WHO recommends dolutegravir with two NRTIs for second-line treatment of HIV infection after failure on an NNRTI-based regimen. There is limited evidence for efficacy of this dolutegravir regimen when prescribed NRTIs lack predicted activity due to drug resistance; or for the recommendation to switch from tenofovir to zidovudine in second-line.
In a two-by-two factorial, open-label, non-inferiority trial, we randomized patients failing an NNRTI/tenofovir/lamivudine first-line regimen with confirmed VL ?1000 copies/ml to receive dolutegravir or ritonavir-boosted darunavir; and to receive tenofovir or zidovudine; all with lamivudine. Treatment was monitored by VL at 24 and 48 weeks, following WHO guidelines. Baseline NRTI resistance testing was batched, and results blinded. The primary outcome was the percentage of patients with week-48 VL <400 copies/ml using FDA snapshot algorithm (non-inferiority margin 12%).
We enrolled 464 patients at 7 sub-Saharan African sites (61% female, 51% CD4<200, 28% VL?100,000). At baseline, 58.5% overall had intermediate-high level resistance to tenofovir and 92% had resistance to lamivudine. Week 48 VL was <400 copies/ml in 90.2% in the dolutegravir group and 91.7% in the darunavir group (difference -1.5%; 95%CI, ?6.7 to 3.7%; P=0.576; indicating non-inferiority of dolutegravir, without superiority). In the subgroup with no predicted-active NRTIs in the prescribed regimen, VL was <400 copies/ml in 92.4% of those in the dolutegravir group and 93.7% of those in the darunavir group. To date, 4 have intermediate-high level dolutegravir resistance; 0 have darunavir resistance. In the other randomized comparison, VL was <400 copies/ml in 92.3% in the tenofovir group and 89.6% in the zidovudine group (difference 2.7%; 95% CI, ?2.6 to 7.9%; indicating non-inferiority of tenofovir). Grade 3/4 adverse events were uncommon and similar in frequency between groups.
Dolutegravir with two NRTIs gives highly effective viral suppression to 48 weeks, even in a patient population where many have extensive NRTI resistance and no predicted activity in prescribed NRTIs. This finding is important for patients switching from NNRTI to dolutegravir with NRTIs after known treatment failure; and for programmes switching stable patients systematically from NNRTI to dolutegravir-based regimens without VL and resistance testing. Tenofovir can be maintained in second-line therapy without switching to zidovudine, with advantages for patients and programmes.
