeys receiving efavirenz from gestational days 20-150 at a dose resulting in plasma concentrations comparable to systemic human exposure at therapeutic dosage, significant malformations were observed in 3 o f 20 infant monkeys2. The malformations included anencephaly and unilateral anophthalmia in 1, microphthalmia in another, and cleft palate in the third. In prospectively reported pregnancies with exposure to efavirenz-based regimens in the Antiretroviral Pregnancy Registry through January 2011, birth defects were observed in 2.7% (17 o f 623) live births with first-trimester exposure; this proportion is not significantly different from that observed among U.S. births in the general popula tion (2.7%) as reported by the Registry3. Defects reported prospectively included 1 report of myelomeningocele and a separate report o f anophthalmia. The case o f anophthalmia included severe oblique facial clefts and amniotic banding that is known to be associated with anophthalmia3. In addi tion, 6 cases o f central nervous system (CNS) defects, including myelomeningocele, have been retro spectively detected in infants born to mothers receiving efavirenz during the first trimester2.
A recent meta-analysis including data from 9 cohorts with prospective reporting on 1,132 first-trimester exposures did not find an increased risk o f overall birth defects among infants born to women on efavirenz during the first trimester compared with those on other ARV drugs during the first trimester (relative risk  0.87; 95% confidence interval , 0.61-1.24)4. One neural tube defect occurred among 1,256 live births. Two subsequent smaller studies had conflicting results. A cohort in West Africa found no visible anomalies among 147 infants born after first-trimester exposure to efavirenz, while an analysis o f the PACTG 219 database found a significantly increased risk o f birth defects among infants born to women after first-trimester exposure to efavirenz (5 o f 32; 15.6%), including 1 neural tube de fect also included in the retrospective Registry cases5-6.
Although a causal relationship has not been established between these events and the use o f efavirenz, in light o f similar findings in primates, efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because o f the po tential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period o f fetal organogene sis. Women o f childbearing potential should undergo pregnancy testing prior to initiation o f efavirenz and should be counseled about the potential risk to the fetus and need to avoid pregnancy. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to be come pregnant or who are sexually active and not using effective contraception. Use after the first trimester can be considered if, after consideration o f other alternatives, it is the best choice for an indi vidual woman. If efavirenz is to be continued postpartum, adequate contraception must be ensured.
Tenofovir has not demonstrated teratogenicity in rodents or monkeys. In infant monkeys with in utero exposure to tenfovir at maternal doses resulting in levels approximately 25 times those used in humans, low birth weights and reductions in fetal bone porosity were seen. Chronic administration o f tenofovir to immature animals o f multiple species has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and species specific. Data from the Antiretroviral Pregnancy Registry show a birth defect incidence o f 2.4% in 1,092 women with first-trimester tenofovir exposure, similar to that in the general population3. However, because of the limited data on use in human pregnancy and concern re garding potential fetal bone effects and potential nephrotoxicity, tenofovir is recommended as an alterna tive rather than a preferred drug for use in pregnancy unless the pregnant woman has HIV/hepatitis B coinfection (see Table 5) . Health care providers who are caring for HIV-infected pregnant women and their newborns are strongly advised to report instances o f prenatal exposure to ARV drugs (either alone or in combination) to the An tiretroviral Pregnancy Registry. This registry is an epidemiologic project to collect observational, nonex perimental data regarding ARV exposure during pregnancy for the purpose o f assessing the potential teratogenicity o f these drugs. Registry data will be used to supplement animal toxicology studies and as sist clinicians in weighing the potential risks and benefits o f treatment for individual patients. The Anti retroviral Pregnancy Registry is a collaborative project o f pharmaceutical manufacturers with an advisory committee o f obstetric and pediatric practitioners. The registry does not use patient names, and registry staff obtain birth outcome follow-up information from the reporting physician.
Referrals should be directed to:

# Panel's Recommendations
- Clinicians should be aware of a possible small increased risk of preterm birth in pregnant women receiving protease inhibitor (Pl)-based combination antiretroviral (ARV) regimens; however, given the clear benefits of such regimens for both the women's health and the prevention of mother-to-child transmission, PIs should not be withheld for fear of alter ing pregnancy outcome (AII).
Early data were conflicting as to whether receipt of combination ARV regimens during pregnancy is asso ciated with adverse pregnancy outcomes and, in particular, preterm delivery. The European Collaborative Study and the Swiss Mother + Child HIV Cohort Study investigated the effects of combination ARV regi mens in a population of 3,920 mother-child pairs. Adjusting for CD4 cell count and intravenous drug use, they found a roughly twofold increase in the odds of preterm delivery for infants exposed to combination regimens with or without PIs compared with no drugs; women receiving combination regimens that had been initiated before their pregnancy were twice as likely to deliver prematurely as those who started drugs during the third trimester1. However, Pi-based combination regimens were received by only 108 (3%) of the women studied; confounding by severity or indication may have biased the results (i.e., sicker women may have received PIs more often, but their advanced HIV infection may have actually caused the preterm births). Exposure to nucleoside reverse transcriptase inhibitor (NRTI) single-drug prophylaxis (primarily zidovudine) was not associated with prematurity.
An updated report from the European Collaborative Study, based on an adjusted analysis that included 2,279 mother-child pairs, found a 1.9-fold increased risk o f delivery at less than 37 weeks with combina tion ARV regimens started during pregnancy and a 2.1-fold increased risk with combination ARV regi mens started prepregnancy compared with mono-or dual-NRTI prophylaxis2. In this report, 767 women received combination ARV regimens during pregnancy, although the proportion receiving PIs was not specified. The risk o f delivery before 34 weeks' gestation was increased by 2.5-fold for those starting combination ARV regimens during pregnancy and 4.4-fold for those entering pregnancy on combination ARV regimens.
In contrast, in an analysis o f 7 prospective clinical studies that included 2,123 HIV-infected pregnant women who delivered infants between 1990 and 1998 and had received antenatal ARV regimens and 1,143 women who did not receive antenatal ARV drugs, the use o f multiple ARV drugs compared with no drugs or treatment with one drug was not associated with increased rates o f preterm labor, low birth weight, low Apgar scores, or stillbirth3. Nor were any significant associations between adverse preg nancy outcome and use of ARV drugs by class or by category (including combination ARV regimens) found in an analysis from the Women and Infants Transmission Study (WITS), including 2,543 HIV-in fected women (some o f whom were included in the previous meta-analysis)4.
More recent data have continued to be conflicting as to whether preterm delivery is increased with com bination ARV regimens. A prospective cohort study including 681 women from Brazil, Argentina, Mex ico, and the Bahamas did not find significant associations between use o f combination ARV regimens and preterm birth or low birth weight5. A single-center study from Miami including 1,337 women did find a 1.8-fold increased chance o f preterm birth among the 134 women in the cohort who received PIcontaining combination ARV regimens compared with other combination regimens, after adjustment for possible confounding variables6. However, women receiving Pi-containing combination ARV regimens uniformly were women with advanced disease or those who had failed other combination drug regi mens. The risk o f low birth weight and stillbirth were not increased in any drug regimen groups. A re cent meta-analysis o f 14 European and American clinical studies found no increase in risk o f preterm birth with either any ARV drug receipt compared with no drugs or combination ARV regimens including PIs compared with no drugs7. However, a significant but modest increased risk o f preterm birth (odds ratio  1.35; 95% confidence interval , 1.08-1.70) was found in women who received combina tion regimens with PIs compared with combination regimens without PIs.
Other studies have detected small but significant increases (OR o f 1.2-1.5 in the largest studies) in preterm birth with PI-or non-PI-based combination ARV regimens as well8-11. Another variable that may confound these observational studies is the increased rate o f preterm birth if the combination ARV regi men is begun before conception compared with later during pregnancy, which itself may reflect con founding by severity or indication12. When data from the IMPAACT P1025 observational cohort were examined by multivariable analysis to correct for HIV disease stage, PI-based combination ARV regi mens were no more likely than non-PI-based combination ARV regimens to be associated with sponta neous preterm birth (OR 1.22; 95% CI, 0.70-2.12)13. A recent combined analysis o f three large studies-two from Europe and one from the United States-found heterogeneity in the association be tween combination ARV regimens and preterm birth, with significant increases in Europe but not the United States. However, increased rates o f preterm birth (adjusted OR  1.5) were found in all three cohorts when combination ARV regimens were compared with dual regimens. Additional factors found to be associated with preterm birth in all three cohorts included injection drug use and more ad vanced HIV disease14. A similar increase in preterm birth in women receiving combination ARV regi mens compared with dual regimens has been reported in the Swiss Mother and Child Cohort as well15.
Clinicians should be aware o f a possible increased risk o f preterm birth with use o f combination ARV drug regimens; however, given the clear benefits for maternal health and reduction in perinatal transmis sion, these agents should not be withheld because o f the possibility o f increased risk o f preterm delivery. Until more information is known, HIV-infected pregnant women who are receiving combination regi mens for treatment of their HIV infection should continue their provider-recommended regimens. They should receive careful, regular monitoring for pregnancy complications and for potential toxicities.
Nevirapine and Hepatic/Rash Toxicity (Updated September 14, 2011)

# Panel's Recommendations
- Nevirapine-based regimens should be initiated in women with CD4 counts >250 cells/mm3 only if the benefits clearly out weigh the risks because of the drug's potential for causing hepatic toxicity/hypersensitivity reaction (AII).
- Women who become pregnant while receiving nevirapine-containing regimens and who are tolerating the regimen well can continue on the therapy regardless of CD4 count (AII).

# Increases in hepatic transaminase levels (alanine aminotransferase  and aspartate aminotransferase 
) associated with rash or systemic symptoms may be observed during the first 18 weeks of treatment with nevirapine. Signs and symptoms of systemic toxicity may be nonspecific and can include fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, or hepatomegaly, with or without initially abnormal hepatic transaminases1. The development of severe nevirapine-associated skin rash has been reported to be 5.5-7.3 times more common in women than men and has been reported in pregnant women2-3. Other stud ies have found that hepatic adverse events with systemic symptoms (predominantly rash) were 3.2-fold more common in women than in men4-5. The degree of risk of rash and hepatic toxicity also appears to vary with CD4 cell count. In a summary analysis of data from 17 clinical trials of nevirapine therapy, women with CD4 cell counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4 cell counts to experience symptomatic, rash-associated, nevirapine-related hepatotoxicity4; a single-center study also found higher CD4 cell counts to be associated with increased risk of severe nevirapine-associ ated skin rash2. CD4 cell counts >250 cells/mm3 predicted rash illness, but not liver enzyme elevation, among pregnant and nonpregnant women initiating nevirapine-based combination antiretroviral (ARV) regimens in three U.S. university clinics6. Other international cohorts of nonpregnant women have experi enced hepatotoxicity and rash at similar rates as in U.S. studies, but not in association with CD4 cell counts >250 cells/mm3 7. In general, in controlled clinical trials, hepatic events, regardless of severity, have occurred in 4.0% (range 0%-11.0%) of patients who received nevirapine; severe or life-threatening rash has occurred in approximately 2% of patients receiving nevirapine8.
Several early reports of death due to hepatic failure in HIV-infected pregnant women receiving nevirapine as part of a combination ARV regimen raised concerns that pregnant women might be at increased risk of hepatotoxicity from nevirapine compared with other ARV drugs9-10. Recent data challenge the notion that nevirapine is uniquely associated with increased hepatotoxicity during pregnancy11. In an analysis of two multicenter, prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (relative risk  4.7; 5% confidence interval , 3.4-6.5), but nevirapine use was not, regardless of pregnancy status11. Additional data from the same cohorts did not show any increased risk of hepatotoxicity in HIVinfected pregnant women receiving nevirapine-based combination ARV regimens versus non-nevirapinebased combination ARV regimens12. These data suggest that nevirapine is no more toxic in pregnant women than in nonpregnant women. Nevertheless, if nevirapine is used in pregnancy, health care providers should be aware of potential hepatotoxicity with or without rash and should conduct frequent and careful monitoring of clinical symptoms and hepatic transaminases (i.e., ALT and AST), particularly during the first 18 weeks of nevirapine use. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through Month 4, and every 1-3 months thereafter (see the He patotoxicity section of the table on Antiretroviral Therapy-Associated Common and/or Severe Adverse Ef fects in the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents). In patients with pre-existing liver disease, monitoring should be performed more frequently when initiating nevirapine and monthly thereafter1. Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patients who develop suggestive clinical symptoms accompanied by ele vation in serum transaminase levels (ALT and/or AST) or who have asymptomatic but severe transaminase elevations (i.e., more than five times the upper limit of normal) should stop nevirapine and not receive nevirapine again in the future.
Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission of HIV13. Women who enter pregnancy on nevirapine-containing regimens and are tolerating them well may continue therapy, regardless of CD4 cell count.
Nucleoside Reverse Transcriptase Inhibitor Drugs and Mitochondrial Toxicity (Updated September 14, 2011)
Panel's Recommendations
- The combination of stavudine and didanosine should not be prescribed during pregnancy due to reports of lactic acidosis and maternal/neonatal mortality with prolonged use in pregnancy (AII).
- Mitochondrial dysfunction should be considered in uninfected children with perinatal exposure to antiretroviral (ARV) drugs who present with severe clinical findings of unknown etiology, particularly neurologic findings (AII).
- Long-term clinical follow-up is recommended for any child with in utero exposure to ARV drugs (AIII).
Nucleoside reverse transcriptase inhibitor (NRTI) drugs are known to induce mitochondrial dysfunction because the drugs have varying affinity for mitochondrial gamma DNA polymerase. This affinity can in terfere with mitochondrial replication, resulting in mitochondrial DNA (mtDNA) depletion and dysfunc tion1. The relative potency of the NRTI drugs in inhibiting mitochondrial gamma DNA polymerase in vitro is highest for zalcitabine, followed by didanosine, stavudine, zidovudine, lamivudine, abacavir, and tenofovir2. In one study, didanosine and didanosine-containing regimens were associated with the great est degree o f mitochondrial suppression3. Toxicity related to mitochondrial dysfunction has been re ported to occur in infected patients receiving long-term treatment with NRTI drugs and generally has resolved with discontinuation o f the drug or drugs; a possible genetic susceptibility to these toxicities has been suggested1. These toxicities may be o f particular concern for pregnant women and infants with in utero exposure to NRTI drugs.

# D uring Pregnancy
Clinical disorders linked to mitochondrial toxicity include neuropathy, myopathy, cardiomyopathy, pancre atitis, hepatic steatosis, and lactic acidosis. Among these disorders, symptomatic lactic acidosis and hepatic steatosis may have a female preponderance4-5. These syndromes have similarities to rare but life-threaten ing syndromes that occur during pregnancy, most often during the third trimester: acute fatty liver and he molysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Data suggest that a disorder of mitochondrial fatty acid oxidation in the mother or her fetus during late pregnancy may play a role in the development of acute fatty liver of pregnancy and HELLP syndrome6-9 and possibly contribute to suscepti bility to ARV-associated mitochondrial toxicity. HELLP syndrome also can occur postpartum in women with severe preeclampsia10. In addition to low platelets and elevated liver enzymes, other laboratory find ings reported among HIV-infected pregnant women on ARV drugs include mitochondrial placental deple tion but without evidence of ultrastructual damage to placental cells. The clinical significance of reduced mtDNA in placentas exposed to ARV drugs remains unknown11.
Lactic acidosis with microvacuolar hepatic steatosis is a toxicity related to NRTI drugs that is thought to be related to mitochondrial toxicity; it has been reported to occur in infected persons treated with NRTI drugs for longer than 6 months. In a report from the Food and Drug Administration (FDA) Spontaneous Adverse Event Program, typical initial symptoms included 1-6 weeks of nausea, vomiting, abdominal pain, dyspnea, and weakness12. Metabolic acidosis with elevated serum lactate levels and elevated hepatic enzymes was common. Patients described in that report were predominantly female and overweight. Al though the apparent incidence of this syndrome may increase with better clinical recognition, the actual in cidence may decrease as stavudine and didanosine are used less often in combination regimens.
The frequency o f this syndrome in pregnant HIV-infected women receiving NRTI drugs is unknown. In 1999, Italian researchers reported a case o f severe lactic acidosis in an infected pregnant woman who was receiving stavudine/lamivudine at the time o f conception and throughout pregnancy and who expe rienced symptoms and fetal death at 38 weeks' gestation13. Bristol-Myers Squibb has reported three m a ternal deaths due to lactic acidosis, two with and one without accompanying pancreatitis, among women who were either pregnant or postpartum and whose antepartum regimen during pregnancy included stavudine and didanosine in combination with other ARV agents (either a protease inhibitor  or nevi rapine)14-15. All women were receiving regimens containing these agents at the time o f conception and continued for the duration o f pregnancy; all presented late in gestation with symptomatic disease that progressed to death in the immediate postpartum period. Two cases were also associated with fetal death. Nonfatal cases o f lactic acidosis also have been reported in pregnant women receiving combina tion stavudine/didanosine16.
It is unclear if pregnancy augments the incidence o f the lactic acidosis/hepatic steatosis syndrome that has been reported for nonpregnant persons receiving NRTI drugs. However, because pregnancy itself can mimic some of the early symptoms o f the lactic acidosis/hepatic steatosis syndrome or be associated with other disorders o f liver metabolism, these cases emphasize the need for physicians caring for HIVinfected pregnant women receiving NRTI drugs to be alert for early signs o f this syndrome.
Additionally, because of the reports o f several cases o f maternal mortality secondary to lactic acidosis with prolonged use o f the combination o f stavudine and didanosine by HIV-infected pregnant women, clinicians should not prescribe this ARV combination during pregnancy. Combination stavudine/didanosine also is not recommended for nonpregnant adults.

# In Utero Exposure
It has been suggested that mitochondrial dysfunction might develop in infants with in utero exposure to NRTI drugs. Data from a French cohort of 1,754 uninfected infants born to HIV-infected women who received ARV drugs during pregnancy identified 8 infants with in utero or neonatal exposure to either zidovudine/lamivudine (4) or zidovudine alone (4) who developed indications o f mitochondrial dysfunc tion after the first few months o f life17. Two o f these infants (both exposed to zidovudine/lamivudine) contracted severe neurologic disease and died; 3 had mild-to-moderate symptoms; and 3 had no symp toms but had transient laboratory abnormalities.
In a larger cohort o f 4,392 uninfected children (including the children in the previous study) followed within the French Pediatric Cohort or identified within a French National Register, the 18-month inci dence o f clinical symptoms o f mitochondrial dysfunction was 0.26% and 0.07% for mortality18. All chil dren had perinatal exposure to ARVs; risk was higher among infants exposed to combination ARV drugs (primarily zidovudine/lamivudine) than to zidovudine alone. The children presented with neurologic symptoms, often with abnormal magnetic resonance imaging and/or episodes o f significant hyperlactatemia, and deficits in mitochondrial respiratory chain complex enzyme function on biopsy o f muscle. The same group also has reported an increased risk o f simple febrile seizures in the first 18 months of life and persistently lower (but clinically insignificant) neutrophil, lymphocyte, and platelet counts in in fants with in utero exposure to NRTIs19-20. More recently, in continued follow-up o f the French Perinatal Cohort, researchers reported severe neurologic symptoms in the first 2 years o f life as a rare event (0.3% -0.5% )21.
Other clinical studies from the United States and Europe generally have not duplicated the French re ports22-28. The Perinatal Safety Review Working Group performed a retrospective review o f deaths oc curring among children born to HIV-infected women and followed from 1986 to 1999 in 5 large, prospective U.S. perinatal cohorts. No deaths similar to those reported from France or with clinical find ings attributable to mitochondrial dysfunction were identified in a database o f more than 16,000 unin fected children born to HIV-infected women with and without exposure to ARV drugs23. However, most o f the infants with exposure to ARVs had been exposed to zidovudine alone and only a relatively small proportion (approximately 6%) had been exposed to zidovudine/lamivudine.
The European Collaborative Study reviewed clinical symptoms in 2,414 uninfected children in their co hort with median follow-up o f 2.2 years (maximum, 16 years); 1,008 had perinatal exposure to ARVs25.
No association was found between clinical manifestations suggestive o f mitochondrial abnormalities and perinatal exposure to ARVs. O f the 4 children with seizures in this cohort, none had perinatal exposure to ARVs. In a report from a long-term follow-up study in the United States (PACTG 219/219C), 20 chil dren with possible symptoms o f mitochondrial dysfunction were identified in a cohort o f 1,037 unin fected infants born to HIV-infected mothers27. Definitive diagnosis was not available because none of the children had biopsies for mitochondrial function. Three o f the 20 children had no exposure to ARV drugs. In the 17 remaining children, although overall exposure to NRTI drugs was not associated with symptoms, there was an association between symptoms and first exposure to zidovudine/lamivudine limited to the third trimester. Some small alterations in mtDNA and oxidative phosphorylation enzyme activities were found in stored specimens from these children, but the clinical significance o f these ob servations remains unknown29-30.
Laboratory abnormalities without clinical symptoms have been reported in infants with perinatal expo sure to ARVs compared with unexposed infants in a number o f studies, most o f which are limited by small numbers o f subjects. In 1 study, mtDNA quantity was lower in cord and peripheral blood white cells at ages 1 and 2 years among 20 infants born to HIV-infected women compared with 30 infants born to uninfected women and was lowest among 10 HIV-exposed infants with zidovudine exposure com pared with 10 without zidovudine exposure31. In a subsequent study, mitochondrial changes were evalu ated in umbilical cord endothelial cells and cord blood from human infants and monkeys with in utero exposure to various NRTI-containing regimens32. Similar morphologic changes and mtDNA depletion were seen in the human and monkey infants. In the monkeys, mitochondrial damage demonstrated a gra dient, with greatest damage with stavudine/lamivudine > zidovudine/didanosine > zidovudine/lamivu dine > lamivudine. In a Canadian study of 73 ARV-exposed infants and 81 controls with blood samples during the first 8 months o f life, investigators found that in the first weeks o f life, blood mtDNA levels were higher and blood mitochondrial RNA levels were lower in the HIV-and ARV-exposed infants com pared with infants without HIV and ARV exposure33. One study reported that peripheral blood mononu clear cell (PBMC) mtDNA levels were lower at birth in HIV-exposed, ARV-exposed infants compared with non-HIV, non-ARV-exposed infants34. However, among the HIV-exposed infants, those with com bination ARV drug exposure in utero had higher mtDNA levels than those exposed only to zidovudine in utero. Umbilical cord mtDNA sequence variants were 3-fold higher among HIV-and zidovudine-ex posed infants compared with infants born to mothers without HIV infection35.
Transient hyperlactatemia during the first few weeks o f life was reported among 17 HIV-exposed infants with perinatal exposure to ARVs; lactate levels returned to normal in all children and none developed symptoms o f mitochondrial dysfunction during follow-up36. Similarly, the French Perinatal Cohort Study has reported asymptomatic hyperlactatemia in one-third o f zidovudine-exposed newborns, which resolved following perinatal exposure to the drug21. Clinically asymptomatic hematologic findings have been reported by several investigators among uninfected infants with in utero exposure to ARV regimens in the United States and Europe37-39, and infants with exposure to triple-combination ARV regimens were found to be at increased risk o f lowered hemoglobin compared with those with perinatal exposure to zi dovudine or zidovudine/lamivudine40.
The clinical significance o f these differences in mtDNA, lactate levels, and hematologic laboratory find ings is unclear, and further long-term studies are needed to validate the findings and assess the degree to which they affect growth and development o f infants exposed to ARV drugs. Thus, data are conflicting on whether mitochondrial dysfunction is associated with perinatal exposure to ARVs, and further studies are needed. Even if an association is more clearly demonstrated, the development o f severe or fatal mito chondrial disease appears to be extremely rare and should be balanced against the clear benefit o f ARV prophylaxis in reducing transmission o f a fatal infection by 70% or more25, 41-42. Development o f new di agnostic techniques, including use o f flow cytometry assays to screen for mitochondrial function, may lead to more accurate assessment o f mitochondrial toxicity43. Mitochondrial dysfunction should be con sidered in uninfected children with perinatal exposure to ARVs who present with severe clinical findings o f unknown etiology, particularly neurologic findings. Current recommendations call for long-term clin ical follow-up for any child with in utero exposure to ARV drugs.
Protease Inhibitor Therapy and Hyperglycemia (Updated September 14, 2011)
Panel's Recommendations
- HIV-infected women taking antiretroviral (ARV) drug regimens during pregnancy should undergo glucose screening with a standard, 1-hour, 50-g glucose loading test at 24-28 weeks' gestation (AIII). Some experts would perform earlier glu cose screening in women receiving ongoing protease inhibitor (Pl)-based regimens initiated before pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance (BIII).
Hyperglycemia, new-onset diabetes mellitus, exacerbation o f existing diabetes mellitus, and diabetic ke toacidosis have been reported in HIV-infected patients taking PIs1-4. In addition, pregnancy is itself a risk factor for hyperglycemia. To date, however, the majority have not shown an increased risk o f glucose in tolerance with Pi-based regimens during pregnancy. One small retrospective study that included 41 women receiving Pi-based combination ARV regimens found an increased risk o f glucose intolerance, but not gestational diabetes, among women on combination ARV regimens compared with zidovudine alone5, while two other retrospective studies did not find an increased risk o f glucose intolerance with Pis6-7. Secondary analyses o f two large cohorts did not find an association between the type o f ARV regi men and gestational diabetes, except for an association between initiation o f PIs before pregnancy or during the first trimester and gestational diabetes in the PACTG 316 cohort8-9. Finally, a prospective study including detailed evaluations for glucose intolerance and insulin resistance among HIV-infected pregnant women did not find differences between women on Pi-containing and non-PI-containing regi mens10. In both groups, however, the rate o f impaired glucose tolerance was high (38%), likely related to high body mass index and race/ethnicity among trial subjects.
HIV-infected women receiving ARV regimens during pregnancy should receive standard glucose screen ing with a standard, 1-hour, 50-g glucose loading test at 24-28 weeks' gestation. Some experts would perform earlier glucose screening in women with ongoing PI-based ARV regimens initiated before preg nancy (particularly in women o f minority race/ethnicity), similar to recommendations for women with high-risk factors for glucose intolerance, such as maternal obesity, advanced maternal age, and family history o f type II diabetes mellitus.

