Prospective Evaluation of Anti-retroviral Combinations for Treatment Naive, HIV Infected Persons in Resource-limited Settings
- Conditions
- HIV Infections
- Interventions
- Registration Number
- NCT00084136
- Lead Sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Brief Summary
This study compared 3 different three-drug combinations in HIV infected individuals starting their first HIV treatment regimens. Participants were recruited from resource-limited areas in Africa, Asia, South America, Haiti, and also from the United States. The study hypothesis was each of the once daily combinations (PI based, or NNRTI based) would not have inferior efficacy compared to the twice daily NNRTI based combination.
- Detailed Description
In developed countries, standard effective antiretroviral (ARV) therapy for treatment-naive HIV infected people includes three-drug combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, direct comparisons of ARV efficacy in persons that more closely reflect the worldwide demographics of HIV-1 infection are needed.\> \> Trial participants were recruited in Africa (Malawi, South Africa, Zimbabwe), Asia (India, Thailand), South America (Brazil, Peru), Haiti, and the United States.\>
\> All participants were randomly assigned to one of three arms, and random allocation was stratified by 2 factors: country, and screening plasma HIV-1 RNA level (\< 100,000 copies/mL versus \>= 100,000 copies/mL). Participants assigned to the ZDV/3TC+EFV arm received lamivudine/zidovudine twice daily and efavirenz once daily. Participants assigned to the ddI+FTC+ATV arm received emtricitabine, atazanavir, and enteric-coated didanosine once daily. Participants assigned to the TDF/FTC+EFV arm received emtricitabine, tenofovir disoproxil fumarate, and efavirenz once daily. \>
\>
\> Physical exam and blood collection occurred at entry and at most study visits. Participants experiencing virologic failure were offered a switch to another regimen. \>
\> On May 23, 2008, the ddI+FTC+ATV was closed following a planned interim review by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based upon compelling evidence that this arm had significantly more virologic failure (and therefore was inferior when) compared to the ZDV/3TC+EFV arm . Participants still receiving ddI+FTC+ATV were offered alternative medications, and all participants continued to be followed. \>
\> On November 3, 2009, the DSMB recommended that the study close to all follow-up on May 31, 2010, before the designed termination (based on 30% of participants meeting the primary outcome) was met. The board observed that the recent accumulation of primary efficacy events (i.e. regimen failures) was very slow. Therefore, if the study were to continue another 1-2 years, the precision gained for treatment comparisons would likely be small.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1571
Not provided
>
- More than 7 days exposure to ARVs (except for single-dose NVP or ZDV for any period for the purpose of pMTCT)>
- Acute therapy for serious medical illnesses within 14 days prior to study entry>
- Certain abnormal laboratory values>
- Radiation therapy or chemotherapy within 45 days prior to study entry. >
- Any immunomodulator, HIV vaccine, or other investigational therapy within 30 days prior to study entry. >
- Current alcohol or drug abuse that, in the opinion of the site investigator, would interfere with study participation>
- Inflamed pancreas within 3 years prior to study entry>
- Allergy/sensitivity to any of the study drugs or their formulations>
- Heart rate less than 40 beats/min>
- History of untreated, active second- or third-degree heart block>
- Currently detained in jail or for treatment of a psychiatric or physical illness>
- Vomiting or inability to swallow medications>
- Pregnancy>
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ddI+FTC+ATV Didanosine (enteric-coated) ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine ZDV/3TC+EFV Lamivudine/Zidovudine ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz TDF/FTC+EFV Emtricitabine/Tenofovir disoproxil fumarate TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz ZDV/3TC+EFV Efavirenz ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz ddI+FTC+ATV Atazanavir ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine ddI+FTC+ATV Emtricitabine ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine TDF/FTC+EFV Efavirenz TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz
- Primary Outcome Measures
Name Time Method Time to Treatment Failure (PI Comparison) Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up until ddI+FTC+ATV arm closed (May 22, 2008). Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005), plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier).
