Antiviral Responses to NNRTI-Based vs. PI-Based ARV Therapy in HIV Infected Infants Who Have or Have Not Received Single Dose NVP for Prevention of Mother-to-Child Transmission of HIV

HIV Infections Clinical Trial

— P1060  

Official title:

Phase II, Parallel, Randomized, Clinical Trials Comparing the Responses to Initiation of NNRTI-Based Versus PI-Based Antiretroviral Therapy in HIV Infected Infants Who Have and Have Not Previously Received Single Dose Nevirapine for Prevention of Mother-to-Child HIV Transmission

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00307151
• Other study ID #: IMPAACT P1060
• Secondary ID: U01AI068632
• Status: Active, not recruiting
• Phase: Phase 2
• First received: March 24, 2006
• Last updated: December 3, 2015
• Start date: December 2005
• Est. completion date: December 2016

Study information

• Verified date: December 2015
• Source: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

A single dose of nevirapine (SD NVP) given to an HIV infected pregnant woman followed by a single dose to her infant has been shown to be an effective way of reducing the risk of mother-to-child transmission (MTCT) of HIV. The purpose of this study was to compare the effectiveness of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimen versus a protease inhibitor (PI)-based regimen in HIV infected infants who had or had not been exposed to SD NVP for prevention of MTCT.

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>> A five year follow up has been added to the study.

Description:

Single dose nevirapine (SD NVP) has greatly reduced the rate of mother-to-child transmission (MTCT) of HIV. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens are recommended for use by the World Health Organization (WHO) in resource-limited settings. However, research suggests that mothers and infants exposed to SD NVP experience higher virologic failure rates when treated with NNRTI-based regimens than their unexposed counterparts. Data show that the use of SD NVP is associated with NNRTI resistance in HIV infected women and infants. The purpose of this trial was to compare and evaluate virologic responses to an NNRTI-based regimen versus a protease-inhibitor (PI)-based regimen in HIV infected infants who had or had not been exposed to SD NVP intrapartum and after birth.

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>> Participants were enrolled into one of two Cohorts with proposed enrollment into each Cohort of 288 participants. Cohort I participants must have received SD NVP for prevention of MTCT. Cohort II participants and their mothers must not have previously received NVP or any other NNRTIs. Participants in both Cohorts were randomly assigned to receive either an NNRTI (Coh I:NVP and Coh II: NVP) or PI (Coh I: LPV/r and Coh II: LPV/r) -based regimen. The NNRTI-based regimen included NVP, zidovudine (ZDV) and lamivudine (3TC). The PI-based regimen included lopinavir/ritonavir (LPV/r), ZDV and 3TC. If participants experienced adverse reactions to ZDV, stavudine (d4T) could be substituted. Randomization was stratified by age (6-<12 months vs. >=12 months, with the 2-<6 month stratum added in protocol version 4.0 when the lower age limit was decreased from 6 months to 2 months).

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>> Study visits were scheduled at entry, weeks 2, 4, 8, 12, 16, 24 and then every 24 weeks. A physical exam, blood collection, and assessments of HIV-related symptoms occurred at all visits.

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>> Based on a Data Safety and Monitoring Committee (DSMB) review of study data on April 20 2009, enrollment to Cohort I was closed and interim results released. Data from this and another similar study (AIDS Clinical Trials Group (ACTG) A5208) conducted in mothers, showed that the PI-based regimen was more effective than the NNRTI-based regimen in infants who had received SD NVP for prevention of MTCT. Cohort II was allowed to remain open for enrollment and the lower age limit for enrollment reduced from 6 months to 2 months.

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>> In June 2010, follow-up for all subjects was extended from the original 24 weeks beyond enrollment of the last subject to 48 weeks. On October 27 2010, the DSMB conducted a final review of Cohort II data, and recommended results be unblinded and released. As found in Cohort I, the PI-based regimen was more effective than the NNRTI-based regimen in infants who had not been previously exposed to SD NVP for PMTCT. Primary and secondary outcome results for Cohort I include all follow-up until April 20, 2009 and for Cohort II, all follow-up until October 27, 2010. Adverse event summaries use all follow-up while on the randomized study treatment regimen in both Cohorts until October 27, 2010.

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>> Version 5.0 of the protocol (March 21, 2011) extends follow-up on all subjects for an additional 5 years to March 2016. The purpose of the extension is to collect long term safety and virologic efficacy data in this study population and to pilot administration of a series of neuropsychological tests. During the extension, participants will not receive any medications through the study, but instead through their local clinics. Clinic visits will take place every 3 months.