# Antiretroviral Drug Resistance and Resistance Testing in Pregnancy (Updated September 14, 2011)_____________

# Indications for Antiretroviral Drug-Resistance Testing in HIV-Infected Pregnant Women
Panel's Recommendations
- HIV drug-resistance testing is recommended for:
- All pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) not currently receiving antiretroviral (ARV) drugs, before starting treatment or prophylaxis (AIII).
- All pregnant women receiving antenatal ARV drugs who have suboptimal viral suppression or persistant viral re bound to detectable levels after prior viral suppression on an ARV regimen (AII).
- Empiric initiation of ARV drugs before results of resistance testing are available may be warranted, with adjustment as needed after the test results are available, for optimal prevention of perinatal transmission (BIII).
Resistance testing is recommended for all ARV-naive pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) before initiating treatment or prophylaxis if prior resistance testing has not been done. For details regarding genotypic and phenotypic resistance testing see Guidelines for the Use o f Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Ideally, resistance testing would have been done at a preconception visit to allow receipt o f results and to select an appropriate ARV drug regimen during pregnancy or before pregnancy if maternal therapy was indicated.
Resistance testing should also be performed before initiation of therapy or prophylaxis in pregnant women with HIV RNA levels above the threshold for resistance testing (e.g., >500-1,000 copies/mL) who re ceived prophylaxis in previous pregnancies and are now restarting ARV drugs for prevention of perinatal transmission. No data currently are available to address the utility of resistance testing during pregnancy in women who do not require treatment for their own health or in women with multiple pregnancies who have received corresponding courses of ARV prophylaxis for prevention of mother-to-child transmission. The identification of baseline resistance mutations may allow selection of more effective and durable ARV regimens for women who need treatment and help ensure a wider range of future treatment options for women receiving ARV drugs solely for perinatal prophylaxis. There is no evidence, however, that baseline resistance testing in pregnancy is associated with a reduction in rates of perinatal transmission.
Resistance testing should also be performed following initiation o f an ARV regimen during pregnancy or in HIV-infected pregnant women who are receiving antiretroviral therapy (ART) when they present for obstetrical care if there is suboptimal viral suppression or persistent viral load rebound to detectable lev els after prior viral suppression on the ARV regimen.
In most settings, the results o f resistance testing guide selection o f the initial ARV regimen. In some situ ations in pregnant women, however, the clinician may choose to initiate empiric ARV drug regimen be fore resistance-testing results are available to optimize prevention o f perinatal transmission o f HIV Once resistance test results are obtained, the ARV drug regimen can be modified as needed. Most ex perts believe that for women in the third trimester, the benefits o f immediate initiation o f ARV drugs for prevention o f mother-to-child transmission, pending results o f resistance testing, outweigh the possible risk o f short-term use o f a regimen that could be suboptimal because o f pre-existing resistance.
The development o f ARV drug resistance is one o f the major factors leading to therapeutic failure in HIV-infected individuals. In pregnancy, it is associated with specific concerns that differ from those seen in the nonpregnant population. Pre-existing resistance to a drug in an ARV prophylaxis regimen may di minish the regimen's efficacy in preventing perinatal transmission. The development o f resistance to drugs used during pregnancy for prophylaxis o f perinatal transmission may limit future maternal treat ment options or decrease the effectiveness o f prophylactic regimens in the current pregnancy or during future pregnancies. Infant treatment options also may be limited if maternal resistance is present or de velops and resistant virus is transmitted to the fetus.
Several factors unique to pregnancy may increase the risk of development o f resistance. If drugs with significant differences in half-life (such as nevirapine or efavirenz combined with two nucleoside ana logue drugs) are included in the ARV regimen, simultaneous postpartum discontinuation o f all regimen components may result in persistent subtherapeutic drug levels and increase the risk o f development of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (see Stopping Antiretroviral Therapy during Pregnancy). Problems such as nausea and vomiting in early pregnancy may compromise adher ence and increase the risk o f resistance in women receiving ARV drugs. Pharmacokinetic (PK) changes during pregnancy, such as increased plasma volume and renal clearance, may lead to subtherapeutic drug levels, increasing the risk that resistance will develop.

# Incidence o f Antiretroviral Resistance Em erging from the Use o f Perinatal Prophylac tic Regim ens
The presence o f mutations conferring resistance to nucleoside analogue drugs appears to be correlated with more advanced maternal disease and longer duration o f prior or current exposure to these drugs1-4.
The development o f zidovudine drug resistance when zidovudine is used alone appears uncommon in women with higher CD4 cell counts and lower viral loads5-6 but is more o f a concern in women with ad vanced disease and lower CD4 cell counts2.
Development o f resistance associated with short-term use o f ARV agents for prevention o f mother-tochild transmission is most common with nevirapine, particularly single-dose nevirapine. Nevirapine has a low genetic barrier to resistance, with a single point mutation conferring resistance to nevirapine and to other first-generation NNRTI drugs. Furthermore, its long half-life, with blood levels detectable up to 21 days after a single dose in labor, increases selection pressure and the risk o f resistance7. Factors asso ciated with an increased risk o f resistance following single-dose nevirapine exposure include high base line viral load, low baseline CD4 cell count, viral subtype, and the number o f maternal doses. The rate of genotypic resistance after exposure to single-dose nevirapine has varied in studies, ranging from 15% to 75%8-18. Studies using more sensitive real-time polymerase chain reaction (PCR) techniques suggest that up to one-half o f resistance that develops is not detected by conventional sequence analysis16, 18-20. The prevalence o f resistance declines rapidly over time and the proportion o f resistant virus in those with de tectable virus 12 months after exposure is low. In a study o f virus from 67 South African women, using a sensitive allele-specific resistance assay, the K103N mutation was seen in 87% o f women at 6 weeks but in only 11% at 12 months after single-dose nevirapine exposure, with a median frequency o f the muta tion of 0.7% (range 0.5%-5.4%) in women with detectable resistance at 12 months20.
In the PACTG 316 trial, the addition o f single-dose nevirapine following antepartum administration of other ARV regimens (primarily combination regimens because 77% o f women received antenatal combi nation ARV regimens still resulted in nevirapine resistance in 14 o f 95 (15%; 95% confidence interval , 8%-23%) women with detectable virus postpartum8. In this study, adding single-dose nevirapine

# Significance o f Antiretroviral Drug Resistance in Pregnancy
did not provide any additional efficacy in prevention o f mother-to-child transmission but was associated with development o f nevirapine resistance. Therefore, this approach is not recommended.
A recent study examined the presence o f resistant mutations in HIV-1-infected women receiving combi nation ARV drug regimens that were stopped postpartum. All women evaluated received zidovudine and lamivudine, with 76% receiving nelfinavir and 8% receiving nevirapine. Rates o f M184V/I mutations postpartum were 65% and 29% in women receiving dual or triple prophylaxis, respectively. NNRTI re sistance was identified postpartum among 38% o f nevirapine recipients, whereas only 1% o f protease in hibitor (PI) recipients developed PI resistance21.

# The Im pact o f Resistance on Pregnancy and the R isk o f Perinatal Transmission o f H IV Perinatal Transmission
Perinatal transmission of resistant virus has been reported, but it appears to be unusual and there is little evidence that the presence o f resistance mutations increases the risk o f transmission when current rec ommendations for ARV management in pregnancy are followed. A substudy o f the Women and Infants Transmission Study (WITS) followed pregnant women receiving zidovudine alone for treatment o f HIV disease in the early 1990s. In this study, the detection o f zidovudine resistance conferred an increased risk o f transmission when analysis was adjusted for duration o f membrane rupture and total lymphocyte count2; however, women in this cohort had characteristics that would indicate a need for ART under the current Department o f Health and Human Services (HHS) recommendations for maternal health and for prevention o f perinatal transmission. When transmitting mothers had mixed viral populations o f wild type and virus with low-level zidovudine resistance, only wild-type virus was detected in the infant22, and other studies have suggested that drug-resistance mutations may diminish viral fitness23, possibly leading to a decrease in transmissibility. In another study, prevalence o f ARV drug resistance among HIV-infected newborns in New York State was examined. Eleven (12.1%) o f 91 infants born between 1989 and 1999 and 8 (19%) o f 42 infants born between 2001 and 2002 had mutations associated with decreased drug susceptibility. However, perinatal exposure to ARVs was not found to be a significant risk factor for the presence o f resistance during either time period24-25. Neither resistance to nevirapine that develops as a result of exposure to single-dose nevirapine nor exposure to single-dose nevirapine in a prior pregnancy has been shown to affect perinatal transmission rates26-27.

# M aternal Response to Subsequent Treatment Regimens
Because nevirapine resistance mutations can be detected postpartum in a significant proportion of women receiving single-dose intrapartum nevirapine prophylaxis, the response to subsequent NNRTI-based com bination therapy given for maternal health has been a concern12, 20, 26-29. A study performed in Zambia, Kenya, and Thailand found that prior exposure to single-dose nevirapine was associated with an increased risk of treatment failure in pregnant women receiving NNRTI-based ART, with the greatest risk being in women receiving ART within 12 months of previous nevirapine exposure30. The Optimal Combination Therapy After Nevirapine Exposure (OCTANE)/A5208 trial conducted in Africa compared nevirapine with lopinavir/ritonavir-based therapy in women requiring therapy who had prior exposure to single-dose nevirapine prophylaxis. The results suggest that prior exposure to single-dose nevirapine within 24 months of initiating therapy may be associated with a higher risk o f viral failure with nevirapine-based therapy compared with lopinavir/ritonavir-based therapy. In this study, significantly more women in the nevirapine arm (29, 24%) failed to achieve a subsequent undetectable viral load (25) or died (4) compared with women in the lopinavir/ritonavir arm (8, 7%; 7 virologic failures and 1 death; P <0.0005). Five of 13 (38%) women with documented nevirapine resistance at the start of therapy either had detectable virus or died. This study demonstrates that women with documented nevirapine resistance are most likely to bene fit from combination therapy that does not contain nevirapine (and because of cross resistance, efavirenz)29.
Few data evaluate response to subsequent therapy in women who receive current combination drug regi mens for prophylaxis and discontinue the drugs postpartum. In theory, however, resistance should not occur if the regimen that was discontinued had fully suppressed viral replication. Issues relating to the discontinuation o f nevirapine-based combination therapy are discussed in Prevention o f Antiretroviral Drug Resistance.
Management of Antiretroviral Drug Resistance during Pregnancy (Updated September 14, 2011)
Panel's Recommendations
- Women who have documented zidovudine resistance and are on regimens that do not include zidovudine for their own health should still receive intravenous zidovudine during labor whenever possible, along with their established antiretro viral (ARV) regimens (AII).
- In women who are receiving a stavudine-containing regimen, the drug should be discontinued during labor while intra venous zidovudine is being administered (see Intrapartum Care) (AII).
- The optimal prophylactic regimen for newborns of women with ARV resistance is unknown (see Infant Antiretroviral Pro phylaxis). Therefore, ARV prophylaxis for an infant born to a woman with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist, preferably before delivery (AIII).
Ideally, ARV regimens used during pregnancy for treatment or prophylaxis should be chosen based upon the results o f ARV resistance testing. Although most transmission occurs intrapartum, 30% -35% of transmission may occur in utero1-3. The majority o f the latter infections are believed to occur later in pregnancy1 and they may be more likely in women with advanced HIV disease and/or high viral load2-3. Therefore, a delay in initiation o f an ARV drug regimen to await results o f resistance testing could result in in utero infection o f the infant, particularly in women at high risk o f transmission or who are late in pregnancy at the time the drugs are initiated. In such circumstances, as noted earlier, empiric initiation of the ARV drug regimen may be warranted, with modification o f the regimen once resistance testing re sults become available.
For women who have documented zidovudine resistance and whose antepartum regimen does not in clude zidovudine, the drug still should be given intravenously during labor whenever possible (see Intra partum Care). Because stavudine may be antagonistic to zidovudine, it should be stopped during the intrapartum period and restarted after delivery (see Intrapartum Care). Other ARVs should be continued orally during labor to the extent possible. The optimal prophylactic regimen for newborns o f women with ARV drug-resistant virus is unknown. Therefore, ARV prophylaxis for infants born to women with known or suspected drug-resistant virus should be determined with a pediatric HIV specialist, preferably before delivery (see Infant Antiretroviral Prophylaxis) .
The rationale for including zidovudine intrapartum when a woman is known to harbor virus with zi dovudine resistance is based on several factors. Data thus far have suggested that only wild-type virus appears to be transmitted to infants by mothers who have mixed populations o f wild-type virus and virus with low-level zidovudine resistance4. Other studies have suggested that drug-resistance mutations may dim inish viral fitness and possibly decrease transmissibility5. The efficacy o f the zidovudine prophylaxis appears to be based not only on a reduction in maternal HIV viral load but also on pre-and post-expo sure prophylaxis in the infant6-8. Zidovudine crosses the placenta readily and has one o f the highest maternal-to-cord blood ratios among the nucleoside analogue agents. In addition, zidovudine is metabolized to the active triphosphate within the placenta9-10, which may provide additional protection against trans mission. Metabolism to the active triphoshate, which is required for activity o f all nucleoside analogue agents, has not been observed within the placenta with other nucleoside analogues that have been evalu ated (didanosine and zalcitabine). Zidovudine penetrates the central nervous system (CNS) better than do other nucleoside analogues except stavudine, which has similar CNS penetration; this may help to eliminate a potential reservoir for transmitted HIV in the infant11-12. Thus, intrapartum intravenous ad ministration o f zidovudine currently is recommended even in the presence o f known resistance because o f the unique characteristics of the drug and its proven record in reducing perinatal transmission.
Prevention of Antiretroviral Drug Resistance (Updated September 14, 2011)
Panel's Recommendations
- HIV-infected pregnant women should be given combination antiretroviral (ARV) drug regimens to maximally suppress viral replication; that is the most effective strategy for preventing development of resistance and minimizing risk of peri natal transmission (AII).
- All pregnant women should be counseled about the importance of adherence to prescribed ARV medications to reduce the potential for development of resistance (AII).
- Pregnant women who are receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination ARV therapy solely for prophylaxis of transmission that will be discontinued after delivery should receive nucleoside analogue agents for at least 7 days after the NNRTI is stopped to minimize risk of resistance (AI). An alternative strategy is to sub stitute a protease inhibitor (PI) for the NNRTI prior to the interruption and to continue the PI with dual nucleoside reverse transcriptase inhibitors (NRTIs) for at least 7 days after stopping the NNRTI (CIII). The optimal interval between stopping an NNRTI and the other ARV drugs is not known (see Stopping Antiretroviral Therapy during Pregnancy and Postpartum Follow-Up of HIV-Infected Women).
- Adding single-dose maternal/infant nevirapine to an ongoing combination ARV regimen given for treatment or prophy laxis does not increase efficacy in reducing perinatal transmission and may result in nevirapine drug resistance in the mother and/or infant; therefore single-dose maternal/infant nevirapine is not recommended in this situation (AI).
The most effective way to prevent the development o f ARV drug resistance in pregnancy is to use and adhere to an effective combination o f ARV drugs to achieve maximal viral suppression.
Several studies have shown that development o f nevirapine resistance is significantly decreased (but not eliminated) after exposure to single-dose intrapartum nevirapine (given alone or in combination with an tenatal ART) when zidovudine/lamivudine is given intrapartum and administered for 3-7 days postpar tum in women who have received single-dose nevirapine1-3. A variety o f other regimens (e.g., tenfovir/emtricitabine, zidovudine/didanosine) given for 7-30 days postpartum following maternal sin gle-dose nevirapine have also been shown to be very effective in reducing the development o f nevirap ine resistance4-6. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual NRTIs for a period of time7. The optimal duration for continuation o f either dual nucleosides or the substituted PI-based regimen after stopping the NNRTI is unknown. NNRTI drugs have long half-lives, and drug levels can persist for up to 1-3 weeks after stopping the drug; efavirenz levels persist longer than nevirapine levels8-9. More research is needed on the optimal duration o f time and regimen to "cover" this period o f prolonged NNRTI exposure to prevent the emergence o f resistance after discon tinuation of NNRTI-based therapy. Many experts will stop the NNRTI drug and continue the other ARV drugs for at least 7 days, although other experts would recommend up to 30 days, particularly if an efavirenz-based regimen is being discontinued.
Intrapartum Care (Updated September 14, 2011)

# Intrapartum Antiretroviral Therapy/Prophylaxis
Panel's Recommendations
- Intrapartum intravenous zidovudine is recommended for all HIV-infected pregnant women, regardless of their antepar tum regimen, to reduce perinatal transmission of HIV (AI).
- For women who are receiving a stavudine-containing antepartum regimen, stavudine should be discontinued during labor while intravenous zidovudine is being administered (AI).
- Women who are receiving an antepartum combination antiretroviral (ARV) drug regimen should continue this regimen on schedule as much as possible during labor and before scheduled cesarean delivery (AIII).
- Women receiving fixed-dose combination regimens that include zidovudine should receive intravenous zidovudine during labor while other oral ARV components are continued (AIII).
- For women who have received antepartum ARV drugs but have suboptimal viral suppression near delivery (i.e., HIV RNA >1,000 copies/mL), scheduled cesarean delivery is recommended (see Mode of Delivery) (AI). The addition of single dose intrapartum/newborn nevirapine is not recommended (AI).
- Women of unknown HIV status who present in labor should undergo rapid HIV antibody testing (AII). If the results are positive, a confirmatory HIV test should be done as soon as possible and maternal/infant ARV drugs should be initiated pending results of the confirmatory test (AII). If the confirmatory HIV test is positive, infant ARV drugs should be contin ued for 6 weeks (see Neonatal Postnatal Care) (AI); if the test is negative, the infant ARV drugs should be stopped.
- Intravenous zidovudine is recommended for HIV-infected women in labor who have not received antepartum ARV drugs and infant combination ARV prophylaxis is recommended for 6 weeks (see Infant Antiretroviral Prophylaxis) (AII).
Table 8 shows dosing for zidovudine, given intravenously as a continuous infusion during labor and dur ing the neonatal period; Table 9 shows intrapartum and neonatal dosing for additional drugs to be con sidered in certain situations, as delineated below.

# Women Who H ave R eceived Antepartum Antiretroviral Drugs

# Use of Intravenous Zidovudine during Labor
Results from PACTG 076 and subsequent epidemiologic studies have proven the efficacy o f the threepart zidovudine chemoprophylaxis regimen, alone or in combination with other ARV agents. The PACTG 076 zidovudine regimen includes a continuous intravenous infusion o f zidovudine during labor (initial loading dose o f 2 mg/kg intravenously over 1 hour, followed by continuous infusion o f 1 mg/kg/hour until delivery). Given results from this trial, intravenous zidovudine during the intrapartum period should be discussed with and recommended to all HIV-infected pregnant women. Administration o f intravenous zidovudine should begin 3 hours before scheduled cesarean delivery, according to stan dard dosing recommendations. Women receiving fixed-dose combination regimens that include zidovu dine, such as a zidovudine/lamivudine combination, should receive intravenous zidovudine during labor while other oral ARV components are continued. For example, in women who are receiving zidovudine/lamivudine during pregnancy, zidovudine should be given intravenously and lamivudine should be given orally during labor.
If antenatal use o f zidovudine was precluded by known or suspected zidovudine resistance, intrapartum use o f the drug still should be recommended, except in woman with documented histories o f hypersensi-tivity. This intrapartum use o f the drug is recommended because o f the unique characteristics of zidovu dine and its proven record in reducing perinatal transmission, even in the presence o f maternal resistance to the drug (see Management o f Antiretroviral Drug Resistance during Pregnancy) . Because there is pharmacologic antagonism between zidovudine and stavudine, those drugs should not be coadministered during labor. Women who are receiving an antepartum stavudine-containing regimen should have the drug temporarily discontinued during labor while intravenous zidovudine is being administered, with other components o f the regimen continued orally.

# Continuation o f Antenatal Antiretroviral Drugs during Labor
Women who are receiving an antepartum combination ARV drug regimen should continue that regimen on schedule as much as possible during the intrapartum period to provide maximal virologic effect and to minimize the chance o f development o f drug resistance. When cesarean delivery is planned, oral med ications can be continued preoperatively with sips o f water. Medications requiring food ingestion for ab sorption can be taken with liquid dietary supplements, contingent on consultation with the attending anesthesiologist in the preoperative period. If the maternal ARV regimen must be interrupted temporar ily (e.g., for less than 24 hours) during the peripartum period, all drugs should be stopped and reinsti tuted simultaneously to minimize the chance that resistance will develop.

# Women Who H ave R eceived Antepartum Antiretroviral D rugs B ut H ave Suboptimal Viral Suppression Near Delivery
Women who have received combination ARV drug regimens may not achieve complete viral suppres sion by the time o f delivery because o f factors such as poor adherence, viral resistance, or late entry into care. Regardless of the reason, all women who have HIV RNA levels >1,000 copies/mL near the time of delivery should be offered a scheduled cesarean delivery at 38 weeks, which may significantly reduce the risk o f transmission (see Transmission and Mode o f Delivery).
The addition o f single-dose nevirapine during labor has not been shown to reduce perinatal transmission o f HIV in this group of women. The PACTG 316 study, conducted in women in the United States, Eu rope, Brazil, and the Bahamas who were receiving ARV drugs during pregnancy (primarily combination therapy), showed that the addition o f single-dose nevirapine did not reduce the risk o f mother-to-child transmission of HIV, even in the setting o f maternal viremia. It was, however, associated with the devel opment o f nevirapine resistance in 15% of women with detectable HIV RNA levels postpartum1-2. Given the risk o f development o f resistance and the lack o f data to suggest added efficacy, addition o f single dose nevirapine is not recommended in women who have received combination antepartum ARV drugs.
Use of additional medications for prophylaxis in infants may be warranted in special circumstances, such as in cases where maternal HIV RNA levels are high at or near the time o f delivery, especially if delivery is not a scheduled cesarean delivery (see Infant Antiretroviral Prophylaxis and Table 9) . How ever, no additional intrapartum interventions are indicated for the mothers.

# Women Who H ave N ot R eceived Antepartum Antiretroviral Drugs

# Women W ho Present in Labor W ithout Documentation of HIV Status
All women with undocumented HIV status or without documentation o f HIV status at the time o f labor should be screened with rapid HIV testing unless they decline (opt-out screening). Rapid HIV testing is also recommended for women presenting in labor who tested negative for HIV in early pregnancy but are at increased risk o f HIV infection and were not retested in the third trimester3. Factors that may in crease risk of infection include diagnosis o f a sexually transmitted infection (STI), illicit drug use or ex change o f sex for money or drugs, multiple sexual partners during pregnancy, a sexual partner at risk of HIV infection, signs/symptoms o f acute HIV infection, or living in a region with an elevated incidence o f HIV in women o f childbearing age and not undergoing repeat HIV testing in the third trimester3.
Rapid HIV antibody testing should be available on a 24-hour basis at all facilities with a maternity serv ice and/or neonatal intensive care unit. Statutes and regulations regarding rapid testing vary from state to state; see  for a review o f state HIV testing laws. Current information on rapid testing also should be available at all facilities with a maternity service and/or neonatal intensive care unit.
Women with positive rapid HIV antibody tests should be presumed to be infected until standard HIV an tibody confirmatory testing clarifies their infection status. Along with confirmatory HIV antibody test ing, these women should receive appropriate assessments as soon as possible to determine their health status and make recommendations for whether antiretroviral therapy (ART) is needed based on that sta tus. Arrangements also should be made for establishing HIV care and providing ongoing psychosocial support after discharge. Intravenous zidovudine should be started immediately in all women with posi tive rapid HIV tests in labor to prevent perinatal transmission o f HIV, as discussed below.

