At 48 weeks, the NADIA trial found non-inferiority of dolutegravir versus darunavir and non-inferiority of maintaining tenofovir versus switching to zidovudine in second-line therapy. WHO guidelines continue to recommend a switch to zidovudine. We report new follow-up data to end of trial at week 96.
Patients failing NNRTl/tenofovir/lamivudine first-line with confirmed VL ?1000 copies/ml were randomised to receive dolutegravir or ritonavir-boosted darunavir; and to receive tenofovir or zidovudine, all with lamivudine. Treatment was monitored by open VL at 24, 48 and 96 weeks (and 72 weeks, if unstable) following WHO guidelines. VL suppression was determined using the FDA snapshot algorithm; we pre-specified the main threshold as 400 copies/ml and non-inferiority margin of 12% for each randomised comparison.
We enrolled 464 patients at 7 sub-Saharan African sites (61% female, 51% CD4<200, 28% VL? 100,000). At baseline, 58% overall had intermediate-high level resistance to tenofovir and 92% had resistance to lamivudine. Week 96 VL was <400 copies/ml in 89.8% in the dolutegravir group and 86.9% in the darunavir group (difference 2.9%; 95%CI, -3.0 to 8.7%; P=0.332; indicating non-inferiority of dolutegravir, without superiority); responses were equally good in the subgroups with no predicted-active NRTIs in the prescribed regimen. To date (>80% sequencing completed), 6 patients have intermediate-high level dolutegravir resistance (2 occurring after week 48) and 0 have darunavir resistance. In the other randomized comparison, VL was <400 copies/ml in 91.8% in the tenofovir group and 84.8% in the zidovudine group (difference 7.0%; 95% Cl, 1.2 to 12.8%; P=0.019 indicating superiority of tenofovir); VL rebound ?1000 copies/ml occurred in 5.6% in the tenofovir group and 14.3% in the zidovudine group (difference -8.7%, 95% CI -14.1 to -3.3%; P=0.002). Of 6 cases of dolutegravir resistance, 5 occurred in the zidovudine group. Grade 3/4 adverse events were similar in frequency between groups.
Dolutegravir and darunavir-based regimens maintain high levels of viral suppression at 96 weeks in second-line therapy, even when used with NRTIs that have no predicted activity. Dolutegravir resistance does not increase substantially during later follow-up. Tenofovir is superior to zidovudine and may protect against dolutegravir resistance. Guidelines that recommend switch from tenofovir to zidovudine for second-line therapy in the public health approach should be reconsidered.