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Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 452
• Est. completion date: December 2016
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Months to 36 Months

Eligibility

Inclusion Criteria for All Participants:

• age >=6 months to < 36 months (decreased to 2 months in protocol version 4.0)

• HIV infected

• Viral load greater than 5,000 copies/ml within 60 days of study entry

• Treatment naive except for antiretrovirals (ARV) used to prevent MTCT (infant ARV use for <=1 week postpartum for prevention of MTCT allowed)

• Eligible for treatment according to WHO pediatric algorithm (updated in protocol version 1.0, Letter of amendment (LOA)#1) and protocol version 2.0, LOA#3). Subjects with active opportunistic infections were not eligible for study participation until they had been treated and were clinically stable

• Parent or legal guardian willing to provide signed informed consent

Inclusion Criteria for Cohort I:

• Documentation of maternal or infant NVP exposure or a highly reliable verbal report. (Updated in protocol version 2.0, LOA#3 to require written clinic/hospital documentation of infant exposure to SD NVP)

• Use of maternal ARV, including NVP, permitted during pregnancy

• One or more of the following: strict formula feeding, initial infant HIV diagnosis occurring while younger than 60 days of age, or an initial AIDS-defining illness diagnosis by WHO criteria while younger than 60 days of age.

Inclusion Criteria for Cohort II:

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• Use of maternal ARVs, excluding NNRTIs, permitted during pregnancy

• Evidence of lack of prior NVP exposure (added in protocol version 2.0, LOA#3) by review of maternal and child medical records or health card (or other written documentation) for evidence of NVP exposure to mother or infant during pregnancy, labor, and delivery. If no written documentation showing lack of NVP use was shown in these records or if these records were not available for review, then a verbal report considered to be highly reliable by the study nurse was acceptable AND one or more of the following:

1. Study subject born before single dose NVP was available for prevention of MTCT of HIV in the location of birth of study subject

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2. Study subject born before the biological mother's first positive HIV test

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3. Site staff had another reason to believe the subject had not been exposed to NVP

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Exclusion Criteria for All Participants:

• Grade 2 or higher aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at study screening >>

• Grade 3 or higher laboratory toxicity at study screening >>

• Received ARVs for anything other than the prevention of intrapartum MTCT. Infants who received ARVs after the first week of life (e.g., for the prevention of MTCT of HIV through breastfeeding) were excluded

• Acute serious infections requiring active treatment. Subjects could be receiving treatment for active TB if it did not include rifamycin drugs

• Receiving chemotherapy for an active tumor >>

• History of a cardiac conduction abnormality and underlying structural heart disease

• Required certain medications

Exclusion Criteria for Cohort I:

• History of or currently breastfeeding. Breastfed infants with a positive HIV test or who had experienced an AIDS-defining illness by WHO criteria at 60 days of age or younger were not excluded

Exclusion Criteria for Cohort II:

• Exposure to any maternal NVP or other NNRTI prior to or during the pregnancy or while breastfeeding

• Exposure of infant to NVP at any time including during the first week of life

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Lamivudine
4 mg/kg twice daily
• Lopinavir/ritonavir
16/4 mg/kg twice daily for participants 2 months of age to less than 6 months of age; 12/3 mg/kg twice daily for participants at least 6 months of age and weighing less than 15 kg; 10/2.5 mg/kg twice daily for participants at least 6 months of age and weighing between 15 kg and 40kg; 400/100 mg twice daily for participants weighing more than 40 kg
• Nevirapine
Initially: 4 mg/kg for 14 days, then 7 mg/kg twice daily. In protocol version 2.0, Letter of Amendment 1 (September 2007), NVP dose increased to conform with WHO guidelines to: 160 to 200 mg/m^2/dose to max 200 mg once daily for 14 days, then 160 to 200 mg/m^2/dose to max 200 mg twice daily
• Zidovudine
180 mg/m^2 twice daily

Locations

Country	Name	City	State
India	BJ Medical College CRS	Pune	Maharashtra
Malawi	University of North Carolina Lilongwe CRS	Mzimba Road	Lilongwe
South Africa	University of Stellenbosch-Tygerberg Hospital, South Africa	Cape Town
South Africa	Harriet Shezi Clinic at Chris Hani Baragwanath Hospital	Johannesburg
South Africa	Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital	Johannesburg
South Africa	Nelson R. Mandela School of Medicine, University of Kwazulu	Natal	Durban
Tanzania	Kilimanjaro Christian Medical CRS	IDC Research Offices	Moshi
Uganda	Makerere University	Kampala
Zambia	George Clinic CRS	Lusaka
Zimbabwe	UZ-College of Health Sciences	Harare

Sponsors (3)

Lead Sponsor	Collaborator
International Maternal Pediatric Adolescent AIDS Clinical Trials Group	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

India,  Malawi,  South Africa,  Tanzania,  Uganda,  Zambia,  Zimbabwe, 

References & Publications (8)

Arrivé E, Newell ML, Ekouevi DK, Chaix ML, Thiebaut R, Masquelier B, Leroy V, Perre PV, Rouzioux C, Dabis F; Ghent Group on HIV in Women and Children. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol. 2007 Oct;36(5):1009-21. Epub 2007 May 28. Review. — View Citation