# Choice of Intrapartum/Postpartum Antiretroviral Regimen for Women without Antepartum Antiretroviral Therapy
All HIV-infected women who have not received antepartum ARV drugs should have intravenous zidovu dine started immediately to prevent perinatal transmission o f HIV (see Table 8 for dosing information).
Although intrapartum/neonatal ARV medications will not prevent perinatal transmission that occurs be fore labor, most transmission occurs near to or during labor and delivery. Pre-exposure prophylaxis for the fetus can be provided by giving mothers a drug that rapidly crosses the placenta, producing fetal sys temic ARV drug levels during intensive exposure to HIV in maternal genital secretions and in blood dur ing birth. In general, zidovudine and other nucleoside reverse transcriptase inhibitor (NRTI) drugs and non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs cross the placenta well, whereas protease inhibitors (PIs) do not (see Table 5).
Epidemiologic data indicate that intravenous maternal intrapartum zidovudine followed by oral zidovu dine for 6 weeks for the infant significantly reduces transmission compared with no treatment4. In a New York State cohort study, transmission rates were 10% with intrapartum and neonatal zidovudine com pared with 27% without zidovudine, a 62% reduction in risk4. The PETRA study demonstrated that in trapartum prophylaxis alone, without an infant post-exposure prophylaxis component, is not effective in reducing perinatal transmission5.
A large international trial (NICHD-HPTN 040/PACTG 1043) demonstrated that adding ARV agents to the neonatal portion o f the intrapartum/neonatal zidovudine regimen can further reduce mother-to-child transmission of HIV for mothers who have received no antepartum ARV drugs (see Infant Antiretroviral Prophylaxis). In this study, women who had not received antepartum ARV drugs received only intra venous zidovudine, whereas their infants received zidovudine in combination with other agents, achiev ing a 50% reduction in transmission. Therefore, no additional intrapartum drugs, including intrapartum maternal single-dose nevirapine, are indicated for the woman in this situation6.
References: Transmission and Mode of Delivery (Updated September 14, 2011)
Panel's Recommendations
- Scheduled cesarean delivery at 38 weeks' gestation is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery, irrespective of administration of antepartum antiretroviral (ARV) drugs, and for women with un known HIV RNA levels near the time of delivery (AII).
- Scheduled cesarean delivery is not routinely recommended for prevention of perinatal transmission in pregnant women receiving combination ARV drugs with plasma HIV RNA levels <1,000 copies/mL near the time of delivery. Data are in sufficient to evaluate the potential benefit of cesarean delivery in this group, and given the low rate of transmission in these patients, it is unclear whether scheduled cesarean delivery would confer additional benefit in reducing transmis sion. This decision should be individualized based on discussion between the obstetrician and the mother (BII).
- It is not clear whether cesarean delivery after rupture of membranes or onset of labor provides benefit in preventing peri natal transmission. Management of women originally scheduled for cesarean delivery who present with ruptured mem branes or in labor must be individualized based on duration of rupture, progress of labor, plasma HIV RNA level, current ARV regimen, and other clinical factors (BII).
- Women should be informed of the risks associated with cesarean delivery; the risks to the woman should be balanced with potential benefits expected for the neonate (AIII).

# Basis fo r Current Recommendations
Scheduled cesarean delivery, defined as cesarean delivery performed before the onset o f labor and be fore rupture of membranes, is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery and for women with unknown HIV RNA levels1.
This recommendation is based on findings from a multicenter, randomized clinical trial2 and from a large individual patient data meta-analysis3. These two studies were conducted at a time when the major ity of HIV-infected women received no ARV medications or zidovudine as a single drug and before the availability o f viral load information. Study results have since been extrapolated to make current recom mendations about the mode o f delivery in an era when combination ARV regimens during pregnancy are recommended and viral load information is readily available.
In the randomized clinical trial, 1.8% of infants born to women randomized to undergo cesarean delivery were HIV infected compared with 10.5% of infants born to women randomized to vaginal delivery (P <0.001). When adjusted for ARV use in pregnancy (zidovudine alone), scheduled cesarean delivery lowered the risk of HIV transmission by 80%, although the results were no longer statistically significant (odds ratio  0.2, 95% confidence interval , 0-1.7). When the data were analyzed by the actual mode of deliv ery, rather than to which group women were allocated, there was still a protective effect of scheduled ce sarean delivery (adjusted OR  0.3; 95% CI, 0.1-0.8) but not with emergency cesarean delivery (AOR 1.0; 95% CI, 0.3-3.7)2. Results from a large meta-analysis of individual patient data from 15 prospective cohort studies also demonstrated the benefit of scheduled cesarean delivery with a 50% reduction in risk3. Primarily based on these data, the American College of Obstetricians and Gynecologists has recommended consideration of scheduled cesarean delivery for HIV-infected pregnant women since 19994.

# HIV RNA Level o f 1,000 copies/mL as a Threshold for Recommendation of Scheduled Cesarean Delivery
The original American College o f Obstetricians and Gynecologists committee opinion was updated in 2000 to include further refinements based on HIV RNA levels1. Currently, the American College o f Ob stetricians and Gynecologists1 recommends that women with HIV RNA >1,000 copies/mL be counseled regarding the potential benefits o f scheduled cesarean delivery. Initially, this threshold o f 1,000 copies/mL was based largely on data from the Women and Infants Transmission Study (WITS), a large prospective cohort study that reported no HIV transmission among 57 women with HIV RNA levels <1,000 copies/mL5. Since that time, newer studies have demonstrated that HIV transmission can occurr among infants born to women with low viral loads.
In an analysis o f 957 women with plasma viral loads <1,000 copies/mL, cesarean delivery (scheduled or urgent) reduced the risk o f HIV transmission when adjusting for potential confounders including receipt o f maternal ARV medications, primarily zidovudine alone as prophylaxis (AOR 0.30; P = 0.022)6. Among infants born to 834 women with HIV RNA <1,000 copies/mL receiving ARV medications, 8 (1%) were HIV infected. In a more recent report from a comprehensive national surveillance system in the United Kingdom and Ireland, 3 (0.1%) o f 2,309 and 12 (1.2%) o f 1,023 infants born to women with HIV RNA o f <50 copies/mL and 50-999 copies/mL, respectively, were HIV infected7.
The recent studies demonstrate that transmission can occur even at very low HIV RNA levels. However, given the low rate of transmission among this group, it is unclear whether scheduled cesarean delivery confers any additional benefit in reducing transmission. Although decisions about mode of delivery for women with HIV RNA levels <1,000 copies/mL should be individualized based on discussion between the obstetrician and the mother, scheduled cesarean delivery is not routinely recommended in this group.

# Scheduled Cesarean Delivery in the Highly Active Antiretroviral Therapy Era
In surveillance data from the United Kingdom and Ireland, pregnant women receiving combination ARV regimens (i.e., at least 3 drugs) had transmission rates o f about 1%, unadjusted for mode o f delivery7.
Given the low transmission rates achievable with use of maternal combination ARV drug regimens, the benefit o f scheduled cesarean delivery is difficult to evaluate. Both the randomized clinical trial2 and meta-analysis3 documenting the benefits o f cesarean delivery included mostly women who were receiv ing either no ARVs or zidovudine only. However, other data partially address this issue.
In a report from the European Collaborative Study that included data from 4,525 women, the overall trans mission rate among the subset of women on a combination ARV regimen was 11(1.2%) of 9188. Among the subset of 560 women with undetectable HIV RNA levels (<50 to <200 copies/mL, depending on site), scheduled cesarean delivery was associated with a significant reduction in perinatal transmission in uni variate analysis (OR 0.07; 95% CI, 0.02-0.31; P = 0.0004). However, after adjustment for ARV drug use (none vs. any), the effect was no longer significant (AOR 0.52; 95% CI, 0.14-2.03; P = 0.359). Similarly, data from a European surveillance study did not demonstrate a statistically significant difference in trans mission rates between scheduled cesarean delivery and planned vaginal delivery (AOR 1.24; 95% CI, 0.34-4.5) among women on combination ARV drug regimens7. The transmission rate among all women who received at least 14 days of ARV medications was 40 (0.8%) of 4,864, regardless of mode of delivery. Therefore, it is not clear whether there is any benefit from scheduled cesarean delivery among women who have been receiving combination ARV medications for several weeks.

# Women Presenting Late in Pregnancy
HIV-infected women who present in late pregnancy and are not receiving ARV drugs may not have HIV RNA results available before delivery. Without current therapy, HIV RNA levels are unlikely to be <1,000 copies/mL at baseline. Even if combination ARV medications were begun immediately, reduc tion in plasma HIV RNA to undetectable levels usually takes several weeks, depending on the kinetics of viral decay for the particular drug regimen9. In this instance, scheduled cesarean delivery is likely to pro vide additional benefit in reducing the risk o f perinatal transmission o f HIV for women, unless viral sup pression can be documented prior to 38 weeks.

# Timing of Scheduled Cesarean Delivery
In general, for women without HIV infection, American College of Obstetricians and Gynecologists rec ommends that scheduled cesarean delivery not be performed before 39 weeks' gestation because of the risk of iatrogenic prematurity10-11. However, in cases of cesarean delivery performed to prevent transmis sion of HIV, American College of Obstetricians and Gynecologists recommends scheduling cesarean de livery at 38 weeks' gestation in order to decrease the likelihood o f onset of labor or rupture of membranes before delivery1. Among all women undergoing repeat cesarean delivery, the risk of any neonatal adverse event-including neonatal death, respiratory complications, hypoglycemia, newborn sepsis, or admission to the neonatal intensive care unit-is 15.3% at 37 weeks, 11.0% at 38 weeks, and 8.0% at 39 weeks11. Gestational age should be determined by last menstrual period and ultrasonography because amniocentesis to document lung maturity should be avoided, when possible, in HIV-infected women.
Among 1,194 infants born to HIV-infected mothers, 9 (1.6%) infants born vaginally had respiratory dis tress syndrome (RDS) compared with 18 (4.4%) of infants born by scheduled cesearean delivery (P <0.001). There was no statistically significant association between mode of delivery and infant RDS in an adjusted model that included infant gestational age and birth weight12. Clinicians should recognize that newborn complications may be increased in planned early term births <39 weeks' gestation. However, for HIV-infected women, the benefits of decreasing HIV transmission by planned delivery at 38 weeks are generally thought to outweigh the risks. When cesarean delivery is performed in HIV-infected women for an indication other than decreasing transmission of HIV, cesarean delivery should be scheduled at 38 weeks gestation based on accepted American College of Obstetricians and Gynecologists guidelines.

# Risk of M aternal Complications
Because maternal infectious morbidity is increased with cesarean delivery even among women without HIV infection, the administration of perioperative antimicrobial prophylaxis is recommended for all women undergoing cesarean delivery. Most studies have demonstrated that HIV-infected women have in creased rates of postoperative complications, mostly infectious, compared with HIV-uninfected women and that the risk of complications is related to the degree of immunosuppression13-18. Furthermore, a Cochrane review of six studies of HIV-infected women concluded that urgent cesarean delivery was asso ciated with the highest risk of postpartum morbidity, that scheduled cesarean delivery was intermediate in risk, and that vaginal delivery had the lowest risk of morbidity19. Complication rates in most studies2, 20-24 were within the range reported in populations of HIV-uninfected women with similar risk factors and were not of sufficient frequency or severity to outweigh the potential benefit of reduced transmission. Therefore, HIV-infected women should be counseled regarding the increased risks and potential benefits associated with cesarean delivery based on their HIV RNA levels and current ARV regimen.

# Management o f Women W ho Present in Early Labor or With Ruptured Membranes
Few data are available to address the question o f whether performing cesarean delivery after the onset of labor or membrane rupture may decrease the risk o f perinatal transmission o f HIV. Most studies have shown a similar risk o f transmission for cesarean delivery performed after labor and membrane rupture for obstetric indications and for vaginal delivery. In one study, the HIV transmission rate was similar in women undergoing emergency cesarean delivery and those delivering vaginally (1.6% vs. 1.9%, respectively)7. A meta-analysis o f women, most o f whom were on zidovudine as a single drug or receiving no ARV medications, demonstrated a 2% increased transmission risk for every additional hour o f ruptured membranes25. However, it is not clear how soon after the onset o f labor or the rupture o f membranes the benefit o f cesarean delivery is lost26. Therefore, the management o f women originally scheduled for ce sarean delivery who present with ruptured membranes or in labor must be individualized based on clini cal factors such as duration o f rupture, progress o f labor, plasma RNA level, and current ARV drug regimen status. When membrane rupture occurs before 37 weeks' gestation, decisions about delivery should be based on gestational age, HIV RNA level, current ARV regimen, and evidence o f acute infec tion such as chorioamnionitis; consultation with an expert is recommended. The ARV drug regimen should be continued and consideration given to initiating intravenous zidovudine if delivery appears im minent. No data exist to suggest that recommendations for administration o f steroids to accelerate fetal lung maturity should be altered among HIV-infected women.
Table 7 provides a summary o f recommendations regarding mode o f delivery for different clinical sce narios.

# Clinical Scenario Recommendations
HIV-infected women presenting in late pregnancy (after about
- Start ARV medications as per Table 6 .
- Provide counseling on the likelihood that scheduled cesarean delivery will reduce the risk 36 weeks' gestation), known to of mother-to-child transmission, if viral suppression cannot be documented prior to 38 be HIV infected but not receiv ing antiretroviral (ARV) medica tions, and who have HIV RNA level and CD4 cell counts pend ing but unlikely to be available before delivery.
weeks. Include information on the increased maternal risks of cesarean delivery, including increased rates of postoperative infection, anesthesia, and other surgical risks.
- When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks' gestation, as determined by last menstrual period and ultrasonography.
- Administer continuous intravenous zidovudine beginning 3 hours before scheduled ce sarean.
- Continue other ARV medications on schedule, as much as possible, before and after surgery.
- Use of prophylactic antibiotics at the time of cesarean delivery is recommended.
HIV-infected women who began prenatal care early in the third trimester, are receiving combina tion ARV drug regimens, and have an initial virologic response but have HIV RNA levels that re main substantially >1,000 copies/mL at 36 weeks' gesta tion.
- Continue the current combination ARV regimen because the drop in HIV RNA level is ap propriate.
- Provide counseling on the timing of response to ARV medications and the likelihood that maternal HIV RNA levels may not fall below 1,000 copies/mL before delivery. Consider scheduled cesarean delivery if viral load suppression is not achieved by 38 weeks be cause of the potential additional benefit in preventing intrapartum transmission of HIV. In form patients about the increased maternal risks associated with cesarean delivery, including risks related to anesthesia and surgery and increased rates of postoperative in fection.
- When the delivery method selected is scheduled cesarean, perform the procedure at 38 weeks' gestation, as determined by last menstrual period and ultrasonography.
- When the delivery method selected is scheduled cesarean delivery, administer continuous intravenous zidovudine beginning 3 hours before scheduled cesarean.
- Continue other ARV medications on schedule, as much as possible, before and after surgery.
- Use of prophylactic antibiotics at the time of cesarean delivery is recommended.
HIV-infected women on combi nation ARV drug regimens with undetectable HIV RNA levels at 36 weeks' gestation.
- Provide counseling on the risk of perinatal transmission of HIV with a persistently unde tectable HIV RNA level, which is probably 1% or less, even with vaginal delivery. No evi dence currently exists to show that this risk can be lowered further by performing scheduled cesarean delivery.
- Risk of complications is increased with cesarean delivery, compared with vaginal delivery, even in the HIV-uninfected population, and the risks must be balanced against the uncer tain benefits of cesarean delivery in women with undetectable viral load.
HIV-infected women who have elected scheduled cesarean de livery but present after rupture of membranes at >37 weeks' gestation.
- Start intravenous zidovudine immediately.
- Individualize the decision regarding mode of delivery, based on clinical factors such as dura tion of rupture, anticipated progress of labor, plasma RNA level, and current ARV regimen.
- When vaginal delivery is chosen, some clinicians may consider administration of oxy tocin, if clinically appropriate, in order to expedite delivery. Scalp electrodes and other in vasive monitoring and operative delivery should be avoided, if possible, unless there are clear obstetric indications.
- When cesarean delivery is chosen, administration of the loading dose of intravenous zi dovudine ideally should be completed prior to the procedure. However, decisions regard ing timing of delivery should be individualized.
Other Intrapartum Management Considerations (Updated September 14, 2011)

# Panel's Recommendations
- Generally avoid artificial rupture of membranes unless there are clear obstetric indications because of a potential in creased risk of transmission (BIII).
- Routine use of fetal scalp electrodes for fetal monitoring should be avoided in the setting of maternal HIV infection unless there are clear obstetric indications (BIII).
- Operative delivery with forceps or a vacuum extractor and/or episiotomy should be performed only if there are clear ob stetric indications (BIII).
The antiretroviral drug (ARV) regimen a woman is receiving should be taken into consideration when treating excessive postpartum bleeding resulting from uterine atony:
- In women who are receiving a cytochrome P (CYP) 3A4 enzyme inhibitor such as a protease inhibitor (PI), methergine should only be used if no alternative treatments for postpartum hemorrhage are available and the need for pharmacologic treatment outweighs the risks. If methergine is used, it should be administered in the lowest ef fective dose for the shortest possible duration (BIII).
- In women who are receiving a CYP3A4 enzyme inducer such as nevirapine or efavirenz, additional uterotonic agents may be needed because of the potential for decreased methergine levels and inadequate treatment effect (BIII).
If spontaneous rupture o f membranes occurs before or early during the course o f labor, interventions to decrease the interval to delivery, such as administration o f oxytocin, may be considered in women with out indications for cesarean delivery.
Artificial rupture o f membranes should be avoided and used only for a clear obstetric indication in women with intact membranes and detectable viral load who present in labor and proceed to vaginal de livery. Data are limited on artificial rupture o f membranes in women with undetectable viral load and planned vaginal delivery. In general, the procedure should be performed only for clear obstetrical indica tions because o f the potential, albeit small, increased risk o f HIV transmission.
Obstetric procedures that increase the risk o f fetal exposure to maternal blood, such as invasive fetal monitoring, have been implicated in increasing vertical transmission rates by some, but not all, investi gators, primarily in studies performed in the pre-combination antiretroviral therapy (ART) era1-4. Data are limited on routine use o f fetal scalp electrodes in labor in women receiving suppressive ARV regi mens and undetectable viral load; routine use o f fetal scalp electrodes for fetal monitoring should be avoided in the setting o f maternal HIV infection unless there are clear obstetric indications.
Similarly, data are limited to the pre-combination ART era regarding the potential risk o f perinatal trans mission o f HIV associated with operative vaginal delivery with forceps or the vacuum extractor and/or use o f episiotomy2, 4. These procedures should be performed only if there are clear obstetric indications. Delayed cord clamping has been associated with improved iron status and benefits such as decreased risk o f intraventricular hemorrhage in preterm births to HIV-uninfected mothers5-7. Even though HIVspecific data on the practice are lacking, there is no reason to modify it in HIV-infected mothers.

# Postpartum Hemorrhage, Antiretroviral Drugs, and M ethergine Use
Oral or parenteral methergine or other ergot alkaloids are often used as first-line treatment for postpar tum hemorrhage resulting from uterine atony. However, methergine should not be coadministered with drugs that are potent CYP3A4 enzyme inhibitors, including PIs. Concomitant use o f ergotamines and PIs has been associated with exaggerated vasoconstrictive responses. When uterine atony results in ex cessive postpartum bleeding in women receiving PIs as a component o f an ARV regimen, methergine should be used in women with excessive postpartum bleeding who are receiving PIs as a component of ART only if alternative treatments such as prostaglandin F 2 alpha, misoprostol, or oxytocin are unavail able. If no alternative medications are available and the need for pharmacologic treatment outweighs the risks, methergine should be used in as low a dosage and for as short a period as possible. In contrast, ad ditional utertonic agents may be needed when other ARV drugs that are CYP3A4 inducers, such as nevi rapine and efavirenz, are used because o f the potential for decreased methergine levels and inadequate treatment effect.
Postpartum Management (Updated September 14, 2011)
Postpartum Follow-up of HIV-Infected Women

