NNRTI vs PI Regimens for HIV Infected Women After They Have Taken Nevirapine to Prevent Mother-To-Child HIV Transmission

NCT00089505 | Completed Phase 3 Results DMC

• 3 other identifiers: ACTG A52081U01AI068636OCTANE
• Study Type: interventional
• Target: 745
• Locations: 6 countries
• Sites: 10

Brief Summary

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly included in anti-HIV drug regimens. However, HIV infected women who have previously taken the single dose NNRTI nevirapine (SD NVP) for the prevention of mother-to-child transmission (MTCT) of HIV may not respond as well to NNRTIs as women who have never taken NVP. Another class of anti-HIV drugs, protease inhibitors (PIs), may be more effective for women who have previously taken NNRTIs. This study will compare the effectiveness of NNRTI- and PI-based regimens in women who have taken NVP for prevention of MTCT of HIV. This study will also compare regimens including an NNRTI with regimens including a PI in women who have never taken NVP.

Conditions

HIV Infections

Keywords

Treatment Experienced; Treatment Naive; MTCT; HIV Seronegativity

Outcome Measures

Primary Outcomes (2)

• Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry

  5th and 10th Percentiles in weeks from randomization to virologic failure (VF) or death. VF is defined as a plasma HIV-1 RNA level that is 1 log10 below baseline 12 weeks after treatment is initiated or as a plasma HIV-1 RNA level that is \>=400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized treatment was being taken at the time of VF.

  Through database cutoff for DSMB review (by October 6, 2008) with median follow-up 72 weeks and range from 0 to 144 weeks.

• Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry

  5th and 10th Percentiles in weeks from randomization to virologic failure (VF) or death. VF is defined as a plasma HIV-1 RNA level that is 1 log10 below baseline 12 weeks after treatment is initiated or as a plasma HIV-1 RNA level that is \>=400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized treatment was being taken at the time of VF.

  Throughout study with median follow-up 72 weeks and range from 0 to 180 weeks.

Secondary Outcomes (7)

• Number of Participants Who Experienced Virologic Failure or Died.

  Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r.

• Percent of Participants Who Experienced Virologic Failure or Died

  Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r arms. Throughout study for NoNVP/NVP and NoNVP/LPV_r arms.

• CD4 Count Change From Randomization

  Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r. Week 48 and 96.

• Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen.

  Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r.

• Number of Participants Who Experienced HIV-related Disease Progression or Death

  Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r.

Study Arms (4)

NVP/NVP

EXPERIMENTAL

For participants who had SD NVP exposure prior to study entry. FTC, TDF, and NVP daily the first 14 days, then twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue NVP will receive LPV/RTV twice daily plus two more NRTIs.

Drug: Emtricitabine; Drug: Emtricitabine/Tenofovir disoproxil fumarate; Drug: Nevirapine; Drug: Tenofovir disoproxil fumarate

NVP/LPV_r

EXPERIMENTAL

For participants who had SD NVP exposure prior to study entry. FTC and TDF daily and LPV/RTV twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue LPV/RTV will receive NVP daily for 14 days before taking it twice daily. plus 2 more NRTIs.

Drug: Emtricitabine; Drug: Emtricitabine/Tenofovir disoproxil fumarate; Drug: Lopinavir/Ritonavir; Drug: Tenofovir disoproxil fumarate

NoNVP/NVP

EXPERIMENTAL

For participants who did NOT have SD NVP exposure prior to study entry.FTC, TDF, and NVP daily the first 14 days, then twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue NVP will receive LPV/RTV twice daily plus two more NRTIs.

Drug: Emtricitabine; Drug: Emtricitabine/Tenofovir disoproxil fumarate; Drug: Nevirapine; Drug: Tenofovir disoproxil fumarate

NoNVP/LPV_r

EXPERIMENTAL

For participants who did NOT have SD NVP exposure prior to study entry. FTC and TDF daily and LPV/RTV twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue LPV/RTV will receive NVP daily for 14 days before taking it twice daily. plus 2 more NRTIs.

Drug: Emtricitabine; Drug: Emtricitabine/Tenofovir disoproxil fumarate; Drug: Lopinavir/Ritonavir; Drug: Tenofovir disoproxil fumarate

