# Presentation: 804753

## Slide 1

## Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the U.S.

**Update January 24, 2001**
**http://www.hivatis.org**

## What’s New in the PHS Guidelines for Reducing Perinatal HIV Transmission

**Preconception counseling section addition.**
**Update on mitochondrial toxicity issues in pregnancy and *****in utero***** antiretroviral exposure.**
**Recommend HAART if HIV RNA >1,000 (can discontinue postpartum).**
**Addition NVP if RNA+ at delivery *****not***** recommended.**
**Resistance testing same as non-pregnant.**
**Recommendations for IP/PP regimens.**
**If only newborn ARV, >48 hours unlikely effective.**
**Elective cesarean section for reducing transmission.**
** **

## Preconceptional Counseling and Care for HIV-Infected Women of Childbearing Age

**Contraception to reduce unintended pregnancy.**
**Counseling re: perinatal transmission and prevention.**
**Initiate/modify ARV therapy before conception:**
**Avoid drugs with possible reproductive toxicity.**
**Choose drugs effective in reducing perinatal transmission.**
**Attain stable, maximally suppressed viral load.**
**Evaluate/treat ARV side effects that could effect maternal-     fetal outcome (hyperglycemia, hepatic toxicity, anemia).**
**Evaluate OIs, need for prophylaxis, immunizations.**
**Optimize nutritional status.**
**Standard (history, STD screen, folate/vitamins).**
**Screening for substance abuse.**

## Principles Related to Antiretroviral Drug Use by HIV+ Pregnant Women and Their Infants

**Therapies of known or potential benefit should not be withheld during pregnancy unless:**
**There are known adverse effects on the mother, fetus or infant; and**
**These side effects outweigh potential benefit to the woman. **
**Special considerations regarding drug choice:**
**Antiretroviral pharmacokinetics in pregnancy.**
**Potential toxicities to pregnant woman and/or her fetus.**

## Principles Related to Antiretroviral Drug Use by HIV+ Pregnant Women and Their Infants

**Decision regarding use of antiretrovirals during pregnancy should be made by the woman following discussion of known and unknown benefits and risks.  Discussion includes:**
**AZT efficacy for reducing transmission.**
**Antiretrovirals recommended for her own health.**
**Relationship between transmission and HIV RNA.**
**Potential efficacy of elective cesarean delivery in reducing transmission.**
**Unknown long-term risks of *****in utero***** exposure.**

## Principles Related to Antiretroviral Drug Use by HIV+ Pregnant Women and Their Infants

**A long-term treatment plan should be developed for the woman and follow-up planned for infant.**
**Discuss general preventable risk factors for transmission (drug use, smoking, multiple  sexual partners).**
**Antiretroviral Pregnancy Registry reporting:**
**Telephone: 800-258-4263**
**Fax: 800-800-1052**

## General Considerations in Therapeutic Decision-Making for HIV+ Pregnant Women

**Gestational age of pregnancy**
**HIV RNA level**
**CD4 cell count**
**Clinical stage**
**Antiretroviral treatment history**
**Prevention of perinatal transmission**
**Safety/toxicity for mother and infant**

## Special Considerations on Antiretroviral Drug Use by HIV+ Pregnant Women and Their Infants

**Issues of special concern:**
**Drugs with higher teratogenic risk (efavirenz, hydroxyurea).**
**Combination antiretroviral therapy and preterm delivery (conflicting data).**
**Protease inhibitors and hyperglycemia.**
**Mitochondrial toxicity and nucleoside analogues:**
**Pregnancy – lactic acidosis, hepatic     steatosis, pancreatitis (d4T/ddI fatalities).**
**Fetus/infant – theoretical mitochondrial  toxicity with *****in utero***** exposure.**

## Possible Mitochondrial Dysfunction and Perinatal Exposure to Nucleoside AnaloguesBlanche S, et al.  Lancet 1999;354:1084-9

**8 children with possible mitochondrial dysfunction (2 deaths) from a cohort of 1754 children. **
**Overall 0.1% mortality, 0.3% morbidity.**
**All were uninfected but had perinatal NRTI exposure (4 AZT/3TC, 4 AZT alone; 1 only IP/PP).**
**2 - died @ 11 and 13 months of classic mitochondrial disease (Leighs’, Alper’s); both exposed AZT/3TC.**
**3 - neurologic symptoms (seizures) and 1 also  had transient cardiomyopathy.**
**3 - asymptomatic but mild transient metabolic abnormalities.**
**No control group; no mitochondrial DNA depletion; uncertain association with perinatal ARV exposure.**

## Lack of Death due to Mitochondrial Disease in Children Who Died at <5 Years in 5 U.S. CohortsPerinatal Safety Review Working Group.  JAIDS 2000;25:261-8

