HIV InfectionsPhase 3OCTANENCT00089505
NNRTI vs PI Regimens for HIV Infected Women After They Have Taken Nevirapine to Prevent Mother-To-Child HIV Transmission
A Phase 3 study testing Emtricitabine, Emtricitabine/Tenofovir disoproxil fumarate and Lopinavir/Ritonavir in people with HIV Infections, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 11 sites in 7 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 13 years and older, women only
- Conditions the study is for
- HIV Infections
- What is being tested?
- Emtricitabine, Emtricitabine/Tenofovir disoproxil fumarate and Lopinavir/Ritonavir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 745 participants
- Where
- 11 sitesin 7 countries
- Study dates
- Nov 2006to Feb 2011
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 years and older
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
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- 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
Trial locations and contacts
11 sites in 7 countries.
11 sites in 7 countries
South Africa3 sites
University of KwaZulu Natal
Durban, KwaZulu-Natal, 4013
Chris Hani Baragwanath Hospital, Johannesburg
Johannesburg
University of Witwatersrand
Johannesburg
Botswana2 sites
The Gaborone BHP Study Clinic
Bontleng, Gaborone
Molepolole BHP Study Clinic, Scottish Livingstone Hospital
Bontleng Gaborone
Kenya2 sites
Moi University International Clnical Trials Unit
Eldoret, 30100
KMRI / Walter Reed Project Clinical Research Center
Kericho
Malawi1 site
University of North Carolina Project (UNC Project)
Lilongwe, (265) 175-5056
About this study
Official title: Optimal Combination Therapy After Nevirapine Exposure
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.
Read the 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.
- Conditions
- HIV Infections
- Being tested
- Emtricitabine, Emtricitabine/Tenofovir disoproxil fumarate, Lopinavir/Ritonavir, Nevirapine, Tenofovir disoproxil fumarate
- Keywords
- Treatment Experienced, Treatment Naive, MTCT, HIV Seronegativity
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EmtricitabineDrug
Also called FTC
200 mg taken orally
Emtricitabine/Tenofovir disoproxil fumarateDrug
Also called FTC/TDF
200/300 mg taken orally
Lopinavir/RitonavirDrug
Also called LPV/RTV
400/100 mg taken orally
NevirapineDrug
Also called NVP
200 mg taken orally
Tenofovir disoproxil fumarateDrug
Also called TDF
300 mg taken orally
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Emtricitabine; Drug: Emtricitabine/Tenofovir disoproxil fumarate; Drug: Lopinavir/Ritonavir; Drug: Tenofovir disoproxil fumarate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Virologic failure (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.
Measured: 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
Results report cumulative percent of participants reaching virologic failure (VF) or death by week 48 and week 96 calculated using the Kaplan-Meier method. 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.
Measured: 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
Change was calculated as the CD4 count at Week 48 (or at Week 96) minus the baseline CD4 count (last CD4 before/on treatment start date). For NVP/NVP and NVP/LPV_r arms, data through DSMB review cutoff (October 6, 2008) were used to report the outcome. For NoNVP/NVP and NoNVP/LPV_r arms, since the follow-up continued as planned, data through overall study were used.
Measured: 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.
The outcome is defined as treatment-related toxicity (as evaluated by sites), regardless of grade, that led to discontinuation of randomized regimen. For NVP/NVP and NVP/LPV_r arms, data through DSMB review cutoff (October 6, 2008) were used to report the outcome. For NoNVP/NVP and NoNVP/LPV_r arms, since the follow-up continued as planned, data through overall study were used.
Measured: 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
Worsening to WHO stage III/IV (among subjects who had WHO stage I/II at baseline) and death were the composite secondary endpoint. WHO Disease Staging System for HIV Infection and Disease in Adults and Adolescents is an approach for use in resource limited settings in studies of progression to symptomatic HIV disease. There are 4 stages of disease staging, 1 being the least severe and 4 being the most severe disease stage based on the HIV related symptoms and diagnoses. Please refer to the following web page for detailed staging criteria: http://www.who.int/docstore/hiv/scaling/anex1.html
Measured: 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 Received NVP-containing Regimens at Randomization and Experienced NVP-associated Rash or Grade 2+ Liver Lab Abnormality
Any grade of rash or grade 2+ liver lab abnormality events that were claimed to be NVP associated (definitely, probably, or possibly) by site investigators were evaluated. Grade 2+ liver lab abnormality is defined as aspartate aminotransferase (AST)>=2.6 x ULN or alanine aminotransferase (ALT)>=2.6 x ULN.
Measured: Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP arm. Throughout study for NoNVP/NVP arm.
Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month
Self-reported adherence at week 48 and 96 while participants remained on randomized regimen. Adherence interviews for each antiretroviral drug drug the participant is taking was performed by site personnel every 24 weeks. For NVP/NVP and NVP/LPV_r arms, data through DSMB review cutoff (October 6, 2008) were used to report the outcome. For NoNVP/NVP and NoNVP/LPV_r arms, since the follow-up continued as planned, data through overall study were used.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Aug 2004 (estimated)
- Study startNov 2006
- Primary completionAug 2010
- Study completionFeb 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 745 participants (actual)
Sponsor and investigators
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Shahin Lockman, MD, MSc, Study chair, Brigham and Women's Hospital and Infectious Diseases Division, Department of Immunology and Infectious Diseases, Harvard School of Public HealthFrederick Sawe, MD, Study chair, The Walter Reed Project/WRAIR
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00089505
- Sponsor's protocol ID
- ACTG A5208
- Other IDs
- 1U01AI068636, OCTANE
- Acronym
- OCTANE
- Status last verified
- Sep 2018
- First submitted
- 5 Aug 2004
- Last updated
- 12 Oct 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Eshleman SH, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Rev. 2002 Apr-Jun;4(2):59-63.