# Panel's Recommendations
- Contraceptive counseling should be included as a critical aspect of postpartum care (AIII).
- Decisions about continuing antiretroviral (ARV) drugs after delivery should take into account current recommendations for initiation of antiretroviral therapy (ART), current and nadir CD4 cell counts and trajectory, HIV RNA levels, adherence issues, whether the woman has an HIV-uninfected sexual partner, and patient preference (AIII).
- For women continuing ARV drugs postpartum, arrangements for new or continued supportive services should be made before hospital discharge because the immediate postpartum period poses unique challenges to adherence (AII).
- Women with a positive rapid HIV antibody test during labor require comprehensive follow-up, including confirmation of HIV infection. If infection is confirmed, a full health assessment is warranted, including evaluation for associated medical conditions, counseling related to newly diagnosed HIV infection, and assessment of need for ART and opportunistic in fection (OI) prophylaxis (AII).
The postpartum period provides an opportunity to review and optimize women's health care. Compre hensive care and support services are particularly important for women with HIV infection and their families, who often face multiple medical and social challenges. Components o f comprehensive care in clude the following medical and supportive care services as needed:
- primary, gynecologic/obstetric, and HIV specialty care for the HIV-infected woman;
- pediatric care for her infant;
- family planning services;
- mental health services;
- substance abuse treatment;
- support services; and
- coordination of care through case management for the woman, her child(ren), and other family members.
Support services should be tailored to individual women's needs and may include case management; child care; respite care; assistance with basic life needs, such as housing, food, and transportation; peer counseling; and legal and advocacy services. Ideally, this care should begin before pregnancy and con tinue throughout pregnancy and the postpartum period.
During the postpartum period, maternal medical services must be coordinated between obstetric care providers and HIV specialists. It is especially critical to ensure continuity o f the antepartum ARV drug regimen when such treatment is required for a woman's health. The decision about whether to continue ARV drugs after delivery should be discussed with a woman and made before delivery.
The postpartum period also is a critical time for addressing the issue of safer sex practices and contracep tion. Lack of breastfeeding is associated with earlier return of fertility; ovulation returns as early as 6 weeks postpartum, and even earlier in some women, putting them at risk of pregnancy shortly after deliv ery1. Interpregnancy intervals of less than 18 months have been associated with increased risk of poor peri natal and maternal outcomes in HIV-uninfected women2. Because of the stresses and demands of a new baby, women may be more receptive to use of effective contraception, yet simultaneously at higher risk of nonadherence to contraceptive use and thus unintended pregnancy3. This is an important concern in women who are on an efavirenz-containing regimen because of the potential risk of teratogencity. A "dual protection" strategy, such as use of condoms plus a second highly effective contraceptive, is ideal for women with HIV infection because it provides simultaneous protection against unintended pregnancy and HIV transmission or sexually transmitted disease (STD) acquisition or transmission4. Longer term, re versible contraceptive methods, such as injectables, implants, and intrauterine devices (IUDs) should be included as options.
Drug interactions have been documented between oral contraceptives (OCs) and many ARV drugs (see Table 4 in Preconception Counseling). These interactions, however, do not necessarily rule out the use of hormonal contraceptives because there is no clear evidence of an effect on contraceptive or ARV efficacy or toxicity. OCs do significantly lower levels of amprenavir/fosamprenavir and, therefore, coadministra tion is not recommended; whether low-dose ritonavir boosting raises amprenavir levels sufficiently to allow coadministration is unknown. Depot medroxyprogesterone acetate (Depo-Provera, DMPA) pharma cokinetics (PKs) are not significantly affected by nevirapine, efavirenz, or nelfinavir, and levels of these drugs were not significantly altered by DMPA5. Adverse effects of DMPA are no different in HIV-infected women on ARV drugs than in HIV-uninfected women6. Other non-oral contraceptives, such as levonorgestrel implants, the combined contraceptive patch, the combined hormonal contraceptive vaginal ring, and the levonorgestrel IUD, are largely unstudied in combination with ARV drugs, but some data do exist on lopinavir/ritonavir interactions with the estrogen patch7. ARV drug interactions may be of less concern with contraceptive methods that exert primarily local activity and have minimal systemic absorp tion, but there is still a potential for interaction if metabolic or elimination pathways are shared5, 8. Perma nent sterilization is appropriate only for women who are certain they do not desire future childbearing.
Women with nadir CD4 cell counts less than the currently recommended threshold for institution of ART9 and/or symptomatic HIV infection should be encouraged to continue their ARV regimens postpar tum without interruption. Decisions about whether to continue ARV drugs after delivery should be made in consultation with the HIV provider for women who began ARV drugs for prophylaxis o f transmission with nadir CD4 cell counts greater than that currently recommended for treatment. Factors to be taken into consideration should include current recommendations for initiation o f ART, current and nadir CD4 lymphocyte counts and trajectory, HIV RNA levels, adherence issues, partner HIV status, and patient preference. The risks versus benefits o f stopping combination ARV drug regimens postpartum in women with high CD4 cell counts are being evaluated in the ongoing PROMISE study (clinical trial number NCT00955968).
Recent data from the HPTN 052 clinical trial showed that earlier initiation o f ARVs led to a significant reduction in sexual transmission o f HIV to uninfected partners in serodiscordant couples (see Preconcep tion Counseling) . HPTN 052 evaluated immediate versus delayed initiation o f ART to HIV-infected indi viduals with CD4 counts between 350 and 550 cells/mm3. Based on the results from that trial, continued administration o f ARV drugs may be recommended for prevention o f sexual transmission o f HIV for postpartum women who have CD4 cell counts between 350 and 550 cells/mm3 and have HIV-uninfected sexual partners, and it may be considered for those with CD4 cell counts greater than 550 cells/mm3 with HIV-uninfected sexual partners. It is important to counsel the woman that no single method (in cluding treatment o f the infected partner) is fully protective against HIV transmission and safer sexual practices should be continued.
Concerns have been raised about adherence to ARV regimens during the postpartum period. Women should be counseled that postpartum physical and psychological changes and the stresses and demands o f caring for a new baby may make adherence more difficult and that additional support may be needed during this period10-12. Health care providers should be vigilant for signs o f depression and illicit drug or alcohol use that may require assessment and treatment and interfere with adherence. Poor adherence has been shown to be associated with virologic failure, development o f resistance, and decreased long-term effectiveness o f ART13-15. Simplification o f an ARV regimen (for example, to once-daily medications) can be considered. It may be preferable to temporarily interrupt ART in women who are unable to ad here to their regimens while they work with a provider on strategies to improve adherence. Efforts to maintain adequate adherence during the postpartum period may prolong the effectiveness o f therapy (see the section on Adherence in the Guidelines for the Use o f Antiretroviral Agents in HIV-1-Infected Adults and Adolescents).
For women whose antepartum regimen included a non-nucleoside reverse transcriptase inhibitor (NNRTI) and who plan to stop ARV prophylaxis after delivery, consideration should be given to stopping the NNRTI and continuing the other ARV drugs for a period of time before stopping electively. The optimal interval be tween stopping an NNRTI and the other ARV drugs is unknown; a minimum of 7 days is recommended.
Because efavirenz-based therapy has potential to result in prolonged, detectable NNRTI concentrations for more than 3 weeks, some experts recommend that patients receiving efavirenz continue their other ARV drugs or substitute a protease inhibitor (PI) for the NNRTI drug in combination with their other ARV drugs for up to 30 days after stopping efavirenz (see Stopping Antiretroviral Therapy during Pregnancy and Prevention of Antiretroviral Drug Resistance). Women whose antepartum regimen did not include an NNRTI and who plan to stop ARV prophylaxis after delivery should stop all ARV drugs at the same time. Doses of some PIs may be increased during pregnancy. For women continuing therapy, available data sug gest that standard doses can be used again, beginning immediately after delivery.
Comprehensive medical assessment, counseling, and follow-up are required for women who test posi tive on rapid HIV antibody assay during labor or at delivery. To minimize the delay in definitive diagno sis, confirmatory HIV antibody testing should be performed as soon as possible after an initial positive rapid test16. Women who test positive on rapid HIV antibody assay should not breastfeed unless a confir matory HIV test is negative. Women with a new HIV diagnosis postpartum should receive the same thorough evaluation as other newly identified infected patients, including consideration o f ART and pro phylaxis for OIs, as indicated. Other children and partner(s) should be referred for HIV testing.
Infants Born to Mothers with Unknown HIV Infection Status (Updated September 14, 2011)
Panel's Recommendations
- For infants born to mothers with unknown HIV status, rapid HIV antibody testing of the mother and/or infant is recommended as soon as possible after birth, with immediate initiation of infant antiretroviral (ARV) prophylaxis (see Infant Antiretroviral Prophylaxis) if the rapid test is positive (AII). In the setting of a positive test, standard antibody con firmatory testing such as a Western blot also should be performed on mothers (or their infants) as soon as possible. If the confirmatory test is negative, ARV prophylaxis can be discontinued (AIII).
- If the HIV antibody confirmatory test is positive, a newborn HIV DNA polymerase chain reaction (PCR) should be ob tained (AIII).
- If the newborn HIV DNA PCR is positive, ARV prophylaxis should be discontinued and the infant promptly referred to a pediatric HIV specialist for confirmation of the diagnosis and treatment of HIV infection with standard combination anti retroviral therapy (ART) (AI).
Rapid HIV antibody testing o f mothers and/or infants is recommended as soon as possible after birth when maternal HIV status is unknown and rapid HIV antibody testing was not performed during labor. If rapid testing is positive, infant ARV prophylaxis should be initiated immediately. Rapid HIV antibody testing should be available on a 24-hour basis at all facilities with a maternity service and/or neonatal in tensive care or newborn nursery. A positive test result in mothers or infants should be presumed to indi cate maternal HIV infection until standard antibody confirmatory testing clarifies maternal status. A standard confirmatory test (e.g., Western blot) should be performed on mothers (or their infants) as soon as possible after the initial positive rapid test1. A positive HIV antibody test in an infant indicates mater nal but not necessarily infant HIV infection; diagnosis o f HIV infection in infants younger than age 18 months requires virologic testing. If the confirmatory test on a mother (or infant) is negative, ARV pro phylaxis can be discontinued. If the confirmatory test is positive, an HIV DNA PCR should be obtained urgently from the newborn. If the HIV DNA PCR is positive, ARV prophylaxis should be promptly dis continued and the infant should receive treatment for HIV infection with standard combination ART ac cording to established Guidelines for the Use o f Antiretroviral Agents in Pediatric HIV Infection developed by The Working Group on Antiretroviral Therapy and Medical Management o f HIV-Infected Children.
Infant Antiretroviral Prophylaxis (Updated September 14, 2011; Erratum issued December 1 , 2011)
Panel's Recommendations
- The 6-week neonatal component of the zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed neonates to reduce perinatal transmission of HIV (A I).
- Zidovudine should be initiated as close to the time of birth as possible, preferably within 6-12 hours of delivery (A II).
- The 6-week zidovudine prophylaxis regimen is recommended at gestational age-appropriate doses; zidovudine should be dosed differently for premature infants less than 35 weeks than for infants at least 35 weeks of age (see Zidovudine Dosing and Table 8) (A II).
- In the United States, the use of antiretroviral (ARV) drugs other than zidovudine cannot be recommended in premature infants because of lack of dosing and safety data (B III) .
- The use of intrapartum/neonatal zidovudine is recommended regardless of maternal history of zidovudine resistance (B III).
- Infants born to HIV-infected women who have not received antepartum ARV drugs should receive prophylaxis with a combination ARV drug regimen, begun as soon after birth as possible (A I). A randomized, controlled trial has shown that a 2-drug regimen of zidovudine given for 6 weeks combined with three doses of nevirapine in the first week of life (at birth, 48 hours later, and 96 hours after the second dose) is as effective as but less toxic than a 3-drug regimen of zi dovudine, nelfinavir and lamivudine. The 2-drug regimen is preferred due to lower toxicity and because nelfinavir powder is no longer available in the United States (see General Considerations for Choice of Infant Prophylaxis and Table 9) (A I).
- In other scenarios, the decision to combine other drugs with the 6-week zidovudine regimen should be made in consulta tion with a pediatric HIV specialist, preferably before delivery, and should be accompanied by counseling of the mother on the potential risks and benefits of this approach (B III).
- The National Perinatal HIV Hotline (1-888-448-8765) provides free clinical consultation on all aspects of perinatal HIV, in cluding infant care.

# Zidovudine Dosing
All HIV-exposed infants should receive postpartum ARV drugs to reduce perinatal transmission o f HIV. The 6-week neonatal zidovudine chemoprophylaxis regimen is recommended for all HIV-exposed in fants1-2. Table 8 shows zidovudine dosing intrapartum, which is a continuous intravenous infusion during labor, and neonatal dosing. Table 9 shows intrapartum and neonatal dosing for other drugs to be consid ered in certain situations as delineated below.
The recommended dose of zidovudine for post-exposure prophylaxis in full-term neonates is 4 mg/kg body weight orally twice daily for the first 6 weeks o f life, beginning as soon after birth as possible and preferably within 6-12 hours o f delivery (Table 8) . Although the ACTG 076 study used a zidovudine regimen o f 2 mg/kg every 6 hours, data from many international studies support twice-daily oral infant dosing for prophylaxis3-12. Most o f these studies used a dose o f 4 mg/kg twice daily, adjusted for weight gain, but others have used a regimen based on birth weight for the entire 6-week treatment period13-14.
The current World Health Organization (WHO) guidelines recommend a simplified zidovudine dosing regimen for the 6-week prophylaxis period consisting o f 10 mg given twice daily for infants weighing less than 2.5 kg at birth and 15 mg twice daily for infants weighing more than 2.5 kg at birth15. The ad vantages o f this simplified regimen are that it avoids the need for dosing calculations and involves ad ministration o f either 1.0 or 1.5 mL o f zidovudine syrup. The disadvantage is that, compared with mg-per-kg dosing, infants with birth weights greater than 3.75 kg will receive a smaller zidovudine dose and infants less than 3.75 kg will receive a larger zidovudine dose. The zidovudine dosing requirements differ for premature infants and term infants. Zidovudine is prima rily cleared through hepatic glucuronidation to an inactive metabolite; this metabolic pathway is imma ture in neonates, leading to prolonged zidovudine half-life and clearance compared with older infants.
Clearance is further prolonged in premature infants because their hepatic metabolic function is even less mature than in term infants16-17. The recommended zidovudine dosage for infants less than 35 weeks' gestation is 2 mg/kg body weight per dose orally every 12 hours (or 1.5 mg/kg body weight intra venously per dose every 12 hours), increasing to 2 mg/kg body weight per dose every 8 hours at age 2 weeks for infants born at 30 weeks' gestation or more or at age 4 weeks in those born at less than 30 weeks' gestation. For infants born at more than 35 weeks' gestation or greater who are unable to tolerate oral zidovudine, the drug can be given intravenously at a dose o f 1.5 mg/kg body weight every 6 hours.
In the United Kingdom and many other European countries, a 4-week neonatal chemoprophylaxis regi men is recommended for infants born to mothers who have received antenatal combination ARV drug regimens18-20. This approach also can be considered in cases where adherence to or toxicity from the 6week zidovudine prophylaxis regimen is a concern. In an Irish observational study, a transmission rate o f 1.1% was observed in 916 infants who received 4 weeks o f zidovudine infant prophylaxis following antenatal maternal combination ARV prophylaxis. That is the standard regimen in Ireland and the trans mission rate was similar to that observed in the United States, where 6 weeks o f infant zidovudine pro phylaxis is standard20. A recent prospective, observational study reported that the 4-week zidovudine regimen allowed earlier recovery from anemia in otherwise healthy infants compared with the 6-week zidovudine regimen21. The optimal duration o f neonatal zidovudine chemoprophylaxis, however, has not been established in clinical trials, and in the United States, the standard 6-week infant zidovudine regi men is recommended unless there are concerns about adherence or toxicity. Consultation with an expert in pediatric HIV infection is advised if early discontinuation o f prophylaxis is considered.  b ZDV dosing regimen is for infants >35 weeks' gestation. See Table 8 for recommended doses for premature infants.

# General Considerations fo r Choice o f Infant Prophylaxis
Infants born to mothers who have received standard antepartum and intrapartum ARV prophylaxis and have undetectable viral loads are at very low risk o f HIV transmission. However, the risk o f transmission is increased when maternal viral load at delivery is high or maternal antepartum and/or intrapartum pro phylaxis was not received. Most experts feel that the potential benefit o f combining zidovudine infant prophylaxis with additional ARV drugs may exceed the risk o f multiple drug exposure to infants born to: a. mothers who received antepartum and intrapartum ARV drugs but who had suboptimal viral suppres sion at delivery, particularly if delivery was vaginal;
b. mothers who received only intrapartum ARV drugs; c. mothers who received no antepartum or intrapartum ARV drugs; and d. mothers with known ARV drug-resistant virus.
In each o f these situations, there is a spectrum o f transmission risk that depends on a number o f maternal and infant factors, including maternal viral load, mode o f delivery, and gestational age at delivery. The risks and benefits o f infant exposure to ARV drugs in addition to zidovudine will differ depending on where the mother/child falls in the risk spectrum. For example, an infant delivered vaginally to a mother with an HIV RNA level >100,000 copies/mL at delivery has a higher risk o f acquiring HIV infection than an infant born by cesarean delivery to a mother with an HIV RNA level o f approximately 10,000 copies/mL at delivery. Thus, a generic recommendation cannot be made regarding use o f combination drug regimens for infant prophylaxis and each situation needs to be considered individually, balancing potential benefits (in terms of preventing perinatal transmission o f HIV) with risks (in terms o f toxicity to the infant). In addition, appropriate drug formulations and dosing regimens for neonates are incom pletely defined and data are minimal on the safety o f combination drugs in the neonate (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis and the Guidelines for the Use o f Anti retroviral Agents in Pediatric HIV Infection). Thus, decisions about use o f combination ARV prophy laxis in infants should be made in consultation with a pediatric HIV specialist before delivery and should be accompanied by a discussion with the mothers about potential risks and benefits o f this approach.
Use of combination ARV prophylaxis for infants in high-risk situations is increasing. Despite widespread use of combination ARV prophylaxis, until recently there were no data evaluating the efficacy of these regimens versus zidovudine alone in the setting of high risk of mother-to-child transmis sion of HIV. Results from a Phase III randomized trial in 4 countries (including the United States) were presented at the 2011 Conference on Retroviruses and Opportunistic Infections (NICHD-HPTN 040/PACTG 1043)14. This study enrolled 1,746 infants born to HIV-infected women who did not receive any ARV drugs during pregnancy and, hence, were at high risk of infection. The study compared infant prophylaxis with the standard 6-week zidovudine regimen and 2 different combination regimens for pre vention of intrapartum transmission of HIV: 6 weeks of zidovudine plus 3 doses of nevirapine given dur ing the first week of life (first dose at birth-48 hours; second dose 48 hours after first dose; and third dose 96 hours after second dose) and 6 weeks of zidovudine plus 2 weeks of lamivudine/nelfinavir. The risk of intrapartum transmission was significantly lower, compared with 6 weeks of zidovudine alone, in the 2and 3-drug arms (2.2% and 2.5%, respectively, vs. 4.9% for zidovudine alone; P = 0.046 for each experi mental arm vs. zidovudine alone). The overall transmission rate of HIV (in utero + intrapartum) was also significantly lower in the 2-and 3-drug arms compared with zidovudine alone (7.1%, 7.4%, and 11.1%, re spectively, P = 0.035 for comparison of each experimental arm with zidovudine alone)14. Although trans mission rates with the two combination regimens were similar, neutropenia was significantly more common with the 3-drug regimen than with the 2-drug or zidovudine-alone regimen (27.5% vs. 15%, P <0.0001). In other studies, significantly higher rates of neutropenia and anemia have been reported with coadministration of zidovudine and lamivudine to infants24.
The NICHD-HPTN 040/PACTG 1043 study provides proof o f principle that use o f a combination drug regimen for infants is more effective than zidovudine alone in the high-risk setting o f no maternal an tepartum administration o f ARV drugs. The two-drug regimen is less complex and had lower rates of toxicity than the three-drug regimen; additionally, nelfinavir powder is no longer commercially available in the United States, is not a preferred ARV drug for pediatric treatment, and drug levels in neonates are highly variable25. Therefore, the two-drug regimen is recommended for prophylaxis in infants born to mothers who have not received antepartum ARV drugs.
Beyond the scenario studied in NICHD-HPTN 040/PACTG 1043, the choice o f ARV drug regimens for neonates is limited (see Short-Term Antiretroviral Drug Safety and Choice for Neonatal Prophylaxis) . Neonatal dosing information is not available for any o f the currently available boosted protease in hibitors (PIs). In addition, use of lopinavir/ritonavir in neonates has been associated with severe and sometimes fatal cardiac, renal, central nervous system (CNS), and metabolic toxicity26. Because o f the potential for toxicity, lopinavir/ritonavir should not be administered to neonates before a postmenstrual age (first day o f the m other's last menstrual period to birth plus the time elapsed after birth) o f 42 weeks and a postnatal age o f at least 14 days.

# The National Perinatal HIV Hotline (1-888-448-8765)
The National Perinatal HIV Hotline is a federally funded service providing free clinical consultation to providers caring for HIV-infected pregnant women and their infants.

# Recommendations fo r Infant Antiretroviral Prophylaxis in Specific Clinical Situations

# Infants Born to Mothers Who Received Antepartum/Intrapartum Antiretroviral Drugs with Effective Viral Suppression
The risk o f HIV acquisition is small in infants born to women who received standard ARV prophylaxis regimens during pregnancy and labor and had undetectable viral loads at delivery or born by scheduled cesarean section to mothers with low viral loads at delivery. For example, in PACTG 316, the infection rate in infants born to women receiving antepartum PI-based therapy was 0.7% in 269 infants with HIV RNA levels o f less than 400 copies/mL at delivery2. Such infants should receive the 6-week zidovudine infant prophylaxis regimen. In that situation, combining zidovudine with additional ARV drugs to reduce transmission risk is not recommended because the benefit would be very limited.

# Infants Born to Mothers Who Have Received Antepartum/Intrapartum Antiretroviral Drugs But Have Suboptimal Viral Suppression Near Delivery
The risk o f perinatal transmission is related to maternal antepartum viral load in women on no ARV drugs as well as women receiving ARVs27-29. Scheduled cesarean delivery is recommended for preven tion of perinatal transmission in women who have received antepartum ARV drugs but have detectable viremia (HIV RNA >1,000 copies/mL) near the time o f delivery (see Intrapartum Care and Transmission and Mode o f Delivery). In PACTG 316, transmission occurred in 0% o f 17 infants when maternal HIV RNA levels at delivery were >10,000 copies/mL and delivery was by scheduled cesarean delivery2. However, not all women with detectable viremia near delivery will undergo cesarean delivery. The risk o f acquisition o f HIV will be higher in infants born to mothers with higher viral loads near delivery, par ticularly if delivery is vaginal. The gradient o f transmission risk is based on HIV RNA levels. In the Women and Infants Transmission Study (WITS), the risk o f transmission o f HIV was 30,000 copies/mL29.
All infants should receive zidovudine for 6 weeks. No specific data address whether a more intensive combination infant prophylaxis regimen (two or three drugs) provides additional protection against transmission when maternal antepartum/intrapartum prophylaxis is received but viral replication near delivery is significant. Elective cesarean section is recommended for pregnant women with HIV RNA levels >1,000 copies/mL near delivery. Extrapolation o f findings from the previously discussed NICHD-HPTN 040/PACTG 1043 study14 suggests that combination infant prophylaxis can be considered, de pending on assessment o f risk based on maternal viral load and mode o f delivery. That decision should be made in consultation with a pediatric HIV specialist before delivery and accompanied by maternal counseling on the potential risks and benefits o f this approach.

# Infants Born to Mothers Who Received Only Intrapartum Antiretroviral Drugs
All infants whose mothers have received only intrapartum ARV drugs should be given zidovudine for 6
weeks. This infant prophylaxis regimen is a critical component o f prevention when no maternal antepar tum ARV drugs have been received. The PETRA study demonstrated that intrapartum prophylaxis alone, without infant prophylaxis, is ineffective in reducing perinatal transmission3. A study in Thailand indi cated that longer infant prophylaxis with zidovudine (6 weeks vs. 3 days) is required for optimal efficacy when maternal antenatal exposure to zidovudine is <4 weeks30.
Infant prophylaxis with zidovudine should be initiated as soon after delivery as possible. In the NICHD-HPTN 040/PACTG 043 trial previously discussed, 41% of women received zidovudine during labor. Admin istration of intrapartum zidovudine did not affect transmission rates. The results of this study support use of a two-drug regimen, involving 6 weeks of zidovudine plus three doses of nevirapine in the first week of life, because combination regimens were found to have increased efficacy in reducing intrapartum transmission compared with use of zidovudine alone and the three-drug regimen was associated with increased toxicity and nelfinavir powder is no longer commercially available in the United States14.

# Infants Born to Mothers Who Did Not Receive Antepartum or Intrapartum Antiretroviral Drugs
Infants o f HIV-infected mothers who have received neither antepartum nor intrapartum ARV drugs should be started on ARV prophylaxis as soon after delivery as possible. Observational and Phase III ran domized studies suggest that prophylaxis provided to infants alone may be helpful in preventing trans mission o f HIV. Epidemiologic data from a New York State study indicated a decline in transmission when infants were given zidovudine for the first 6 weeks o f life compared with no prophylaxis31. Trans mission rates were 9% (95% confidence interval , 4.1%-17.5%) with zidovudine-alone prophylaxis in newborns (initiated within 48 hours after birth) versus 27% (95% CI, 21%-33%) with no zidovudine prophylaxis. For most infants in this study, prophylaxis was initiated within 12 hours o f birth32. The interval during which infant prophylaxis can be initiated and still be o f benefit is undefined. In the New York State study, when prophylaxis was delayed beyond 48 hours after birth, no efficacy could be demonstrated. Data from animal studies indicate that the longer the delay in institution o f prophylaxis, the less likely that infection will be prevented. In most studies o f animals, ARV prophylaxis initiated 24 36 hours after exposure usually has been ineffective in preventing infection, although a delay in adminis tration has been associated with decreased viremia33-35. In the NICHD-HPTN 040/PACTG 1043 study, infant regimens were initiated within 48 hours o f life and usually within 12 hours o f life14. Initiation of infant prophylaxis after age 2 days is not likely to be efficacious in preventing transmission and, by age 14 days, infection already would be established in most infants36. Initiating prophylaxis as soon after de livery as possible increases its potential efficacy and minimizes potential harm, such as development of resistant virus, if infection has occurred.

# Infants Born to Mothers with Antiretroviral Drug-Resistant Virus
The optimal prophylactic regimen for newborns delivered by women with ARV drug-resistant virus is un known. ARV prophylaxis for infants born to mothers with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist before delivery.
Data from the WITS suggest that in women who have mixed zidovudine-resistant and -sensitive viral populations, the zidovudine-sensitive rather than -resistant virus may be preferentially transmitted37-38.
Thus, the 6-week infant zidovudine prophylaxis (along with maternal intravenous intrapartum zidovu dine prophylaxis) continues to be recommended, even when maternal zidovudine-resistant virus with thymidine-associated mutations (TAMs) is identified.
Some studies have suggested that ARV drug-resistant virus may have decreased replicative capacity (re duced viral fitness) and transmissibility38. However, transmission from mother to child o f multidrug-re sistant virus has been reported39-41.
For these newborns, use o f zidovudine in combination with other ARV drugs, selected on the basis of maternal virus resistance testing, can be considered. The efficacy o f this approach for prevention of transmission, however, has not been proven in clinical trials, and for many drugs, appropriate dosing regimens for neonates are incompletely defined. Decisions regarding use o f additional drugs should be made in consultation with a pediatric HIV specialist and will depend on maternal history o f past and cur rent ARV drug exposure, HIV RNA levels at or near delivery, current and previous maternal resistance testing, and availability o f drug formulation and dosing information in the infant. ARV drugs with phar macokinetic (PK) and safety data in neonates sufficient to support their addition to zidovudine include lamivudine and nevirapine; although there are pharmacokinetic data in neonates for nelfinavir, nelfinavir powder for oral use is no longer commercially available in the United States.

