People with HIV-1 infection (PWHIV) who have virologic failure can safely omit nucleoside reverse transcriptase inhibitors (NRTIs) in new regimens that include more than active drugs, according to a study by the ACTG A5241 Study Team of researchers at Massachusetts General Hospital. 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.
In total, 360 participants with virologic failure and anticipated antiretroviral susceptibility were included. Of these participants, 179 were randomly assigned to an optimised regimen that omitted NRTIs, 181 were randomly assigned to an optimised regimen that added NRTIs, and 53 participants had highly resistance virus and received an optimised 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.
Abstract
Background: Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain.
Methods: Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs.
Results: At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA <200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA <200 copies/mL at week 96.
Conclusions: 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. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression.
Authors
Rajesh T Gandhi, Karen T Tashima, Laura M Smeaton, Vincent Vu, Justin Ritz, Adriana Andrade, Joseph J Eron, Evelyn Hogg, Carl J Fichtenbaum
[link url="https://www.infectiousdiseaseadvisor.com/home/topics/hiv-aids/using-2-active-art-medications-without-nrtis-are-sufficient-for-hiv-salvage-therapy/"]Infectious Disease Advisor report[/link]
[link url="https://academic.oup.com/jid/article/221/9/1407/5499329"]The Journal of Infectious Diseases abstract[/link]