HIV-1 InfectionPhase 4MULTI-OCTAVENCT01641367
A5288/MULTI-OCTAVE: Management Using Latest Technologies to Optimize Combination Therapy After Viral Failure
A Phase 4 study testing Darunavir, Etravirine and Emtricitabine/tenofovir disoproxil fumarate in people with HIV-1 Infection, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 19 sites in 10 countries.
Trial summary
The study was done to: test a strategy of using a resistance test to choose anti-HIV drugs see how well combinations of new anti-HIV drugs work to lower HIV infection see if taking new anti-HIV drugs together is safe and tolerable see if text messages improve people's anti-HIV drug-taking behavior (only at sites… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV-1 Infection
- What is being tested?
- Darunavir, Etravirine and Emtricitabine/tenofovir disoproxil fumarate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 545 participants
- Where
- 19 sitesin 10 countries
- Study dates
- 22 Feb 2013to 31 Dec 2018
- Phase
- Phase 4
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA VL.
- Any previous combination of ARV treatment at any time with at least one regimen that contained one NNRTI and two NRTIs which was replaced with a PI-based regimen because of virologic, immunologic, or clinical treatment failure, or because of toxicity.
- NOTE: All potential participants with prior RAL exposure were assigned to either Cohort A or Cohort D.
- At screening, receipt of a PI-based regimen with no regimen change for a minimum of 24 weeks prior to screening.
- Confirmation of VF of current second-line PI-based ART. NOTE A: Failure of the current second-line regimen was defined as two consecutive measurements of plasma HIV-1 RNA ≥1000 copies/mL obtained at least 1 day apart while on the current PI-based regimen. "Current PI-based regimen" and "current regimen" were understood to be the regimen described (ie, the regimen that the candidate was taking when the first VF sample was drawn plus only those modifications allowed).
- CD4+ T-cell count result from a specimen drawn within 103 days prior to study entry
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- Laboratory values obtained within 30 days prior to study entry:
- Absolute neutrophil count (ANC) ≥ 500/mm^3
- Hemoglobin ≥7.5 g/dL
- Platelet count ≥40,000/mm^3
- Creatinine ≤2 X upper limit of normal (ULN)
- Aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase ≤5 x ULN
- Total bilirubin ≤2.5 x ULN
- Creatinine clearance (CrCl) >30 mL/min, either measured or estimated by Cockcroft-Gault equation
- Hepatitis B panel that includes HbsAB, HBcAB, and HBsAG or only HBsAG, with plasma stored for later anti-HBs and anti-HBc.
- NOTE A: Candidates who were eligible for cohort B and who were positive for active hepatitis B infection were assigned to sub-cohort B3 at registration/randomization.
- NOTE B: Candidates with CrCl <60 mL/min who were also positive for active hepatitis B infection were not eligible.
- Females of reproductive potential (women who have not been post-menopausal for at least 24 consecutive months, ie, who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, hysterectomy or bilateral salpingectomy or bilateral oophorectomy or tubal ligation) must have had a negative serum or urine pregnancy test prior to the submission of the screening genotype testing sample and again within 48 hours prior to randomization or registration.
- Female participants of reproductive potential must have agreed not to participate in the conception process (ie, active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female participant must have used at least one reliable form of contraceptive. Female participants must have continued to use contraceptives while receiving study treatment and for 6 weeks after stopping study treatment.
- Acceptable forms of contraceptives included:
- Condoms (male or female) with or without a spermicidal agent
- Diaphragm or cervical cap with spermicide
- Intrauterine device (IUD)
- Hormonal contraception
- Female participants who were not of reproductive potential or whose male partner(s) had documented azoospermia) were not required to use contraceptives. Any statement of self-reported sterility or that of her partner's must have been entered in the source documents.
- NOTE: Acceptable documentation of lack of reproductive potential was oral or written documentation from the participant.
- Karnofsky performance score >/= 70 within 30 days prior to study entry.
- Ability and willingness of potential participant to provide informed consent.
- Willingness of potential participant to adhere to protocol requirements, especially with respect to treatment assignment and ability to obtain non-study provided ART, if needed.
- Ability to take oral study medications.
- No intention of permanent relocation that would preclude attending Step 1 and 2 study follow-up visits.
- Availability of a successful, interpretable resistance genotype report from a DAIDS-approved regional genotyping facility from testing performed on a plasma sample that was collected during screening (ie, at or after the date that a sample is collected to confirm HIV-1 virologic failure) and which was shipped to a regional resistance testing laboratory once documentation of two screening plasma HIV-1 RNA values ≥1000 copies/mL were available.
- Identification of a cohort assignment and ARV regimen for use on study, selected from the recommended options provided by the site investigator, and reviewed and approved by the A5288 Clinical Management Committee (CMC).
Who cannot join
- Pregnancy or breast-feeding.
- Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
- Active drug or alcohol use or dependence that, in the opinion of the site investigator, would have interfered with adherence to study requirements.
- Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or was clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.
- Concurrent illness or condition that would compromise the ability to take study medication, follow the protocol, or that would make participation not in the best interest of the participant, per the site investigator.
- Requirement for taking any of the prohibited medications with the selected ARV study regimen, or within 14 days prior to study entry.
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- NOTE: Study candidates should not have discontinued any component of their ART during screening. The 14-day restriction on prohibited medications did not apply to ARVs.
- Active tuberculosis (TB) or rifampin exposure less than 2 weeks prior to study entry.
- Any exposure to darunavir or etravirine.
Trial locations and contacts
19 sites in 10 countries.
