This is a phase IIIb, multicenter, randomized controlled trial to determine whether a regimen of Dolutegravir (DTG) with two NRTIs is non-inferior to a regimen of DRV/r with two NRTIs as second-line therapy in patients failing on an NNRTI-based first-line regimen in the setting of the public health approach in sub-Saharan Africa. The study also aims to determine whether continuing tenofovir and lamivudine is non-inferior to switching to zidovudine and lamivudine in a second-line therapy regimen in patients failing on an NNRTI-based first-line regimen in the setting of the public health approach.

Background and Aims

The standard-of-care second-line regimen in patients who have failed a first-line NNRTI-based regimen comprises a boosted protease inhibitor (PI) with two NRTIs. It is known that the PI + 2NRTI regimen performs well in second-line, even when there is extensive resistance to the NRTI drugs in the second-line regimen.

Darunavir (DRV) is considered to be the best-tolerated protease inhibitor and can be given once-daily (co-administered with ritonavir; DRV/r). Dolutegravir (DTG), an integrase strand transfer inhibitor, is also well tolerated, can be given once daily and may represent an alternative to the PI in the standard second-line combination. However, the performance of DTG is untested when used with NRTIs that have extensive cross-resistance from the first-line regimen.

After failure on a tenofovir-containing first-line regimen, WHO guidelines recommend switching to zidovudine in second-line (with lamivudine continued throughout). However, because NRTIs with cross-resistance have demonstrated activity in second-line (at least when given with a PI), maintaining tenofovir might give similar efficacy to zidovudine, but with better tolerability. 

The aims of this trial are:

1. To determine whether a regimen of DTG with two NRTIs is non-inferior to a regimen of DRV/r with two NRTIs as second-line therapy in patients failing on an NNRTI-based first-line regimen in the setting of the public health approach in sub-Saharan Africa, with substantial NRTI cross-resistance.

2. To determine whether continuing tenofovir and lamivudine is non-inferior to switching to zidovudine and lamivudine in a second-line therapy regimen in patients failing on an NNRTI-based first-line regimen in the setting of the public health approach.

Trial design

This is a parallel group, open-label, multi-centre, factorial (2X2) randomised, controlled Phase IIIb trial.

Patients

The trial will enrol 440 HIV-infected adolescents or adults who have taken a first-line regimen comprising tenofovir plus lamivudine/emtricitabine plus an NNRTI for total period of at least 6 months, and who have developed virological failure defined as:

Viral load ≥ 1000 copies/ml at screening AND

                              EITHER

Viral load ≥ 1000 copies/ml on the previous test, taken after at least 6 months on ART, and at no more than 6 months prior to screening and at no less than 4 weeks prior to screening, with adherence counselling given after the previous test

OR

Viral load ≥ 1000 copies/ml on a confirmatory test taken no less than 4 weeks after screening with adherence counselling given after the screening test

Patients who have poor adherence to therapy, require concomitant medication with known major interactions with study drugs, or women who are pregnant, breastfeeding or unwilling to use effective contraception will not be enrolled. For more details refer to section 4, selection of patients.

Trial interventions – research and control arm

Patients will be randomised (2X2 factorial) in equal proportions to one of the following 4 arms: 

Arm A (Standard-of-care)

Patients randomised to this arm will receive:

Arm B  

Patients randomised to this arm will receive:

Arm C  

Patients randomised to this arm will receive:

Arm D  

Patients randomised to this arm will receive:

Tenofovir will be added to Arms A and C for patients who are Hepatitis B surface antigen positive. Treatment will be monitored clinically and by sparse (open) viral load measurements at weeks 24, 48 and 96 (following WHO recommendations), and at week 72 if does not meet criteria for stability at week 48. Additional (open) tests will be done to confirm any viral load result ≥ 1000 copies/ml. Additional (blinded) tests will be done at weeks 12 and 72 (week 72 may be open test if criteria for stability at week 48 are not met) and results reviewed by the IDMC (see below).  

Duration of trial

The trial will have a recruitment period of 6 months and each patient will be followed for 96 weeks. For more details, refer to section 7, assessments and follow-up.

Outcome measures

Analyses will compare DRV/r (Arms A and B combined) with DTG (Arms C and D combined); and zidovudine (Arms A and C combined) with tenofovir (Arms B and D combined) by intention to treat analysis (ITT) on the following parameters:

Primary outcome measure

Plasma viral load < 400 copies at 48 weeks

Secondary outcome measures

Plasma viral load < 1000 copies/ml at 48 and 96 weeks

Plasma viral load < 400 copies/ml at 96 weeks

Plasma viral load < 50 copies/ml at 48 and 96 weeks

Viral load rebound (≥ 1000 copies/ml, confirmed) by 48 and 96 weeks

Viral load rebound (≥ 400 copies/ml, confirmed) by 48 and 96 weeks

Viral load rebound (≥ 1000 copies/ml, confirmed) with ≥ 1 major resistance mutation (IAS list) to DRV or DTG by 48 and 96 weeks

Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to DRV or DTG by 48 and 96 weeks

Viral load rebound (≥ 1000 copies/ml, confirmed) with intermediate or high-level resistance (Stanford algorithm) to both zidovudine and tenofovir by 48 and 96 weeks

CD4+ cell count change from baseline at 48 and 96 weeks

Incident (new or recurrent) WHO stage 4 event by 48 and 96 weeks

Incident serious non-AIDS event by 48 and 96 weeks

Death by 48 and 96 weeks

Time to new or recurrent WHO Stage 4 event, serious non-AIDS event, or death

Grade 3 or 4 clinical adverse events by 48 and 96 weeks

Grade 3 or 4 clinical adverse events (possibly, probably or definitely related to ART) by 48 and 96 weeks

Serious adverse events by 48 and 96 weeks