**Retrospective review of all deaths at **_**<**_**5 years old in children born to HIV+ mothers in U.S. databases**
**PACTG, WITS, PACTS, PSD & CDC Surveillance **
**Database included 16,313 uninfected children.**
**>50% ARV-exposed (89% AZT, rest mostly AZT/3TC). **
**30 deaths reported in cohort.**
**No death was attributable to mitochondrial disease or had symptoms, signs or laboratory findings suggestive of mitochondrial disease.**
**Review of living children ongoing.**
**Long-term follow-up and surveillance of children with ARV exposure important.**

## Antiretroviral Prophylaxis Scenario 1:HIV+ pregnant women who have not received prior antiretroviral therapy

**Conduct standard clinical, CD4 and RNA evaluations.**
**3-part 076 AZT regimen recommended to reduce perinatal transmission.**
**Combine AZT prophylaxis with additional drugs to treat HIV infection: **
**Recommend for women whose clinical, CD4 or RNA status requires treatment. **
**Strongly consider for any woman with RNA >1,000.**
**Women in 1****st**** trimester may consider delaying therapy until after 10-12 weeks gestation.**

##  Delivery Plasma HIV RNA Levels and Perinatal Transmission in WITS, 1990-1999Blattner W.  XIII AIDS Conf, July 2000, Durban S Africa (LBOr4) 

## 7-Cohort Meta-analysis of Transmission from Mothers with Delivery HIV RNA <1,000 Ioannidis JPA et al.  J Infect Dis 2001;183

**44 cases transmission among 1,202 HIV+ women with HIV RNA <1,000 at delivery.**
**Transmission differed by antiretroviral therapy:**
**Mothers receiving antiretrovirals: 8/834, 1.0%**
**Mothers not receiving antiretrovirals: 36/368, 9.8%**
**Multivariate analysis, transmission lower with:**
**Antiretroviral therapy:  OR 0.10, p<0.001**
**Cesarean section:  OR 0.30, p=0.02**
**Higher birth weight:  OR 0.89 per 100 gm, p=0.003**
**Higher maternal CD4:  OR 0.85 per 100 cells, p=0.04**

## Antiretroviral Prophylaxis Scenario 2:HIV+ pregnant women receiving antiretroviral therapy during the current pregnancy

**If pregnancy identified after 1****st**** trimester, continue therapy.**
**If pregnancy identified during 1****st**** trimester, discuss risks/benefits; if discontinue, all drugs should be stopped and restarted at same time.**
**AZT should be a component of regimen after 1****st**** trimester whenever possible.**
**AZT is recommended intrapartum and to newborn *****regardless***** of maternal antenatal regimen.**
**Resistance testing recommendations same as for non-pregnant (acute infection, virologic failure).**

## PACTG 316 Study Design

**	****	****	****	****    ****Mother in  ****	****   **
**	****	****	****        ****	****  ****Active Labor****	****	****    Infant**
**	****  ****All women receive****	**** Continue current****	****  AZT perinatal****	**
**	****antiretroviral therapy ****	****    antiretroviral ****	****    prophylaxis**
**	****   ****during pregnancy                               therapy (PACTG ****	****     regimen**
**      ****(PACTG 076 or other) ****	****     076 or other) ****	****      ****	****	****	****	****	****	****      **
_**Stratify by:**_
**	****	****	****	****	****Single 2 mg/kg**
**	****1)  Antiretroviral****	****Single 200 mg ****	****oral dose of ****	****	****	****     therapy during the ****	****oral dose of NVP ****	****NVP at age **
**	****	**** ****current pregnancy ****	****	****48-72 hours**
**	****	**** ****(none, mono, multiple)**
**	****	****	****        ****	****         ****OR****	****       OR**
**	****2)  CD4 cell count at ****	**
**	****     ****randomization ****	****NVP Placebo****	**** NVP Placebo****	**

**R****A****N****DOM****I****Z****E**

## Transmission in PACTG 316 by Treatment Arm Dorenbaum A.  8th Retro Conf, Feb 2001, Chicago, IL (Abs LB7) 

## PACTG 316:  NVP Resistance in Women Receiving ARV Treatment with Delivery HIV RNA >3,000Sullivan J.  XIII AIDS Conf, July 2000, Durban S Africa (LbOr014) 

**32 women with delivery & 6 wk postpartum samples & delivery RNA >3,000.**
**All women receiving minimum of ZDV prophylaxis.**
** **
**1 woman had pre-existing NVP resistance.**
** **
**4/32 ****(12.5%, 95% CI 3.5-25.0%)**** in NVP group had new NVP resistance mutation at 6 weeks postpartum.**
** **
**0/38 in placebo group had a new mutation.**
** **
** **

## Antiretroviral Prophylaxis Scenario 3:HIV+ pregnant women in labor who have had no prior antiretroviral therapy

**Several intra-/postpartum regimens are available:**
**2-dose nevirapine **
**AZT/3TC **
**AZT**
**2-dose nevirapine plus AZT**
**In immediate postpartum period, standard assessments (CD4, RNA) should be performed to determine whether antiretroviral therapy should be recommended for treatment of HIV disease.**
**	**