# Breastfeeding Infants of Mothers Diagnosed with HIV Infection Postpartum
Breastfeeding should be stopped until infection is confirmed or ruled out in women who are breastfeed ing at the time of HIV diagnosis or suspected to be HIV infected. Pumping and temporarily discarding breast milk can be recommended to mothers who are suspected o f being HIV infected but whose infec tion is not yet confirmed and who want to continue to breastfeed. If HIV infection is ruled out, breast feeding can resume.
The risk o f acquisition o f HIV associated with breastfeeding depends on multiple infant and maternal factors, including maternal viral load and CD4 cell count42. Infants o f women who develop acute HIV infection while breastfeeding are at greater risk o f becoming infected than are those o f women with chronic HIV infection43 because acute HIV infection is accompanied by a rapid increase in viral load and a corresponding decrease in CD4 cell count44.
Other than discontinuing breastfeeding, optimal strategies for managing infants born to HIV-infected mothers who breastfed their infants prior to HIV diagnosis have yet to be defined. Some experts would consider the use of post-exposure prophylaxis in infants for 4 -6 weeks after cessation o f breastfeeding. Post-exposure prophylaxis, however, is less likely to be effective in this circumstance compared with other nonoccupational exposures because the exposure to breast milk is likely to have occurred over a prolonged period rather than in a single exposure45.
Several studies o f infants breastfed by women with chronic HIV infection have shown that daily infant nevirapine or nevirapine plus zidovudine can reduce the risk o f postnatal infection during breastfeeding8, 46-47. The NICHD-HPTN 040/PACTG 043 study demonstrated that combination ARV prophylaxis was more effective than zidovudine prophylaxis alone for preventing intrapartum transmission in mothers who have not received antepartum ARV drugs14. However, whether the combination regimens in this trial are effective for preventing transmission after cessation o f breastfeeding in mothers with acute HIV infection is unknown.
An alternative approach favored by some experts would be to offer a combination ARV regimen that would be effective for treatment o f HIV, should the infant become infected. If this route is chosen, cur rent recommendations for treatment should guide selection o f an appropriate combination ARV regimen (see Guidelines for the Use o f Antiretroviral Agents in Pediatric HIV Infection). Regardless o f whether post-exposure prophylaxis or "preemptive therapy" is chosen, the duration o f the intervention is un known. A 28-day course seems reasonable based on current recommendations for nonoccupational HIV exposure45. As in other situations, decisions regarding administration o f a prophylactic or preemptive treatment regimen should be accompanied by consultation with a pediatric HIV specialist and maternal counseling on the potential risks and benefits o f this approach.
Infants should be tested for HIV infection at baseline and 4 -6 weeks, 3 months, and 6 months after recogni tion of maternal infection to determine whether they are HIV infected. In infants younger than age 18 months, HIV DNA or RNA polymerase chain reaction (PCR) tests should be used for diagnosis. HIV DNA PCR is preferable for infants who are receiving combination ARV prophylaxis or preemptive treatment.
HIV antibody assays can be used in infants older than age 18 months. Post-exposure ARV prophylaxis or preemptive treatment should be discontinued in infants who are found to be HIV infected while receiving one of these regimens. Resistance testing then should be performed and an appropriate combination therapy regimen initiated (see Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection) .

# Short-Term Antiretroviral D rug Safety and Choice fo r N eonatal Prophylaxis
Infant prophylaxis with zidovudine has been associated with only minimal toxicity, consisting primarily o f transient hematologic toxicity (mainly anemia), which generally resolves by age 12 weeks (see Initial Postnatal Management). Data are limited on the toxicity to infants o f exposure to multiple ARV drugs.
The latest information on neonatal dosing for ARV drugs can be found in the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Other than zidovudine, lamivudine is the nucleoside re verse transcriptase inhibitor (NRTI) with the most experience in use for neonatal prophylaxis. In early studies, neonatal exposure to combination zidovudine/lamivudine was generally limited to 1 week3, 14, 48. Six weeks o f infant zidovudine/lamivudine exposure also has been reported; these studies suggest that hematologic toxicity may be increased over that seen with zidovudine alone, although the infants also had in utero exposure to maternal combination therapy.
In a French study, more severe anemia and neutropenia were observed in infants exposed to 6 weeks of zidovudine/lamivudine for prophylaxis plus maternal antepartum zidovudine/lamivudine than in a his torical cohort exposed only to maternal and infant zidovudine. Anemia was reported in 15% and neu tropenia in 18% o f infants exposed to zidovudine/lamivudine, with 2% o f infants requiring blood transfusion and 4% requiring treatment discontinuation for toxicity24. Similarly, in a Brazilian study of maternal antepartum and 6-week infant zidovudine/lamivudine prophylaxis, neonatal hematologic toxic ity was common, with anemia seen in 69% and neutropenia in 13% o f infants49. In a Phase I study of stavudine in pregnant women, infants received 6 weeks o f zidovudine/lamivudine and a single dose of stavudine at ages 1 and 6 weeks; 6 o f 14 (43%) infants experienced Grade 3 hematologic toxicity after birth (36% neutropenia and 7% anemia)50. Finally, in three Phase I studies o f PIs (saquinavir/ritonavir, indinavir, or nelfinavir) in pregnancy, a total o f 52 infants received 6 weeks o f zidovudine/lamivudine (in 26 infants, zidovudine/lamivudine was combined with nelfinavir); Grade 2 or higher hematologic toxicity was observed in 46% -62% o f infants51-53. In the NICHD-HPTN 040/PACTG 1043 study, signifi cantly higher rates o f Grade 3 or 4 neutropenia were seen with a three-drug regimen including zidovu dine and lamivudine than with zidovudine alone or a two-drug regimen with zidovudine and nevirapine (27.5% vs. 16% and 15%, respectively, P <0.0001)14. In contrast, Grade 3 or 4 anemia occurred in 23% -27% o f infants, with no differences between study arms14.
Experience with other NRTI drugs for neonatal prophylaxis is more limited54-55. Hematologic and mito chondrial toxicity may be more common with exposure to multiple versus single NRTI drugs24, 56-59.
Nevirapine is the only non-nucleoside reverse transcriptase inhibitor (NNRTI) drug with a pediatric drug formulation and neonatal dosing information (see Guidelines for the Use of Antiretroviral Agents in Pedi atric HIV Infection) 60. In rare cases, chronic multiple-dose nevirapine has been associated with severe and potentially life-threatening rash and hepatic toxicity. These toxicities have not been observed in infants re ceiving single-dose nevirapine, the two-drug zidovudine regimen plus three doses of nevirapine in the first week of life in NICHD-HPTN 040/PACTG 1043), or in breastfeeding infants receiving nevirapine prophy laxis daily for 6 weeks to 6 months to prevent transmission of HIV via breast milk8, Dosing for premature infants is available for only zidovudine (see Table 8), making use o f other ARV drugs in this group more problematic. In preterm infants immature renal and hepatic metabolism in creases the risk o f overdosing and toxicity. Because zidovudine is the only ARV drug available in an in travenous formulation, the 6-week zidovudine prophylaxis regimen is recommended for preterm infants at gestational age-appropriate doses. Use o f ARV drugs other than zidovudine cannot be recommended in premature infants because data on dosing and safety are lacking.
Initial Postnatal Management of the HIV-Exposed Neonate (Updated September 14, 2011)
Panel's Recommendations
- A complete blood count (CBC) and differential should be performed on newborns as a baseline evaluation (B III).
- Decisions about the timing of subsequent monitoring of hematologic parameters in infants depend on baseline hemato logic values, gestational age at birth, clinical condition of the infants, the zidovudine dose being administered, receipt of concomitant medications, and maternal antepartum therapy (C III).
- Some experts recommend more intensive monitoring of hematologic and serum chemistry and liver function assays at birth and when diagnostic HIV polymerase chain reaction (PCR) tests are obtained in infants exposed to combination antiretroviral (ARV) drug regimens in utero or during the neonatal period (C III).
- If hematologic abnormalities are identified in infants receiving prophylaxis, decisions on whether to continue infant ARV prophylaxis need to be individualized. Consultation with an expert in pediatric HIV infection is advised if discontinuation of prophylaxis is considered (C III).
- Routine measurement of serum lactate is not recommended. However, measurement can be considered if an infant de velops severe clinical symptoms of unknown etiology (particularly neurologic symptoms) (C III) .
- Virologic tests are required to diagnose HIV infection in infants <18 months of age and should be performed within the first 14-21 days of life, at 1-2 months, and at 4 -6 months of age (A II). A CBC and differential should be performed on HIV-exposed newborns before initiation o f infant ARV drug prophylaxis. Decisions about the timing o f hematologic monitoring o f infants after birth depend on a number of factors, including baseline hematologic values, gestational age at birth, clinical condition of the infants, which ARV drugs are being administered, receipt o f concomitant medications, and maternal antepartum ARV drug regimen. Anemia is the primary complication seen in neonates given the standard 6-week postnatal zidovudine regimen. In PACTG 076, infants in the zidovudine group had lower hemo globin at birth than those in the placebo group, with the maximal difference (1 gm/dL) occurring at age 3 weeks1. The lowest mean value for hemoglobin (10 gm/dL) occurred at age 6 weeks in the zidovudine group. By age 12 weeks, hemoglobin values in both groups were similar. No significant differences in other laboratory parameters were observed between groups.
Some experts recheck hematologic values in healthy infants receiving zidovudine prophylaxis only if symptoms are present. Hematologic safety data are limited on administration o f 4 mg/kg o f zidovudine twice daily in infants. When administering this dosing regimen, some experts recheck hemoglobin and neutrophil counts routinely after 4 weeks o f zidovudine prophylaxis and/or when diagnostic HIV PCR tests are obtained.
In utero exposure to maternal combination ARV drug regimens may be associated with some increase in anemia and/or neutropenia compared with that seen in infants exposed to zidovudine alone2-5. In PACTG 316, where 77% o f mothers received antenatal combination therapy, significant Grade 3 or higher ane mia was noted in 13% and neutropenia in 12% o f infants, respectively. Depending on the combination regimen the mother has received, some experts advise more intensive laboratory monitoring, including serum chemistry and transaminases at birth plus a CBC at the time that diagnostic HIV PCR testing is done; monitoring o f bilirubin levels should be considered for infants exposed antenatally to atazanavir6.
In addition, data are limited on infants receiving zidovudine in combination with other ARVs for pro phylaxis. However, higher rates o f hematologic toxicity have been observed in infants receiving zidovu dine/lamivudine combination prophylaxis compared with those receiving zidovudine alone or zidovudine plus nevirapine7. A recheck o f hemoglobin and neutrophil counts, therefore, is recommended for infants who receive combination zidovudine/lamivudine-containing ARV prophylaxis regimens 4 weeks after initiation of prophylaxis and/or at the time that diagnostic HIV PCR testing is done8.
If hematologic abnormalities are found, decisions on whether to continue infant ARV prophylaxis need to be individualized. Considerations include the extent o f the abnormality, whether related symptoms are present, duration o f infant prophylaxis, risk o f HIV infection (as assessed by the m other's history of ARV prophylaxis, viral load near delivery, and mode o f delivery), and the availability o f alternative in terventions such as erythropoietin and transfusion. Consideration can be given to reducing the duration o f infant prophylaxis from 6 to 4 weeks, as is the case in many European centers. In a recent prospec tive, observational study, the 4-week regimen was found to allow earlier recovery from anemia in other wise healthy infants compared with the 6-week regimen9. Consultation with an expert in pediatric HIV infection is advised if discontinuation of prophylaxis is considered.
Hyperlactatemia has been reported in infants with in utero exposure to ARVs, but it appears to be tran sient and, in most cases, asymptomatic10-11. Routine measurement o f serum lactate is not recommended in asymptomatic neonates to assess for potential mitochondrial toxicity because the clinical relevance is unknown and the predictive value for toxicity appears poor10-11. Serum lactate measurement should be considered, however, for infants who develop severe clinical symptoms o f unknown etiology, particu larly neurologic symptoms. In infants with symptoms, if the levels are significantly abnormal (>5 mmol/L), ARV prophylaxis should be discontinued and an expert in pediatric HIV infection should be consulted regarding potential alternate prophylaxis.
To prevent PCP, all infants born to women with HIV infection should begin trimethoprim-sulfamethoxa zole (TMP-SMX) prophylaxis at age 6 weeks, after completion o f the infant ARV prophylaxis regimen, unless there is adequate virologic test information to presumptively exclude HIV infection (see USPHS/IDSA Guidelines for the Prevention and Treatment o f Opportunistic Infections in HIV-Exposed and Infected Children)12.
HIV infection in infants should be diagnosed using HIV DNA PCR or RNA virologic assays. Maternal HIV antibody crosses the placenta and will be detectable in all HIV-exposed infants up to age 18 months; therefore, standard antibody tests should not be used for HIV diagnosis in newborns. HIV viro logic testing should be performed within the first 14-21 days o f life, at 1-2 months, and at 4 -6 months o f age13. Some experts also perform a virologic test at birth, especially in women who have not had good virologic control during pregnancy or if adequate follow-up o f the infant may not be assured. A positive HIV virologic test should be confirmed as soon as possible with a second HIV virologic test on a differ ent specimen. Two positive HIV tests constitute a diagnosis o f HIV infection. Data do not indicate any delay in HIV diagnosis with HIV DNA PCR assays in infants who have received the zidovudine regi men1,14. However, the effect o f maternal or infant exposure to combination ARV drug regimens on the sensitivity o f infant virologic diagnostic testing-particularly using HIV RNA assays-is unknown. Therefore, although HIV RNA assays may be acceptable for diagnosis (particularly in older infants), HIV DNA PCR assays may be optimal for diagnosing infection in the neonatal period. Any newly diag nosed infant should undergo viral resistance testing by genotype and/or phenotype to assess for suscepti bility to combination ART.
HIV may be presumptively excluded with two or more negative tests, one at age 14 days or older and the other at age 1 month or older.

# Infant Feeding Practices and R isk o f H IV Transmission
In the United States, where safe infant feeding alternatives are available and free for women in need, HIV-infected women should not breastfeed their infants. Maternal receipt o f combination ARV regimens is likely to reduce free virus in the breast milk, but the presence o f cell-associated virus (intracellular HIV DNA) remains unaffected and, therefore, may continue to pose a transmission risk15.
Late HIV transmission events in infancy have recently been reported among three HIV-infected children suspected to have acquired HIV infection as a result o f consuming premasticated food given to them by their caregivers. Phylogenetic comparisons o f virus from cases and suspected sources and supporting clinical history and investigations identified the practice o f feeding premasticated foods to infants as a potential risk factor for HIV transmission. Health care providers should routinely inquire about this feed ing practice and instruct HIV-infected caregivers on safer feeding options16.
Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants (Updated September 14, 2011)

# Panel's Recommendations
- Children with in utero/neonatal exposure to antiretroviral (ARV) drugs who develop significant organ system abnormali ties of unknown etiology, particularly of the nervous system or heart, should be evaluated for potential mitochondrial dysfunction (C III).
- Follow-up of children with exposure to ARVs should continue into adulthood because of the theoretical concerns regard ing the potential for carcinogenicity of nucleoside analogue ARV drugs (C III).
Data remain insufficient to address the effect that exposure to zidovudine or other ARV agents in utero might have on long-term risk of neoplasia or organ system toxicities in children. Data from follow-up of PACTG 076 infants through age 6 years do not indicate any differences in immunologic, neurologic, and growth pa rameters between infants who were exposed to the zidovudine regimen and those who received placebo, and no malignancies have been seen1-3. As discussed earlier in NRTI Drugs and Mitochondrial Toxicity, data are conflicting regarding whether mitochondrial dysfunction is associated with perinatal exposure to ARVs. Mi tochondrial dysfunction should be considered in uninfected children with perinatal exposure to ARVs who present with severe clinical findings of unknown etiology, particularly neurologic findings.
Evaluation is ongoing o f early and late effects o f in utero exposure to ARVs, including the Pediatric HIV/AIDS Cohort Study (PHACS), Surveillance Monitoring o f Antiretroviral Toxicity Study, natural his tory studies, and HIV/AIDS surveillance conducted by state health departments and the Centers for Dis ease Control and Prevention (CDC). Because most o f the available follow-up data relate to in utero exposure to antenatal zidovudine alone and most pregnant women with HIV infection currently receive combination ARV drug regimens, it is critical that studies to evaluate potential adverse effects o f in utero drug exposure continue to be supported.
Innovative methods are needed to provide follow-up o f infants with in utero exposure to ARV drugs. In formation regarding such exposure should be part o f ongoing permanent medical records for children, particularly those who are uninfected. Children with in utero exposure to ARVs who develop significant organ system abnormalities o f unknown etiology, particularly o f the nervous system or heart, should be evaluated for potential mitochondrial dysfunction4-6. Follow-up o f children with exposure to ARVs should continue into adulthood because o f the theoretical concerns regarding the potential for carcinogenicity of the nucleoside analogue ARV drugs. Long-term follow-up should include annual physical examinations o f all children exposed to ARV drugs.
HIV surveillance databases from states that require HIV reporting provide an opportunity to collect popu lation-based information concerning in utero exposure to ARVs. To the extent permitted by federal law and regulations, data from these confidential registries can be compared with information from birth de fect and cancer registries to identify potential adverse outcomes.
with abacavir during organogenesis at doses o f 1,000 mg/kg (about 35 times that o f human therapeu tic exposure based on area under the curve ). Toxicity to the developing embryo and fetus (in creased resorptions and decreased fetal body weight) occurred with abacavir administration o f 500 mg/kg/day to pregnant rodents. The offspring of female rats were treated with 500 mg/kg o f aba cavir, beginning at embryo implantation and ending at weaning. In these animals, an increased inci dence o f stillbirth and lower body weight was seen throughout life. However, in the rabbit, no evidence of drug-related developmental toxicity was observed and no increase in fetal malformations was observed at doses up to 700 mg/kg (about 8.5 times that o f human therapeutic exposure).
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to abacavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with abacavir. Among cases o f first trimester abacavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 3.0% (22 of 744 births; 95% confidence interval , 1.9%-4.5%) compared with 2.7% in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance1.
- Placental and breast m ilk passage
Abacavir crosses the placenta and is excreted into the breast milk o f lactating rats.
- Hum an studies in pregnancy
A Phase I study of abacavir in pregnant women indicates that the AUC drug concentration during preg nancy was similar to that at 6-12 weeks postpartum and in nonpregnant individuals2. Thus, no dose ad justment for abacavir is needed during pregnancy. Serious hypersensitivity reactions have been associated with abacavir therapy in nonpregnant adults and have rarely been fatal; symptoms include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdomi nal pain. Abacavir should not be restarted following a hypersensitivity reaction because more severe symptoms will occur within hours and may include life-threatening hypotension and death.
weight gains; however, the physical and functional development o f the offspring was not impaired and there were no major changes in the F2 generation.
- Teratogenicity/developm ental toxicity
No evidence o f teratogenicity or toxicity was observed with administration o f didanosine at 12 and 14 times human exposure, respectively, in pregnant rats and rabbits. Among cases o f first-trimester didanosine exposure reported to the Antiretroviral Pregnancy Registry, prevalence o f birth defects was 4.7% (19 o f 406 births; 95% CI, 2.8%-7.2%) compared with 2.7% in the U.S. population, based on CDC surveillance1. All defects were reviewed in detail by the Registry, and no pattern o f defects was discovered. The rate and types o f defects will continue to be closely monitored.

# Placental and breast m ilk passage
Placental transfer o f didanosine was limited in a Phase I/II safety and pharmacokinetic (PK) study2. This was confirmed in a study o f 100 HIV-infected pregnant women who were receiving NRTIs (generally as part of a two-or three-drug combination antiretroviral  regimen). At the time of delivery, cord-to-maternal blood ratio for didanosine (n = 10) was 0.38 (range 0.0-2.0) and in 15 of 24 (62%) samples, cord blood concentrations for didanosine were below the limits o f detection3. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. It is not known if didanosine is excreted in human breast milk.
- Hum an studies in pregnancy
A Phase I study (PACTG 249) of didanosine was conducted in 14 HIV-infected pregnant women en rolled at gestational age 26-36 weeks and treated through 6 weeks postpartum2. The drug was well tolerated during pregnancy by the women and the fetuses. PK parameters after oral administration were not significantly affected by pregnancy, and dose modification from the usual adult dosage is not needed.
Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combina tion of didanosine and stavudine along with other ARV agents4-6; the FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see NRTI Drugs and Mitochondrial Toxicity in perinatal guidelines). These two drugs should be prescribed together to pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nu cleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects.
Chemother.  Emtricitabine (Emtriva, FTC) is classified as FDA pregnancy category B.

# A nim al carcinogenicity studies
Emtricitabine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screen ing tests. In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 26 times the human systemic exposure at a thera peutic dose o f 200 mg/day or in rats at doses up to 31 times the human systemic exposure at the ther apeutic dose.

# Reproduction/fertility
No effect o f emtricitabine on reproduction or fertility was observed with doses that produced sys temic drug exposures (as measured by AUC) approximately 60-fold higher in female mice and 140 fold higher in male mice than observed with human exposure at the recommended therapeutic dose.
- Teratogenicity/developm ental toxicity
Incidence o f fetal variations and malformations was not increased with emtricitabine dosing in mice that resulted in systemic drug exposure 60-fold higher than observed with human exposure at recom mended doses or in rabbits with dosing resulting in drug exposure 120-fold higher than human expo sure.
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to emtric itabine in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with emtricitabine. Among cases of first-trimester emtricitabine exposure reported to the Antiretroviral Pregnancy Registry, the preva lence o f birth defects was 2.7% (17 o f 641 births; 95% CI, 1.7%-4.8%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1.
- Placental and breast m ilk passage Emtricitabine has been shown to cross the placenta in mice and rabbits; the average fetal/maternal drug concentration was 0.4 in mice and 0.5 in rabbits2. Emtricitabine has been shown to have good placental transfer in pregnant women. In 18 women who received 200 mg emtricitabine daily during pregnancy, mean cord blood concentration was 300  268 ng/mL and mean ratios o f cord blood/ma ternal emtricitabine concentrations were 1.17  0.6 (n = 9)3. When 35 women were administered 400 mg o f emtricitabine in combination with tenofovir at delivery, median maternal and cord concentra tions were 1.02 (0.034-2.04) and 0.74 (0.0005-1.46) mg/L, respectively4. It is unknown if emtric itabine is excreted in human milk.
- Hum an studies in pregnancy Emtricitabine PKs have been evaluated in 18 HIV-infected pregnant women receiving combination antiretroviral therapy (ART) including emtricitabine (200 mg once daily) at 30-36 weeks gestation and 6-12 weeks postpartum3. Emtricitabine exposure was modestly lower during the third trimester (8.6 p,g*h/mL ) compared with the postpartum period (9.8 p,g*h/mL ). Twothirds (12 o f 18) o f pregnant women versus 100% (14 o f 14) o f postpartum women met the AUC tar get (10th percentile in nonpregnant adults). Trough emtricitabine levels were also lower during pregnancy (minimum plasma concentration  52 ng/mL ) compared with the postpar tum period (86 ng/mL ). In another study o f 35 women who received 400 mg o f emtric itabine with tenofovir at delivery, median population AUC, maximum plasma concentration (Cmax), and Cmin were 14.3 p,g*h/mL, 1,680 ng/mL, and 76 ng/mL, respectively4. Currently, data are insuffi cient to recommend a dosage adjustment during pregnancy.
dine in humans have been monitored to detect at least a 1.5-fold increase in risk o f overall birth de fects and a 2-fold increase in the most commonly occurring birth defects, such as defects o f the car diovascular and genitourinary systems. No such increase in birth defects has been observed with lamivudine. Among cases o f first-trimester lamivudine exposure reported to the Antiretroviral Preg nancy Registry, the prevalence o f birth defects was 3.1% (118 o f 3,864 births, 95% CI, 2.5%-3.7%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1.
- Placental and breast m ilk passage
Lamivudine readily crosses the placenta in humans, achieving comparable cord blood and maternal concentrations2. Lamivudine is excreted into human breast milk. In a study in Kenya o f 67 HIV-in fected nursing mothers receiving a combination regimen o f zidovudine, lamivudine, and nevirapine, the median breast milk lamivudine concentration was 1,214 ng/mL and the median ratio o f lamivu dine concentration in breast milk to that in plasma was 2.563. In infants who received lamivudine only via breast milk, median plasma lamivudine concentration was 23 ng/mL (half-maximal in hibitory concentration  o f wild-type HIV against lamivudine = 0.6-21 ng/mL).
- Hum an studies in pregnancy
A small Phase I study in South Africa evaluated the safety and PKs of lamivudine alone or in combina tion with zidovudine in 20 HIV-infected pregnant women; therapy was started at 38 weeks' gestation, continued through labor, and given to the infants for 1 week following birth2. The drug was well toler ated in the women at the recommended adult dose of 150 mg orally twice daily; PKs were similar to those observed in nonpregnant adults, and no PK interaction with zidovudine was observed.
Intrapartum oral administration of combination zidovudine and lamivudine was well tolerated. Lamivudine was well tolerated in the neonates, but clearance was about 50% that o f older children, requiring a reduced dosing regimen (4 mg/kg/day in neonates compared with 8 mg/kg/day for infants older than 3 months). No data currently exist on the PKs o f lamivudine in infants 2 -6 weeks o f age, and the exact age at which lamivudine clearance begins to approximate that in older children is un known.
carcinogenicity studies in mice and rats, stavudine was noncarcinogenic in doses producing expo sures 39 (mice) and 168 (rats) times human exposure at the recommended therapeutic dose. At higher levels o f exposure (250  and 732  times human exposure at therapeutic doses), be nign and malignant liver tumors occurred in mice and rats and urinary bladder tumors occurred in male rats.
- Reproduction/fertility
Stavudine has not been shown to have an effect on reproduction or fertility in rodents. A dose-related cytotoxic effect has been observed on preimplantation mouse embryos, with inhibition o f blastocyst formation at a concentration o f 100 pM and o f postblastocyst development at 10 pM 1.
- Teratogenicity/developm ental toxicity studies
No evidence o f teratogenicity was noted in rats or rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, o f that seen at a clinical dosage o f 1 mg/kg/day. In rat fetuses, the inci dence o f a common skeletal variation-unossified or incomplete ossification o f sternebra-was in creased with 399 times human exposure, although no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times human exposure, with no effect noted at approximately 135 times human exposure. An increase in early rat neonatal mortality (birth-Day 4) occurred at 399 times human exposure, although survival o f neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma.
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to stavudine in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with stavudine. Among cases o f first trimester stavudine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.4% (19 o f 797 births; 95% CI, 1.4%-3.7%) compared with a total prevalence in the U.S. population o f 2.7%, based on CDC surveillance2.