Chi BH, Sinkala M, Stringer EM, Cantrell RA, Mtonga V, Bulterys M, Zulu I, Kankasa C, Wilfert C, Weidle PJ, Vermund SH, Stringer JS. Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine. AIDS. 2007 May 11;21(8):957-64. — View Citation

Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis. 2006 Feb 15;193(4):479-81. Epub 2006 Jan 11. — View Citation

Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers T, Bwakura-Dangarembizi M, Chi BH, Musoke P, Kamthunzi P, Schimana W, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Violari A. Antiretroviral treatment for — View Citation

Palumbo P, Violari A, Lindsey J, Hughes M, Jean-Philippe P, Mofenson L, Bwakura-Dangarembizi M, Kamthunzi P, Eshleman S and Prudue L for the IMPAACT P1060 Team. Nevirapine (NVP)-vs. Lopinavir-Ritonavir (LPV/r)-based antiretroviral therapy (ART) among HIV-

Palumbo P, Violari A, Lindsey J, Hughes M, Jean-Philippe P, Mofenson L, Purdue L, Eshleman S for the IMPAACT P1060 Study Team. Nevirapine vs Lopinavir-ritonavir-based antiretroviral therapy in single dose Nevirapine-exposed HIV-infected infants: prelimina

Sankatsing RR, Wit FW, Pakker N, Vyankandondera J, Mmiro F, Okong P, Kastelein JJ, Lange JM, Stroes ES, Reiss P. Effects of nevirapine, compared with lamivudine, on lipids and lipoproteins in HIV-1-uninfected newborns: the stopping infection from mother-to-child via breast-feeding in Africa lipid substudy. J Infect Dis. 2007 Jul 1;196(1):15-22. Epub 2007 May 16. — View Citation

White PD. What causes prolonged fatigue after infectious mononucleosis: and does it tell us anything about chronic fatigue syndrome? J Infect Dis. 2007 Jul 1;196(1):4-5. Epub 2007 May 24. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent of Participants With Treatment Failure, Defined as a Confirmed Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment	Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR permanent discontinuation of the randomized NNRTI or PI component of study treatment at or prior to 24 weeks of treatment for any reason including death. Results report percent of participants reaching a treatment failure endpoint by week 24 calculated using the Kaplan-Meier method.	Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)	No
Secondary	Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment	Treatment failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR a confirmed viral rebound >4000 copies/mL after week 24 OR permanent discontinuation of the randomized NNRTI or PI component of study treatment for any reason including death.	Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)	No
Secondary	Percent of Participants Experiencing Virologic Failure	Virologic failure is defined as a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR death on or before 24 weeks. Results report percent of participants reaching a virologic failure endpoint by week 24 calculated using the Kaplan-Meier method.	Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)	No
Secondary	Time From Randomization to Virologic Failure	Virologic failure is defined as the earlier of a confirmed plasma HIV-1 RNA level that is <1 log10 copies/mL below the study entry value at 12 to 24 weeks after treatment is initiated OR a confirmed plasma HIV-1 RNA level >400 copies/mL at 24 weeks OR a confirmed viral rebound >4000 copies/mL after week 24 OR death.	Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)	No
Secondary	Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on Study Treatment	Safety events include lab abnormalities, signs or symptoms of grade 3 or higher. Events were graded according to the Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events, Version 1.0. Events defined as new if first occurrence was after initiation of study treatment or if severity increased from entry and while on the NNRTI or PI component of study treatment.	On randomized NNRTI or PI component of study treatment and until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)	Yes
Secondary	Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus	Numbers of participants developing new NRTI, NNRTI or PI-resistant virus after reaching a virologic failure endpoint	Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)	No
Secondary	Change in CD4 Percent From Entry to Week 48	Change was calculated as CD4 percent at week 48 minus entry CD4 percent (last CD4 percent before randomization date). Only subjects who reached 48 weeks of follow-up before DSMB decisions to unblind each Cohort were included in summary.	48 weeks if before date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)	No
Secondary	Time From Randomization to HIV-related Disease Progression or Death	HIV-related disease progression was defined as progression in WHO clinical stage from stage at entry or death. For subjects in WHO Stage IV at entry, disease progression was defined as death.	Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)	No
Secondary	Time From Randomization to Death	Results report 2nd percentile of time from randomization to death	Until date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009 - median follow-up 48 weeks and range 0 - 125 weeks; Coh II: October 27, 2010 - median follow-up 72 weeks and range from 0 to 204 weeks)	Yes

External Links

•   Click here for more information about lamivudine
•   Click here for more information about lopinavir/ritonavir
•   Click here for more information about nevirapine
•   Click here for more information about zidovudine
•   Click here for more information on after birth care for HIV positive women and their babies
•   Click here for more information on medication regimens for HIV positive pregnant women
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