After viral rebound, dolutegravir-based treatment more likely to suppress HIV

Dolutegravir-based treatment is significantly more likely to result in re-suppression of HIV after viral rebound than treatment containing efavirenz, a meta-analysis of four large clinical trials has reported.

The findings were presented this week at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) by Dr Andrew Hill of Liverpool University.

The capacity of an antiretroviral regimen to re-suppress HIV after viral rebound above the limit of detection is an especially important question for lower- and middle-income settings where a limited number of regimens are available.

If first-line treatment fails, second-line treatment is considerably more expensive, so it is critical to understand the likelihood of viral re-suppression when people continue with their existing regimen and receive enhanced adherence counselling, in line with World Health Organization guidelines for the management of viral rebound.

The question becomes even more critical in second-line treatment, where there are fewer options for replacement treatment.

Dolutegravir-based treatment is recommended as a preferred option for first-line treatment due to its high barrier to resistance. Treatment with dolutegravir is also better tolerated than efavirenz-based treatment.

To evaluate whether dolutegravir-based treatment is more likely to lead to re-suppression of HIV after viral rebound, investigators pooled data from four large studies that compared dolutegravir to efavirenz-based or protease inhibitor-based treatment in sub-Saharan Africa.

The studies included in the analysis were:

• ADVANCE, a comparison of dolutegravir or efavirenz, paired with either tenofovir disoproxil/emtricitabine or tenofovir alafenamide/emtricitabine, carried out in previously untreated people in South Africa.
• NAMSAL, a comparison of dolutegravir or lower-dose efavirenz, paired with tenofovir disoproxil/lamivudine, carried out in previously untreated people in Cameroon.
• DOLPHIN-2, a comparison of dolutegravir and efavirenz, paired with tenofovir disoproxil/lamivudine, carried out in previously untreated pregnant women in Uganda.
• VISEND, a comparison of several NRTI combinations when switching to second-line treatment containing dolutegravir or a boosted protease inhibitor.

The analysis looked at viral re-suppression rates in participants in the four studies who had experienced viral failure (a viral load above 1000 copies after week 24) and did not change treatment. Participants with viral failure could be classified either as re-suppressing HIV, having persistent virus levels above 1000 copies or lost to follow-up.

In ADVANCE, viral failure rates were similar across the three study arms (8-13%) but re-suppression rates ranged from 23% in the efavirenz study arm to 41% and 59% in the dolutegravir arms. The same pattern was evident in NAMSAL; 15% and 17% experienced viral failure in the two study arms but whereas 60% in the dolutegravir arm re-suppressed viral load, only 27% in the efavirenz arm did so.

In VISEND, people who entered the study with viral load above 1000 copies/ml were more likely to experience viral failure than those with baseline viral load below 1000 copies/ml. Viral failure occurred more often in the boosted protease inhibitor study arms (20-27%) than in the dolutegravir arms (12-18%). Re-suppression occurred less often in the boosted protease inhibitor arms (17-19%) than in the dolutegravir arms (34-41%).

In DOLPHIN-2, viral failure and re-suppression did not differ substantially between the dolutegravir and efavirenz arms.

In the meta-analysis, the rate of viral re-suppression was significantly higher for dolutegravir than efavirenz (p=0.04).

In three of the four studies, sustained viraemia above 1000 copies/ml was more common in those with viral failure who did not receive dolutegravir. For example, in ADVANCE, 52% of those with viral failure in the efavirenz arm had a sustained viral load above 1000 copies/ml after week 24 of the study, compared with 14% and 27% in the dolutegravir arms. The same pattern was seen in NAMSAL and VISEND, but not in DOLPHIN-2.

Presenting the study findings, Dr Andrew Hill said that more research was needed to assess how much adherence counselling and sustained viraemia are required before people taking dolutegravir are offered a new regimen. He pointed out that new South African treatment guidelines only recommend a switch from dolutegravir if integrase inhibitor resistance is detected.

Professor Linda-Gail Bekker of the Desmond Tutu HIV Centre at the University of Cape Town said that long-term follow-up of people who re-suppress viral load on dolutegravir is needed. She asked whether people who re-suppress ultimately fail on dolutegravir, as has been previously shown for NNRTI-based treatment.