Interventions

Emtricitabine DRUG

200 mg taken orally

Also known as: FTC

NVP/LPV_r; NVP/NVP; NoNVP/LPV_r; NoNVP/NVP

Emtricitabine/Tenofovir disoproxil fumarate DRUG

200/300 mg taken orally

Also known as: FTC/TDF

NVP/LPV_r; NVP/NVP; NoNVP/LPV_r; NoNVP/NVP

Lopinavir/Ritonavir DRUG

400/100 mg taken orally

Also known as: LPV/RTV

NVP/LPV_r; NoNVP/LPV_r

Nevirapine DRUG

200 mg taken orally

Also known as: NVP

NVP/NVP; NoNVP/NVP

Tenofovir disoproxil fumarate DRUG

300 mg taken orally

Also known as: TDF

NVP/LPV_r; NVP/NVP; NoNVP/LPV_r; NoNVP/NVP

Eligibility Criteria

• Age: 13 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV infected
• CD4 count less than 200 cells/mm\^3 within 90 days prior to study entry
• Plasma HIV-1 RNA using standard Roche Amplicor HIV-1 Monitor Assay within 45 days prior to study entry
• the following laboratory values obtained within 45 days prior to study entry: absolute neutrophil count\>=750/mm\^3;Hemoglobin\>=7.0g/dL;platelet count\>=50000/mm\^3;aspartate aminotransferase (AST),Alanine aminotransferase (ALT), and alkaline phosphatase \<=2.5 x ULN; total bilirubin \<=2.5 x ULN
• Normal renal function within 45 days prior to study entry
• Willing to use acceptable forms of contraception
• Karnofsky performance score \>=70 on at least one occasion within 45 days prior to study entry
• Parent or guardian willing to provide informed consent, if applicable
• Planning to remain in the same geographical area of residence and are willing to attend study visits as required
• Previously received NVP for prevention of MTCT of HIV
• Has documentation of all prior doses of NVP used for prevention of MTCT of HIV
• Last dose of NVP for prevention of MTCT of HIV taken at least 6 months prior to study entry

You may not qualify if:

• Previously received any antiretrovirals, excluding NVP for MTCT prophylaxis for Trial 1 participants. Participants who have received up to 10 weeks of zidovudine alone and completed this course at least 6 months prior to study entry are not excluded.
• Use of systemic cancer chemotherapy, systemic investigational agents, immunomodulators, or rifampin within 30 days of study entry
• Pregnant or breastfeeding
• Known allergy or sensitivity to study drugs or their formulations
• Any condition, including drug or alcohol abuse, that, in the opinion of the investigator, may interfere with adherence to study regimens
• Serious illness requiring systemic treatment or hospitalization. Participants who complete therapy or are clinically stable on therapy for at least 30 days prior to study entry are not excluded.
• Tuberculosis (TB) treatment within 30 days prior to study entry
• Use of any prohibited medications within 30 days prior to study entry
• Involuntary incarceration in a correctional facility, prison, or jail for legal reasons or in a medical facility for treatment of either a psychiatric or physical illness

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (11)

The Gaborone BHP Study Clinic

Bontleng, Gaborone, Botswana

Location

Molepolole BHP Study Clinic, Scottish Livingstone Hospital

Bontleng Gaborone, Botswana

Location

Moi University International Clnical Trials Unit

Eldoret, 30100, Kenya

Location

KMRI / Walter Reed Project Clinical Research Center

Kericho, Kenya

Location

University of North Carolina Project (UNC Project)

Lilongwe, (265) 175-5056, Malawi

Location

University of KwaZulu Natal

Durban, KwaZulu-Natal, 4013, South Africa

Location

Chris Hani Baragwanath Hospital, Johannesburg

Johannesburg, South Africa

Location

University of Witwatersrand

Johannesburg, South Africa

Location

Joint Clinical Research Centre (JCRC)

Kampala, Uganda

Location

Centre for Infectious Disease Research in Zambia (CIDRZ)

Lusaka, Zambia

Location

University of Zimbabwe

Avondale, Harare, Zimbabwe

Location

Related Publications (14)

• Eshleman SH, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Rev. 2002 Apr-Jun;4(2):59-63.

  PMID: 12152519 BACKGROUND

• Eshleman SH, Mracna M, Guay LA, Deseyve M, Cunningham S, Mirochnick M, Musoke P, Fleming T, Glenn Fowler M, Mofenson LM, Mmiro F, Jackson JB. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS. 2001 Oct 19;15(15):1951-7. doi: 10.1097/00002030-200110190-00006.

  PMID: 11600822 BACKGROUND

• Harris M. Efficacy and durability of nevirapine in antiretroviral-experienced patients. J Acquir Immune Defic Syndr. 2003 Sep;34 Suppl 1:S53-8. doi: 10.1097/00126334-200309011-00008.

  PMID: 14562858 BACKGROUND

• Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, Ariyadej S, Leenasirimakul P, Hammer S, Lallemant M; Perinatal HIV Prevention Trial Group. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004 Jul 15;351(3):229-40. doi: 10.1056/NEJMoa041305. Epub 2004 Jul 9.

  PMID: 15247339 BACKGROUND

• Nightingale S, Dabis F. Evidence behind the WHO guidelines: hospital care for children: what antiretroviral agents and regimens are effective in the prevention of mother-to-child transmission of HIV? J Trop Pediatr. 2006 Aug;52(4):235-8. doi: 10.1093/tropej/fml033. No abstract available.

  PMID: 16877674 BACKGROUND

• Turner D, Wainberg MA. HIV transmission and primary drug resistance. AIDS Rev. 2006 Jan-Mar;8(1):17-23.

  PMID: 16736948 BACKGROUND

• Boltz VF, Shao W, Bale MJ, Halvas EK, Luke B, McIntyre JA, Schooley RT, Lockman S, Currier JS, Sawe F, Hogg E, Hughes MD, Kearney MF, Coffin JM, Mellors JW. Linked dual-class HIV resistance mutations are associated with treatment failure. JCI Insight. 2019 Oct 3;4(19):e130118. doi: 10.1172/jci.insight.130118.

