Evaluating the Response to Two Antiretroviral Medication Regimens in HIV-Infected Pregnant Women, Who Begin Antiretroviral Therapy Between 20 and 36 Weeks of Pregnancy, for the Prevention of Mother-to-Child Transmission

Study Overview
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Brief Summary
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HIV-infected pregnant women who begin taking antiretroviral (ARV) medications in the late stages of pregnancy need an effective medication regimen to reduce the risk of transmitting HIV to their children. This study examined the virologic response, safety, and tolerability of two different ARV medication regimens in HIV-infected pregnant women who were between 20 and 36 weeks pregnant when they entered the study.

Detailed Description
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When initiating this study there were many ARV medications and combination regimens available to treat HIV-infected people. However, the number of ARV medications that had been studied in HIV-infected pregnant women for the prevention of mother-to-child transmission was limited. Although HIV-infected pregnant women who began taking ARV medications late in their pregnancies required effective therapy to reduce the risk of transmitting HIV to their children, there were no published data available that compared the effects of non-nucleoside reverse transcriptase inhibitors (NNRTI) and integrase inhibitors (which are two classes of ARV medications) in pregnant women. The purpose of this study was to compare the safety, tolerability, and virologic responses to two different medication regimens, each of which included an NNRTI or integrase inhibitor, in pregnant HIV-infected women who began ARV therapy late in their pregnancies (i.e., had gestational age between 20 and 36 weeks). This study was originally opened under IMPAACT P1081, protocol version 2.0 (version 1.0 never opened to accrual) as a three arm study. However, IMPAACT P1081 was closed due to slow accrual, at which point NICHD took over the study, streamlined it to two arms, and reopened it as NICHD P1081 under protocol Version 3.0. Women who enrolled under IMPAACT P1081 (N=20) and were randomized to one of the two continuing arms (efavirenz- or raltegravir-based ART; N=14) were included in NICHD P1081, while IMPAACT P1081 women randomized to the dropped arm (lopinavir/ritonavir-based ART; N=6) were not eligible for inclusion in NICHD P1081. In this study HIV-infected pregnant women were randomly assigned to one of two arms. Women in Arm A received lamivudine 150 mg/zidovudine 300 mg twice a day and efavirenz 600 mg each night. Women in Arm B received lamivudine 150 mg/zidovudine 300 mg twice a day and raltegravir 400 mg twice a day. All women were scheduled to receive their assigned medications from study entry through delivery. Antepartum study visits were scheduled at entry and Weeks 1, 2, and 4; and thereafter, every two weeks until labor and delivery. Study visits included a medical history review, physical examination, questionnaires, blood collection, and a vaginal swab procedure. While women were in labor, they were scheduled to continue to receive their study medications. Some women may have received additional or alternate medications according to local standard of care/guidelines. Women had a physical examination and blood collection at the delivery visit. After delivery, some women continued to receive ARV medications according to the local guidelines, and could have received study ARV for up to eight weeks postpartum while they transitioned to the ARV regimen indicated per their local standard of care. Women were scheduled to attend study visits following delivery at Weeks 2, 6, 16, and 24, which included a medical history review, physical examination, and blood collection. Select visits were scheduled to include a vaginal swab procedure. Some women had vaginal specimens stored for future research. Infants delivered on study were scheduled to receive ARV medications as prescribed by the babies' doctors per local standard of care/guidelines. Study visits for infants were scheduled at birth, and at Weeks 2, 6, 16, and 24. Each study visit included a medical history review, physical examination, and blood collection. Select visits included oral and nasopharyngeal swab collection.Some infants had oral and/or nasopharyngeal specimens stored for future research.

