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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 175
- 试验地点
- 7
- 主要终点
- Area Under the Curve Pharmacokinetic Outcome for LPV/r. (AUC ug*hr/mL)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm A: LPV/r x 7d
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.
干预措施: Didanosine, enteric-coated (Drug)
Arm A: LPV/r x 7d
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.
干预措施: Lopinavir/ritonavir (Drug)
Arm A: LPV/r x 7d
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.
干预措施: Nevirapine (Drug)
Arm A: LPV/r x 7d
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.
干预措施: Zidovudine (Drug)
Arm B: no LPV/r
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.
干预措施: Didanosine, enteric-coated (Drug)
Arm B: no LPV/r
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.
干预措施: Nevirapine (Drug)
Arm B: no LPV/r
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.
干预措施: Zidovudine (Drug)
Arm C: LPV/r x 30d
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.
干预措施: Didanosine, enteric-coated (Drug)
Arm C: LPV/r x 30d
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.
干预措施: Lopinavir/ritonavir (Drug)
Arm C: LPV/r x 30d
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.
干预措施: Nevirapine (Drug)
Arm C: LPV/r x 30d
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.
干预措施: Zidovudine (Drug)
结局指标
主要结局
Area Under the Curve Pharmacokinetic Outcome for LPV/r. (AUC ug*hr/mL)
时间窗: Within 72 hours postpartum and during the first 30 days postpartum
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.
Maximum Concentration Pharmacokinetic Outcome for LPV/r (Cmax ug/mL) .
时间窗: Within 72 hours postpartum and during the first 30 days postpartum
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.
Four (4) Hour Concentration Pharmacokinetic Outcome for LPV/r (C4hour ug/mL).
时间窗: Within 72 hours postpartum and during the first 30 days postpartum
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.
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).
时间窗: within 8 weeks 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.
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
时间窗: at Day 10 or Week 6 postpartum.
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.
Pre-dose Concentration Pharmacokinetic Outcome for LPV/r (Cpredose ug/mL).
时间窗: Within 72 hours postpartum and during the first 30 days postpartum
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.
次要结局
- 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).)
- Median HIV-1 Viral Load at 24 Weeks Postpartum in Women(at 24 weeks postpartum)
- Proportion of Women With New NVP Resistance Mutation Within 8 Weeks Postpartum Who Had a NVP Resistance Mutation Detected at 72 Weeks Postpartum.(within 72 weeks postpartum)
- Resistance Mutations in HIV Infected Infants(24 weeks postpartum)
- 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(at Day 10 or Week 6 postpartum.)
- Number of Women With Grade >=3 Events After Start of Study Treatment(After start of study Treatment (postpartum))