19 sites in 10 countries
South Africa4 sites
Family Clinical Research Unit (FAM-CUR) CRS (8950)
Cape Town, West Cape, 7505
Durban Adult HIV CRS (11201)
Durban, 4013 SF
University of the Witwatersrand Helen Joseph (WITS HJH) CRS (11101)
Johannesburg, Gauteng, 2193
Soweto ACTG CRS (12301)
Johannesburg
Brazil2 sites
Hospital Nossa Senhora da Conceicao CRS (12201)
Porto Alegre, Rio Grande do Sul, 9043010
Instituto de Pesquisa Clinica Evandro Chagas (12101)
Rio de Janeiro, 21045
Haiti2 sites
Les Centres GHESKIO CRS (30022)
Port-au-Prince, Bicentaire, HT-6110
GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
Port-au-Prince
India2 sites
Chennai Antiviral Research and Treatment (CART) CRS (11701)
Chennai, Taramani, 600113
BJ Medical College CRS (31441)
Pune, Maharashtra, 411001
Kenya2 sites
AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)
Eldoret, 30100
Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)
Kisumu, 40100
Peru2 sites
Barranco CRS (11301)
Lima, 18 PE
San Miguel CRS (11302)
San Miguel, Lima region
Thailand2 sites
31802 Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
Bangkok, Patumwan, 10330
31784 Chiang Mai University HIV Treatment CRS
Chiang Mai, 50200
About this study
Official title: Management Using the Latest Technologies in Resource-limited Settings to Optimize Combination Therapy After Viral Failure (MULTI-OCTAVE)
The study was done to:
- test a strategy of using a resistance test to choose anti-HIV drugs
- see how well combinations of new anti-HIV drugs work to lower HIV infection
- see if taking new anti-HIV drugs together is safe and tolerable
- see if text messages improve people's anti-HIV drug-taking behavior (only at sites participating in the adherence study)
- in people taking certain combinations of anti-HIV drugs with an anti-TB drug, compare how these drugs act in the body
- to see how people do after they stop having frequent clinic visits as part of a research study
Read the detailed description
A5288 was an open-label phase IV, prospective interventional, strategy study in resource-limited settings (RLS) for HIV-1 infected participants with triple-class experience or resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs) and who were failing their current regimen. The use of novel agents and contemporary clinical decision management tools that include standard genotyping and plasma HIV viral load (VL) monitoring were evaluated. The screening genotype results and antiretroviral (ARV) history were used to allocate potential participants to one of four Cohorts (A, B, C or D) and to select an associated ARV regimen based on the Cohort assignment. In brief, individuals assigned to Cohort A continued on the same PI as in their second-line regimen, with the ability to modify NRTIs. Those assigned to Cohort B who were negative for hepatitis B were randomized to receive RAL and DRV/RTV with either the best available NRTIs (Cohort B1) or ETR (Cohort B2). If they were positive for hepatitis B they were assigned to Cohort B3 and received RAL, DRV/RTV and either FTC/TDF or 3TC/TDF. Individuals assigned to Cohort C received RAL and DRV/RTV with the best available NRTIs. Those ineligible for Cohorts A, B or C were assigned to Cohort D and received the best available regimen that included study provided drugs and any locally provided drugs.
At sites where feasible and relevant, the study evaluated an adherence support intervention. This involved a randomized comparison of a cell phone-based adherence support intervention plus local standard-of-care adherence support procedures (CPI+SOC) versus the SOC adherence support procedures.
Participants enrolled to the study in Step 1. If a participant experienced a confirmed virologic failure (defined as two consecutive HIV-1 RNA measures >= 1000 copies/mL) at/after 22 weeks on their Step 1 regimen, they had another genotype test performed and cohort/regimen selected for Step 2. With the exception of one additional visit 4 weeks after enrollment to Step 2, the visit schedule for Step 2 followed the participant's original Step 1 schedule throughout the remainder of follow up.
Participants were followed in Steps 1 and 2 until 48 weeks after the last participant was enrolled to Step 1. During the first 48 weeks after Step 1 enrollment, clinic visits occurred at weeks 4, 12, 24, 36 and 48. After week 48, visits occurred every 12 weeks for adherence, safety and efficacy measures.
Participants had a final step 1/2 visit between November 22, 2016 and February 13, 2017. At the final step 1/2 visit, participants taking RAL, ETR, or DRV who were unable to obtain these drugs locally (e.g., through local treatment programs), and were otherwise eligible, entered Step 3 and continued to receive these drugs through the study for up to 96 additional weeks. Step 3 participants were dispensed ARVs every 12 weeks and had clinical assessments every 24 weeks. The purpose of Step 3 was to assist participants with the transition back to local care.
The primary analysis specified in the protocol and in the Statistical Analysis Plan was to estimate the proportion of participants in the overall study population who were virologically suppressed (HIV-1 RNA ≤200 copies/mL) at week 48 with a 95% confidence interval.
- Conditions
- HIV-1 Infection
- Being tested
- Darunavir, Etravirine, Emtricitabine/tenofovir disoproxil fumarate, Raltegravir, Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DarunavirDrug
Also called DRV, Prezista
Participants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day])
EtravirineDrug
Also called ETR, Intelence
Patients were administered Etravirine orally as two 100 mg tablets or one 200 mg tablet twice a day (400 mg per day) following a meal.
Emtricitabine/tenofovir disoproxil fumarateDrug
Also called FTC/TDF, Truvada
Patients were administered FTC/TDF orally as one fixed dose combination tablet (FTC 200 mg/TDF 300 mg) once daily, with or without food.