Official Title
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A Phase IV Randomized Trial to Evaluate the Virologic Response and Pharmacokinetics of Two Different Potent Regimens in HIV Infected Women Initiating Triple Antiretroviral Regimens Between 20 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission: NICHD P1081

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Lamivudine/zidovudine
* Drug: Efavirenz
* Drug: Raltegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Naive to antiretroviral therapy (ART) or have received ART with short course zidovudine (maximum of 8 weeks) for prevention of mother-to-child transmission in previous pregnancies Willing and able to sign informed consent. Participant must be of an age to provide legal informed consent as defined by the country in which the participant resides. If not, the informed consent must be signed by a legal guardian/parent, as per country guidelines. Documentation of HIV-1 infection defined as positive results from two samples collected at different time points. The same method may be used at both time points. All samples tested must be whole blood, serum, or plasma. Documentation may be abstracted from medical records to satisfy these criteria for infection. More information on this criterion can be found in the protocol. Viable pregnancy with gestational age of greater than or equal to 20 weeks to less than or equal to 36 weeks based upon menstrual history and/or ultrasound. Note: If menstrual history is unknown or if there is a discrepancy between menstrual history and ultrasound, determination of gestational age should be based upon best available methodology at each site. Intends to continue pregnancy Willingness and intent to deliver at the participating clinical site and to be followed for the duration of the study at the site or associated outpatient facility Willing to comply with the study regimen Agrees to use two reliable methods of contraception after delivery if randomized to the efavirenz arm and is sexually active. A barrier method of contraception (condoms, diaphragm, or cervical cap) together with another reliable form of contraception must be used for 4 weeks after stopping efavirenz. Exclusion Criteria: Active labor defined as onset of regular contractions or cervical dilatation greater than 2 cm Use of ART during current pregnancy Chemotherapy for active malignancy HIV genotypic resistance, as defined in the protocol, to efavirenz or raltegravir or to NRTIs that will be included in the ART regimen. Note: A lack of HIV drug resistance test results at the time of enrollment is not exclusionary. Serious active opportunistic infection and/or serious bacterial infection including active tuberculosis (TB) or unstable or severe medical condition within 14 days of study entry Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study Vomiting or inability to swallow medications due to an active, pre-existing condition that prevents adequate swallowing and absorption of study medication Known allergy/sensitivity to any study drugs or their formulations or sulfonamide allergy The following laboratory values (within 30 days of enrollment): Hemoglobin greater than or equal to Grade 3 Absolute neutrophil count greater than or equal to Grade 2 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to Grade 2 Serum creatinine greater than or equal to Grade 1 Platelet count greater than or equal to Grade 3 Evidence of pre-eclampsia (such as persistent diastolic blood pressure greater than 90 mm Hg) Receipt of disallowed medications as described in the protocol

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Women)<br>Pregnant women received ZDV/3TC + EFV | Drug: Lamivudine/zidovudine<br>* Participants received one lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet twice a day from entry through delivery*. * Participants may have received a locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone in place of lamivudine/zidovudine with permission of the protocol team obtained prior to randomization.<br>* Other names: ZDV/3TC;Drug: Efavirenz<br>* Participants received one 600 mg tablet of efavirenz each night from entry through delivery.<br>* Other names: EFV;|
| Experimental: Arm B (Women)<br>Pregnant women received ZDV/3TC + RAL | Drug: Lamivudine/zidovudine<br>* Participants received one lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet twice a day from entry through delivery*. * Participants may have received a locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone in place of lamivudine/zidovudine with permission of the protocol team obtained prior to randomization.<br>* Other names: ZDV/3TC;Drug: Raltegravir<br>* Participants received one 400 mg raltegravir tablet twice a day from entry through delivery.<br>* Other names: RAL;|
| No Intervention: Arm A (Infants)<br>Infants born to women in Arm A; infants received no study intervention. | |
