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

NCT00109590 | Completed Phase 2 Results

• 3 other identifiers: P103210137PACTG P1032
• Study Type: interventional
• Target: 175
• Locations: 1 country
• Sites: 7

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).

Conditions

HIV Infections

Keywords

HIV Seronegativity; Treatment Naive; Pregnancy; Perinatal Transmission; Vertical Transmission; Mother-To-Child Transmission; MTCT

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (6)

• 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.

• 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

  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.

  within 72 weeks postpartum

• Resistance Mutations in HIV Infected Infants

  24 weeks postpartum

Study Arms (3)

Arm A: LPV/r x 7d

EXPERIMENTAL

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; Drug: Lopinavir/ritonavir; Drug: Nevirapine; Drug: Zidovudine

Arm B: no LPV/r

EXPERIMENTAL

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; Drug: Nevirapine; Drug: Zidovudine

Arm C: LPV/r x 30d

EXPERIMENTAL

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; Drug: Lopinavir/ritonavir; Drug: Nevirapine; Drug: Zidovudine

Interventions

Didanosine, enteric-coated DRUG

once daily

Arm A: LPV/r x 7d; Arm B: no LPV/r; Arm C: LPV/r x 30d

Lopinavir/ritonavir DRUG

twice daily

Arm A: LPV/r x 7d; Arm C: LPV/r x 30d

Nevirapine DRUG

single-dose at the onset of labor

Arm A: LPV/r x 7d; Arm B: no LPV/r; Arm C: LPV/r x 30d

Zidovudine DRUG

twice daily

Arm A: LPV/r x 7d; Arm B: no LPV/r; Arm C: LPV/r x 30d

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (7)

Bhumibol Adulyadej Hosp. CRS

Saimai, Bangkok, 10220, Thailand

Location

Siriraj Hospital Mahidol University CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Prapokklao Hosp. CRS

Chanthaburi, 22000, Thailand

Location

Chiang Mai University Pediatrics-Obstetrics CRS

Chiang Mai, 50200, Thailand

Location

Chiangrai Prachanukroh Hospital CRS

Chiangrai, 57000, Thailand

Location

Chonburi Hosp. CRS

Chon Buri, 20000, Thailand

Location

Phayao Provincial Hosp. CRS

Phayao, 56000, Thailand

Location

Related Publications (6)

• 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.

  PMID: 12134253 BACKGROUND

• 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.

  PMID: 15627034 BACKGROUND

• 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.

  PMID: 14562860 BACKGROUND

• 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.

  PMID: 15794723 BACKGROUND

• 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.

  PMID: 19237646 RESULT

• 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.

  PMID: 22144539 RESULT

MeSH Terms

Conditions

HIV Infections

Interventions

Didanosine; Lopinavir; Nevirapine; Zidovudine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Inosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Pyridines; Thymidine; Pyrimidine Nucleosides

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Russell Van Dyke, MD

  Tulane University Medical School

  STUDY CHAIR

• Gonzague J. Jourdain, MD

  Program for HIV Prevention and Treatment / IRD054, Department of Immunology and Infectious Diseases, Harvard School of Public Health

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2005
• First Posted: May 2, 2005
• Study Start: June 1, 2006
• Primary Completion: October 1, 2008
• Study Completion: November 1, 2009
• Last Updated: November 5, 2021
• Results First Posted: November 6, 2012

Record last verified: 2019-01

Locations

TH (7)