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

NCT00307151 | Completed Phase 2 Results DMC

• 2 other identifiers: IMPAACT P1060U01AI068632
• Study Type: interventional
• Target: 452
• Locations: 6 countries
• Sites: 9

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

Conditions

HIV Infections

Keywords

Treatment Naive; Mother-To-Child Transmission; MTCT; Pediatrics; Viral resistance

Outcome Measures

Primary Outcomes (1)

• 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)

Secondary Outcomes (8)

• Time From Randomization to Treatment Failure, Defined as Virologic Failure or Permanent Discontinuation of the Randomized NNRTI or PI Component of Study Treatment

  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)

• Percent of Participants Experiencing Virologic Failure

  Earlier of 24 weeks or date of DSMB decision to unblind Cohort results (Coh I: April 20, 2009; Coh II: October 27, 2010)

• Time From Randomization to Virologic Failure

  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)

• Time From Start of Study Treatment to First New Grade >=3 Lab Abnormality, Sign or Symptom Occurring on 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)

• Number of Participants Developing New NRTI, NNRTI or PI-resistant Virus

  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)

Study Arms (4)

Coh I: NVP

EXPERIMENTAL

Cohort I: Previously received single dose nevirapine (SD NVP). Randomly assigned to receive an NNRTI-based regimen.

Drug: Lamivudine; Drug: Nevirapine; Drug: Zidovudine

Coh I: LPV/r

EXPERIMENTAL

Cohort I: Previously received SD NVP. Randomly assigned to receive a PI-based regimen.

Drug: Lamivudine; Drug: Lopinavir/ritonavir; Drug: Zidovudine

Coh II: NVP

EXPERIMENTAL

Cohort II: Did not previously receive SD NVP. Randomly assigned to receive an NNRTI-based regimen

Drug: Lamivudine; Drug: Nevirapine; Drug: Zidovudine

Coh II: LPV/r

EXPERIMENTAL

Cohort II: Did not previously receive SD NVP. Randomly assigned to receive a PI-based regimen

Drug: Lamivudine; Drug: Lopinavir/ritonavir; Drug: Zidovudine

Interventions

Lamivudine DRUG

4 mg/kg twice daily

Also known as: 3TC, Epivir

Coh I: LPV/r; Coh I: NVP; Coh II: LPV/r; Coh II: NVP

Lopinavir/ritonavir DRUG

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

Also known as: LPV/r, Kaletra, LPV/RTV

Coh I: LPV/r; Coh II: LPV/r

Nevirapine DRUG

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

Also known as: NVP, Viramune

Coh I: NVP; Coh II: NVP

Zidovudine DRUG

180 mg/m\^2 twice daily

Also known as: ZDV, AZT, Retrovir

Coh I: LPV/r; Coh I: NVP; Coh II: LPV/r; Coh II: NVP

Eligibility Criteria

• Age: 2 Months - 36 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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\>\>
• 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. \>\>
• 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: \>\>
• Study subject born before single dose NVP was available for prevention of MTCT of HIV in the location of birth of study subject\>\>
• Study subject born before the biological mother's first positive HIV test\>\>

You may not qualify if:

• 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\>\>
• 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\>\>
• 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

Sponsors & Collaborators

• International Maternal Pediatric Adolescent AIDS Clinical Trials Group: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (10)

BJ Medical College CRS

Pune, Maharashtra, 411001, India

Location

University of North Carolina Lilongwe CRS

Mzimba Road, Lilongwe, Malawi

Location

Nelson R. Mandela School of Medicine, University of Kwazulu

Natal, Durban, 50202, South Africa

Location

University of Stellenbosch-Tygerberg Hospital, South Africa

Cape Town, 7700, South Africa

Location

Harriet Shezi Clinic at Chris Hani Baragwanath Hospital

Johannesburg, 2013, South Africa

Location

Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital

Johannesburg, South Africa

Location

Kilimanjaro Christian Medical CRS

IDC Research Offices, Moshi, Tanzania

Location

Makerere University

Kampala, Uganda

Location

George Clinic CRS

Lusaka, Zambia

Location

UZ-College of Health Sciences

Harare, Zimbabwe

Location

Related Publications (13)

• Arrive 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. doi: 10.1093/ije/dym104. Epub 2007 May 28.