RaltegravirDrug
Also called RAL, Isentress
Participants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food
Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs)Drug
LPV/r and ATV/r were the preferred bPIs for second-line ART. TDF + (3TC or FTC) or AZT + 3TC were the most frequent NRTI backbones. Cohort A did not include any of the new drugs; therefore, it is distinct from Cohorts B, C, and D.
Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & availableDrug
For Cohort D, in many situations a participant received the same regimen that patients are getting in Cohorts B and C if that was the best combination that can be obtained according to his/her resistance profile and drug availability (as for many countries there were no further drug options beyond the available study drugs).
SOC adherence versus SOC+CPI adherenceOther
- not participating in the adherence randomization; OR
- randomized to SOC adherence; OR
- randomized to SOC+CPI adherence.
| Study group | Role | What they receive |
|---|---|---|
| Cohort A | Experimental | Under Protocol version 1.0:
No resistance to NRTIs, PIs, or NNRTI
• Continue current second-line regimen; NRTIs could be modified
Changed under LOA#2 to:
No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure
• Continue second-line regimen which may include LPV/RTV; NRTIs could be modified
Changed under LOA#3 to:
No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure
• Continue PI backbone; NRTIs could be modified. If on a RAL-containing regimen, RAL must be discontinued. Receives: Drug: Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs); Other: SOC adherence versus SOC+CPI adherence |
| Sub-cohort B1 | Experimental | Under Protocol version 1.0:
Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening
• Best available NRTIs, RAL, \& DRV/RTV
Changed under LOA#2 to:
Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening)
• Best available NRTIs, RAL, \& DRV/RTV Receives: Drug: Darunavir; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence |
| Sub-cohort B2 | Experimental | Under Protocol version 1.0:
Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening
• ETR, RAL, and DRV/RTV
Changed under LOA#2 to:
Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening)
• ETR, RAL, and DRV/RTV Receives: Drug: Darunavir; Drug: Etravirine; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence |
| Sub-cohort B3 | Experimental | Under Protocol version 1.0:
Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and with active hepatitis B infection at screening
• RAL, DRV/RTV, and FTC/TDF or TDF+3TC
Changed under LOA#2 to:
Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (with active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (with active hepatitis B infection at screening)
• RAL, DRV/RTV, and FTC/TDF or TDF+3TC Receives: Drug: Darunavir; Drug: Emtricitabine/tenofovir disoproxil fumarate; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence |
| Cohort C | Experimental | Under Protocol version 1.0:
Resistance to NRTIs and ETR or resistance to ETR alone (and may have resistance to PIs other than DRV)
• Best available NRTIs, RAL, and DRV/RTV
Changed under LOA#2:
Resistance to LPV/RTV and ETR but susceptible to DRV/RTV and with no prior RAL exposure and regardless of NRTI resistance OR Resistance to ETR and to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and with no prior RAL exposure
• Best available NRTIs, RAL, and DRV/RTV Receives: Drug: Darunavir; Drug: Raltegravir; Other: SOC adherence versus SOC+CPI adherence |
| Cohort D | Experimental | Under Protocol version 1.0:
Multiple NRTI resistance and/or DRV/RTV resistance or prior RAL exposure:
• Best available regimen, including study-provided and any locally available drugs
Changed under LOA#2:
Not eligible for Cohort A, B, or C:
• Best available regimen, including study-provided and any locally available drugs
Updated under protocol v2.0:
• Best available ART regimen, including study-provided and any locally available non-experimental drugs Receives: Drug: Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available; Other: SOC adherence versus SOC+CPI adherence |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks
The measurement closest to exactly 48 weeks (ie, 7x48=336 days) after the date of entry, within the window of 48 weeks ± 6 weeks (specifically 295 to 378 days after randomization, inclusive).
The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 48 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 48 was considered as HIV-1 RNA>200 copies/mL at week 48. Missing results at week 48 were considered as HIV-1 RNA >200 copies/mL at week 48 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 48. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.
Measured: 48 weeks after the date of entry
Secondary outcomes (59)
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks
The measurement closest to exactly 24 weeks (ie, 7x24=168 days) after the date of entry, within the window of 24 weeks ± 6 weeks (specifically 127 to 210 days after randomization, inclusive).
The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 24 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 24 was considered as HIV-1 RNA>200 copies/mL at week 24. Missing results at week 24 were considered as HIV-1 RNA >200 copies/mL at week 24 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 24. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.
Measured: 24 weeks after the date of entry
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks
The measurement closest to exactly 72 weeks (ie, 7x72=504 days) after the date of entry, within the window of 72 weeks ± 6 weeks (specifically 463 to 546 days, inclusive).
The analysis in the protocol and in the Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 72 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 72 was considered as HIV-1 RNA>200 copies/mL at week 72. If a result was expected, missing results at week 72 were considered as HIV-1 RNA >200 copies/mL at week 72 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 72. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.
Measured: 72 weeks after the date of entry
Number of Weeks of Follow-up
All participants were followed on step 1/2 until 48 weeks after the last participant was enrolled to step 1 regardless of virologic status or treatment switches. Length of follow-up varied by Cohort.
Measured: From study entry through Step 1/2 follow-up
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. Length of follow-up varied by Cohort.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Length of follow-up varied by Cohort.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. Length of follow-up varied by Cohort.
Measured: From week 24 to Week 48
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. Length of follow-up varied by Cohort. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Length of follow-up varied by Cohort. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing, by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure.Event times were the scheduled week of the initial failing measurement(RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after).Censoring times were the scheduled week of the last RNA result.Length of follow-up varied by Cohort.A new resistance-associated mutation is defined as one not present in the genotype prior to entry.
