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HIV Salvage Regimens Can Safely Omit NRTIs, Study Says

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) can be safely omitted from HIV salvage therapy, investigators from Brown University report in the December 15, 2015 Annals of Internal Medicine. "Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population," the study authors conclude.

[Produced in collaboration with Aidsmap.com]

The findings come from a randomized study conducted between 2008 and 2011. The study population comprised patients with ongoing HIV replication despite second- or third-line antiretroviral therapy (ART). All the participants were switched to an optimized regimen that included at least 2 active drugs. Half were randomly assigned to receive NRTIs, the other half to NRTI-sparing combinations.

Outcomes at week 48 were similar in the 2 study arms, and the NRTI-sparing regimens were non-inferior to the NRTI-containing regimens.

"This trial showed that the addition of NRTIs, the cornerstone of initial antiretroviral regimens, can be safely omitted if a new optimized regimen contains several fully or partially active antiretroviral medications," comment the authors. "This study adds substantially to our knowledge of optimal therapy for treatment-experienced patients."

HIV treatment guidelines recommend that patients with ongoing viral replication despite ART should be switched to a new regimen that includes at least 2 and preferably 3 fully active drugs. The standard of care includes NRTIs. However, treatment-experienced patients are likely to have resistance to drugs in this class and it is therefore questionable if their addition has any benefits.

Karen Tashima and colleagues hypothesized that developments in HIV treatment -- especially the introduction of new antiretroviral drug classes and agents that work against resistant virus -- would mean that NRTIs can be safely omitted from salvage regimens. They therefore designed the OPTIONS (Optimized Treatment that Includes or Omits NRTIs) trial to test their theory.

Patients were recruited between 2008 and 2011 from 62 HIV outpatient clinics across the U.S. To be eligible, individuals were required to have experience using therapy with a protease inhibitor-based regimen and previous experience of, or resistance to, nucleoside/nucleotide and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). Each patient received an optimized salvage regimen that included at least 2 active drugs from the following classes: NNRTIs, boosted protease inhibitors, integrase inhibitors, or entry inhibitors.

Individual regimens were selected after considering treatment history, resistance profile, and tropism (CCR5 or CXCR4 co-receptor) profile. Participants were then randomized to receive NRTIs in addition to their optimized combination or to omit NRTIs.

The primary outcome of the study was the proportion of patients with treatment failure at week 48, defined as treatment discontinuation or ongoing viral replication). Data were also gathered on CD4 cell changes, the emergence of new resistance mutations, and safety.

A total of 360 patients were recruited and 337 (94%) completed 48 weeks of follow-up. In both arms the most commonly assigned regimen was raltegravir (Isentress) plus ritonavir-boosted darunavir (Prezista) and etravirine (Intelence) (56%). In the add-NRTI arm 85% of participants added tenofovir (Viread) and either emtricitabine (Emtriva or FTC ) or lamivudine (Epivir or 3TC).

There were 53 regimen failures in the omit-NRTI group compared to 48 in the add-NRTI arm. The cumulative probability of treatment failure at week 48 was 29.8% for the omit-NRTI arm compared to 25.9% for the add-NRTIs patients. The 3.2% difference between the groups meant that the NRTI-sparing regimens were non-inferior to the NRTI-containing combinations.

"The non-inferiority conclusion was robust and consistent across sensitivity analyses," wrote the authors.

Similar numbers of omit- and add-NRTI patients experienced viral failure (41 vs 42). A viral load below 50 copies/mL was achieved by 64% of omit-NRTI patients and 66% of individuals in the add-NRTIs arm. CD4 count increases were comparable between the 2 strategies and there were no differences in safety.

No deaths were observed in the NRTI-sparing arm, but 7 patients in the add-NRTIs arm died. However, none of these deaths appeared to be treatment related.

"The causes of death were similar to those described in large HIV cohort studies and could not be clearly attributed to NRTI toxicities," noted the investigators. "The small number of events limited our ability to conclude that omitting NRTIs leads to reduced mortality."

The study was open-label therapy (patients and clinicians knew what drugs they were receiving) and the authors acknowledge this as a limitation of their findings. They also acknowledge that the study may not be applicable to resource-limited settings because of the high cost of resistance and tropism testing.

"In patients who have previously received antiretroviral drugs, NRTIs can be safely omitted from new active regimens provided that the cumulative activity of the regimen exceeds that of 2 fully active agents," the authors concluded. "The potential benefits of omitting NRTIs include reduced pill burden; reduced cost; and, probably, a decrease in NRTI-associated toxicity over the long term."

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Reference

KT Tashima, LM Smeaton, CJ Fichtenbaum, et al (A5241 Study Team). HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial. Annals of Internal Medicine 163(12):908-917. December 15, 2015.