| No Intervention: Arm B (Infants)<br>Infants born to women in Arm B; infants received no study intervention. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Women With Plasma HIV-1 RNA Viral Load Less Than 200 Copies/mL at Delivery | If there was no viral load measurement at the delivery visit, the last viral load within three weeks prior to delivery was considered. | Measured at participants' delivery visit (or last visit within three weeks prior to delivery) | 
| Proportion of Participants Who Discontinued Randomized Study Drug Prior to Labor and Delivery. | Only women who initiated (i.e. received at least one dose of) their randomized treatment were eligible for this outcome measure. Women were considered to have discontinued study drug if they stopped receiving efavirenz or raltegravir (whichever was assigned) prior to labor and delivery for any reason, including loss to follow-up. | Measured from entry through participants' delivery visit (approximately 36 to 40 weeks gestation) | 
| Proportion of Women Who Experienced at Least One New Adverse Event of Greater Than or Equal to Grade 3 as Defined in the Division of AIDS (DAIDS) Toxicity Table | New adverse events were those with an onset date on or after randomization. Adverse events present at baseline would only be considered New if they increased in grade on or after randomization. All women who received at least one dose of study drug were eligible for this analysis. | Measured from entry through participants' last study visit, approximately 24 weeks after delivery | 
| Proportion of Infants Who Experienced at Least One Adverse Event of Greater Than or Equal to Grade 3. | All infants who were live births on study were eligible for this analysis. Adverse event grades were defined based on the DAIDS toxicity table. | Measured from birth through infants' last study visit, approximately 24 weeks after delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Women Who Achieved HIV-1 RNA Virologic Suppression Below the Lower Limit of Quantification of the Assay at Delivery | A successful outcome was defined as maternal HIV-1 RNA plasma viral load less than the lower limit of quantification (LLQ) for the testing assay, which could vary. Most (99%) women had their viral load measured using an assay with LLQ equal to 40 or 20 copies/mL. If the viral load at delivery was missing, the last observed viral load within 21 days prior to the delivery date was considered. | Measured at participants' delivery visit (or last visit within three weeks prior to delivery) | 
| Proportion of Women With 1) Successful Viral Load (Plasma HIV-1 RNA VL) Decrease From Entry to Week 2 and VL Less Than 1,000 Copies/ml at All Time Points After 4 Weeks on Study Drugs, Until Delivery; and 2) Who Remain on the Assigned Study Regimen | A successful viral load decrease was defined as follows: for women having HIV-1 RNA viral load greater than or equal to 10,000 copies/mL at entry, a viral load <200 copies/mL; for women with VL less than 10,000 copies/mL at entry, a Log10 viral load decrease of at least 2.0 from entry. | Measured from entry through delivery (approximately 36 to 40 weeks gestation). | 
| Log10 Change in Viral Load From Entry to Each Time Point Prior to Delivery | Change in viral load from entry (or screening, if there was no entry viral load) to each study week prior to delivery, calculated on the log10 scale as log10(week X RNA) - log10(baseline RNA). For this analysis, HIV-1 RNA values that were censored below the lower limit of quantification (LLQ) were imputed to be equal to the LLQ - 1. | Measured at antepartum Weeks 1, 2, 4, 6, 8, 10, 12, 14, and 16. | 
| Proportion of Women With HIV-1 RNA Plasma Viral Load Less Than 200 Copies/mL at Weeks 4 and 6 From Treatment Initiation | The Week 4 and 6 participant viral loads were the viral load results obtained closest to (within four days of) the target date for that visit from initiation of treatment (for Week 4, day 24-32 after first dose; for Week 6, day 38-46 after first dose). | Measured at Weeks 4 and 6 from first dose of randomized treatment, prior to delivery | 
| Proportion of Women With HIV-1 RNA Vaginal Viral Load Less Than 1200 Copies/mL at Weeks 4 and 6 From Treatment Initiation | The Week 4 and 6 participant viral loads were the viral load results obtained closest to (within four days of) the target date for that visit from initiation of treatment (for Week 4, day 24-32 after first dose; for Week 6, day 38-46 after first dose). Vaginal swabs produce much less testable sample volume than blood plasma draws. Each vaginal swab specimen had to be diluted, and this dilution factor raised the lower limit of quantification (LLQ). The most commonly observed LLQs were 300 and 1200. For consistency, the higher LLQ was considered the threshold for this outcome measure. | Measured at Weeks 4 and 6 from first dose of randomized treatment, prior to delivery | 
| Infectivity of Plasma | The goal of this outcome measure was to address an objective relevant to protease inhibitors, one of which was originally included as a third arm in the Version 2.0 of the study. This outcome measure was included to assess how the infectivity of plasma changed over time among women receiving protease inhibitors, and whether this differed from other classes of antiretroviral drugs. However, the lopinavir/ritonavir arm was later dropped in Version 3.0, and only Version 2.0 women who received efavirenz or raltegravir were included in the study analyses. Therefore, because no women included in the study analyses received lopinavir/ritonavir, this outcome measure was not analyzed. | Measured on or after delivery up to participants' last postpartum study visit (approximately 26 weeks after delivery) | 
