DESIGN                      A5288 is an open-label phase IV, prospective interventional, strategy study in resource-limited settings (RLS) for HIV-infected participants with triple-class experience or resistance to [nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs)] and who are failing their current regimen. The use of novel agents and contemporary management tools that include standard genotyping, plasma viral load (VL) monitoring will be evaluated. The screening genotype results and antiretroviral (ARV) history will be used to allocate potential participants to one of the four cohorts and for selection of ARV regimen for each potential participant. Refer to the flow chart, Figure 1.

At sites where feasible and relevant, the study will also conduct an adherence study. This will be a randomized comparison of cell phone-based adherence intervention plus local standard-of-care adherence procedures (CPI+SOC) versus the SOC adherence procedures.

Genotyping and Identification of Cohort and ARV Regimen

                                    A standard viral population-based genotype assay determining resistance in protease and partial reverse transcriptase (RT) will be performed in real time at screening. 

Following receipt of the genotype resistance report, the site investigator will make the initial recommendation for each potential participant (ie, candidate) with regard to the following:

1. Selection of the appropriate cohort

AND

2. Planned ARV regimen if the potential participant will be placed in Cohort A (switch of NRTIs to study-provided NRTIs is allowed but not required)

OR

Choice of at least two NRTIs if the potential participant is to be placed into Cohort B or Cohort C

OR

The proposed ARV regimen if the potential participant is to be placed into Cohort D.

The Clinical Management Committee (CMC) of the A5288 protocol team will review and confirm the site’s recommendation via the CoSPAR System (ACS). After CMC approval of the site-selected cohort and site-recommended regimen options, candidates will be assigned to one of the following cohorts, as outlined below.

In the event of a confirmed VF on study, participants agreeing to continue in the study will have another genotype resistance test and will be assigned to a Step 2 cohort/ARV treatment group following receipt of the genotype resistance report. The Step 2 cohort selection and confirmation process will be the same as for Step 1 except that for the Step 2 cohort and regimen selection, both genotype resistance reports from screening and Step 1 will be considered.

At the completion of Steps 1 and 2 (see Duration below), participants taking RAL, DRV, or ETR may remain on study by entering Step 3. In Step 3, RAL, DRV, and ETR will be provided through the study for up to 96 additional weeks. Participants will have twice yearly clinic visits and sites will be asked to provide information about the local standard of care follow-up that is being provided outside of the study.

DURATION                48 weeks after registration/randomization of the last participant (Steps 1 and 2); study completion is defined as remaining in study follow up for this period of time. Step 3, an optional step for participants taking RAL, DRV, or ETR at the study completion, is an additional 96 weeks beginning at study completion.

SAMPLE SIZE            500 participants.

POPULATION            HIV-1-infected males and females at non-US sites, aged ≥18 years, who have experience with or resistance to NRTIs, NNRTIs, and PIs, and are currently failing a PI-containing regimen.

RANDOMIZATION    Following cohort registration (Cohort A, sub-cohort B3, or Cohorts C or and D) or randomization (to sub-cohorts B1 or B2; see below), participants at sites that are participating in the adherence study will be randomized 1:1 to either CPI+SOC or to SOC adherence procedures.

Candidates assigned to Cohort B will be randomized 1:1 at study entry to sub-cohort B1 or B2 if they do not have active hepatitis B infection. Candidates assigned to Cohort B who have active hepatitis B infection will be placed into sub-cohort B3 at study entry. Active hepatitis B infection is defined as HBsAg+ at screening or having a history of HBsAg+ in the past with no subsequent documented positive anti-HBsAb and currently on therapy with drugs active against hepatitis B.

REGIMEN                  Cohort Profiles and Proposed ARV Regimens (Steps 1 and 2)

Cohort A:  No resistance to NRTIs, PIs, or NNRTI

• Continue current second-line regimen; NRTIs can be modified

Cohort B:  Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs)

Participants without active hepatitis B infection at screening will be randomized 1:1 to sub-cohort B1 or B2

• Sub-cohort B1: Best available NRTIs, RAL, and DRV/RTV

• Sub-cohort B2: ETR, RAL, and DRV/RTV

Participants with active hepatitis B infection at screening will be assigned to:

• Sub-cohort B3: RAL, DRV/RTV, and FTC/TDF or TDF plus 3TC

Cohort C:  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

Cohort D:  Multiple NRTI resistance and/or DRV/RTV resistance or prior RAL exposure

• Best available regimen, including study-provided and any locally available drugs

DRV, ETR, RAL, FTC/TDF, and RTV will be provided by the study for use in study regimens. All other study-required regimen drugs must be obtained locally by the participants from their providers before registration/randomization. Support for the provision of rifabutin (RBT) will be provided through the study as specified in section 5.3.1.  Refer to section 5.0 for additional details.