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NRTIs can be safely omitted from HIV-1 salvage therapy
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Nucleoside reverse transcriptase inhibitors, or NRTIs, can safely be omitted from HIV-1 salvage therapy regimens without compromising the efficacy and durability of response, but the new regimen must contain the cumulative activity of two or more active drugs, according to 96-week findings from the OPTIONS trial.
“When people with HIV develop resistance to antiretroviral medications, ID doctors often prescribe nucleoside reverse transcriptase inhibitors (NRTIs), along with other drugs, in the new regimen thinking that the NRTIs may improve the chances the patients will respond to treatment,” Rajesh T. Gandhi, MD, professor of medicine at Harvard Medical School and director of the HIV Clinical Services and Education at Massachusetts General Hospital, told Infectious Disease News.
In a related editorial, Martin Hoenigl, MD, a research scientist in the division of infectious diseases at the University of California, San Diego, and Susan J. Little, MD, an associate professor of medicine in the division of infectious diseases at UCSD, explained that although NRTIs are an important component in ART regimens, they are associated with short- and long-term side effects, including nausea, diarrhea and lipodystrophy. Additionally, the HIV virus has shown resistance to NRTIs, indicating a need for NRTI-sparing therapies.
“Current HIV treatment guidelines include several NRTI-sparing regimens that are recommended as initial therapy in special circumstances or NRTI-free regimens that could be considered as switch regimens in special circumstances,” Hoenigl and Little wrote. “Although NRTI-sparing regimens have proven effective in ART-naive people with HIV-1 infection, and as switch regimens in ART-experienced [people with HIV infection] who are virally suppressed, their role for salvage therapy in people with virologic failure on ART is less clear.”
The short-term, 48-week data from the OPTIONS trial — an open-label, phase 3, partially randomized study — demonstrated the safety of omitting NRTIs from salvage therapy, but the long-term durability and outcomes among people with more extensive HIV-1 drug resistance are uncertain, according to Gandhi and colleagues. Therefore, they reported on patients’ outcomes through 96 weeks.
After receiving an optimized regimen, 360 participants with virologic failure and anticipated antiretroviral susceptibility were randomly assigned to either omit or add NRTIs.
According to the 96-week data, 70% of patients with a regimen that omitted NRTIs achieved virologic suppression with less than 200 copies/mL of HIV-1 RNA compared with 65% of patients who received a regimen that added NRTIs.
Gandhi and colleagues reported that virologic failure was uncommon after week 48, suggesting that “even in highly treatment-experienced persons who have drug-resistant HIV-1, once virologic suppression is achieved, it is typically sustained.”
Younger age and starting fewer new ART medications were associated with higher odds for virologic failure, and the researchers noted that those populations “require careful monitoring.”
“By not prescribing NRTIs when they are not needed, our treatments will be less expensive and we may prevent long-term side effects of these additional medicines,” Gandhi said. “We also need to make extra efforts to ensure that people who are at higher risk of not responding to salvage therapy — like younger people and those starting fewer new medications — achieve virologic suppression.” – by Marley Ghizzone
Disclosures: Gandhi reports receiving funding to his institution from Gilead Sciences, Janssen, Merck, Theratechnologies and ViiV Healthcare, and serving on scientific advisory boards for Gilead, Merck and Theratechnologies. Please see the study for all other authors’ relevant financial disclosures. Hoenigl and Little report receiving research grants to their institutions from Gilead Sciences, outside of the submitted work.
Perspective
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Raghavendra Tirupathi, MD, FACP
The OPTIONS follow-up (A5241) by Gandhi and colleagues is a pivotal study that decisively answers a compelling question about the efficacy and durability of NRTI-free salvage therapy in a challenging cohort of patients with virologic failure and limited ART options. Standard of care for salvage therapy is to include NRTI even when ART-experienced patients have NRTI mutations, and most salvage regimen studies have used NRTI recycling. This trial informed guidelines and will change standard of care with respect to choosing salvage therapy, leading to better metabolic and renal adverse effect profiles. It is also important to note that the INSTI used in the trial was the first-generation INSTI, raltegravir. Hence, including newer agents like dolutegravir or bictegravir might further improve virologic suppression in these subgroups of patients. Further studies are needed to examine the impact of the NRTI-sparing salvage regimen on long-term cardiovascular and other nonvirologic outcomes beyond 96 weeks.
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