Measured: From week 24 to Week 48
Time From Study Entry/Randomization to Death
Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants Experiencing Death by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event
Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events. Length of follow-up varied by Cohort.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants Experiencing Death, AIDS-defining Event or a Non-AIDS-defining Event by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to the First of Death or Hospitalization.
Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis. Length of follow-up varied by Cohort.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Death or Hospitalization by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to Treatment Modification or Discontinuation.
Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Treatment Modification or Discontinuation by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to Treatment Modification or Discontinuation Due to Toxicity
Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Treatment Modification or Discontinuation Due to Toxicity by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to the Development of Immune Reconstitution Inflammatory Syndrome (IRIS)
Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants That Developed Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.
Measured: From study entry to week 48
Time to First Dose Modification Due to Grade 3 or 4 Toxicity
Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. Length of follow-up varied by Cohort. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With a Dose Modification Due to Grade 3 or 4 Toxicity by Week 48
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry to week 48
Change From Baseline in CD4+ T-cell Count
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)
Measured: Baseline, week 24, 48, and 72
Change From Baseline in Fasting Values of Total Cholesterol
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)
Measured: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of High-density Lipoprotein Cholesterol
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)]
Measured: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of Calculated Low-density Lipoprotein Cholesterol
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)
Measured: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of Triglycerides
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)
Measured: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of Glucose
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)
Measured: Baseline, week 24, 48 and 72
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks [CPI+SOC v SOC]
The measurement closest to exactly 48 weeks (ie, 7x48=336 days) after the date of entry, within the window of 48 weeks ± 6 weeks (specifically 295 to 378 days after randomization, inclusive).
The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 48 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 48 was considered as HIV-1 RNA>200 copies/mL at week 48. Missing results at week 48 were considered as HIV-1 RNA >200 copies/mL at week 48 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL.
Measured: 48 weeks after the date of entry
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks [CPI+SOC v SOC]
The measurement closest to exactly 24 weeks (ie, 7x24=168 days) after the date of entry, within the window of 24 weeks ± 6 weeks (specifically 127 to 210 days after randomization, inclusive).
The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 24 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 24 was considered as HIV-1 RNA>200 copies/mL at week 24. Missing results at week 24 were considered as HIV-1 RNA >200 copies/mL at week 24 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL.
Measured: 24 weeks after the date of entry
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks [CPI+SOC v SOC]
The measurement closest to exactly 72 weeks (ie, 7x72=504 days) after the date of entry, within the window of 72 weeks ± 6 weeks (specifically 463 to 546 days, inclusive).
The analysis in the protocol and in the Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 72 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 72 was considered as HIV-1 RNA>200 copies/mL at week 72. If a result was expected, missing results at week 72 were considered as HIV-1 RNA >200 copies/mL at week 72 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL.
Measured: 72 weeks after the date of entry
Number of Weeks of Follow-up [CPI+SOC v SOC]
All participants were followed on step 1/2 until 48 weeks after the last participant was enrolled to step 1 regardless of virologic status or treatment switches.
Measured: From study entry through Step 1/2 follow-up
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study [CPI+SOC v SOC]
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study [CPI+SOC v SOC]
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result.
Measured: From week 24 to Week 48
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing [CPI+SOC v SOC]
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure [specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit). HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. Event times were the scheduled week of the initial failing measurement (RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after). Censoring times were the scheduled week of the last RNA result. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing [CPI+SOC v SOC]
Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry (to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement, allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure. A new resistance-associated mutation is defined as one not present in the genotype prior to entry.
Measured: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing, by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Virologic failure was confirmed by the next HIV-1 RNA measurement ≥1000 copies/mL (irrespective of time between initial and confirmatory measure[specimens on separate dates] and treatment status). A week 24 measurement included HIV-1 RNA obtained ≥7*22=154 days after study entry(to allow for 14 day window for scheduling the visit).HIV-1 RNA measurements through and including 21 November 2016 were considered in identifying an initial failing measurement,allowing HIV-1 RNA at the close-out visit between 22 November 2016 and 13 February 2017 to be a confirmatory measure.Event times were the scheduled week of the initial failing measurement(RNA scheduled at week 0, 12, 24, 48 and every 24 weeks after).Censoring times were the scheduled week of the last RNA result.A new resistance-associated mutation is defined as one not present in the genotype prior to entry.
Measured: From week 24 to Week 48
Time From Study Entry/Randomization to Death [CPI+SOC v SOC]
Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants Experiencing Death by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event [CPI+SOC v SOC]
Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants Experiencing Death, AIDS-defining Event or a Non-AIDS-defining Event by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death, AIDS-defining event or non-AIDS defining event. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. Only new events were considered, an event that was also reported at or prior to study entry was not included. If a participant experienced multiple events, then the time of the first event was used in the analysis. AIDS defining events included parasitic, fungal, bacterial, and viral infections as well as neoplastic diseases, and neurological disorders. Non-AIDS defining events included malignancies, diabetes, neuropathies, cardiac and renal events.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to the First of Death or Hospitalization [CPI+SOC v SOC]
Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Death or Hospitalization by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of death or hospitalization. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit. If a participant experienced multiple events, then the time of the first event was used in the analysis.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to Treatment Modification or Discontinuation [CPI+SOC v SOC]
Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Treatment Modification or Discontinuation by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to Treatment Modification or Discontinuation Due to Toxicity [CPI+SOC v SOC]
Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Treatment Modification or Discontinuation Due to Toxicity by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen, a temporary hold lasting 7 days or longer, or the addition of a new drug to the regimen, due to an adverse event. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination. Event time was the exact week of the modification or discontinuation. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry to Week 48
Time From Study Entry/Randomization to the Development of Immune Reconstitution Inflammatory Syndrome (IRIS) [CPI+SOC v SOC]
Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants That Developed Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the diagnosis. Censoring time was the earlier of last contact week and the week of the last step 1/2 visit.
