Clinical trial NCT00089505: NNRTI vs PI Regimens for HIV Infected Women After They Have Taken Nevirapine to Prevent Mother-To-Child HIV Transmission
Official title: Optimal Combination Therapy After Nevirapine Exposure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Treatment Experienced
Treatment Naive
MTCT
HIV Seronegativity
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2004-08-06
Enrollment: 745
Sex: FEMALE
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: NVP is the NNRTI of choice to prevent MTCT of HIV, especially in resource-limited settings. However, prolonged use of NVP may result in drug resistance, decreasing the efficacy of future anti-HIV regimens containing NVP. PIs are more expensive and cause different adverse effects than NNRTIs, but PI-containing regimens may be more effective than NNRTI-containing regimens in treating HIV infected women who previously took NVP for MTCT prophylaxis. This study will compare the efficacy of NNRTI- and PI-containing anti-HIV regimens in women who have previously taken NVP for MTCT of HIV and in women who have never taken NVP.

The study will last a minimum of 48 weeks. Participants will be grouped by previous NVP exposure: participants who have previously taken NVP as MTCT prophylaxis (Trial 1 participants), and participants who have never taken NVP (Trial 2 participants). Participants in each trial will be randomly assigned to one of two arms, NVP-containing arm(NVP/NVP for trial 1 participants and NoNVP/NVP for trial 2 participants) or PI-containing arm(NVP/LPV_r for Trial 1 participants and NoNVP/LPV_r for Trial 2 participants). At the start of the study, Arm NVP/NVP and NoNVP/NVP participants will receive emtricitabine (FTC) daily, tenofovir disoproxil fumarate (TDF) daily, and NVP daily for the first 14 days and then twice daily. Arm NVP/LPV_r and NoNVP/LPV_r participants will receive both FTC and TDF daily and lopinavir/ritonavir (LPV/RTV) twice daily. FTC and TDF may be replaced in either arm with the combination drug FTC/TDF.

If participants experience virologic failure, toxicity, or otherwise cannot tolerate their regimens, they will switch to a different regimen. Arm NVP/NVP and NoNVP/NVP participants will switch to a regimen of two or more nucleoside reverse transcriptase inhibitors (NRTIs) and LPV/RTV; Arm NVP/LPV_r and NoNVP/LPV_r participants will switch to a regimen of two or more NRTIs and NVP. Study visits will occur at entry and at Weeks 2, 4, 8, 12, 16, 24, and then every 12 weeks thereafter. Visits will consist of a physical exam, medication assessment, and blood collection. Participants will be asked to complete adherence questionnaires at Weeks 4, 12, 24, and every 24 weeks thereafter, and quality of life questionnaires at Weeks 24 and ever 24 weeks thereafter. Study drugs will be provided for all participants through 48 weeks after the final participant is randomized.

As per an amendment (dated April 13, 2009), participants will be asked to take part in an extension of this study. Enrollment in the extension is completely voluntary. The purpose of the extension is to monitor, in greater extent, the participants' health as they transition from study treatment to local, clinical care. During the study extension participants will not receive any medications through the study; it is expected that participants will receive their treatments through a local clinic.

Participants enrolling in the extension will enter the extension at the same time as their last visit in the current study. For the extension, participants will be asked to come back to the clinic two times for study visits: at 12 and 72 weeks after entry into the extension. Because there will be a long time between these study visits, participants will also be contacted by phone (or through some other means) close to 48 weeks after entry into the extension.

At each of these visits, participants will be asked about their health and medications, including current anti-HIV drugs. Participants will also be asked about any HIV care received outside of the study. As part of this study, investigators may need to review participants' non-study medical records and speak with their non-study care providers, to find out more about their HIV care and medical problems, and also to check results of lab tests.

During the study extension period, participants will have blood drawn and also be tested for pregnancy.

Eligibility criteria: Inclusion Criteria for All Participants:

* 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

Inclusion Criteria for Trial 1 Participants:

* 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

Exclusion Criteria for All Participants:

* 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

Primary outcomes:
measure: Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry
timeFrame: Through database cutoff for DSMB review (by October 6, 2008) with median follow-up 72 weeks and range from 0 to 144 weeks.
measure: Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry
timeFrame: Throughout study with median follow-up 72 weeks and range from 0 to 180 weeks.
Secondary outcomes:
measure: Number of Participants Who Experienced Virologic Failure or Died.
timeFrame: 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.
measure: Percent of Participants Who Experienced Virologic Failure or Died
timeFrame: 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.
measure: CD4 Count Change From Randomization
timeFrame: 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.
measure: Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen.
timeFrame: 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.
measure: Number of Participants Who Experienced HIV-related Disease Progression or Death
timeFrame: 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.
measure: Number of Participants Who Received NVP-containing Regimens at Randomization and Experienced NVP-associated Rash or Grade 2+ Liver Lab Abnormality
timeFrame: Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP arm. Throughout study for NoNVP/NVP arm.
measure: Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month
timeFrame: 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.
Other outcomes:
Locations:
city: Bontleng
country: Botswana
facility: The Gaborone BHP Study Clinic
state: Gaborone
city: Bontleng Gaborone
country: Botswana
facility: Molepolole BHP Study Clinic, Scottish Livingstone Hospital
city: Eldoret
country: Kenya
facility: Moi University International Clnical Trials Unit
city: Kericho
country: Kenya
facility: KMRI / Walter Reed Project Clinical Research Center
city: Lilongwe
country: Malawi
facility: University of North Carolina Project (UNC Project)
city: Durban
country: South Africa
facility: University of KwaZulu Natal
state: KZN
city: Johannesburg
country: South Africa
facility: Chris Hani Baragwanath Hospital, Johannesburg
city: Johannesburg
country: South Africa
facility: University of Witwatersrand
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre (JCRC)
city: Lusaka
country: Zambia
facility: Centre for Infectious Disease Research in Zambia (CIDRZ)
city: Avondale
country: Zimbabwe
facility: University of Zimbabwe
state: Harare
Study officials:
affiliation: Brigham and Women's Hospital and Infectious Diseases Division, Department of Immunology and Infectious Diseases, Harvard School of Public Health
name: Shahin Lockman, MD, MSc
role: STUDY_CHAIR
affiliation: The Walter Reed Project/WRAIR
name: Frederick Sawe, MD
role: STUDY_CHAIR
References:
citation: Eshleman SH, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Rev. 2002 Apr-Jun;4(2):59-63.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Turner D, Wainberg MA. HIV transmission and primary drug resistance. AIDS Rev. 2006 Jan-Mar;8(1):17-23.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.