Reducing the Incidence of Nevirapine Resistance Mutations in Pregnant HIV Infected Women Who Receive Anti-HIV Drugs Prior to and After Giving Birth

Study Overview
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Brief Summary
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The purpose of this study is to determine which of 3 different anti-HIV drug regimens given to HIV infected pregnant women during and after their pregnancies is most effective in reducing the incidence of nevirapine (NVP) resistance mutations. Blood levels of NVP and lopinavir/ritonavir (LPV/r) will also be studied. Study hypothesis: NVP resistance following single-dose NVP can be prevented with the concomitant administration of additional antiretroviral therapy (ART).

Detailed Description
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A single dose of nevirapine (SD-NVP) given to an HIV infected pregnant woman in labor followed by a single dose to her infant had been shown to be a simple and effective means of reducing mother-to-child transmission (MTCT) of HIV among women who had not received antiretroviral (ART) during pregnancy. However, development of NVP and other nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant virus was a concern. An optimal ART regimen that can prevent selection of resistant virus while efficiently preventing MTCT was needed. This study evaluated 3 different ART strategies for preventing the development of NVP resistance in HIV infected pregnant women and compared the incidence of NVP resistance mutations postpartum observed with each regimen to the incidence among historical controls. NVP and LPV/r pharmacokinetics (PK) were also evaluated in this study. Participants were randomly assigned to one of three study arms. All study participants received a single dose of oral NVP at the onset of labor and, oral zidovudine (ZDV) at the onset of labor, and every three hours during labor. Arm A: (LPV/r x 7d) participants received enteric-coated didanosine (ddI) and LPV/r orally twice daily beginning at the onset of labor and continuing through 7 days postpartum; oral ZDV was also taken twice daily for 7 days postpartum. Arm B: (no LPV/r) participants received enteric-coated ddI beginning at the onset of labor and continued through 30 days postpartum; oral ZDV was also taken twice daily for 30 days postpartum. Arm C : (LPV/r x 30d) participants received enteric-coated ddI and LPV/r orally twice daily beginning at the onset of labor and continued through 30 days postpartum; oral ZDV was also taken twice daily for 30 days postpartum. All women were followed for at least 24 weeks postpartum. Women with resistance mutations identified within 8 weeks postpartum were to be followed until 72 weeks postpartum to evaluate the persistence of the mutations. All infants were followed until at least 12 weeks of age. HIV-infected infants were to be followed until 24 weeks of age. There were 11 study visits for women at day 10, 21, and 30 and week 5, 6, 8, 12, 24, 36, 48, and 72. Medical history assessment, a physical exam, and blood collection occurred at all visits. Blood collection for PK studies occurred at Days 10, 21, and 30. All women were asked to complete an adherence questionnaire at Day 10; women assigned to Arms A : LPV/r x 7d and B: no LPV/r were also asked to complete an adherence questionnaire at Day 30. There were 6 study visits for infants at birth - 48 hours, day 21, week 5, 12, 16 and 24. Medical history assessment and a physical exam occurred at most visits; blood collection occurred at all visits. Data and specimens for the historical control comparison group were obtained from the PHPT-2 trial*, in which five of the P1032 study sites had participated between 2001 and 2003. PHPT-2 was a study of the efficacy of SD-NVP to prevent MTCT among women who received ZDV after 27 weeks gestation but no postpartum ART. Criteria for inclusion in the historical comparison group included receipt of SD-NVP, a CD4 count of more than 250 cells per cubic millimeter within 30 days of screening or entry, and the availability of plasma samples at 10 days or 6 weeks post-partum. * Lallement M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004; 351:217-28.

Official Title
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Phase II Study of the Pharmacokinetics of Nevirapine and the Incidence of Nevirapine Resistance Mutations in HIV-Infected Women Receiving a Single Intrapartum Dose of Nevirapine With the Concomitant Administration of Zidovudine/Didanosine or Zidovudine/Didanosine/Lopinavir/Ritonavir

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Didanosine, enteric-coated
* Drug: Lopinavir/ritonavir
* Drug: Nevirapine
* Drug: Zidovudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Mothers: HIV infected Pregnant with a viable fetus Between 28 and 38 weeks of pregnancy CD4 count greater than 250 cells/mm3 within 30 days prior to study entry Able to receive oral ART during labor Willing to use acceptable forms of contraception while on study treatment Able to provide written informed consent Exclusion Criteria for Mothers: Known allergy or hypersensitivity to ddI, LPV, NVP, ritonavir (RTV), or ZDV Any ART other than ZDV during a previous pregnancy or the current pregnancy Certain medications Planning to receive additional ART during the first 8 weeks postpartum Planning to breastfeed Unlikely to comply with postpartum study requirements, in the opinion of the investigator Certain abnormal laboratory values within 30 days prior to study entry

