Dolutegravir and ritonavir-boosted darunavir are equally effective second-line treatments for HIV-1, even for patients with resistance to nucleoside reverse-transcriptase inhibitors (NRTIs) in the regimen, a new randomized trial suggests. Researchers also found that recycling tenofovir was noninferior to switching to zidovudine for second-line therapy.

Dr Nicholas Paton

The results are “very reassuring” that switching to a dolutegravir-based regimen is safe and effective in populations in which drug resistance testing may not be available, said Nicholas Paton, MD, first author of the study, in an interview with Medscape Medical News. Paton is a professor of medicine at the National University of Singapore Yong Loo Lin School of Medicine.

World Health Organization (WHO) guidelines recommend switching to dolutegravir after failure of first-line therapy with a non-NRTI (NNRTI) or boosted protease inhibitor; however, it is unclear how effective this approach is in the absence of resistance testing for NRTIs, which pose a higher risk for drug resistance and treatment failure. WHO also recommends switching one NRTI from tenofovir to zidovudine (AZT) in second-line therapy to prevent resistance.

Dr Rajesh Gandhi

“The trouble with that is, for large parts of the world, AZT is a poorly tolerated drug,” Rajesh Gandhi, MD, co-director of the Harvard University Center for AIDS Research, in Boston, Massachusetts, told Medscape. He was not involved in the research. “It’s taken twice a day, but it also comes with both short- and long-term side effects,” he said. Observational data suggest that switching to zidovudine may not be beneficial, but clinical trial evidence is needed, the authors write.

To answer these questions, an international team organized a two-by-two factorial, randomized trial called the Nucleosides and Darunavir/Dolutegravir in Africa (NADIA) trial. The study recruited 464 people living with HIV from seven sites in Kenya, Uganda, and Zimbabwe from July 30 to December 18, 2019. All participants were at least 12 years old, had previously received NNRTI-based first-line therapy that included tenofovir and lamivudine for at least 6 months, and had viral loads >1000 copies/mL.

In the open-label, noninferiority trial, researchers randomly assigned participants to a treatment regimen with dolutegravir or ritonavir-boosted darunavir, an alternative second-line therapy known to be effective even with NRTI resistance. Dolutegravir or darunavir was given in combination with either tenofovir or zidovudine over 48 weeks. All participants received lamivudine as the second NRTI. The trial results were published July 20 in The New England Journal of Medicine.

The median age of participants was 34 years; about 61% of the study population were women. At screening for the trial, 27.6% of the study population had a viral load >100,000 copies/mL, and over half (51.2%) had a CD4+ count <200. These findings indicate that the study population had advanced HIV infection and that there was limited residual activity from their first-line treatment. At baseline, 91.8% of trial participants had resistance to lamivudine, 58.5% had resistance to tenofovir, and 18.3% had resistance to zidovudine.

Despite a high prevalence of NRTI resistance, both dolutegravir and darunavir regimes effectively suppressed viral loads. At week 48, 90.2% of the dolutegravir group and 91.7% of the darunavir group had viral loads <400 copies/mL, with neither showing superiority. There was no difference between the groups in the rate of virologic rebound; 6.0% of the dolutegravir group and 5.7% of the darunavir group had viral loads >1000 copies/mL after they were switched to their prescribed regimens. Impressively, across both groups, more than 90% of patients with resistance to all NRTIs prescribed in their regimen had viral suppression at 48 weeks.

“Programmatic switches between regimens are often implemented without viral load testing and inevitably involve some patients with occult viral replication and accumulated NRTI resistance,” Paton and colleagues write. “Our trial provides evidence that such patients, even if they have extensive NRTI resistance, are likely to have viral suppression after a switch to dolutegravir.”

Tenofovir and zidovudine were found to be equally effective in the trial, with 92.3% and 89.6% of patients achieving viral loads <400 copies/mL, respectively. The results indicate that switching to zidovudine offers no benefit in comparison with recycling tenofovir, which is “a big plus” for patients, says Paton. The findings will also help standardize program regimens in global health efforts. “It tells us that AZT as a drug doesn’t have advantages, and we’ve known its disadvantages for many years now,” added Gandhi. “Worldwide, I think this is going to accelerate the trend away from AZT.”

New Engl J Med. Published online July 20, 2021.

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