Measured: From study entry to Week 48
Time to First Dose Modification Due to Grade 3 or 4 Toxicity [CPI+SOC v SOC]
Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With a Dose Modification Due to Grade 3 or 4 Toxicity by Week 48 [CPI+SOC v SOC]
Results report percent of participants reaching outcome by week 48 using Kaplan-Meier method. Event time was the exact week of the modification. Censoring time was the earliest time point between last dose week and the week of the last step 1/2 visit. DAIDS AE Grading Table, Version 1.0 was used.
Measured: From study entry to Week 48
Change From Baseline in CD4+ T-cell Count [CPI+SOC v SOC]
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.
Measured: Baseline, week 24, 48, and 72
Change From Baseline in Fasting Values of Total Cholesterol [CPI+SOC v SOC]
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.
Measured: Baseline, week 24, 48, and 72
Change From Baseline in Fasting Values of High-density Lipoprotein Cholesterol [CPI+SOC v SOC]
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.
Measured: Baseline, week 24, 48, and 72
Change From Baseline in Fasting Values of Calculated Low-density Lipoprotein Cholesterol [CPI+SOC v SOC]
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.
Measured: Baseline, week 24, 48, and 72
Change From Baseline in Fasting Values of Triglycerides [CPI+SOC v SOC]
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.
Measured: Baseline, week 24, 48, and 72
Change From Baseline in Fasting Values of Glucose [CPI+SOC v SOC]
Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of entry/randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen.
Measured: Baseline, week 24, 48, and 72
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jul 2012 (estimated)
- Study start22 Feb 2013
- Primary completion23 Nov 2016
- Study completion31 Dec 2018
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 (4)Papers the sponsor has linked to this study.
- Other trials for HIV-1 InfectionStudies 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 545 participants (actual)
Sponsor and investigators
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Sponsor type
- Research network
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID), AbbVie, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme LLC, Dimagi Inc.
- Responsible party
- Sponsor
- Investigators
- Beatriz Grinsztejn, MD, PhD, Study chair, Instituto de Pesquisa Clinica Evandro Chagas-FiocruzPeter Mugyenyi, MB ChB, FRCP, DSc, Study chair, Joint Clinical Research Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01641367
- Sponsor's protocol ID
- ACTG A5288
- Other IDs
- 1U01AI068636
- Acronym
- MULTI-OCTAVE
- Status last verified
- Mar 2019
- First submitted
- 28 Jun 2012
- Last updated
- 15 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Avihingsanon A, Hughes MD, Salata R, Godfrey C, McCarthy C, Mugyenyi P, Hogg E, Gross R, Cardoso SW, Bukuru A, Makanga M, Badal-Aesen S, Mave V, Ndege BW, Fontain SN, Samaneka W, Secours R, Van Schalkwyk M, Mngqibisa R, Mohapi L, Valencia J, Sugandhavesa P, Montalban E, Munyanga C, Chagomerana M, Santos BR, Kumarasamy N, Kanyama C, Schooley RT, Mellors JW, Wallis CL, Collier AC, Grinsztejn B; A5288 Study team. Third-line antiretroviral therapy, including raltegravir (RAL), darunavir (DRV/r) and/or etravirine (ETR), is well tolerated and achieves durable virologic suppression over 144 weeks in resource-limited settings: ACTG A5288 strategy trial. J Int AIDS Soc. 2022 Jun;25(6):e25905. doi: 10.1002/jia2.25905.
PubMed 36039892Godfrey C, Hughes MD, Ritz J, Coelho L, Gross R, Salata R, Mngqibisa R, Wallis CL, Mumbi ME, Matoga M, Poongulali S, Van Schalkwyk M, Hogg E, Fletcher CV, Grinsztejn B, Collier AC; A5288 team. Brief Report: Sex Differences in Outcomes for Individuals Presenting for Third-Line Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2020 Jun 1;84(2):203-207. doi: 10.1097/QAI.0000000000002324.
PubMed 32049773Gross R, Ritz J, Hughes MD, Salata R, Mugyenyi P, Hogg E, Wieclaw L, Godfrey C, Wallis CL, Mellors JW, Mudhune VO, Badal-Faesen S, Grinsztejn B, Collier AC. Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial. Lancet Digit Health. 2019 May;1(1):e26-e34. doi: 10.1016/S2589-7500(19)30006-8. Epub 2019 May 6.
PubMed 31528850Grinsztejn B, Hughes MD, Ritz J, Salata R, Mugyenyi P, Hogg E, Wieclaw L, Gross R, Godfrey C, Cardoso SW, Bukuru A, Makanga M, Faesen S, Mave V, Wangari Ndege B, Nerette Fontain S, Samaneka W, Secours R, van Schalkwyk M, Mngqibisa R, Mohapi L, Valencia J, Sugandhavesa P, Montalban E, Avihingsanon A, Santos BR, Kumarasamy N, Kanyama C, Schooley RT, Mellors JW, Wallis CL, Collier AC; A5288 Team. Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study. Lancet HIV. 2019 Sep;6(9):e588-e600. doi: 10.1016/S2352-3018(19)30146-8. Epub 2019 Jul 29.