## 6 Week PETRA ZDV/3TC Trial Results:  What Can We Learn?	

**6 Week PETRA ZDV/3TC Trial Results:  ****What Can We Learn?****	**

## HIVNET 012 Results:  What Can We Learn?	

## Scenario 3:Intrapartum/Postpartum Prophylaxis Regimens

## Antiretroviral Prophylaxis Scenario 4:Infants born to HIV+ women with no therapy during pregnancy or intrapartum

**6-week neonatal AZT prophylaxis recommended.**
**AZT should be initiated within 6-12 hours of birth;      >48 hours unlikely to be effective.**
**Some clinicians may choose to give AZT combined   with other antiretrovirals, but efficacy unknown and appropriate dosage and safety incompletely defined.**
**In immediate postpartum period, standard assays   (CD4, RNA) should be performed to see whether antiretroviral therapy recommended for mother.**
**Infant should have early diagnostic testing to allow  early treatment if found to be infected.**

## ZDV Components and Perinatal Transmission of HIV

## European Randomized Mode of Delivery Trial:  Elective Cesarean at 38 Weeks vs Vaginal DeliveryEuropean Mode of Delivery Collaboration.  Lancet 1999;353:1035-9

## Mode of Delivery Scenario A:HIV+ woman >36 wks gestation, no ARV therapy, HIV RNA/CD4 pending but unlikely available before delivery

**Start antiretroviral therapy, including at least AZT.**
**Discuss therapy options.**
**Counsel elective C/S likely to reduce transmission.**
**Inform C/S risks (surgical, anesthesia, post-op infection).**
**Schedule C/S at 38 weeks gestation.**
**Intrapartum IV (start 3 hours before C/S) and infant 6 week AZT should be given.**
**Discuss options to continue or start combination antiretrovirals postpartum once RNA/CD4 return****.**

## Mode of Delivery Scenario B:HIV+ woman starting HAART 3rd trimester with initial viral response but HIV RNA substantially >1,000 copies/ml at 36 weeks gestation

**Continue HAART, as RNA level dropping appropriately.**
**Counsel that unlikely RNA will be <1,000 by delivery.**
**Therefore, elective C/S may provide additional benefit  in reducing intrapartum transmission to infant.**
**Inform C/S risks.**
**Intrapartum and infant 6 week AZT should be given.**
**Continue other antiretrovirals on schedule as much    as possible before/after surgery.**
**Emphasize importance of HAART adherence.**

## Mode of Delivery Scenario C:HIV+ woman on HAART with HIV RNA level undetectable at 36 weeks gestation

**Continue HAART.**
**Counsel that risk transmission when on ARV and with persistent undetectable RNA is low (<2%), even with vaginal delivery.**
**There is currently no information to evaluate whether elective C/S will substantially lower risk further.**
**C/S has increased risk of complications for woman compared to vaginal delivery, which should be balanced against uncertain benefit of C/S in this case.**
**Intrapartum and infant 6 week AZT should be given.**
** **

## Mode of Delivery Scenario D:HIV+ woman with planned elective C/S but who present early in labor or shortly after membrane rupture

**Start IV AZT immediately since woman in labor and/or ruptured membranes.**
**If labor progressing rapidly, allow vaginal delivery.**
**If cervical dilatation minimal and long labor anticipated, some clinicians may choose to give AZT IV loading dose and proceed with C/S to minimize duration membrane rupture and avoid vaginal delivery.**
**Others might begin pitocin augmentation to enhance contractions and potentially expedite delivery; avoid invasive procedures (e.g., scalp electrodes).**
**Infant should receive 6 weeks AZT.**
** **

## Virologic, Immunologic and Other Monitoring During Pregnancy

**CD4 count:  same  as non-pregnant.**
**Baseline (diagnosis pregnancy), q 3-4 months.**
**HIV RNA:  same as non-pregnant.**
**Baseline (diagnosis pregnancy), prior to therapy, 4 weeks after start/change therapy, q 3-4 months.**
**Resistance testing:  same as non-pregnant**
**Acute infection or virologic failure**
**Additional monitoring based on antiretroviral drug:**
**NRTI – lactic acidosis, hepatic steatosis**
**NNRTI – rash, hepatitis**
**PI – hyperglycemia, preterm delivery (?)**

## Monitoring of the Newborn

**CBC:  Minimum monitoring for hemoglobin/ neutrophil count:**
**At birth/baseline**
**6 weeks**
**12 weeks**
**More frequent if anemic at birth or premature**
**If other antiretrovirals are given, more frequent or intensive (e.g. liver function tests) monitoring may be warranted.**

## Monitoring of the Newborn

**PCP prophylaxis:**
**Initiate at age 4-6 weeks**
**HIV virologic diagnostic testing:**
**Birth – 48 hours**
**2 weeks**
**1-2 months (after chemoprophylaxis finished)**
**3-6 months**