Time to Treatment Failure (NRTI Comparison) Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up through study closure (May 31, 2010). Time from randomization to the earliest of: scheduled week of first plasma sample meeting virologic failure (two consecutive plasma HIV-1 RNA values 1,000 copies/mL or higher, regardless of whether ARV medications being taken at the time); scheduled week of first AIDS defining diagnosis (WHO Stage 4 (2005) plus microsporidiosis, cyclospora gastroenteritis and Chaga's disease), not attributed to Immune Reconstitution Inflammatory Syndrome (reviewed by chairs); date of death (due to any cause). Plasma drawn every 8 weeks (except confirmation samples could be drawn earlier).
- Secondary Outcome Measures
Name Time Method Time to Immunologic Failure (PI Comparison) At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008) Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.
Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (NRTI Comparison) At Weeks 24 and 48 (including follow-up through to study closure on May 31, 2010) Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored.
Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison) Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008) Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir).
Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison) weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008) Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3).
Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison) Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008) Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.
Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison) At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008) Number of participants with plasma HIV-1 Viral load fewer than 400 copies/mL at study visit weeks 24 and 48. Closest observed result between 20 and up to 28 weeks (for week 24), and between 44 and up to 52 (for week 48) used if multiple results available. Missing values excluded, and both study treatment status and history ignored.
Change in CD4 Count From Screening to Weeks 24, 48, 96 (NRTI Comparison) weeks 24, 48 and 96 (including all follow-up through to study closure on May 31, 2010) Available pre-randomization CD4 cell counts were limited to the single CD4 cell count used for study eligibility (and therefore must have been fewer than 300 cells/mm3).
Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(PI Comparison) Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values \< 400 copies/mL; two consecutive plasma HIV-1 RNA values \> 400 copies/mL following virologic suppression.
Time to Immunologic Failure (NRTI Comparison) At or after Week 48 (including all follow-up through study closure - May 31,2010) Time from randomization to the first scheduled study visit (week 48 or later) with a CD4+ cell count fewer than 100 cells/mm3.
Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) Week 96 (using follow-up through to study closure on May 31,2010) Time from randomization to any of the following events occurring prior to week 96: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values \< 400 copies/mL; two consecutive plasma HIV-1 RNA values \> 400 copies/mL following virologic suppression.
Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) Week 48 using follow-up through study closure on May 31,2010 Time from randomization to any of the following events occurring prior to week 48: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values \< 400 copies/mL; two consecutive plasma HIV-1 RNA values \> 400 copies/mL following virologic suppression.
Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison) Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) Time from randomization to any of the following events occurring prior to week 48: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values \< 400 copies/mL; two consecutive plasma HIV-1 RNA values \> 400 copies/mL following virologic suppression.
Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison) Week 48 (using follow-up through study closure on May 31,2010) Time from randomization to any of the following events occurring prior to week 48: discontinued ARV regimen (see time to discontinuation of initial ARV therapy above); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values \< 400 copies/mL; two consecutive plasma HIV-1 RNA values \> 400 copies/mL following virologic suppression.
Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison) Throughout follow-up until study closed (May 31,2010) Time is measured from date of treatment initiation to earliest of the following: date of last participant contact (premature discontinuation of study follow-up); date all ARV medications were held (if all medications held for at least 8 weeks, for any reason); date that any ARV medication was changed (excluding the following single ARV substitutions: stavudine or tenofovir for zidovudine, nevirapine for efavirenz, or didanosine for tenofovir).
Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison) Week 96 using follow-up through study closure on May 31,2010 Time to any of the following events occurring prior to week 96: changed any ARV medication (including permanent discontinuation of all medications); discontinued study follow-up or died; absence of virologic suppression defined as 2 consecutive plasma HIV-1 RNA values \< 400 copies/mL; two consecutive plasma HIV-1 RNA values \> 400 copies/mL following virologic suppression.