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: LPV/r x 7d<br>NVP 200 mg orally, single dose at onset of labor, ZDV 300 mg orally at onset of labor, every 3 hours during labor and BID for 7 days postpartum, ddI 250 mg orally daily (if body weight <60 kg) or 400 mg orally twice daily (if body weight >= 60 kg) at the onset of labor, during labor, and for 7 days postpartum, LPV/r 400/100mg orally twice daily at the onset of labor, during labor and for 7 days postpartum. | Drug: Didanosine, enteric-coated<br>* once daily<br>Drug: Lopinavir/ritonavir<br>* twice daily<br>Drug: Nevirapine<br>* single-dose at the onset of labor<br>Drug: Zidovudine<br>* twice daily<br>|
| Experimental: Arm B: no LPV/r<br>NVP 200 mg orally, single dose at onset of labor, ZDV 300 mg orally at onset of labor, every 3 hours during labor and twice daily for 7 days postpartum , ddI 250 mg orally daily (if body weight <60 kg) or 400 mg orally daily (if body weight >= 60 kg) at the onset of labor, during labor, and for 30 days postpartum. | Drug: Didanosine, enteric-coated<br>* once daily<br>Drug: Nevirapine<br>* single-dose at the onset of labor<br>Drug: Zidovudine<br>* twice daily<br>|
| Experimental: Arm C: LPV/r x 30d<br>NVP 200 mg orally, single dose at onset of labor, ZDV 300 mg orally at onset of labor, every 3 hours during labor and twice daily for 7 days postpartum , ddI 250 mg orally daily (if body weight <60 kg) or 400 mg orally daily (if body weight >= 60 kg) at the onset of labor, during labor, and for 30 days postpartum,LPV/r 400/100mg orally twice daily at the onset of labor, during labor and for 30 days postpartum. | Drug: Didanosine, enteric-coated<br>* once daily<br>Drug: Lopinavir/ritonavir<br>* twice daily<br>Drug: Nevirapine<br>* single-dose at the onset of labor<br>Drug: Zidovudine<br>* twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Women Who Develop One or More New NVP Resistance Mutations as Identified by Consensus Sequencing or Oligonucleotide Ligation Assay in Plasma (Sampling Was Done at Days 10,21,30, and Weeks 5,6, and 8 Postpartum). | The incidence of new NVP resistance mutation in plasma HIV within 8 weeks postpartum in each randomized arm was estimated using an exact binomial confidence interval. If a resistance mutation was detected at any of the timepoints then an endpoint was met. Samples with VL <500 copies/mL were considered free of mutations. If a resistance result was missing for reasons other than VL <500 copies/ml (e.g.missed visit), it was conservatively imputed as resistant in the primary analysis. | within 8 weeks postpartum. | 
| The Proportion of Women in Each Randomized Arm Who Have One or More New NVP Resistance Mutations as Identified by Consensus Sequencing or Oligonucleotide Ligation Assay (OLA) in Plasma | The incidence of new NVP resistance mutations at day 10 or week 6 postpartum in each randomized arm. Samples with viral load <500 copies/mL were considered free of mutations. If a resistance result was missing for reasons other than VL <500 copies/ml it was conservatively imputed as resistant in the primary analysis. | at Day 10 or Week 6 postpartum. | 
| Area Under the Curve Pharmacokinetic Outcome for LPV/r. (AUC ug*hr/mL) | Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test. | Within 72 hours postpartum and during the first 30 days postpartum | 
| Maximum Concentration Pharmacokinetic Outcome for LPV/r (Cmax ug/mL) . | Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test. | Within 72 hours postpartum and during the first 30 days postpartum | 
| Pre-dose Concentration Pharmacokinetic Outcome for LPV/r (Cpredose ug/mL). | Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test. | Within 72 hours postpartum and during the first 30 days postpartum | 
| Four (4) Hour Concentration Pharmacokinetic Outcome for LPV/r (C4hour ug/mL). | Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test. | Within 72 hours postpartum and during the first 30 days postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Women in Each Randomized Arm Who Have One or More New NVP Resistance Mutations for the Subgroup of Women With Plasma HIV RNA >= 500 Copies/ml At Entry | The incidence of new NVP resistance mutations at day 10 or week 6 postpartum in each randomized arm. Samples with viral load <500 copies/mL were considered free of mutations. If a resistance result was missing for reasons other than VL <500 copies/ml it was conservatively imputed as resistant in the primary analysis. | at Day 10 or Week 6 postpartum. | 
| The Proportion of Women With Any New ZDV, ddI, or LPV/r Resistance Mutations. |  | At Week 5 postpartum (ZDV) and at the first timepoint with viral load >=500 copies/ml after treatment discontinuation (ddI and LPV/r). | 
| Number of Women With Grade >=3 Events After Start of Study Treatment | Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading > the Severity of Adult and Pediatric Adverse Events (December 2004). All grade 3 and higher signs, symptoms, and laboratory toxicities (and events of any grade that led to a change in study treatment) were included. | After start of study Treatment (postpartum) | 
| Proportion of Women With New NVP Resistance Mutation Within 8 Weeks Postpartum Who Had a NVP Resistance Mutation Detected at 72 Weeks Postpartum. | Resistance mutations as identified by OLA in plasma samples or PBMC at 72 weeks postpartum amongst women who had new NVP resistance mutations within 8 weeks postpatrum. These results were based on the 13 women who developed a new NVP resistance mutation in the first 8 weeks postpartum. For the primary outcome measure 1, one particpant in arm A was unavailable for follow-up after week 5 and was conservatively imputed to have developed resistance mutation. | within 72 weeks postpartum | 
| Resistance Mutations in HIV Infected Infants | Resistance mutations as identified by consensus sequencing or OLA | 24 weeks postpartum | 
| Median HIV-1 Viral Load at 24 Weeks Postpartum in Women |  | at 24 weeks postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Seronegativity, Treatment Naive, Pregnancy, Perinatal Transmission, Vertical Transmission, Mother-To-Child Transmission, MTCT