PubMed 31371262
Study at a glance
From the registry record, last updated by the sponsor on 15 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Management Using the Latest Technologies in Resource-limited Settings to Optimize Combination Therapy After Viral Failure (MULTI-OCTAVE)
- ClinicalTrials.gov ID
- NCT01641367
- Acronym / sponsor ID
- MULTI-OCTAVE / ACTG A5288
- Conditions
- HIV-1 Infection
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 545 participants (actual)
- Lead sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other InfectionsResearch network
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID), AbbVie, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme LLC, Dimagi Inc.
- Study start
- 22 Feb 2013 (actual)
- Primary completion
- 23 Nov 2016 (actual)
- Study completion
- 31 Dec 2018 (actual)
- First posted
- 16 Jul 2012 (estimated)
- Results
- Posted 20 Feb 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study was done to:
- test a strategy of using a resistance test to choose anti-HIV drugs
- see how well combinations of new anti-HIV drugs work to lower HIV infection
- see if taking new anti-HIV drugs together is safe and tolerable
- see if text messages improve people's anti-HIV drug-taking behavior (only at sites participating in the adherence study)
- in people taking certain combinations of anti-HIV drugs with an anti-TB drug, compare how these drugs act in the body
- to see how people do after they stop having frequent clinic visits as part of a research study
Detailed description
A5288 was an open-label phase IV, prospective interventional, strategy study in resource-limited settings (RLS) for HIV-1 infected participants with triple-class experience or resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs) and who were failing their current regimen. The use of novel agents and contemporary clinical decision management tools that include standard genotyping and plasma HIV viral load (VL) monitoring were evaluated. The screening genotype results and antiretroviral (ARV) history were used to allocate potential participants to one of four Cohorts (A, B, C or D) and to select an associated ARV regimen based on the Cohort assignment. In brief, individuals assigned to Cohort A continued on the same PI as in their second-line regimen, with the ability to modify NRTIs. Those assigned to Cohort B who were negative for hepatitis B were randomized to receive RAL and DRV/RTV with either the best available NRTIs (Cohort B1) or ETR (Cohort B2). If they were positive for hepatitis B they were assigned to Cohort B3 and received RAL, DRV/RTV and either FTC/TDF or 3TC/TDF. Individuals assigned to Cohort C received RAL and DRV/RTV with the best available NRTIs. Those ineligible for Cohorts A, B or C were assigned to Cohort D and received the best available regimen that included study provided drugs and any locally provided drugs.
At sites where feasible and relevant, the study evaluated an adherence support intervention. This involved a randomized comparison of a cell phone-based adherence support intervention plus local standard-of-care adherence support procedures (CPI+SOC) versus the SOC adherence support procedures.
Participants enrolled to the study in Step 1. If a participant experienced a confirmed virologic failure (defined as two consecutive HIV-1 RNA measures >= 1000 copies/mL) at/after 22 weeks on their Step 1 regimen, they had another genotype test performed and cohort/regimen selected for Step 2. With the exception of one additional visit 4 weeks after enrollment to Step 2, the visit schedule for Step 2 followed the participant's original Step 1 schedule throughout the remainder of follow up.
Participants were followed in Steps 1 and 2 until 48 weeks after the last participant was enrolled to Step 1. During the first 48 weeks after Step 1 enrollment, clinic visits occurred at weeks 4, 12, 24, 36 and 48. After week 48, visits occurred every 12 weeks for adherence, safety and efficacy measures.
Participants had a final step 1/2 visit between November 22, 2016 and February 13, 2017. At the final step 1/2 visit, participants taking RAL, ETR, or DRV who were unable to obtain these drugs locally (e.g., through local treatment programs), and were otherwise eligible, entered Step 3 and continued to receive these drugs through the study for up to 96 additional weeks. Step 3 participants were dispensed ARVs every 12 weeks and had clinical assessments every 24 weeks. The purpose of Step 3 was to assist participants with the transition back to local care.
The primary analysis specified in the protocol and in the Statistical Analysis Plan was to estimate the proportion of participants in the overall study population who were virologically suppressed (HIV-1 RNA ≤200 copies/mL) at week 48 with a 95% confidence interval.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Cohort A | Experimental | Drug: Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs), Other: SOC adherence versus SOC+CPI adherenceUnder Protocol version 1.0: No resistance to NRTIs, PIs, or NNRTI • Continue current second-line regimen; NRTIs could be modified Changed under LOA#2 to: No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure • Continue second-line regimen which may include LPV/RTV; NRTIs could be modified Changed under LOA#3 to: No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure • Continue PI backbone; NRTIs could be modified. If on a RAL-containing regimen, RAL must be discontinued. |
| Sub-cohort B1 | Experimental | Drug: Darunavir, Drug: Raltegravir, Other: SOC adherence versus SOC+CPI adherenceUnder Protocol version 1.0: Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening • Best available NRTIs, RAL, \& DRV/RTV Changed under LOA#2 to: Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening) • Best available NRTIs, RAL, \& DRV/RTV |
| Sub-cohort B2 | Experimental | Drug: Darunavir, Drug: Etravirine, Drug: Raltegravir, Other: SOC adherence versus SOC+CPI adherenceUnder Protocol version 1.0: Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening • ETR, RAL, and DRV/RTV Changed under LOA#2 to: Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening) • ETR, RAL, and DRV/RTV |
| Sub-cohort B3 | Experimental | Drug: Darunavir, Drug: Emtricitabine/tenofovir disoproxil fumarate, Drug: Raltegravir, Other: SOC adherence versus SOC+CPI adherenceUnder Protocol version 1.0: Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and with active hepatitis B infection at screening • RAL, DRV/RTV, and FTC/TDF or TDF+3TC Changed under LOA#2 to: Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (with active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (with active hepatitis B infection at screening) • RAL, DRV/RTV, and FTC/TDF or TDF+3TC |
| Cohort C | Experimental | Drug: Darunavir, Drug: Raltegravir, Other: SOC adherence versus SOC+CPI adherenceUnder Protocol version 1.0: Resistance to NRTIs and ETR or resistance to ETR alone (and may have resistance to PIs other than DRV) • Best available NRTIs, RAL, and DRV/RTV Changed under LOA#2: Resistance to LPV/RTV and ETR but susceptible to DRV/RTV and with no prior RAL exposure and regardless of NRTI resistance OR Resistance to ETR and to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and with no prior RAL exposure • Best available NRTIs, RAL, and DRV/RTV |
| Cohort D | Experimental | Drug: Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available, Other: SOC adherence versus SOC+CPI adherenceUnder Protocol version 1.0: Multiple NRTI resistance and/or DRV/RTV resistance or prior RAL exposure: • Best available regimen, including study-provided and any locally available drugs Changed under LOA#2: Not eligible for Cohort A, B, or C: • Best available regimen, including study-provided and any locally available drugs Updated under protocol v2.0: • Best available ART regimen, including study-provided and any locally available non-experimental drugs |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (33 listed)
- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA VL.