  PMID: 31487271 DERIVED

• Asmelash A, Zheng Y, Kaloustian KW, Shaffer D, Sawe F, Ogwu A, Salata R, Currier J, Hughes MD, Lockman S. Predictors of suboptimal CD4 response among women achieving virologic suppression in a randomized antiretroviral treatment trial, Africa. BMC Infect Dis. 2014 Jun 17;14:331. doi: 10.1186/1471-2334-14-331.

  PMID: 24938526 DERIVED

• Boltz VF, Bao Y, Lockman S, Halvas EK, Kearney MF, McIntyre JA, Schooley RT, Hughes MD, Coffin JM, Mellors JW; OCTANE/A5208 Team. Low-frequency nevirapine (NVP)-resistant HIV-1 variants are not associated with failure of antiretroviral therapy in women without prior exposure to single-dose NVP. J Infect Dis. 2014 Mar 1;209(5):703-10. doi: 10.1093/infdis/jit635. Epub 2014 Jan 16.

  PMID: 24443547 DERIVED

• Lockman S, Hughes M, Sawe F, Zheng Y, McIntyre J, Chipato T, Asmelash A, Rassool M, Kimaiyo S, Shaffer D, Hosseinipour M, Mohapi L, Ssali F, Chibowa M, Amod F, Halvas E, Hogg E, Alston-Smith B, Smith L, Schooley R, Mellors J, Currier J; OCTANE (Optimal Combination Therapy After Nevirapine Exposure) ACTG A5208/OCTANE Study Team. Nevirapine- versus lopinavir/ritonavir-based initial therapy for HIV-1 infection among women in Africa: a randomized trial. PLoS Med. 2012;9(6):e1001236. doi: 10.1371/journal.pmed.1001236. Epub 2012 Jun 12.

  PMID: 22719231 DERIVED

• Skinner-Adams TS, Butterworth AS, Porter KA, D'Amico R, Sawe F, Shaffer D, Siika A, Hosseinipour MC, Stringer E, Currier JS, Chipato T, Salata R, Lockman S, Eron JJ, Meshnick SR, McCarthy JS. The frequency of malaria is similar among women receiving either lopinavir/ritonavir or nevirapine-based antiretroviral treatment. PLoS One. 2012;7(4):e34399. doi: 10.1371/journal.pone.0034399. Epub 2012 Apr 3.

  PMID: 22509297 DERIVED

• Dong BJ, Zheng Y, Hughes MD, Frymoyer A, Verotta D, Lizak P, Sawe F, Currier JS, Lockman S, Aweeka FT; AIDS Clinical Trials Group Study 5208 Team. Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women. AIDS. 2012 Apr 24;26(7):833-41. doi: 10.1097/QAD.0b013e328351a521.

  PMID: 22301417 DERIVED

• Porter KA, Cole SR, Eron JJ Jr, Zheng Y, Hughes MD, Lockman S, Poole C, Skinner-Adams TS, Hosseinipour M, Shaffer D, D'Amico R, Sawe FK, Siika A, Stringer E, Currier JS, Chipato T, Salata R, McCarthy JS, Meshnick SR. HIV-1 protease inhibitors and clinical malaria: a secondary analysis of the AIDS Clinical Trials Group A5208 study. Antimicrob Agents Chemother. 2012 Feb;56(2):995-1000. doi: 10.1128/AAC.05322-11. Epub 2011 Nov 28.

  PMID: 22123685 DERIVED

• Lockman S, Hughes MD, McIntyre J, Zheng Y, Chipato T, Conradie F, Sawe F, Asmelash A, Hosseinipour MC, Mohapi L, Stringer E, Mngqibisa R, Siika A, Atwine D, Hakim J, Shaffer D, Kanyama C, Wools-Kaloustian K, Salata RA, Hogg E, Alston-Smith B, Walawander A, Purcelle-Smith E, Eshleman S, Rooney J, Rahim S, Mellors JW, Schooley RT, Currier JS; OCTANE A5208 Study Team. Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med. 2010 Oct 14;363(16):1499-509. doi: 10.1056/NEJMoa0906626.

  PMID: 20942666 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Lopinavir; Nevirapine; Tenofovir

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)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Drug Combinations; Pharmaceutical Preparations; Pyrimidinones; Pyridines

Results Point of Contact

• Title: ACTG ClinicalTrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Shahin Lockman, MD, MSc

  Brigham and Women's Hospital and Infectious Diseases Division, Department of Immunology and Infectious Diseases, Harvard School of Public Health

  STUDY CHAIR

• Frederick Sawe, MD

  The Walter Reed Project/WRAIR

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2004
• First Posted: August 6, 2004
• Study Start: November 1, 2006
• Primary Completion: August 1, 2010
• Study Completion: February 1, 2011
• Last Updated: October 12, 2018
• Results First Posted: February 4, 2011

Record last verified: 2018-09

Locations

BO (2); KE (2); ZA (3); ZI (1); UG (1); MA (1)