PubMed 12152519Eshleman 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.
PubMed 11600822Harris 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.
PubMed 14562858Jourdain 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.
PubMed 15247339Nightingale 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.
PubMed 16877674Turner D, Wainberg MA. HIV transmission and primary drug resistance. AIDS Rev. 2006 Jan-Mar;8(1):17-23.
PubMed 16736948Boltz 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.
PubMed 31487271Asmelash 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.
PubMed 24938526Boltz 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.
PubMed 24443547Lockman 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.
PubMed 22719231Skinner-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.
PubMed 22509297Dong 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.
PubMed 22301417Porter 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.
PubMed 22123685Lockman 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.
PubMed 20942666
Study at a glance
From the registry record, last updated by the sponsor on 12 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimal Combination Therapy After Nevirapine Exposure
- ClinicalTrials.gov ID
- NCT00089505
- Acronym / sponsor ID
- OCTANE / ACTG A5208
- Conditions
- HIV Infections
- Keywords
- Treatment Experienced, Treatment Naive, MTCT, HIV Seronegativity
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 745 participants (actual)
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other InfectionsResearch network
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
- Study start
- Nov 2006
- Primary completion
- Aug 2010 (actual)
- Study completion
- Feb 2011 (actual)
- First posted
- 6 Aug 2004 (estimated)
- Results
- Posted 4 Feb 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| NVP/NVP | Experimental | Drug: Emtricitabine, Drug: Emtricitabine/Tenofovir disoproxil fumarate, Drug: Nevirapine, Drug: Tenofovir disoproxil fumarateFor 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. |
| NVP/LPV_r | Experimental | Drug: Emtricitabine, Drug: Emtricitabine/Tenofovir disoproxil fumarate, Drug: Lopinavir/Ritonavir, Drug: Tenofovir disoproxil fumarateFor 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. |
| NoNVP/NVP | Experimental | Drug: Emtricitabine, Drug: Emtricitabine/Tenofovir disoproxil fumarate, Drug: Nevirapine, Drug: Tenofovir disoproxil fumarateFor 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. |
| NoNVP/LPV_r | Experimental | Drug: Emtricitabine, Drug: Emtricitabine/Tenofovir disoproxil fumarate, Drug: Lopinavir/Ritonavir, Drug: Tenofovir disoproxil fumarateFor 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. |
Who may qualify
- Ages
- 13 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EmtricitabineAlso: FTC200 mg taken orally | Drug | NVP/LPV_r, NVP/NVP, NoNVP/LPV_r, NoNVP/NVP |
| Emtricitabine/Tenofovir disoproxil fumarateAlso: FTC/TDF200/300 mg taken orally | Drug | NVP/LPV_r, NVP/NVP, NoNVP/LPV_r, NoNVP/NVP |
| Lopinavir/RitonavirAlso: LPV/RTV400/100 mg taken orally | Drug | NVP/LPV_r, NoNVP/LPV_r |
| NevirapineAlso: NVP200 mg taken orally | Drug | NVP/NVP, NoNVP/NVP |
| Tenofovir disoproxil fumarateAlso: TDF300 mg taken orally | Drug | NVP/LPV_r, NVP/NVP, NoNVP/LPV_r, NoNVP/NVP |
Primary outcome
Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry
Time frame: Through database cutoff for DSMB review (by October 6, 2008) with median follow-up 72 weeks and range from 0 to 144 weeks.
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.
Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry
Time frame: Throughout study with median follow-up 72 weeks and range from 0 to 180 weeks.
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.
7 secondary outcomes
Number of Participants Who Experienced Virologic Failure or Died.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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 Received NVP-containing Regimens at Randomization and Experienced NVP-associated Rash or Grade 2+ Liver Lab Abnormality
Time frame: Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP arm. Throughout study for NoNVP/NVP arm.
Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month
Time frame: 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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Oct 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 12152519Eshleman SH, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Rev. 2002 Apr-Jun;4(2):59-63.
- Background: PubMed 11600822Eshleman 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.
- Background: PubMed 14562858Harris 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.
- Background: PubMed 15247339Jourdain 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.
- Background: PubMed 16877674Nightingale 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.
- Background: PubMed 16736948Turner D, Wainberg MA. HIV transmission and primary drug resistance. AIDS Rev. 2006 Jan-Mar;8(1):17-23.
- Derived from this study: PubMed 31487271Boltz 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.
- Derived from this study: PubMed 24938526Asmelash 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.
- Derived from this study: PubMed 24443547Boltz 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.
- Derived from this study: PubMed 22719231Lockman 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.
- Derived from this study: PubMed 22509297Skinner-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.
- Derived from this study: PubMed 22301417Dong 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shahin Lockman, MD, MSc study chair
Brigham and Women's Hospital and Infectious Diseases Division, Department of Immunology and Infectious Diseases, Harvard School of Public Health
Frederick Sawe, MD study chair
The Walter Reed Project/WRAIR
11 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Emtricitabine, Emtricitabine/Tenofovir disoproxil fumarate and Lopinavir/Ritonavir in people with HIV Infections, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 11 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in South Africa, Botswana, Kenya, Malawi, Uganda and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Feb 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry (time frame: Through database cutoff for DSMB review (by October 6, 2008) with median follow-up 72 weeks and range from 0 to 144 weeks.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00089505, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Oct 2018.