  PMID: 17533166 BACKGROUND

• 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. doi: 10.1097/QAD.0b013e32810996b2.

  PMID: 17457089 BACKGROUND

• 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. doi: 10.1086/499967. Epub 2006 Jan 11.

  PMID: 16425125 BACKGROUND

• 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. doi: 10.1086/518615. Epub 2007 May 24. No abstract available.

  PMID: 17538875 BACKGROUND

• 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. doi: 10.1086/518248. Epub 2007 May 16.

  PMID: 17538878 BACKGROUND

• 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 children with peripartum nevirapine exposure. N Engl J Med. 2010 Oct 14;363(16):1510-20. doi: 10.1056/NEJMoa1000931.

  PMID: 20942667 RESULT

• 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: preliminary results from the IMPAACT P1060 Trial. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Capetown, July, 2009.

  RESULT

• 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-infected infants in resource-limited settings: The IMPAACT P1060 Trial. 18th Conference on Retroviruses and Opportunistic Infections, Boston, February, 2011.

  RESULT

• Patel K, Lindsey J, Angelidou K, Aldrovandi G, Palumbo P; IMPAACT P1060 Study Team. Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children. AIDS. 2018 Oct 23;32(16):2327-2336. doi: 10.1097/QAD.0000000000001980.

  PMID: 30102656 DERIVED

• Angelidou K, Palumbo P, Lindsey J, Violary A, Archary M, Barlow L, Claggett B, Hughes M, Wei LJ; International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1060 Study Team. Defining Study Outcomes That Better Reflect Individual Response to Treatment. Pediatr Infect Dis J. 2018 Mar;37(3):258-262. doi: 10.1097/INF.0000000000001766.

  PMID: 29189677 DERIVED

• Barlow-Mosha L, Angelidou K, Lindsey J, Archary M, Cotton M, Dittmer S, Fairlie L, Kabugho E, Kamthunzi P, Kinikar A, Mbengeranwa T, Msuya L, Sambo P, Patel K, Barr E, Jean-Phillipe P, Violari A, Mofenson L, Palumbo P, Chi BH. Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial. Clin Infect Dis. 2016 Oct 15;63(8):1113-1121. doi: 10.1093/cid/ciw488. Epub 2016 Jul 20.

  PMID: 27439527 DERIVED

• Lindsey JC, Hughes MD, Violari A, Eshleman SH, Abrams EJ, Bwakura-Dangarembizi M, Barlow-Mosha L, Kamthunzi P, Sambo PM, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Zimmer B, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P; P1060 Study Team. Predictors of virologic and clinical response to nevirapine versus lopinavir/ritonavir-based antiretroviral therapy in young children with and without prior nevirapine exposure for the prevention of mother-to-child HIV transmission. Pediatr Infect Dis J. 2014 Aug;33(8):846-54. doi: 10.1097/INF.0000000000000337.

  PMID: 25222305 DERIVED

• Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P, Chi BH, Cotton MF, Moultrie H, Khadse S, Schimana W, Bobat R, Purdue L, Eshleman SH, Abrams EJ, Millar L, Petzold E, Mofenson LM, Jean-Philippe P, Palumbo P. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012 Jun 21;366(25):2380-9. doi: 10.1056/NEJMoa1113249.

  PMID: 22716976 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Lamivudine; Lopinavir; lopinavir-ritonavir drug combination; 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)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides; Pyrimidinones; Pyridines; Thymidine

Limitations and Caveats

Accrual to Cohort I was terminated early by the Data Safety Monitoring Committee after enrollment of 164 of the planned 288 subjects.

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

• Paul Palumbo, MD

  Division of Infectious Diseases and International Health, Dartmouth-Hitchcock Medical Center

  STUDY CHAIR

• Avy Violari, MD

  Perinatal HIV Research Unit, University of Witwatersrand

  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: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2006
• First Posted: March 27, 2006
• Study Start: December 1, 2005
• Primary Completion: December 1, 2010
• Study Completion: December 1, 2016
• Last Updated: April 13, 2017
• Results First Posted: August 3, 2011

Record last verified: 2017-03

Locations

TA (1); ZA (4); IN (1); ZI (1); UG (1); MA (1)