HIV-1 Salvage Therapy Can Omit NRTIs and Remain Efficacious and Safe

HIV viral load test
HIV viral load test
People with HIV-1 infection who have virologic failure can safely omit nucleoside reverse transcriptase inhibitors (NRTIs) in new regimens that include > 2 active drugs.

People with HIV-1 infection (PWHIV) who have virologic failure can safely omit nucleoside reverse transcriptase inhibitors (NRTIs) in new regimens that include > 2 active drugs, according to a study published in The Journal of Infectious Diseases.

Guidelines recommend starting ³2 new active antiretroviral medications in PWHIV who have virologic failure to antiretroviral therapy. Whether to include NRTIs in the new regimen when other agents were available remained unclear, but was addressed in the OPTIONS trial (AIDS clinical trials group A5241). This study included participants who were failing protease inhibitor (PI)-based therapy but whose virus was still sensitive to a new regimen of > 2 active agents. Participants were random assigned to receive either add or omit NRTIs from their new regimen. Additionally, there was a third nonrandomized group that included participants with more drug resistance (sensitivity only to a regimen with cumulative phenotypic susceptibility score of £ 2 active agents as opposed to > 2). Participants in this group were treated with a combination of active and partially active agents, including NRTIs.

The short-term week 48 results showed that salvage therapy could safety omit NRTIs, as long as there was a cumulative activity of > 2 active antiretroviral medications included in the regimen. However, whether this approach has long-term durability in those with highly drug-resistant HIV-1 is unclear. Therefore, this study reported, for the first time, the 96-week outcomes following treatment in these individuals with highly drug-resistant HIV-1 ( identifier: NCT00537394).

In total, 360 participants with virologic failure and anticipated antiretroviral susceptibility were included. Of these participants, 179 were randomly assigned to an optimized regimen that omitted NRTIs, 181 were randomly assigned to an optimized regimen that added NRTIs, and 53 participants had highly resistance virus and received an optimized regimen of £2 active agents that included NRTIs. The primary efficacy outcome was regimen failure, which included a composite outcome of first confirmed virologic failure or discontinuation of NRTI assignment.

Results demonstrated that most participants were able to achieve virologic suppression, even with extensive resistance. At week 96, 70% of the participants who omitted NRTIs and 65% of the participants who added NRTIs had HIV-1 RNA < 200 copies/mL; 61% and 59%, respectively demonstrated < 50 copies/mL of HIV-1 RNA. In the highly resistant group, 53% of participants had HIV-1 RNA <200 copies/mL at week 96. Virologic failures were uncommon after week 48, with > 85% occurring before this point, which suggested that even the highly resistant group, virologic suppression that is achieved is sustained. Moreover, at week 96, the mean CD4 cell count was 391/mm3 (95% CI, 357-425) for the omit NRTIs group and 428/mm3 (95% CI, 383-473) for the add NRTIs group. The fact that the highly resistant group had lower rates of viral suppression highlights the importance of active agents in achieving suppression. Higher odds of virologic failure were associated with the characteristics of younger age and starting fewer new antiretroviral medications.

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Overall, the study authors concluded that, “HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of > 2 active drugs.”


Gandhi RT, Tashima KT, Smeaton LM, et al. Long-term outcomes in a large randomized trial of HIV-1 salvage therapy: 96-week results of AIDS clinical trials group A5241 (OPTIONS). J Infect Dis. 2020;221(9):1407-1415.