# Placental and breast m ilk passage
Stavudine crosses the rat placenta in vivo and the human placenta ex vivo, resulting in a fetal/mater nal concentration o f approximately 0.50. In primates (pigtailed macaques), fetal/maternal plasma concentrations were approximately 0.803. Stavudine is excreted into the breast milk o f lactating rats.
- Hum an studies in pregnancy A Phase I/II safety and PK study has been conducted o f combination stavudine and lamivudine in pregnant HIV-infected women and their infants (PACTG 332). Both drugs were well tolerated, with stavudine PKs similar to those in nonpregnant adults4. Data from primate studies also indicated that pregnancy did not affect the PKs o f stavudine5.
Lactic acidosis, in some cases fatal, has been described in pregnant women receiving the combina tion of didanosine and stavudine along with other ARV agents6-8. The FDA and Bristol-Myers Squibb have issued a warning to health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed didanosine and stavudine in combination (see NRTI Drugs and Mitochondrial Toxicity in the perinatal guidelines). These drugs should be prescribed together for pregnant women only when the potential benefit clearly outweighs the potential risk. Clinicians should prescribe this ARV combination in pregnancy with caution and generally only when other nu cleoside analog drug combinations have failed or have caused unacceptable toxicity or side effects.
Tenofovir disoproxil fumarate (Viread, TDF) is classified as FDA pregnancy category B.

# A nim al carcinogenicity studies
Tenofovir is mutagenic in one o f two in vitro assays and has no evidence o f clastogenic activity. Long-term oral carcinogenicity studies o f tenofovir DF in mice and rats were carried out at 16 times (mice) and 5 times (rats) human exposure. In female mice, liver adenomas were increased at expo sures 16 times that observed in humans at therapeutic doses. In rats, the study was negative for car cinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

# Reproduction/fertility
Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence o f impaired fertility or harm to the fetus due to tenofovir. There were also no effects on fertility, mating performance, or early embryonic development when tenofovir DF was administered to male rats (600 mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days prior to mating and to female rats for 15 days prior to mating through Day 7 o f gestation. There was, however, an alter ation o f the estrous cycle in female rats administered 600 mg/kg/day.
- Teratogenicity/developm ental toxicity Chronic exposure of fetal monkeys to tenofovir at a high dose of 30 mg/kg (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) from Days 20-150 of gestation did not re sult in gross structural abnormalities1. However, significantly lower fetal circulating insulin-like growth factor-1 (a primary regulator of linear growth) and higher insulin-like growth factor binding protein-3 levels were shown and were associated with overall body weights approximately 13% lower than un treated controls. A slight reduction in fetal bone porosity was also observed. Effects on these parameters were observed within 2 months of maternal treatment. Significant changes in maternal monkey bone biomarkers were noted but were primarily limited to the treatment period and were reversible.
Continued administration o f tenofovir at 30 mg/kg/day to infant monkeys resulted in significant growth restriction and severe bone toxicity in 2 o f 8 (25%) infants and effects on bone biomarkers and defective bone mineralization in all animals. Chronic administration o f tenofovir to immature animals o f multiple species has resulted in reversible bone abnormalities; these effects were dose, exposure, age, and species specific. Abnormalities ranged from minimal decrease in bone mineral density and content (with oral dosing in rats and dogs that achieved drug exposures 6-10 times that achieved with therapeutic dosing in humans) to severe, pathologic osteomalacia (with subcutaneous dosing given to monkeys). Juvenile monkeys given chronic subcutaneous tenofovir at 30 mg/kg/day (exposure equivalent to 25 times the AUC achieved with therapeutic dosing in humans) developed osteomalacia, bone fractures, and marked hypophosphatemia. However, no clinical or radiologic bone toxicity was seen when juvenile monkeys received subcutaneous dosing o f 10 mg/kg/day (ex posure equivalent to 8 times the AUC achieved with therapeutic dosing in humans). Evidence of nephrotoxicity was observed in newborn and juvenile monkeys given tenofovir in doses resulting in exposures 12-50 times higher than the human dose, based on body surface area comparisons.
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to tenofovir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with tenofovir. Among cases o f first trimester tenofovir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.4% (26 o f 1,092 births, 95% CI, 1.6%-3.5%) compared with a 2.7% total preva lence in the U.S. population, based on CDC surveillance2.

# Placental and breast m ilk passage
Studies in rats have demonstrated that tenofovir is secreted in milk. Intravenous administration of teno fovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%, demonstrat ing that tenofovir does cross the placenta3. In 3 studies of pregnant women on chronic dosing, the cord-to-maternal blood ratio ranged from 0.60 to 0.99, indicating high placental transfer4-6. In 2 studies of single-dose tenofovir (in some cases with emtricitabine) in labor that included 82 mother-infant pairs, the drugs were well tolerated and cord-to-maternal blood ratios were 0.61-0.677-9.
Among women receiving a single 600-mg dose during labor, tenofovir was detectable in only 4 o f 25 (16%) breast milk samples during the first week after delivery, with a median concentration o f 13 (range 6-18) ng/mL9. In another study, 16 breast milk samples were obtained from 5 women who re ceived 600 mg o f tenofovir at the start of labor followed by 300 mg daily for 7 days. Tenofovir lev els in breast milk ranged from 5.8 to 16.3 ng/mL, and nursing infants received an estimated 0.03% of the proposed oral dose o f tenofovir for neonates10.
- H um an studies in pregnancy
In study P1026s, tenofovir PKs were evaluated in 19 pregnant women receiving tenofovir-based combination therapy at 30-36 weeks' gestation and 6-12 weeks postpartum4. The percentage of women with tenofovir AUC exceeding the target o f 2 p,g*hour/mL (the 10th percentile in nonpreg nant adults) was lower in the third trimester (74%, 14 o f 19 women) than postpartum (86%, 12 o f 14 women) (P = 0.02); however, trough levels were similar in the two groups.
A recent case series found tenofovir to be well tolerated among 76 pregnant women, with only 2 stopping therapy, 1 for rash and the other for nausea. All 78 infants were healthy with no signs of toxicity, and all were HIV uninfected11. A follow-up study o f 20 o f the tenofovir-exposed infants and 20 controls found no differences between the groups in renal function, including cystatin C levels, through 2 years o f age12. A retrospective review o f 16 pregnancy outcomes among 15 heavily ARV experienced women demonstrated that tenofovir was well tolerated by the women and associated with normal growth and development in the infants13. Zalcitabine (HIVID, ddC) is no longer available in the United States.
Zidovudine (Retrovir, AZT, ZDV) is classified as FDA pregnancy category C.

# A nim al carcinogenicity studies
Zidovudine was shown to be mutagenic in two in vitro assays and clastogenic in one in vitro and two in vivo assays, but not cytogenic in a single-dose in vivo rat study. Long-term carcinogenicity studies have been performed with zidovudine in mice and rats1. In mice, seven late-appearing (>19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell pa pilloma occurred in the vagina o f an animal given an intermediate dose. No vaginal tumors were found at the lowest dose. In rats, two late-appearing (>20 months), nonmetastasizing vaginal squa mous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex in either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose o f 100 mg every 4 hours. How predictive the results o f rodent car cinogenicity studies may be for humans is unknown.
Two transplacental carcinogenicity studies were conducted in mice2-3. In one study, zidovudine was ad ministered at doses of 20 mg/kg/day or 40 mg/kg/day from gestation Day 10 through parturition and lactation, with postnatal dosing continuing in offspring for 24 months3. The drug doses administered in this study produced zidovudine exposures approximately 3 times the estimated human exposure at rec ommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no in crease in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. In a second study, zidovudine was administered at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1,000 mg/kg nonpregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from Days 12-18 of gestation2. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.

# Reproduction/fertility
When administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, zidovudine had no effect on fertility, as judged by rates o f conception.
Zidovudine has been shown to have no effect on reproduction or fertility in rodents. A dose-related cytotoxic effect on preimplantation mouse embryos can occur, with inhibition o f blastocyst and post blastocyst development at zidovudine concentrations similar to levels achieved with human thera peutic doses4.
- Teratogenicity/developm ental toxicity
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity, as evi denced by an increase in the incidence o f fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half o f the daily dose) in rats 66-226 times, and in rabbits 12-87 times, mean steady-state peak human plasma concentrations (after one-sixth o f the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose o f 3,000 mg/kg/day (very near the oral median lethal dose in rats o f 3,683 mg/kg) caused marked maternal toxicity and an increase in the in cidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence o f teratogenicity was seen in this experi ment at doses of 600 mg/kg/day or less.
Increased fetal resorption occurred in pregnant rats and rabbits treated with zidovudine doses that pro duced drug plasma concentrations 66-226 times (rats) and 12-87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100-mg dose of zidovudine. No other develop mental anomalies were reported. In another developmental toxicity study, pregnant rats received zi dovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily AUC in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. How ever, there were no signs of teratogenicity at doses up to one-fifth the lethal dose.
In humans, in the placebo-controlled perinatal trial PACTG 076, the incidence o f minor and major congenital abnormalities was similar between zidovudine and placebo groups and no specific pat terns of defects were seen5-6. A report from the Women and Infants Transmission Study (WITS), a cohort study enrolling women during pregnancy, described an association between first-trimester ex posure to zidovudine and a 10-fold increased risk o f hypospadias7. However, in the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to zidovudine have been moni tored to be able to detect at least a 1.5-fold increase in risk o f overall birth defects and a 2-fold in crease in defects in the more common classes, defects o f the cardiovascular and genitourinary systems. No such increase in birth defects has been observed with zidovudine. With first-trimester zidovudine exposure, the prevalence o f birth defects was 3.3% (118 o f 3,620 births, 95% CI, 2.7% -3.9%) compared with a total prevalence in the U.S. population o f 2.7%, based on CDC surveillance8.

# Placental and breast m ilk passage
Zidovudine rapidly crosses the human placenta, achieving cord-to-maternal blood ratios o f about 0.80. Zidovudine is excreted into human breast milk. In one study in Kenya in 67 mothers receiving a combination regimen o f zidovudine, lamivudine, and nevirapine, zidovudine concentration in the breast milk o f mothers averaged 9 ng/mL and the ratio o f breast milk to maternal plasma zidovudine concentration averaged 44%9. No zidovudine was detectable in the plasma o f the nursing infants, who received zidovudine only via breast milk.

# H um an studies in pregnancy
Zidovudine is well tolerated in pregnancy at recommended adult doses and in the full-term neonate at 2 mg/kg body weight orally every 6 hours5, 10. Long-term data on the safety o f in utero drug expo sure in humans are not available for any ARV drug; however, short-term data on the safety o f zi dovudine are reassuring. In PACTG 076, no difference in disease progression was seen between women who received zidovudine and those who received placebo, based on follow-up through 4 years postpartum11. Additionally, no differences in immunologic, neurologic, or growth parameters were seen between infants with in utero zidovudine exposure and those who received placebo, based on nearly 6 years of follow up6, 12.
Non-Nucleoside Reverse Transcriptase Inhibitors (Updated September 14, 2011)

# Glossary of Terms for Supplement
Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes:
- Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.
- Genetic mutations and/or chromosomal damage can contribute to cancer formation.
Five non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) currently are approved (delavirdine is no longer available in the United States). Nevirapine and efavirenz have been studied in human pregnancy. No adequate and well-controlled studies o f etravirine or rilpivirine use in pregnant women have been conducted.
For information about potential interactions between NNRTIs and methergine, see Postpartum Hemor rhage. Antiretroviral Drugs, and Methergine Use in the perinatal guidelines. For more information regard ing nevirapine hepatic/rash toxicity. see Nevirapine and Hepatic/Rash Toxicity in the perinatal guidelines.
Delavirdine (Rescriptor, DLV) is no longer available in the United States.
Efavirenz (Sustiva, EFV) is classified as FDA pregnancy category D.

# A nim al carcinogenicity studies
Efavirenz was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies with efavirenz have been completed in mice and rats. A t systemic drug exposures approximately 1.7-fold higher than in humans receiving standard therapeutic doses. no increase in tumor incidence above background was observed in male mice. but in female mice. an increase above background was seen in hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas. No increase in tumor incidence above background was observed in male and female rats with systemic drug exposures lower than that in humans re ceiving therapeutic doses.

# R eproduction/fertility anim al studies
No effect o f efavirenz on reproduction or fertility in rodents has been seen.
- Teratogenicity/developm ental toxicity An increase in fetal resorption was observed in rats at efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values in female rats equivalent to or lower than those achieved in humans at the recommended human dose (600 mg once daily). Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma con-centrations similar to and AUC values approximately half o f those achieved in humans administered efavirenz (600 mg once daily). Central nervous system (CNS) malformations were observed in 3 of 20 infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational Days 20-150 at a dose o f 30 mg/kg twice daily (resulting in plasma concentrations comparable to systemic human therapeutic exposure)1. The malformations included anencephaly and unilateral anophthalmia in 1 fetus, microphthalmia in another fetus, and cleft palate in a third fetus.
In pregnancies with prospectively reported exposure to efavirenz-based regimens in the Antiretrovi ral Pregnancy Registry through January 2011, birth defects were observed in 17 o f 623 live births with first-trimester exposure (2.7%, 95% confidence interval , 1.6%-4.3%). Although these data provide sufficient numbers of first-trimester exposures to rule out a 2-fold or greater increase in the risk o f overall birth defects, the low incidence o f neural tube defects in the general population means that a larger number o f exposures are still needed to be able to definitively rule out an increased risk of this specific defect. Prospective reports to the Antiretroviral Pregnancy Registry o f defects after first-trimester efavirenz exposure have documented 1 neural tube defect case (sacral aplasia, myelomeningocele, and hydrocephalus with fetal alcohol syndrome) and 1 case o f bilateral facial clefts, anophthalmia, and amniotic band2. Among retrospective cases, there are 6 reports o f CNS de fects, including 3 cases o f meningomyelocele in infants born to mothers receiving efavirenz during the first trimester3. Although a causal relationship has not been established between these events and the use o f efavirenz, similar defects have been observed in preclinical studies o f the drug.

# Placental and breast m ilk passage
Efavirenz crosses the placenta in rats, rabbits, and primates, producing cord blood concentrations similar to concentrations in maternal plasma. In a study o f 13 women in Rwanda, efavirenz was given during the last trimester o f pregnancy and for 6 months after delivery4. Efavirenz concentra tions were measured in maternal plasma, breast milk, and infant plasma. Efavirenz passed into breast milk with a ratio o f 0.54 (mean breast milk to mean maternal plasma concentration) and 4.08 (mean skim milk to mean newborn plasma concentration). Mean infant plasma efavirenz concentrations were 13.1% o f maternal plasma levels. No data currently are available about efavirenz in neonates.
- Hum an studies in pregnancy However, the number of reported first-trimester efavirenz exposures still remains insufficient to rule out a significant increase in low-incidence birth defects (0.1-0.4% incidence o f neural tube defect in the general population).
Efavirenz is classified as FDA Pregnancy Category D and may cause fetal harm when administered to a pregnant woman during the first trimester. Because of the potential for teratogenicity, pregnancy should be avoided in women receiving efavirenz, and treatment with efavirenz should be avoided during the first trimester, which is the primary period of fetal organogenesis. Women of childbearing age should undergo pregnancy testing prior to initiation of efavirenz and should be counseled about the potential risk to the fetus and the need to avoid pregnancy. Higher rates of failure for hormonal contraceptives containing estrogen and progesterone may be associated with antiretroviral (ARV) drugs such as efavirenz. Alternate ARV regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contra ception. Barrier contraception should always be used in combination with other methods of contracep tion such as hormonal contraceptives and intrauterine devices. A study evaluating the interaction between efavirenz and depot medroxyprogesetrone (DMPA) in 17 women found no change in the phar macokinetic (PK) profile of either efavirenz or DMPA with concomitant use8. DMPA levels remained above the level needed for inhibition of ovulation throughout the dosing interval.
Limited PK data exist for efavirenz in pregnancy. In a study o f 25 pregnant women receiving efavirenz during the third trimester as part o f clinical care, efavirenz clearance was increased and C24h was decreased compared with postpartum. These differences are not o f sufficient magnitude to warrant dose adjustment during pregnancy9.
Nevirapine (Viramune, NVP) is c la s s ifie d as F D A p r e g n a n c y c a t e g o r y B .

# A nim al carcinogenicity studies
Nevirapine showed no evidence o f mutagenic or clastogenic activity in a battery o f in vitro and in vivo studies. Hepatocellular adenomas and carcinomas were increased at all doses in male mice and rats and at higher doses in female mice and rats. Systemic exposure at all doses studied was lower than systemic exposure in humans receiving therapeutic nevirapine doses. Given the lack o f genotoxic activity of nevirapine, the relevance to humans o f hepatocellular neoplasms in nevirapinetreated mice and rats is not known.

# Reproduction/fertility
Evidence o f impaired fertility was seen in female rats at nevirapine doses providing systemic expo sure comparable to human therapeutic exposure.
- Teratogenicity/developm ental toxicity Teratogenic effects o f nevirapine have not been observed in reproductive studies with rats and rab bits at systemic exposures approximately equivalent to or 50% greater than the recommended human dose (based on AUC). In rats, however, a significant decrease in fetal weight occurred at doses pro ducing systemic concentrations approximately 50% higher than human therapeutic exposure.
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to nevirapine in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth de fects. No such increase in birth defects has been observed with nevirapine. Among cases of first trimester nevirapine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.5% (25 of 987 births, 95% CI, 1.6%-3.7 %) compared with a total prevalence of 2.7% in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance1.

# Placental and breast m ilk passage
Nevirapine crosses the placenta and achieves neonatal blood concentrations equivalent to that in the mother (cord-to-maternal blood ratio approximately 0.90)2. Nevirapine is excreted into human breast milk; the median concentration in 4 breast milk samples obtained from 3 women during the first week after delivery was approximately 76% (range 54%-104%) o f serum levels2. In 19 women re ceiving combination therapy with nevirapine, lamivudine, and zidovudine, breast milk nevirapine concentration was 6,795 ng/mL, which was 0.67 times that o f maternal serum3. Median nevirapine breast milk concentration was 4,564 ng/mL in a Kenyan study o f 67 HIV-infected nursing mothers receiving a combination o f zidovudine, lamivudine, and nevirapine3. The median nevirapine concen tration was 734 ng/mL in the infants, who received the drug only via breast milk.
- Hum an studies in pregnancy

# Short-Term Peripartum Prophylaxis:
A Phase I study (PACTG 250) evaluated the safety and PKs o f nevirapine administered to infected pregnant women as a single 200-mg dose at the onset o f labor and as a single 2-mg/kg dose to in fants 48-72 hours o f age2. No adverse effects were seen in the women or the infants.
The PK parameters o f intrapartum nevirapine were similar in pregnant women and in nonpregnant adults, but variability was increased during pregnancy, possibly as a result o f incomplete drug ab sorption associated with impaired gastrointestinal function during labor. Nevirapine elimination was prolonged in the infants. The regimen maintained serum concentrations associated with antiviral ac tivity in the infants for the first week o f life.
The safety, toxicity, and PKs o f nevirapine were also studied in HIV-infected pregnant women begin ning chronic therapy late in the third trimester and their infants4. Initial-dose PK profiles in pregnant women were similar to those seen in nonpregnant adults. Serum nevirapine concentrations fell below the 100 ng/mL target concentration by Day 7 o f life in four o f eight infants, suggesting that nevirap ine elimination was accelerated in infants whose mother received chronic nevirapine administration compared with newborns whose mothers received only a single intrapartum dose.
The HIVNET 012 study in Uganda compared nevirapine (200 mg orally to the mother at the onset of labor and 2 mg/kg to the neonate within 72 hours o f birth) with zidovudine (600 mg orally to the mother at the onset o f delivery and 300 mg every 3 hours until delivery, and 4 mg/kg orally twice daily for the first 7 days o f life to the neonate). In this study, nevirapine lowered the risk o f transmis sion o f HIV by nearly 50% during the first 14-16 weeks o f life compared with zidovudine5. How ever, the women in this African trial were not receiving any other ARV drugs.
In the United States, most infected women who know their HIV status during pregnancy receive combination ARV prophylaxis regimens, usually including zidovudine, as well as intravenous zi dovudine during delivery, with 6 weeks o f zidovudine given to their infants. A Phase III perinatal trial (PACTG 316) conducted in the United States, Europe, the Bahamas, and Brazil evaluated whether the HIVNET 012 single-dose nevirapine regimen in combination with standard combination prophylaxis regimens (at minimum the PACTG 076 zidovudine regimen; 77% o f women in the trial received combination ARV regimens) would provide additional benefits in reducing transmission. Transmission was not significantly different between those who received single-dose nevirapine (1.4%) and those who did not (1.6%)6.
Nevirapine resistance can be induced by a single mutation. As a result o f its long half-life, the drug can be detected in plasma up to 3 weeks after administration o f a single intrapartum dose7. This pe riod o f persistent subtherapeutic drug levels exerts selective pressure that predisposes to the develop ment o f resistant strains o f HIV8. Nevirapine resistance mutations were detected at 6 weeks postpartum in 19% o f ARV-naive women in HIVNET 012 and 15% o f a subset o f women receiving additional ARV drugs during pregnancy in PACTG 316 who received single-dose nevirapine during labor9-10. In HIVNET 012, these mutations were no longer detectable in plasma virus in women at 13-18 months postpartum11. Evaluation at later time points was not done in PACTG 316. Single dose nevirapine appears to be as effective in preventing HIV transmission in subsequent pregnancies as when it is used for the first time12-13. Current data suggest that women starting NNRTI-based ther apy within 12-24 months o f single-dose nevirapine exposure have higher rates o f viral failure than those without single-dose nevirapine exposure and that use o f a protease inhibitor (PI)-based regi men (such as lopinavir/ritonavir) would be recommended in such situations14-16. Administration of postpartum ARVs to the mother can significantly reduce the frequency o f detection o f nevirapine-re sistant strains8, 17-22.