- Any previous combination of ARV treatment at any time with at least one regimen that contained one NNRTI and two NRTIs which was replaced with a PI-based regimen because of virologic, immunologic, or clinical treatment failure, or because of toxicity.
- NOTE: All potential participants with prior RAL exposure were assigned to either Cohort A or Cohort D.
- At screening, receipt of a PI-based regimen with no regimen change for a minimum of 24 weeks prior to screening.
- Confirmation of VF of current second-line PI-based ART. NOTE A: Failure of the current second-line regimen was defined as two consecutive measurements of plasma HIV-1 RNA ≥1000 copies/mL obtained at least 1 day apart while on the current PI-based regimen. "Current PI-based regimen" and "current regimen" were understood to be the regimen described (ie, the regimen that the candidate was taking when the first VF sample was drawn plus only those modifications allowed).
Key exclusion criteria (9 listed)
- Pregnancy or breast-feeding.
- Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
- Active drug or alcohol use or dependence that, in the opinion of the site investigator, would have interfered with adherence to study requirements.
- Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or was clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.
- Concurrent illness or condition that would compromise the ability to take study medication, follow the protocol, or that would make participation not in the best interest of the participant, per the site investigator.
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 |
|---|---|---|
| DarunavirAlso: DRV, PrezistaParticipants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day]) | Drug | Cohort C, Sub-cohort B1, Sub-cohort B2, Sub-cohort B3 |
| EtravirineAlso: ETR, IntelencePatients were administered Etravirine orally as two 100 mg tablets or one 200 mg tablet twice a day (400 mg per day) following a meal. | Drug | Sub-cohort B2 |
| Emtricitabine/tenofovir disoproxil fumarateAlso: FTC/TDF, TruvadaPatients were administered FTC/TDF orally as one fixed dose combination tablet (FTC 200 mg/TDF 300 mg) once daily, with or without food. | Drug | Sub-cohort B3 |
| RaltegravirAlso: RAL, IsentressParticipants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food | Drug | Cohort C, Sub-cohort B1, Sub-cohort B2, Sub-cohort B3 |
| Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs)LPV/r and ATV/r were the preferred bPIs for second-line ART. TDF + (3TC or FTC) or AZT + 3TC were the most frequent NRTI backbones. Cohort A did not include any of the new drugs; therefore, it is distinct from Cohorts B, C, and D. | Drug | Cohort A |
| Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & availableFor Cohort D, in many situations a participant received the same regimen that patients are getting in Cohorts B and C if that was the best combination that can be obtained according to his/her resistance profile and drug availability (as for many countries there were no further drug options beyond the available study drugs). | Drug | Cohort D |
| SOC adherence versus SOC+CPI adherence* not participating in the adherence randomization; OR * randomized to SOC adherence; OR * randomized to SOC+CPI adherence. | Other | Cohort A, Cohort C, Cohort D, Sub-cohort B1, Sub-cohort B2, Sub-cohort B3 |
Primary outcome
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks
Time frame: 48 weeks after the date of entry
The measurement closest to exactly 48 weeks (ie, 7x48=336 days) after the date of entry, within the window of 48 weeks ± 6 weeks (specifically 295 to 378 days after randomization, inclusive). The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 48 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 48 was considered as HIV-1 RNA>200 copies/mL at week 48. Missing results at week 48 were considered as HIV-1 RNA >200 copies/mL at week 48 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 48. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.
59 secondary outcomes
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks
Time frame: 24 weeks after the date of entry
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks
Time frame: 72 weeks after the date of entry
Number of Weeks of Follow-up
Time frame: From study entry through Step 1/2 follow-up
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure by Week 48
Time frame: From week 24 to Week 48
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing, by Week 48
Time frame: From week 24 to Week 48
Time From Study Entry/Randomization to Death
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants Experiencing Death by Week 48
Time frame: From study entry to Week 48
Time From Study Entry/Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants Experiencing Death, AIDS-defining Event or a Non-AIDS-defining Event by Week 48
Time frame: From study entry to Week 48
Time From Study Entry/Randomization to the First of Death or Hospitalization.
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Death or Hospitalization by Week 48
Time frame: From study entry to Week 48
Time From Study Entry/Randomization to Treatment Modification or Discontinuation.
