Dolutegravir in combination with nucleoside reverse-transcriptase inhibitors (NRTI) was an effective second-line treatment for patients with HIV infection, including those with extensive NRTI resistance and no predicted activity with prescribed NRTIs, according to study results published in the New England Journal of Medicine. In addition, study results showed that maintaining treatment with tenofovir was as effective as switching to zidovudine.
In this perspective, two-by-two factorial, open-label, noninferiority trial (NADIA; ClinicalTrials.gov identifier: NCT03988452), researchers enrolled a total of 464 patients with HIV infection for whom first-line therapy with a non-NRTI had failed for at least 6 months. Patients were randomly assigned in a 1:1:1:1 fashion to receive either dolutegravir or ritonavir-boosted darunavir in combination with either tenofovir/lamivudine or zidovudine/lamivudine. The primary outcome was viral suppression at week 48, defined as HIV RNA less than 400 copies/mL with a noninferiority margin of 12%.
Of the 464 patients (median age, 34 years), 60.8% were women, 51.2% had CD4+ cell counts of less than 200/mm3, and 27.6% had HIV viral loads of 100,000 copies/mL or greater. Baseline characteristics were similar between the treatment groups in each factorial comparison, with 58.5% of patients with intermediate- or high-level resistance to tenofovir, and 91.8% with resistance to lamivudine.
In the intention-to-treat population, 90.2% (212/235) of patients in the dolutegravir group and 91.7% (210/229) of patients in the darunavir group achieved HIV viral loads of less than 400 copies/mL (difference, –1.5%; 95% CI, –6.7% to 3.7%). Similar to the patients in the dolutegravir and darunavir groups, 92.3% (215/233) of those in the tenofovir group and 89.6% (207/231) of those in the zidovudine group achieved HIV viral loads of less than 400 copies/mL (difference, 2.7%; 95% CI, –2.6% to 7.9%).
The noninferiority criterion was also met in the per-protocol population, with no evidence of superiority among patients treated with either dolutegravir (P =.58) or tenofovir (P =.32). In sensitivity analyses, 92.4% of patients in the dolutegravir group and 93.8% of patients in the darunavir had no predicted activity from combination treatment with NRTIs, and patients from both groups achieved HIV viral loads of less than 400 copies/mL.
The incidence of adverse events was similar between patients who received dolutegravir vs those who received darunavir in each factorial comparison.
The researchers noted that these findings are generalizable to most populations because the trial did not rely on genotypic resistance testing to guide the selection of NRTIs. In addition, given the toxicity of zidovudine and the need to administer it twice daily, maintaining tenofovir may simplify current World Health Organization guidelines.
“Our trial continues follow-up to assess the longer-term durability of viral load suppression, emergence of resistance, and drug toxicity,” concluded the researchers.
Disclosure: Janssen funded this clinical trial but was not involved in trial conduct, data analysis, or the decision to publish the results.
Paton NI, Musaazi J, Kitya C, et al; NADIA trial team. Dolutegravir or darunavir in combination with zidovudine or tenofovir to treat HIV. N Engl J Med. 2021;385(4):330-341. doi:10.1056/NEJMoa2101609