| Proportion of Deliveries That Had an Outcome of a Stillbirth/Fetal Demise. | The unit of analysis was the mother-infant set. All sets where the woman received at least one dose of study treatment and remained on study through delivery were eligible. In the case of twins, the worst outcome (i.e. a stillbirth) was used. | Measured at delivery (approximately 36 to 40 weeks gestation) | 
| Proportion of Deliveries That Were Premature (Less Than 37 Weeks Gestation) | The unit of analysis for this outcome measure was the mother-infant set. A mother-infant set was counted as having a premature delivery if any infant in the mother-infant set was delivered prior to 37 weeks gestation (i.e. in the case of twins, if either of the twins was delivered prior to 37 weeks gestation then this set would count as one premature delivery outcome). All mother-infant sets that delivered at least one live birth on study were eligible for this outcome. | Measured at delivery (within 72 hours). | 
| Proportion of Deliveries That Were Extremely Premature (Less Than 34 Weeks Gestation). | The unit of analysis for this outcome measure was the mother-infant set. A mother-infant set was counted as having an extremely premature delivery if any infant in the mother-infant set was delivered prior to 34 weeks gestation (i.e. in the case of twins, if either of the twins was delivered prior to 34 weeks gestation then this set would count as one extremely premature delivery outcome). Only women who enrolled prior to 34 weeks gestation were included in this analysis. Those that enrolled from 34 to less than 37 weeks gestation were excluded because they were already past the gestational age where this outcome could have occurred at entry. | At delivery (within 72 hours). | 
| Proportion of Deliveries With a Low Birth Weight (Less Than 2,500 Grams) | The unit of analysis was the mother-infant pair or set; in the case of multiple gestation, the worst outcome was considered in analysis (e.g. if two twins were delivered to one mother, one at 2,000 grams and one at 3,000 grams, this mother-infant set would count as one instance of low birth weight in analysis because at least one of the infants had the outcome). | Measured within 72 hours after delivery | 
| Proportion of Deliveries With an Extremely Low Birth Weight (<1,500 Grams). | The unit of analysis was the mother-infant pair or set; in the case of multiple gestation, the worst outcome was considered in analysis (e.g. if two twins were delivered to one mother, one at 2,000 grams and one at 1,000 grams, this mother-infant set would count as one instance of extremely low birth weight in analysis because at least one of the infants had the outcome). | Measured within 72 hours after delivery | 
| Infant HIV Infection Status (Per International Maternal Pediatric Adolescent AIDS Clinical Trials Group [IMPAACT] Definitions) | Infants were considered infected if they had both a positive HIV nucleic acid test and a subsequent confirmatory test on a different sample. Uninfected infants were those that had no positive test results and negative test results obtained at two or more of the following visits: Week 6, Week 16, and/or Week 24 postpartum. | Measured from birth through infants' last study visit at Week 24 | 
| Proportion of HIV-infected Infants With Genotypic Resistance to Study Drugs | Genotypic resistance to each class of study drug (reverse transcriptase inhibitors and integrase inhibitors) was assessed separately among HIV infected infants. | Measured on or after confirmation of HIV-infection up to the infants' last study visit at Week 24 | 
| Proportion of Women With HIV-1 Drug Resistance Mutations at Screening, 2-4 Weeks Postpartum in Women Who Stopped Antiretroviral Therapy, and at the Time of Inadequate Virologic Response Using Standard and Ultrasensitive Methods. | Consensus sequencing was performed on a sample from screening. Women were evaluated for integrase and reverse transcriptase resistance mutations separately. Additionally, consensus sequencing was performed among women who had an inadequate virologic response (defined in the protocol) on a sample taken at that time of inadequate virologic response. Genotypic resistance among women who stopped antiretroviral therapy was not assessed. Because World Health Organization guidelines have been updated to indicate all people living with HIV should remain on antiretroviral therapy, even postpartum women, no women stopped antiretroviral therapy after delivery. Therefore, this aspect of the outcome measure is no longer relevant and was not assessed. | Measured at screening and at the time of inadequate virologic response (from Week 2 antepartum through participants' last study visit 24 weeks after delivery). |