Time to First Dose Modification or Grade 3 or 4 Adverse Event (NRTI Comparison) Throughout study follow-up until study closure (May 31, 2010) Time from treatment dispensation to the first occurring of the following: week of first ARV medication change; week of first grade 3 or higher sign/symptom or laboratory abnormality (total bilirubin was excluded) that was at least one grade higher than baseline. Grading used the Division of AIDS (DAIDS) 2004 Severity of Adverse Events Tables.
Trial Locations
- Locations (42)
University of Texas, Galveston
🇺🇸Galveston, Texas, United States
College of Med. JHU CRS
🇲🇼P.O. Box 1131, Blantyre, Malawi
UZ-Parirenyatwa CRS
🇿🇼AIDS Research Unit P.O. Box A178, Harare, Zimbabwe
University of Southern California
🇺🇸Los Angeles, California, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
YRG CARE Medical Ctr., VHS Chennai CRS
🇮🇳Rajiv Gandhi Salai Taramani, Chennai, India
Asociacion Civil Impacta Salud y Educacion - Miraf CRS
🇵🇪Barranco, Lima, Peru
Northwestern University
🇺🇸Chicago, Illinois, United States
Univ. of Hawaii at Manoa, Leahi Hosp.
🇺🇸Honolulu, Hawaii, United States
UCLA CARE Center CRS
🇺🇸Los Angeles, California, United States
Rush-Presbyterian/St. Lukes (Chicago)
🇺🇸Chicago, Illinois, United States
Univ. of Rochester ACTG CRS
🇺🇸Rochester, New York, United States
NY Univ. HIV/AIDS CRS
🇺🇸New York, New York, United States
Washington University (St. Louis)
🇺🇸Saint Louis, Missouri, United States
HIV Prevention & Treatment CRS
🇺🇸HVTN 722 West 168th Street MSPH Bldg., New York, United States
NARI Clinic at NIV CRS
🇮🇳Maharashtra State, Pune, India
Dr. Kotnis Dispensary
🇮🇳Pune, India
The Miriam Hosp. ACTG CRS
🇺🇸Providence, Rhode Island, United States
University of Texas, Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
🇧🇷Manguinhos, Rio De Janeiro, Brazil
Les Centres GHESKIO CRS
ðŸ‡ðŸ‡¹Bicentenaire, Port-au-Prince, Haiti
San Miguel CRS
🇵🇪San Miguel, Lima, Peru
NARI Pune CRS
🇮🇳Pune, Maharashtra, India
Wits HIV CRS
🇿🇦Johannesburg, Gauteng, South Africa
Durban Adult HIV CRS
🇿🇦Durban, KwaZulu Natal, South Africa
Cook County Hospital Core Center
🇺🇸Chicago, Illinois, United States
Beth Israel Medical Center
🇺🇸New York, New York, United States
Cornell CRS
🇺🇸New York, New York, United States
Harbor General/UCLA
🇺🇸Torrance, California, United States
Community Health Network, Inc.
🇺🇸Rochester, New York, United States
The Ohio State Univ. AIDS CRS
🇺🇸Columbus, Ohio, United States
Stanley Street Treatment and Resource
🇺🇸Providence, Rhode Island, United States
Hosp. of the Univ. of Pennsylvania CRS
🇺🇸Philadelphia, Pennsylvania, United States
Hospital Nossa Senhora da Conceicao
🇧🇷Porto Alegre, RS, Brazil
Chiang Mai Univ. ACTG CRS
🇹ðŸ‡P.O. Box 80, Chiang Mai, Thailand
University of North Carolina Lilongwe CRS
🇲🇼Mzimba Road, Lilongwe, Malawi
Univ. of Colorado Health Sciences Center, Denver
🇺🇸Denver, Colorado, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
Wake County Health and Human Services Clinical Research Site
🇺🇸Chapel Hill, North Carolina, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Vanderbilt Therapeutics CRS
🇺🇸Nashville, Tennessee, United States