# Longer Term Antenatal Combination Therapy:
The PKs of nevirapine have been evaluated in pregnant women receiving nevirapine as part o f com bination ART during pregnancy. A study that determined nevirapine PKs in 26 women during preg nancy (7 second trimester, 19 third trimester) and again in the same women 4-12 weeks after delivery found that pregnancy did not alter nevirapine PK parameters23. In contrast, nevirapine clear ance was 20% greater, AUC was 28% lower, and maximum plasma concentration (Cmax) was 30% lower in 16 pregnant women compared with 13 nonpregnant women, based on nevirapine PK data from a therapeutic drug monitoring program that included 12-hour sampling24.
Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hep atitis, hepatic necrosis, and hepatic failure and severe, life-threatening hypersensitivity skin reactions, including Stevens-Johnson syndrome, have been reported in HIV-infected patients receiving nevirapine in combination with other drugs for treatment of HIV disease and in a small number of individuals re ceiving nevirapine as part of a combination regimen for post-exposure prophylaxis of nosocomial or sexual exposure to HIV25. These toxicities have not been reported in women or infants receiving twodose nevirapine (the HIVNET 012 regimen) for prevention of perinatal transmission. The greatest risk of severe rash or hepatic events occurs during the first 6-18 weeks of therapy, although the risk of toxi city continues past this period and monitoring should continue at frequent intervals.
Incidence o f severe nevirapine-associated skin rash has been reported to be 5.5-7.3 times more com mon in women than men and has been reported in pregnant women26-28. Other studies have found that hepatic adverse events with systemic symptoms (often rash) were 3.2-fold more common in women than men29. Several studies suggest that the degree o f risk o f hepatic toxicity varies with CD4 cell count. In a summary analysis o f data from 17 clinical trials o f nevirapine therapy, women with CD4 counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4 counts to experience symptomatic, often rash-associated, nevirapine-related hepatotoxicity29. Higher CD4 cell counts have also been associated with increased risk o f severe nevirapine-associated skin rash27.
Rates o f hepatotoxicity and rash similar to those in U.S. studies have been seen in international co horts o f nonpregnant women but not in association with CD4 cell counts >250 cells/mm3 30. In gen eral, in controlled clinical trials, clinical hepatic events, regardless o f severity, occurred in 4.0% (range 2.5% -11.0%) o f patients who received nevirapine; however, the risk o f nevirapine-associated liver failure or hepatic mortality has been lower, in the range o f 0.04%-0.40%29, 31. Severe or lifethreatening rash occurs in approximately 2% o f patients receiving nevirapine31.
Although deaths due to hepatic failure have been reported in HIV-infected pregnant women receiv ing nevirapine as part o f a combination ARV regimen, it is uncertain if pregnancy increases the risk of hepatotoxicity in women receiving nevirapine or other ARV drugs32. In an analysis o f 2 multicen ter prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (RR 4.7; 95% CI: 3.4-6.5), although nevirapine use was not, regardless o f pregnancy status33. Additional data from the same cohorts did not show any increased risk o f hepatotoxicity in HIV-infected pregnant women receiving nevirapine-based combination ART versus non-nevirapine-based combination ART34. In a cohort of 612 pregnant and nonpregnant women starting nevirapine-based therapy, CD4 cell count at initiation o f therapy but not liver enzyme elevation was a predictor o f rash; pregnancy was not an in dependent risk factor for the development o f toxicity35. These data suggest that nevirapine is no more toxic in pregnant women than in nonpregnant women.
Women initiating nevirapine with CD4 cell counts >250 cells/mm3, including pregnant women re ceiving ARV drugs solely for prevention o f transmission, have an increased risk o f developing symp tomatic, often rash-associated, nevirapine-related hepatotoxicity, which can be severe, life-threatening and, in some cases fatal36. Therefore, nevirapine should be used as a component o f a combination regimen in this setting only if the benefit clearly outweighs the risk. Women with CD4 cell counts < 250/mm3 can receive nevirapine-based regimens, and women who become pregnant while taking nevirapine and who are tolerating their regimens well can continue therapy, regardless of CD4 cell count. Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission o f HIV.
Because pregnancy itself can mimic some o f the early symptoms o f hepatotoxicity, health care providers caring for women receiving nevirapine during pregnancy should be aware o f this potential complication. Frequent and careful monitoring o f clinical symptoms and hepatic transaminases (i.e., alanine aminotransferase  and aspartate aminotransferase ) is necessary, particularly dur ing the first 18 weeks o f therapy. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through 4 months, and every 1-3 months thereafter (Adult Anti retroviral Guidelines); in patients with pre-existing liver disease, monitoring should be performed more frequently when initiating therapy and monthly thereafter37. Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patients who develop sugges tive clinical symptoms accompanied by elevation in serum transaminase levels (ALT and/or AST) or have asymptomatic but severe transaminase elevations should stop nevirapine and not receive the drug in the future.
- Teratogenicity/developm ental toxicity
No evidence o f embryonic or fetal toxicity or an effect on reproductive function was observed in rat and rabbit dams treated with rilpivirine during pregnancy and lactation at doses 15 and 70 times higher, respectively, than exposure in humans at the recommended dose o f 25 mg once daily.

# Placental and breast m ilk passage
No data exist on whether rilpivirine crosses the placenta or is excreted in breast milk in humans. Studies in lactating rats and their offspring indicate that rilpivirine is present in rat milk.
- Hum an studies in pregnancy
No adequate and well-controlled studies o f rilpivirine use in pregnant women have been conducted.
Protease Inhibitors (Updated September 14, 2011)

# Glossary of Terms for Supplement
Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes:
- Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.
- Genetic mutations and/or chromosomal damage can contribute to cancer formation. In in vitro and in vivo assays, atazanavir shows evidence o f clastogenicity but not mutagenicity. Twoyear carcinogenicity studies in mice and rats were conducted with atazanavir. In female mice, the in cidence of benign hepatocellular adenomas was increased at systemic exposures 2.8-2.9-fold higher than those in humans at the recommended therapeutic dose (300 mg/day atazanavir boosted with 100 mg/kg/day ritonavir). There were no increases in the incidence o f tumors in male mice at any dose. In rats, no significant positive trends in the incidence o f neoplasms occurred at systemic exposures up to 1.1-fold (males) or 3.9-fold (females) higher than those in humans at the recommended thera peutic dose.

# Reproduction/fertility
No effect o f atazanavir on reproduction or fertility in male and female rodents was seen at systemic drug exposures. The area under the curve (AUC) at this exposure level in rats was 0.9-fold in males and 2.3-fold in females compared with the exposures achieved in humans at the recommended thera peutic dose.
- Teratogenicity/developm ental toxicity
In animal reproduction studies, there was no evidence o f teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In developmental toxicity studies in rats, maternal dosing that resulted in maternal toxicity and produced systemic drug exposure 1.3 times the human exposure also resulted in weight loss or suppression o f weight gain in the offspring. However, offspring were unaffected at lower maternal doses that produced systemic drug exposure equivalent to that observed in humans at the recommended therapeutic dose.
In a retrospective analysis from London o f atazanavir used in 31 women during 33 pregnancies (20 of whom were receiving atazanavir at conception), there were 2 miscarriages at 12 and 16 weeks, 26 infants born, and 5 women still pregnant1. No infant required phototherapy and no birth defects were seen; none of the infants was HIV infected. In the Antiretroviral Pregnancy Registry, sufficient num bers o f first-trimester exposure to atazanavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been ob served with atazanavir. The prevalence o f birth defects with first-trimester atazanavir exposure was 2.4% (12 o f 502 births, 95% confidence interval , 1.2%-4.1%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention (CDC) sur veillance2.
Elevation in indirect (unconjugated) bilirubin attributable to atazanavir-related inhibition o f hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with atazanavir. Studies have demonstrated that infants born to mothers who received atazanavir during pregnancy do not have pathologic or dangerous bilirubin elevations in the neonatal period1, 3-7.

# Placental and breast m ilk passage
In studies o f women receiving atazanavir/ritonavir-based combination therapy during pregnancy, the median cord blood atazanavir concentration was 13%-21% o f maternal serum levels at delivery3, 5-6.
Atazanavir is excreted in the milk o f lactating rats. In a study o f three women, the median ratio of breast milk atazanavir concentration to that in plasma was 13%8.
- Hum an studies in pregnancy
Several studies have investigated the pharmacokinetics (PKs) o f atazanavir with ritonavir in preg nancy. In some o f these studies, virological results were also analyzed. Overall, most pregnant pa tients were able to achieve HIV RNA less than 50 copies/mL at time o f delivery9. In some studies, almost all pregnant patients achieved HIV RNA 100 ng/mL1. Three studies have evaluated full PK profiles o f atazanavir when administered daily as 300 mg with 100 mg ritonavir during pregnancy. In all of these studies, atazanavir AUC was lower during pregnancy than in his toric data from HIV-infected nonpregnant patients3, 5 10. In 1 o f the 3 studies, there was no difference between atazanavir AUC during pregnancy and postpartum, but AUC at both times was lower than in nonpregnant HIV-infected historic controls3. In the other 2 studies, atazanavir AUC was 25% lower during pregnancy than in the same patients postpartum5, 10. However, in both these studies (BMS AI424182 and IMPAACT P1026 atazanavir cohort), the postpartum AUC was elevated com pared with nonpregnant HIV-infected historic control patients. For example, in study AI424182, 34 women were treated with 300 mg atazanavir plus 100 mg ritonavir at 4-12 weeks postpartum and were observed to have a 34% increase in geometric AUC compared with the historic control o f HIVinfected, nonpregnant patients (62 pg*hr/mL vs. 46.1 pg*hr/mL respectively)6. Because o f the post partum elevation in AUC in this study, the atazanavir drug label recommends that postpartum patients should be closely monitored for adverse events during the first 2 months after delivery.
Although use o f atazanavir with ritonavir combined with tenofovir and emtricitabine as a complete once-a-day dosing combination ARV regimen is becoming increasingly common in pregnancy, tenofovir reduces atazanavir exposure by 25% in nonpregnant adults11. This drug-drug interaction also is present during pregnancy, with a 25% reduction in atazanavir AUC in pregnant women also receiv ing tenofovir compared with the same women postpartum and a 50% reduction compared with post partum levels in women who did not receive tenofovir5.
Use of an increased dose of atazanavir o f 400 mg with 100 mg ritonavir during pregnancy has been investigated in two studies10 5. In both studies pregnant women receiving the increased dose without tenofovir had an atazanavir AUC equivalent to that seen in historic nonpregnant HIV-infected con trols receiving standard-dose atazanavir without tenofovir. Pregnant women receiving the increased atazanavir dose with tenofovir had an AUC equivalent to that seen in nonpregnant HIV-infected pa tients receiving standard-dose atazanavir and tenofovir9.
In the prescribing information for atazanavir6, the dose recommended for most pregnant women is 300 mg with 100 mg o f ritonavir. For additional details about dosing with interacting concomitant medications, please see Table 5 (Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharma cokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy) .
Neonatal elevations in bilirubin have been reported in some-but not all-studies o f infants born to mothers receiving atazanavir during pregnancy3, 5 10. Phototherapy was needed to control hyperbiliru binemia in 5 o f 29 infants in 1 study7. In study AI424182, 6 o f 39 infants received phototherapy12. Decisions to use phototherapy to treat infants with hyperbilirubinemia frequently are subjective and guidelines for phototherapy of infants vary between countries, making it difficult, therefore, to com pare the severity o f hyperbilirubinemia between patients within a study and in different studies. Ele vated neonatal bilirubin is more likely in infants with uridine diphosphate glucuronosyltransferase 1 (UGT1A1) genotypes associated with decreased UGT function10.
Hypoglycemia (glucose <40 mg/dL) that could not be attributed to maternal glucose intolerance, dif ficult delivery, or sepsis has been reported in 3 o f 38 atazanavir-exposed infants with glucose sam ples collected in the first day o f life. All 3 hypoglycemic infants' glucose samples were adequately collected and processed in a timely fashion13. This finding o f infant hypoglycemia is similar to a prior report in which 2 (both nelfinavir) o f 14 infants exposed to PIs (nelfinavir, saquinavir, and indi navir) developed hypoglycemia in the first day o f life14. Fosamprenavir (Lexiva, FPV) is classified as FDA pregnancy category C.

# A nim al carcinogenicity studies
Fosamprenavir and amprenavir were neither mutagenic nor clastogenic in a series o f in vitro and ani mal in vivo screening tests. Carcinogenicity studies o f fosamprenavir showed an increase in the inci dence o f hepatocellular adenomas and carcinomas at all doses tested in male mice and at the highest dose tested in female mice. In rats, the incidence o f hepatocellular adenomas and thyroid follicular cell adenomas in males (all doses tested) and in females (two highest doses tested) was also in creased. Repeat dose studies in rats produced effects consistent with enzyme activation, which pre disposes rats, but not humans, to thyroid neoplasms. In rats only there was an increase in interstitial cell hyperplasia at higher doses and an increase in uterine endometrial adenocarcinoma at the highest dose tested. The incidence o f endometrial findings was slightly increased over concurrent controls but was within background range for female rats. Thus the relevance o f the uterine endometrial ade nocarcinomas is uncertain. Exposures in the carcinogenicity studies were 0.3-to 0.7-fold (mice) and 0.7-to 1.4-fold (rats) those in humans given 1,400 mg twice daily o f fosamprenavir alone, and 0.2to 0.3-fold (mice) and 0.3-to 0.7-fold (rats) those in humans given 1,400 mg once daily o f fosampre navir plus 200 mg ritonavir once daily or 0.1-to 0.3-fold (mice) and 0.3-to 0.6-fold (rats) those in humans given 700 mg o f fosamprenavir plus 100 mg ritonavir twice daily.

# R eproduction/fertility
No impairment o f fertility or mating was seen in rats at doses providing 3-4 times the human expo sure to fosamprenavir alone or exposure similar to that with fosamprenavir and ritonavir dosing in humans. At those doses, no affect was seen on the development or maturation o f sperm in rats.
- Teratogenicity/developm ental toxicity Fosamprenavir was studied in rabbits at 0.8 and in rats at twice the exposure in humans to fosampre navir alone and at 0.3 (rabbits) and 0.7 (rats) times the exposure in humans to the combination of fosamprenavir and ritonavir. In rabbits administered fosamprenavir (alone or in combination) the in cidence of abortion was increased. In contrast, administration o f amprenavir at a lower dose in rab bits was associated with abortions and an increased incidence o f minor skeletal variations from deficient ossification of the femur, humerus, and trochlea. Fosamprenavir administered to pregnant rats (at twice human exposure) was associated with a reduction in pup survival and body weights in rats. F1 female rats had an increased time to successful mating, an increased length o f gestation, a re duced number o f uterine implantation sites per litter, and reduced gestational body weights com pared with controls.

# Placental and breast m ilk passage
It is unknown whether fosamprenavir crosses the placenta. Amprenavir is excreted in the milk o f lac-defects. No such increase in birth defects has been observed with indinavir. Among cases o f first trimester indinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.1% (6 o f 285 births, 95% CI, 0.8%-4.5%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1.
- Placental and breast m ilk passage
Significant placental passage o f indinavir occurs in rats and dogs, but only limited placental transfer occurs in rabbits. In a Phase I study in pregnant women and their infants (PACTG 358, see below), transplacental passage o f indinavir was minimal2. In addition, in a study o f cord blood samples from 21 women treated with indinavir during pregnancy, the cord blood concentration o f indinavir was less than the assay limit o f detection in samples from all women3. Indinavir is excreted in the milk of lactating rats at concentrations slightly greater than maternal levels (milk-to-plasma ratio 1.26 to 1.45); it is not known if indinavir is excreted in human milk.
- Hum an studies in pregnancy
The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A Phase I/II safety and PK study (PACTG 358) was conducted of indinavir (800 mg three times a day) in com bination with zidovudine and lamivudine in pregnant HIV-infected women and their infants2. The mean indinavir plasma AUC0-8hr at 30-32 weeks' gestation (n =11) was 74% (95% CI, 50%-86%) lower than that observed 6 weeks postpartum. The PKs of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in nonpregnant patients in another study. In an other study, two pregnant HIV-infected women receiving combination therapy including indinavir (800 mg three times a day) had significantly reduced AUC indinavir exposures in the third trimester com pared with postpartum evaluations (52% and 86%, respectively)4. Therefore, given the substantially lower antepartum exposures observed in these studies and the generally limited data in this patient population, use of indinavir as a sole PI is not recommended in HIV-infected pregnant patients. Lopinavir + Ritonavir (Kaletra, LPV/r) is classified as FDA pregnancy category C.

# A nim al carcinogenicity studies
Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery o f in vitro and in vivo assays. The lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the inci dence o f benign hepatocellular adenomas and an increase in the combined incidence o f hepatocellu lar adenomas plus carcinoma in male and female mice and male rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure at the recommended therapeutic dose o f 400 mg/100 mg (based on AUC0-24hr measurement). Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence o f any other be nign or malignant neoplasm in mice or rats.
- Reproduction/fertility
Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and fe male rats with exposures approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir o f the expo sures in humans at the recommended therapeutic dose.
- Teratogenicity/developm ental toxicity
No evidence exists of teratogenicity with administration o f lopinavir/ritonavir to pregnant rats or rabbits. In rats treated with a maternally toxic dosage (100 mg lopinavir/50 mg ritonavir/kg/day), embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence o f skeletal variations, and skeletal ossification delays) were observed. Drug exposure in the pregnant rats was 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose. In a peri-and postnatal study in rats, a decrease in survival o f pups between birth and postnatal Day 21 occurred with exposure to 40 mg lopinavir/20 mg ritonavir/kg/day or greater. In rabbits, no embryonic or fetal developmental toxicities were observed with a maternally toxic dosage, where drug exposure was 0.6-fold for lopinavir and 1-fold for ritonavir of the exposures in humans at the recommended therapeutic dose.
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to lopinavir/ritonavir have been monitored to be able to detect at least a 2-fold increase in risk o f over all birth defects. No such increase in birth defects has been observed with lopinavir/ritonavir. Among cases o f first-trimester lopinavir/ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 2.2% (16 o f 738 births, 95% CI, 1.2%-3.5%) compared with a total prevalence of 2.7% in the U.S. population, based on CDC surveillance1.

# Placental and breast m ilk passage
Lopinavir crosses the human placenta; in the P1026s PK study, the average ratio o f lopinavir concen tration in cord blood to maternal plasma at delivery was 0.20  0.13. For ritonavir, data in humans indicate only minimal transplacental passage (see ritonavir). Lopinavir and ritonavir are secreted in the breast milk of lactating rats; it is not known if either drug is excreted in human milk.
- Hum an studies in pregnancy
The capsule formulation of lopinavir/ritonavir is no longer available; it has been replaced by a new tablet formulation o f lopinavir 200 mg/ritonavir 50 mg that is heat stable and does not have a food requirement.
In nonpregnant adults, plasma concentrations o f lopinavir and ritonavir after administration o f two 200/50 mg lopinavir/ritonavir tablets are similar to those achieved with three 133/33 mg lopinavir/ri tonavir capsules given with food, although with less PK variability. In a study o f 51 pregnant women, plasma trough lopinavir levels during the third trimester were compared among 28 women receiving the capsule and 23 women receiving the tablet formulations at standard dosing. No statisti cal difference was found between the groups, with a mean lopinavir trough level o f 4.86 mg/L (cap sule) and 4.57 mg/L (tablets)2. However, the inter-individual variability was lower with the tablets than with the capsules. Five o f 28 women (17.8%) in the capsule group and 4 o f 23 women (17.4%) in the tablet group had trough levels less than the target (3 mg/L); 7 o f the 9 women had HIV RNA levels less than detection at the time of their sampling, and 2 with subtherapuetic levels (0.7 and 2.44 mg/L) had plasma RNA of 83 and 56 copies/mL, respectively, at the time o f their sampling.
P1026s evaluated lopinavir PKs following standard dosing with the new lopinavir/ritonavir tablet formulation (2 tablets twice daily) until 30 weeks' gestation, followed by an increase to 3 tablets twice daily and return to standard dosing at postpartum hospital discharge. Median AUC was 72 p,g*h/mL in 7 women receiving standard dosing during the second trimester, 97 p,g*h/mL in 25 women receiving the increased dose during the third trimester, and 129 p,g*h/mL in 19 women re ceiving standard dosing at 2 weeks postpartum. These data suggest that the higher lopinavir/ritonavir dose should be used in the third trimester; that it should be considered in the second trimester, partic ularly in women who are PI experienced; and that lopinavir/ritonavir can be reduced to standard dos ing shortly after delivery3. An alternative strategy for increasing lopinavir/ritonavir exposure during pregnancy is to add a pediatric lopinavir/ritonavir tablet (100/25 mg) to the standard dose o f 2 adult tablets (200/50 mg)4.
Once-daily dosing o f lopinavir/ritonavir capsules or tablets is not recommended in pregnancy be cause no data exist to address whether drug levels are adequate with such administration.
Lopinavir/ritonavir oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/vol ume) propylene glycol. Reduced metabolism by the liver and reduced kidney function in newborns can lead to an accumulation o f lopinavir (the active ingredient) as well as alcohol and propylene gly col. Preterm babies may be at increased risk o f health problems because they cannot metabolize propylene glycol; this could lead to accumulation and adverse events such as serious heart, kidney, or breathing problems. Postmarketing surveillance has identified 10 neonates (babies <4 weeks of age), 9 o f whom were born prematurely, who received lopinavir/ritonavir and experienced lifethreatening events5. Lopinavir/ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day o f the m other's last menstrual period to birth, plus the time elapsed after birth) o f 42 weeks and a postnatal age o f at least 14 days has been attained.

# A nim al carcinogenicity studies
Nelfinvair was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. However, incidence of thyroid follicular cell adenomas and carcinomas was increased over baseline in male rats receiving nelfinavir dosages o f 300 mg/kg/day or higher (equal to a systemic exposure similar to that in humans at therapeutic doses) and female rats receiving 1,000 mg/kg/day (equal to a systemic exposure 3-fold higher than that in humans at therapeutic doses).

# Reproduction/fertility
No effect o f nelfinavir has been seen on reproductive performance, fertility, or embryo survival in rats at exposures comparable to human therapeutic exposure. Additional studies in rats indicated that exposure to nelfinavir in females from midpregnancy through lactation had no effect on the survival, growth, and development o f the offspring to weaning. Maternal exposure to nelfinavir also did not affect subsequent reproductive performance o f the offspring.
- Teratogenicity/developm ental toxicity
No evidence o f teratogenicity has been observed in pregnant rats at exposures comparable to human exposure and in rabbits with exposures significantly less than human exposure.
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to nelfinavir have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with nelfinavir. Among cases o f first-trimester nelfinavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 3.9% (46 o f 1,193 births, 95% CI, 2.8%-5.1%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance1.
- Placental and breast m ilk transfer
In a Phase I study in pregnant women and their infants (PACTG 353, see below), transplacental pas sage o f nelfinavir was minimal2. In addition, in a study o f cord blood samples from 38 women who were treated with nelfinavir during pregnancy, the cord blood nelfinavir concentration was less than the assay limit o f detection in 24 (63%), and the cord blood concentration was low (median, 0.35 p,g/mL) in the remaining 14 women3. Nelfinavir is excreted in the milk o f lactating rats; it is not known if it is excreted in human milk.
- Hum an studies in pregnancy A Phase I/II safety and PK study (PACTG 353) o f nelfinavir in combination with zidovudine and lamivudine was conducted in pregnant HIV-infected women and their infants2. In the first nine preg nant HIV-infected women enrolled in the study, nelfinavir administered at a dose o f 750 mg three times daily produced drug exposures that were variable and generally lower than those reported in nonpregnant adults with both twice-and three-times-daily dosing. Therefore, the study was modified to evaluate an increased dose o f nelfinavir given twice daily (1,250 mg twice daily), which resulted in adequate levels o f the drug in pregnancy. However, in another study o f women given 1,250 mg nelfinavir twice daily in the second and third trimesters, drug concentrations in the third trimester were lower than in the second trimester or in nonpregnant women4.
In a PK study o f combination therapy including the new nelfinavir 625-mg tablet formulation (given as 1,250 mg twice daily) in 25 women at 30-36 weeks' gestation (and 12 at 6-12 weeks postpar tum), peak levels and AUC were lower in the third trimester than postpartum5. Only 16% (4 o f 25) of women during the third trimester and 8% (1 o f 12) women postpartum had trough values greater than the suggested minimum trough o f 800 ng/mL; however, viral load was <400 copies/mL in 96% of women in the third trimester and 86% postpartum. is classified as FDA pregnancy category B.

# A nim al carcinogenicity studies
Ritonavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies in mice and rats have been completed. In male mice, a dose-dependent increase in adenomas of the liver and combined adenomas and carcinomas o f the liver was observed at levels o f 50, 100, or 200 mg/kg/day; based on AUC, exposure in male mice at the highest dose was approximately 0.3-fold that in male humans at the recommended therapeutic dose. No carcino genic effects were observed in female mice with exposures 0.6-fold that o f female humans at the rec ommended therapeutic dose. No carcinogenic effects were observed in rats at exposures up to 6% of recommended therapeutic human exposure.

