World Health Organization (WHO) guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. In The Lancet HIV, Paton et al (2022) report the 96-week data of the randomised, noninferiority NADIA trial comparing dolutegravir vs ritonavir-boosted darunavir (800mg of darunavir plus 100mg of ritonavir) and zidovudine vs tenofovir in second-line ART.

The study was designed to be relevant to the settings in which treatment is delivered and was done at seven sites in Kenya, Uganda, and Zimbabwe. The researchers randomly assigned patients where first-line therapy was failing (HIV-1 viral load, ≥1000 copies per millilitre) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine. All patients received lamivudine.

The researchers enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per millilitre was observed in 90.2% of the patients in the dolutegravir group and in 91.7% of those in the darunavir group and in 89.6% of those in the zidovudine group. In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per millilitre was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison.

FINDINGS

Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks. Dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy.

Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine. The 96-week results of theNADIA trial, taken together with results of two other trials, now provide sufficient evidence to support WHO’s existing recommendation to use dolutegravir with two NRTIs in second-line therapy in the public health approach, and show that this combination will produce durable viral suppression, even when substantial NRTI resistance is present and when delivered with sparse viral load monitoring.

“Darunavir therefore merits an expanded role in the public health approach as a preferred protease inhibitor; its high genetic barrier to resistance also confers a possible advantage over dolutegravir. WHO’s longstanding recommendation to switch from tenofovir to zidovudine for second-line therapy in the public health approach should be revised to recommend maintaining tenofovir (and lamivudine) when introducing a new third drug (either dolutegravir or darunavir),” the researches commented.

REFERENCES:

Llibre J. Game-changing study of second-line HIV treatment. Lancet HIV 2022. Published Online April 20, 2022. https://doi.org/10.1016/S2352-3018(22)00096-0.

Paton N et al. Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial. 2022 Lancet HIV. DOI:https://doi.org/10.1016/S2352-3018(22)00092-3.

Paton N et al. Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV. N Engl J Med 2021; 385:330-341. DOI: 10.1056/NEJMoa2101609.