Clinical trial NCT00109590: Reducing the Incidence of Nevirapine Resistance Mutations in Pregnant HIV Infected Women Who Receive Anti-HIV Drugs Prior to and After Giving Birth
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: HIV Seronegativity
Treatment Naive
Pregnancy
Perinatal Transmission
Vertical Transmission
Mother-To-Child Transmission
MTCT
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2005-05-02
Enrollment: 175
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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).
timeFrame: within 8 weeks postpartum.
measure: 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
timeFrame: at Day 10 or Week 6 postpartum.
measure: Area Under the Curve Pharmacokinetic Outcome for LPV/r. (AUC ug*hr/mL)
timeFrame: Within 72 hours postpartum and during the first 30 days postpartum
measure: Maximum Concentration Pharmacokinetic Outcome for LPV/r (Cmax ug/mL) .
timeFrame: Within 72 hours postpartum and during the first 30 days postpartum
measure: Pre-dose Concentration Pharmacokinetic Outcome for LPV/r (Cpredose ug/mL).
timeFrame: Within 72 hours postpartum and during the first 30 days postpartum
measure: Four (4) Hour Concentration Pharmacokinetic Outcome for LPV/r (C4hour ug/mL).
timeFrame: Within 72 hours postpartum and during the first 30 days postpartum
Secondary outcomes:
measure: 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
timeFrame: at Day 10 or Week 6 postpartum.
measure: The Proportion of Women With Any New ZDV, ddI, or LPV/r Resistance Mutations.
timeFrame: At Week 5 postpartum (ZDV) and at the first timepoint with viral load >=500 copies/ml after treatment discontinuation (ddI and LPV/r).
measure: Number of Women With Grade >=3 Events After Start of Study Treatment
timeFrame: After start of study Treatment (postpartum)
measure: Proportion of Women With New NVP Resistance Mutation Within 8 Weeks Postpartum Who Had a NVP Resistance Mutation Detected at 72 Weeks Postpartum.
timeFrame: within 72 weeks postpartum
measure: Resistance Mutations in HIV Infected Infants
timeFrame: 24 weeks postpartum
measure: Median HIV-1 Viral Load at 24 Weeks Postpartum in Women
timeFrame: at 24 weeks postpartum
Other outcomes:
Locations:
city: Bangkok
country: Thailand
facility: Siriraj Hospital Mahidol University CRS
state: Bangkoknoi
city: Saimai
country: Thailand
facility: Bhumibol Adulyadej Hosp. CRS
state: Bangkok
city: Chantaburi
country: Thailand
facility: Prapokklao Hosp. CRS
city: Chiang Mai
country: Thailand
facility: Chiang Mai University Pediatrics-Obstetrics CRS
city: Chiangrai
country: Thailand
facility: Chiangrai Prachanukroh Hospital CRS
city: Chonburi
country: Thailand
facility: Chonburi Hosp. CRS
city: Phayao
country: Thailand
facility: Phayao Provincial Hosp. CRS
Study officials:
affiliation: Tulane University Medical School
name: Russell Van Dyke, MD
role: STUDY_CHAIR
affiliation: Program for HIV Prevention and Treatment / IRD054, Department of Immunology and Infectious Diseases, Harvard School of Public Health
name: Gonzague J. Jourdain, MD
role: STUDY_CHAIR
References:
citation: Cunningham CK, Chaix ML, Rekacewicz C, Britto P, Rouzioux C, Gelber RD, Dorenbaum A, Delfraissy JF, Bazin B, Mofenson L, Sullivan JL. Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: a substudy of pediatric AIDS clinical trials group protocol 316. J Infect Dis. 2002 Jul 15;186(2):181-8. doi: 10.1086/341300. Epub 2002 Jun 26.
citation: Lyons FE, Coughlan S, Byrne CM, Hopkins SM, Hall WW, Mulcahy FM. Emergence of antiretroviral resistance in HIV-positive women receiving combination antiretroviral therapy in pregnancy. AIDS. 2005 Jan 3;19(1):63-7. doi: 10.1097/00002030-200501030-00007.
citation: Sullivan JL. Prevention of mother-to-child transmission of HIV--what next? J Acquir Immune Defic Syndr. 2003 Sep;34 Suppl 1:S67-72. doi: 10.1097/00126334-200309011-00010.
citation: Thorne C, Newell ML. The safety of antiretroviral drugs in pregnancy. Expert Opin Drug Saf. 2005 Mar;4(2):323-35. doi: 10.1517/14740338.4.2.323.
citation: Cressey TR, Van Dyke R, Jourdain G, Puthanakit T, Roongpisuthipong A, Achalapong J, Yuthavisuthi P, Prommas S, Chotivanich N, Maupin R, Smith E, Shapiro DE, Mirochnick M; IMPAACT P1032 Team. Early postpartum pharmacokinetics of lopinavir initiated intrapartum in Thai women. Antimicrob Agents Chemother. 2009 May;53(5):2189-91. doi: 10.1128/AAC.01091-08. Epub 2009 Feb 23.
citation: Van Dyke RB, Ngo-Giang-Huong N, Shapiro DE, Frenkel L, Britto P, Roongpisuthipong A, Beck IA, Yuthavisuthi P, Prommas S, Puthanakit T, Achalapong J, Chotivanich N, Rasri W, Cressey TR, Maupin R, Mirochnick M, Jourdain G; IMPAACT P1032 Protocol Team. A comparison of 3 regimens to prevent nevirapine resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine. Clin Infect Dis. 2012 Jan 15;54(2):285-93. doi: 10.1093/cid/cir798. Epub 2011 Dec 5.