# Reproduction/fertility
No effect o f ritonavir has been seen on reproductive performance or fertility in rats at drug exposures 40% (male) and 60% (female) o f that achieved with human therapeutic dosing; higher doses were not feasible because of hepatic toxicity in the rodents.
- Teratogenicity/developm ental toxicity
No ritonavir-related teratogenicity has been observed in rats or rabbits. Developmental toxicity, in cluding early resorptions, decreased body weight, ossification delays, and developmental variations such as wavy ribs and enlarged fontanelles, was observed in rats; however, these effects occurred only at maternally toxic dosages (exposure equivalent to 30% o f human therapeutic exposure). In ad dition, a slight increase in cryptorchidism was also noted in rats at exposures equivalent to 22% of the human therapeutic dose. In rabbits, developmental toxicity (resorptions, decreased litter size, and decreased fetal weight) was observed only at maternally toxic doses ( 1.8 times human therapeutic exposure based on body surface area).
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to ritonavir have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth defects. No such increase in birth defects has been observed with ritonavir. Among cases o f first-trimester ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence o f birth defects was 2.4% (33 o f 1,401 births; 95% CI, 1.6%-3.3%) compared with a total prevalence o f 2.7% in the U.S. population, based on CDC surveillance1.
- Placental and breast m ilk transfer
Transplacental passage o f ritonavir has been observed in rats with fetal tissue to maternal serum ra tios >1.0 at 24 hours post-dose in mid-and late-gestation fetuses. In a human placental perfusion model, the clearance index o f ritonavir was very low, with little accumulation in the fetal compart ment and no accumulation in placental tissue2. In a Phase I study in pregnant women and their in fants (PACTG 354, see below), transplacental passage o f ritonavir was minimal3. Additionally, in a study o f cord blood samples from six women treated with ritonavir during pregnancy, the cord blood concentration was less than the assay limit o f detection in 83% and was only 0.38 p,g/mL in the re maining woman4. Ritonavir is excreted in the milk o f lactating rats; it is unknown if it is excreted in human milk.
- Hum an studies in pregnancy A Phase I/II safety and PK study (PACTG 354) o f ritonavir (500 or 600 mg twice daily) in combina tion with zidovudine and lamivudine in pregnant HIV-infected women and their infants showed lower levels o f ritonavir during pregnancy than postpartum3. Ritonavir concentrations are also re duced during pregnancy versus postpartum when the drug is used at a low dose (100 mg) to boost the concentrations o f other PIs5-6.
rabbit) o f those obtained in humans at the recommended clinical dose boosted with ritonavir.
- Placental and breast m ilk transfer Placental transfer o f saquinavir in the rat and rabbit was minimal. In a Phase I study in pregnant women and their infants (PACTG 386, see below), transplacental passage o f saquinavir was mini m al1. In addition, in a study of cord blood samples from eight women treated with saquinavir during pregnancy, the cord blood concentration o f saquinavir was less than the assay limit o f detection in samples from all women2. Saquinavir is excreted in the milk o f lactating rats; it is not known if it is excreted in human milk.
- Hum an studies in pregnancy
Three studies have evaluated the PKs o f saquinavir-hard gel capsules combined with low-dose riton avir (saquinavir-hard gel capsules 1,000 mg/ritonavir 100 mg given twice daily) in a total o f 19 preg nant women; trough levels were greater than the target in all but 1 woman3-4. In a small study o f 2 women who received saquinavir-hard gel capsules 1,200 mg/ritonavir 100 mg given once daily, trough levels were 285 and 684 ng/mL and the AUC0-24 were 28,010 and 16,790 ng hour/mL, greater than the target AUC o f 10,000 ng hour/mL5. Thus, the limited available data suggest that saquinavir-hard gel capsules 1,000 mg/ritonavir 100 mg given twice daily should achieve adequate trough levels in HIV-infected pregnant women. Data are too limited to recommend once-daily dos ing at present. However, a recent analysis o f saquinavir-hard gel capsules administered once daily at 1,200 mg/100 mg ritonavir combined with various NRTIs during 46 pregnancies demonstrated saquinavir levels greater than the target minimum plasma concentration (Cmin) in 46 (93.4%) of pregnancy episodes and undetectable viral load at delivery in 88% o f episodes6. Target levels were achieved in the other 3 women with a dose o f 1,600 mg/100 mg. The drug was well tolerated.
The PKs of the new 500-mg tablet formulation o f saquinavir boosted with ritonavir in a dose of saquinavir 1,000 mg/ritonavir 100 mg given twice daily were studied in 14 HIV-infected pregnant women at 33 weeks gestation and parameters were comparable to those observed in nonpregnant in dividuals; none o f the women had a subtherapeutic trough level7.
One study o f a saquinavir/ritonavir-based combination ARV drug regimen in 42 women during preg nancy reported abnormal transaminase levels in 13 women (31%) within 2 -4 weeks o f treatment ini tiation, although the abnormalities were mild (toxicity Grade 1-2 in most, Grade 3 in 1 woman)8. ) at all dose levels tested were below those in humans receiving the recommended dose level. Rats were administered 30, 100, or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ritonavir in com bination, or 10 mg/kg/day ritonavir. No drug-related findings were observed in male rats. At the highest dose o f tipranavir, an increased incidence o f benign follicular cell adenomas o f the thyroid gland was observed in female rats. Based on AUC measurements, exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction.

# R eproduction/fertility
Tipranavir had no effect on fertility or early embryonic development in rats at exposure levels similar to human exposures at the recommended clinical dose (500/200 mg per day of tipranavir/ritonavir).
- Teratogenicity/developm ental toxicity No teratogenicity was detected in studies o f pregnant rats and rabbits at exposure levels approxi mately 1.1-fold and 0.1-fold human exposure. Fetal toxicity (decreased ossification and body weights) was observed in rats exposed to 400 mg/kg/day or more o f tipranavir (~0.8-fold human ex posure). Fetal toxicity was not seen in rats and rabbits at levels o f 0.2-fold and 0.1-fold human expo sures. In rats, no adverse effects on developments were seen at levels o f 40 mg/kg/day (~0.2-fold human exposure), but at 400 mg/kg/day (~0.8-fold human exposure), growth inhibition in pups and maternal toxicity were seen.
- Placental and breast m ilk transfer
No animal studies o f placental or breast milk passage o f tipranavir have been reported. It is unknown if placental or breast milk passage o f tipranavir occurs in humans.
- Hum an studies in pregnancy
No studies of tipranavir have been completed in pregnant women or neonates. Tipranavir is one of the study drugs in the ongoing IMPAACT P1026: "Pharmacokinetic Study o f Anti-HIV Drugs Dur ing Pregnancy" .
- Placental and breast m ilk passage Studies of radio-labeled enfuvirtide administered to lactating rats indicated radioactivity in the milk; however, it is not known if this reflected radio-labeled enfuvirtide or metabolites (e.g., amino acid and peptide fragments) o f enfuvirtide. It is not known if enfuvirtide crosses the human placenta or is excreted in human milk. A published case report o f two peripartum pregnant patients and their neonates and data from an ex vivo human placental cotyledon perfusion model suggest that enfuvir tide does not cross the placenta1-2.
- Hum an studies in pregnancy
Very limited data exist on the use o f enfuvirtide in pregnant women1, 3-4; no data exist in neonates.
Maraviroc (Selzentry, MVC) is classified as FDA pregnancy category B.

# A nim al carcinogenicity studies
Maraviroc was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies found no increase in tumor incidence in mice (trans genic rasH2 mice) and rats at exposures up to 11-fold higher than experienced with human therapeu tic exposure at the recommended clinical dose (300 mg twice daily).

# R eproduction/fertility anim al studies
Reproductive toxicity has been evaluated in rats. Maraviroc produced no adverse effects on fertility of male or female rats or sperm of male rats at exposures up to 20-fold higher than experienced with human therapeutic exposure at the recommended clinical dose (300 mg twice daily).
- Teratogenicity/developm ental toxicity anim al studies
Studies in rats and rabbits revealed no evidence o f harm to the fetus from maraviroc administered in doses up to 20-fold higher in rats and 5-fold higher in rabbits than experienced with human therapeu tic exposure at the recommended clinical dose (300 mg twice daily).

# Placental and breast m ilk passage
It is unknown if maraviroc crosses the placenta in humans. In a study o f four macaques, a single oral dose o f either 60 mg/kg or 100 mg/kg was given 2 hours before cesarean delivery. Median maternal concentration at delivery was 974 ng/mL (range 86-2,830 ng/mL) and median infant concentration was 22 ng/mL (range 4-99 ng/mL) for a cord/matemal ratio o f .0231. Maternal levels were de tectable for 48 hours after a single dose, whereas infant levels were detectable for only 3.5 hours after birth. Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk.
- Hum an studies in pregnancy
No studies of maraviroc have been conducted in pregnant women or neonates.

# A dditional concerns
Although no increase in cancer has been observed with maraviroc, the drug has the potential to in crease risk because o f its mechanism o f action and possible effects on immune surveillance.
Integrase Inhibitors (Updated September 14, 2011)

# Glossary of Terms for Supplement
Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes:
- Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.
- Genetic mutations and/or chromosomal damage can contribute to cancer formation.
One drug has been approved in this new class of antiretrovirals (ARVs) aimed at inhibiting integrase, the viral enzyme that catalyzes the two-step process of insertion of HIV DNA into the genome of the host cell.
Integrase catalyzes a preparatory step that excises two nucleotides from one strand at both ends of the HIV DNA and a final "strand transfer" step that inserts the viral DNA into the exposed regions of cellular DNA. This second step in the integration process is targeted by the integrase inhibitor drug class. Integration is required for the stable maintenance of the viral genome as well as for efficient viral gene expression and replication. Integrase also affects retrotranscription and viral assembly. Host cells lack the integrase en zyme. Because HIV integrase represents a distinct therapeutic target, integrase inhibitors would be ex pected to maintain activity against HIV that is resistant to other classes of ARV drugs.
Raltegravir (Isentress) is classified as FDA pregnancy category C.

# A nim al carcinogenicity studies
Raltegravir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies o f raltegravir are ongoing.

# R eproduction/fertility anim al studies
Raltegravir produced no adverse effects on fertility of male or female rats at doses up to 600 mg/kg/ day (providing exposures 3-fold higher than the exposure at the recommended adult human dose).
- Teratogenicity/developm ental toxicity anim al studies
Studies in rats and rabbits revealed no evidence of treatment-related effects on embryonic/fetal sur vival or fetal weights from raltegravir administered in doses producing systemic exposures approxi mately 3-to 4-fold higher than the exposure at the recommended adult human daily dose. In rabbits, no treatment-related external, visceral, or skeletal changes were observed. However, treatment-related increases in the incidence of supernumerary ribs were seen in rats given raltegravir at 600 mg/kg/day (providing exposures 3-fold higher than the exposure at the recommended human daily dose).

# Placental and breast m ilk passage
Placental transfer o f raltegravir was demonstrated in both rats and rabbits. In rats given a maternal dose o f 600 mg/kg/day, mean fetal blood concentrations were approximately 1.5-to 2.5-fold higher than in maternal plasma at 1 and 24 hours post-dose, respectively. However, in rabbits, the mean drug concentrations in fetal plasma were approximately 2% o f the mean maternal plasma concentra tion at both 1 and 24 hours following a maternal dose o f 1,000 mg/kg/day. In a case report o f use in late pregnancy, the raltegravir cord blood-to-maternal blood ratio at delivery was 1.061. Raltegravir is secreted in the milk o f lactating rats, with mean drug concentrations in milk about 3-fold higher than in maternal plasma at a maternal dose o f 600 mg/kg/day. No effects in rat offspring were attrib utable to raltegravir exposure through breast milk.
- Hum an studies in pregnancy
Only limited data exist on the use of raltegravir in pregnancy. Raltegravir pharmacokinetics (PKs) were evaluated in 10 women in the IMPAACT P1026s study. Raltegravir PKs showed extensive variability but did not appear to be consistently altered during the third trimester compared with postpartum and historical data in nonpregnant individuals; thus the standard dose appears appropri ate in pregnancy2. Raltegravir readily crossed the placenta; in 6 deliveries with evaluation, the ratio of cord blood to maternal plasma was 0.98 (95% confidence interval , 0.09-2.26). In a separate report, 3 pregnant women with multiresistant HIV-1 were given raltegravir in late pregnancy to rap idly reduce maternal viral load3. Raltegravir concentrations within 3 hours o f delivery in the neonates o f 2 patients were approximately 7 and 9.5 times higher than in the m other's paired sample; in the third infant, maternal plasma was not available but neonatal concentration was still high 2.5 hours after delivery. However, no adverse reactions were observed in mothers or infants. Whether raltegravir is secreted in human milk is unknown.
Some nelfinavir manufactured before 2008 may have contained low levels o f ethyl methane sul fonate (EMS), a process-related impurity. EMS is teratogenic, mutagenic, and carcinogenic in ani mals, although no data exist in humans and no increase in birth defects has been observed in the Antiretroviral Pregnancy Registry. All nelfinavir manufactured and released since March 31, 2008, meets the new final EMS limits established by the FDA for prescribing to all patient populations, in cluding pregnant women and pediatric patients.

# Glossary of Terms for Supplement
Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes:
- Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.
- Genetic mutations and/or chromosomal damage can contribute to cancer formation.
Six nucleoside analogue reverse transcriptase inhibitors (nucleoside NRTIs) and one nucleotide reverse transcriptase inhibitor (nucleotide NRTI) are currently approved (zalcitabine is no longer available in the United States). Data are available from clinical trials in human pregnancy for the nucleoside NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine, and the nucleotide NRTI tenofovir. The nucleoside analogue drugs require three intracellular phosphorylation steps to form the triphosphate nucleoside, which is the active drug moiety. Tenofovir, an acyclic nucleotide analogue drug, contains a monophosphate component attached to the adenine base, and hence requires only two phos phorylation steps to form the active moiety.
For information regarding the nucleoside analogue drug class and potential mitochondrial toxicity in pregnancy and to the infant, see NRTI Drugs and Mitochondrial Toxicity in the perinatal guidelines.
Abacavir (Ziagen, ABC) is classified as Food and Drug Administration (FDA) pregnancy category C.

# A nim al carcinogenicity studies
Abacavir is mutagenic and clastogenic in some in vitro and in vivo assays. In long-term carcino genicity studies in mice and rats, malignant tumors o f the preputial gland o f males and the clitoral gland o f females were observed in both species, and malignant hepatic tumors and nonmalignant he patic and thyroid tumors were observed in female rats. The tumors were seen in rodents at doses that were 6-32 times that of human therapeutic exposure.

# Reproduction/fertility
No effect of abacavir on reproduction or fertility in male and female rodents has been seen at doses of up to 500 mg/kg/day (about 8 times that of human therapeutic exposure based on body surface area).

# Teratogenicity/developm ental toxicity
Abacavir is associated with developmental toxicity (decreased fetal body weight and reduced crownrump length) and increased incidence o f fetal anasarca and skeletal malformations in rats treated Didanosine (Videx, ddl) is classified as FDA pregnancy category B.

# A nim al carcinogenicity studies
Didanosine is both mutagenic and clastogenic in several in vitro and in vivo assays. Long-term ani mal carcinogenicity screening studies at human exposures o f 0.7-1.7 and 3 times, respectively, in mice and rats have been negative.

# Reproduction/fertility
At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid-and late lactation. These rats showed reduced food intake and body Lamivudine (Epivir, 3TC) is classified as FDA pregnancy category C.

# A nim al carcinogenicity studies
Lamivudine has weak mutagenic activity in one in vitro assay but no evidence o f in vivo genotoxicity in rats at 35-45 times human exposure. Long-term animal carcinogenicity screening studies at 10 and 58 times human exposure have been negative in mice and rats, respectively.
- Reproduction/fertility Lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47-70 times those in humans, revealed no evidence o f impaired fertility and no effect on the offsprings' sur vival, growth, and development up to the time o f weaning.

# Teratogenicity/developm ental toxicity studies
There is no evidence o f lamivudine-induced teratogenicity at 35 times human plasma levels in rats and rabbits. Early embryolethality was seen in rabbits at doses similar to human therapeutic expo sure but not in rats at 35 times the human exposure level.
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposures to lamivu-Etravirine (Intelence, ETR) is c la s s ifie d as F D A p r e g n a n c y c a t e g o r y B .

# A nim al carcinogenicity studies
Etravirine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies o f etravirine in rodents are ongoing.

# Reproduction/fertility
No effect on fertility and early embryonic development was observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure equivalent to the recommended human dose (400 mg/day).

# Teratogenicity/developm ental toxicity
Animal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the rec ommended human dose o f 400 mg/day revealed no evidence o f fetal toxicity or altered development. Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1,000 mg/kg/day). In both species, no treatment-related embryo-fetal effects, including malformations, were observed. In addition, no treatment effects were observed in a sepa rate pre-and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic ex posures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day).

# Placental and breast m ilk passage
There are no data on whether etravirine crosses the placenta or is excreted in breast milk in humans.

# Hum an studies in pregnancy
No adequate and well-controlled studies of etravirine use in pregnant women have been conducted and very limited case report data are available on etravirine use in pregnancy. One small study described use of etravirine in combination with darunavir/ritonavir and other ARV drugs in four pregnant women; PK sampling was done to determine etravirine plasma concentration during the third trimester1. PK data from these women were similar to those in nonpregnant adults. Data on etravirine in postpartum cord blood and concurrent maternal plasma specimens were available for one patient with values of 112 ng/mL and 339 ng/mL (cord/maternal blood ratio 0.33). No maternal, fetal, or neonatal toxicity was reported; one infant was born with a small accessory auricle on the right ear with no other malformations; no birth defects were noted in the other children. Placental passage of etravirine was noted in another report of use of etravirine, darunavir/ritonavir, and enfuvirtide in a pregnant woman who gave birth to twins (cord blood levels 414 ng/mL in Twin 1 and 345 ng/mL in Twin 2)2. In a separate report on two women receiving etravirine, darunavir/ritonavir, and raltegravir during pregnancy, no perinatal transmission of HIV or congenital abnormalities were observed.

# Rilpivirine (Edurant) is classified as FDA pregnancy category B. - A nim al carcinogenicity studies
Rilpivirine was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Rilpivirine was not carcinogenic in rats when administered at doses 3 times higher than expo sure in humans at the recommended dose o f 25 mg once daily. Hepatocellular neoplasms were ob served in both male and female mice at doses 21 times that o f human therapeutic exposure; the observed hepatocellular findings in mice may be rodent specific1.

# R eproduction/fertility
No effect on fertility was observed when rilpivirine was tested in rats at maternal doses up to 400 mg/kg/day, resulting in systemic drug exposure equivalent to 40 times the recommended human dose.
Darunavir (Prezista, DRV) is classified as FDA pregnancy category C.

# A nim al carcinogenicity studies
Darunavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. A dose-related increase in the incidence o f hepatocellular adenomas and carcinomas was ob served in both male and female mice and rats as well as an increase in thyroid follicular cell adeno mas in male rats. The observed hepatocellular findings in rodents are considered to be o f limited relevance to humans. Repeated administration o f darunavir to rats caused hepatic microsomal en zyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4-and 0.7-fold (mice) and 0.7-and 1-fold (rats) o f those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).

# Reproduction/fertility
No effects on fertility and early embryonic development were seen with darunavir in rats.
- Teratogenicity/developm ental toxicity
No embryotoxicity or teratogenicity was seen in mice, rats, or rabbits. Because o f limited bioavail ability of darunavir in animals and dosing limitation, the plasma exposures were approximately 50% (mice and rats) and 5% (rabbits) o f those obtained in humans. In the rat pre-and postnatal develop ment study, a reduction in pup weight gain was observed with darunavir alone or with ritonavir ex posure via breast milk during lactation. In juvenile rats, single doses o f darunavir (20 mg/kg-160 mg/kg at ages 5-11 days) or multiple doses o f darunavir (40 mg/kg-1,000 mg/kg at age 12 days) caused mortality. The deaths were associated with convulsions in some o f the animals. Within this age range, exposures in plasma, liver, and brain were dose and age dependent and were considerably greater than those observed in adult rats. tating rats; it is not known if it is excreted in human milk.
- Hum an studies in pregnancy Very limited data exist on fosamprenavir in pregnant women. Fosamprenavir PKs have been re ported in 15 women during pregnancy and postpartum. Following standard dosing with fosampre navir 700 mg and ritonavir 100 mg, amprenavir AUC and 12-hour trough concentrations were somewhat lower during pregnancy and higher postpartum compared with historical data. Amprenavir exposure during pregnancy appeared to be adequate for patients without PI resistance mutations1.
A pediatric liquid formulation o f fosamprenavir has been approved for children older than 2 years of age, but there is no dosing information for neonates. Indinavir (Crixivan, IDV) is classified as FDA pregnancy category C.

# A nim al carcinogenicity studies
Indinavir is neither mutagenic nor clastogenic in both in vitro and in vivo assays. No increased inci dence o f any tumor types occurred in long-term studies in mice. At the highest dose studied in rats (640 mg/kg/day or 1.3-fold higher than systemic exposure at human therapeutic doses), thyroid ade nomas were seen in male rats.

# Reproduction/fertility
No effect o f indinavir has been seen on reproductive performance, fertility, or embryo survival in rats.
- Teratogenicity/developm ental toxicity There has been no evidence of teratogenicity or treatment-related effects on embryonic/fetal survival or fetal weights of indinavir in rats, rabbits, or dogs at exposures comparable to or slightly greater than therapeutic human exposure. In rats, developmental toxicity manifested by an increase in supernumer ary and cervical ribs was observed at doses comparable to those administered to humans. No treat ment-related external or visceral changes were observed in rats. No treatment-related external, visceral, or skeletal changes were seen in rabbits (fetal exposure limited, approximately 3% of mater nal levels) or dogs (fetal exposure approximately 50% of maternal levels). Indinavir was administered to pregnant Rhesus monkeys during the third trimester (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, in dinavir exacerbated the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately 4-fold greater than controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester. In Rhesus monkeys, fetal plasma drug levels were approximately 1%-2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily.
In the Antiretroviral Pregnancy Registry, sufficient numbers o f first-trimester exposure to indinavir in humans have been monitored to be able to detect at least a 2-fold increase in risk o f overall birth
Acquir Immune Defic Syndr. Jan 28 2011.
Saquinavir (Invirase , SQV) is classified as FDA pregnancy category B.

# A nim al carcinogenicity studies
Saquinavir was neither mutagenic nor clastogenic in a series o f in vitro and animal in vivo screening tests. Carcinogenicity studies found no indication o f carcinogenic activity in rats and mice adminis tered saquinavir for approximately 2 years at plasma exposures approximately 60% o f those ob tained in humans at the recommended therapeutic dose (rats) and at exposures equivalent to those in humans at the recommended therapeutic dose (mice).

# Reproduction/fertility
No effect o f saquinavir has been seen on reproductive performance, fertility, or embryo survival in rats. Because o f limited bioavailability o f saquinavir in animals, the maximal plasma exposures achieved in rats were approximately 26% o f those obtained in humans at the recommended clinical dose boosted with ritonavir.
- Teratogenicity/developm ental toxicity
No evidence o f embryotoxicity or teratogenicity o f saquinavir has been found in rabbits or rats. Be cause o f limited bioavailability o f saquinavir in animals and/or dosing limitations, the plasma expo sures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using Entry Inhibitors (Updated September 14, 2011)

# Glossary of Terms for Supplement
Clastogenic = causing disruption of or breakages in chromosomes Mutagenic = inducing or capable of inducing genetic mutation Genotoxic = damaging to genetic material such as DNA and chromosomes Carcinogenic = producing or tending to produce cancer Notes:
- Some agents, such as certain chemicals or forms of radiation, are both mutagenic and clastogenic.
- Genetic mutations and/or chromosomal damage can contribute to cancer formation.
Two drugs have been approved in this new class o f antiretrovirals (ARVs) aimed at inhibiting viral bind ing or fusion o f HIV to host target cells. Binding o f the viral envelope glycoprotein (gp)120 to the CD4 receptor induces conformational changes that enable gp120 to interact with a chemokine receptor such as CCR5 or CXCR4 on the host cell; binding o f gp120 to the coreceptor causes subsequent conforma tional changes in the viral transmembrane gp41, exposing the "fusion peptide" o f gp41, which inserts into the cell membrane. A helical region o f gp41, called HR1, then interacts with a similar helical region, HR2, on gp41, resulting in a "zipping" together o f the two helices and mediating the fusion o f cellular and viral membranes. Enfuvirtide, which requires subcutaneous administration, is a synthetic 36-aminoacid peptide derived from a naturally occurring m otif within the HR2 domain o f viral gp41, and the drug binds to the HR1 region, preventing the HR1-HR2 interaction and correct folding o f gp41 into its sec ondary structure, thereby inhibiting virus-cell fusion. Enfuvirtide was approved for use in combination with other ARV drugs to treat advanced HIV infection in adults and children 6 years o f age or older. Maraviroc interferes with viral entry at the chemokine coreceptor level; it is a CCR5 coreceptor antago nist approved for combination therapy for HIV infection in adults infected with CCR5-tropic virus.
Enfuvirtide (Fuzeon, T-20) is classified as FDA pregnancy category B.

# A nim al carcinogenicity studies
Enfuvirtide was neither mutagenic or clastogenic in a series o f in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies o f enfuvirtide have not been conducted.

# R eproduction/fertility anim al studies
Reproductive toxicity has been evaluated in rats and rabbits. Enfuvirtide produced no adverse effects on fertility of male or female rats at doses up 30 mg/kg/day administered subcutaneously (1.6 times the maximum recommended adult human daily dose on an m2 body surface area basis).
- Teratogenicity/developm ental toxicity anim al studies
Studies in rats and rabbits revealed no evidence o f harm to the fetus from enfuvirtide administered in doses up to 27 times and 3.2 times, respectively, the adult human daily dose on an m 2 body surface area basis.
Antiretroviral Pregnancy Registry (Updated September 14, 2011)
The Antiretroviral Pregnancy Registry is an epidemiologic project to collect observational, nonexperi mental data on ARV exposure during pregnancy for the purpose o f assessing the potential teratogenicity o f these drugs. Registry data will be used to supplement animal toxicology studies and assist clinicians in weighing the potential risks and benefits o f treatment for individual patients. The registry is a collabo rative project o f the pharmaceutical manufacturers with an advisory committee o f obstetric and pediatric practitioners.
It is strongly recommended that health care providers who are treating HIV-infected pregnant women and their newborns report cases o f prenatal exposure to ARV drugs (either alone or in combination) to the Antiretroviral Pregnancy Registry. The registry does not use patient names, and birth outcome fol low-up is obtained from the reporting physician by registry staff.