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Treatment Modification or Discontinuation by Week 48
Time frame: From study entry to Week 48
Time From Study Entry/Randomization to Treatment Modification or Discontinuation Due to Toxicity
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Treatment Modification or Discontinuation Due to Toxicity by Week 48
Time frame: From study entry to Week 48
Time From Study Entry/Randomization to the Development of Immune Reconstitution Inflammatory Syndrome (IRIS)
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants That Developed Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48
Time frame: From study entry to week 48
Time to First Dose Modification Due to Grade 3 or 4 Toxicity
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With a Dose Modification Due to Grade 3 or 4 Toxicity by Week 48
Time frame: From study entry to week 48
Change From Baseline in CD4+ T-cell Count
Time frame: Baseline, week 24, 48, and 72
Change From Baseline in Fasting Values of Total Cholesterol
Time frame: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of High-density Lipoprotein Cholesterol
Time frame: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of Calculated Low-density Lipoprotein Cholesterol
Time frame: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of Triglycerides
Time frame: Baseline, week 24, 48 and 72
Change From Baseline in Fasting Values of Glucose
Time frame: Baseline, week 24, 48 and 72
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks [CPI+SOC v SOC]
Time frame: 48 weeks after the date of entry
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 24 Weeks [CPI+SOC v SOC]
Time frame: 24 weeks after the date of entry
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 72 Weeks [CPI+SOC v SOC]
Time frame: 72 weeks after the date of entry
Number of Weeks of Follow-up [CPI+SOC v SOC]
Time frame: From study entry through Step 1/2 follow-up
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study [CPI+SOC v SOC]
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study [CPI+SOC v SOC]
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure by Week 48 [CPI+SOC v SOC]
Time frame: From week 24 to Week 48
Time to Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing [CPI+SOC v SOC]
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Number of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing [CPI+SOC v SOC]
Time frame: From week 24 through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Percent of Participants With Confirmed Virologic Failure, Defined as First HIV-1 RNA ≥1000 Copies/mL at or After 24 Weeks on Study, With a New Resistance-associated Mutation Detected in Population-based Sequencing, by Week 48 [CPI+SOC v SOC]
Time frame: From week 24 to Week 48
Time From Study Entry/Randomization to Death [CPI+SOC v SOC]
Time frame: From study entry through Step 1/2 follow-up; median (IQR) step 1/2 follow-up was 72 (72,108) weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36039892Avihingsanon A, Hughes MD, Salata R, Godfrey C, McCarthy C, Mugyenyi P, Hogg E, Gross R, Cardoso SW, Bukuru A, Makanga M, Badal-Aesen S, Mave V, Ndege BW, Fontain SN, Samaneka W, Secours R, Van Schalkwyk M, Mngqibisa R, Mohapi L, Valencia J, Sugandhavesa P, Montalban E, Munyanga C, Chagomerana M, Santos BR, Kumarasamy N, Kanyama C, Schooley RT, Mellors JW, Wallis CL, Collier AC, Grinsztejn B; A5288 Study team. Third-line antiretroviral therapy, including raltegravir (RAL), darunavir (DRV/r) and/or etravirine (ETR), is well tolerated and achieves durable virologic suppression over 144 weeks in resource-limited settings: ACTG A5288 strategy trial. J Int AIDS Soc. 2022 Jun;25(6):e25905. doi: 10.1002/jia2.25905.
- Derived from this study: PubMed 32049773Godfrey C, Hughes MD, Ritz J, Coelho L, Gross R, Salata R, Mngqibisa R, Wallis CL, Mumbi ME, Matoga M, Poongulali S, Van Schalkwyk M, Hogg E, Fletcher CV, Grinsztejn B, Collier AC; A5288 team. Brief Report: Sex Differences in Outcomes for Individuals Presenting for Third-Line Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2020 Jun 1;84(2):203-207. doi: 10.1097/QAI.0000000000002324.
- Derived from this study: PubMed 31528850Gross R, Ritz J, Hughes MD, Salata R, Mugyenyi P, Hogg E, Wieclaw L, Godfrey C, Wallis CL, Mellors JW, Mudhune VO, Badal-Faesen S, Grinsztejn B, Collier AC. Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial. Lancet Digit Health. 2019 May;1(1):e26-e34. doi: 10.1016/S2589-7500(19)30006-8. Epub 2019 May 6.
- Derived from this study: PubMed 31371262Grinsztejn B, Hughes MD, Ritz J, Salata R, Mugyenyi P, Hogg E, Wieclaw L, Gross R, Godfrey C, Cardoso SW, Bukuru A, Makanga M, Faesen S, Mave V, Wangari Ndege B, Nerette Fontain S, Samaneka W, Secours R, van Schalkwyk M, Mngqibisa R, Mohapi L, Valencia J, Sugandhavesa P, Montalban E, Avihingsanon A, Santos BR, Kumarasamy N, Kanyama C, Schooley RT, Mellors JW, Wallis CL, Collier AC; A5288 Team. Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study. Lancet HIV. 2019 Sep;6(9):e588-e600. doi: 10.1016/S2352-3018(19)30146-8. Epub 2019 Jul 29.
- DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009Link provided by the sponsor.
- Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010Link provided by the sponsor.
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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.
Beatriz Grinsztejn, MD, PhD study chair
Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz
Peter Mugyenyi, MB ChB, FRCP, DSc study chair
Joint Clinical Research Center
19 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Darunavir, Etravirine and Emtricitabine/tenofovir disoproxil fumarate in people with HIV-1 Infection, run by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections at 19 sites in 10 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 33 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 15 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in South Africa, Brazil, Haiti, India, Kenya and 5 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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 20 Feb 2018). 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?
Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks (time frame: 48 weeks after the date of entry). 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 NCT01641367, which also lists 4 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 15 Mar 2019.