HIV salvage regimens can safely omit NRTIs, says US study

Nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from HIV salvage therapy, investigators from the United States report in the Annals of Internal Medicine. The findings come from a randomised study conducted between 2008 and 2011.

The study population comprised patients with ongoing viral replication despite second- or third-line antiretroviral therapy. All the patients were switched to an optimised regimen that included at least two active drugs. Half were randomised to receive NRTIs, the other half to NRTI-sparing combinations. Outcomes at week 48 were similar in the two 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.”



The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

salvage therapy

Any treatment regimen used after a number of earlier regimens have failed. People with HIV who have experienced side-effects and/or developed resistance to many HIV drugs receive salvage therapy, sometimes consisting of a large number of medications.


A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.


When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

Treatment guidelines recommend that patients with ongoing viral replication despite antiretroviral therapy should be switched to a new regimen that includes at least two and preferably three 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.

A team of US investigators hypothesised that developments in HIV treatment – especially the introduction of new 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 US. To be eligible, individuals were required to have experience of therapy with a protease inhibitor-based regimen and previous experience of, or resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). Each patient received an optimised salvage regimen that included at least two active drugs from the following classes: NNRTIs, boosted protease inhibitors, integrase inhibitors, entry inhibitors.

Individual regimens were selected after considering treatment history, resistance profile and tropism profile. Patients were then randomised to receive NRTIs in addition to their optimised combination or to omit NRTIs.

The primary outcome of the study was the proportion of patients with treatment failure at week 48 (treatment discontinuation or ongoing viral replication). Data were also gathered on CD4 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 and either emtricitabine or lamivudine.

There were 53 regimen failures in the NRTI-sparing 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 two groups meant that the NRTI-sparing regimens were non-inferior to the add-NRTIs combinations.

“The non-inferiority conclusion was robust and consistent across sensitivity analyses,” write 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 two strategies and there were no differences in safety.

No deaths were observed in the NRTI-sparing arm but seven 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,” note the investigators. “The small number of events limited our ability to conclude that omitting NRTIs leads to reduced mortality.”

The patients receive study was open-label therapy, 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,” conclude the authors. “The potential benefits of omitting NRTIs include reduced pill burden; reduced cost’ and, probably, a decrease in NRTI-associated toxicity over the long term.”


Tashima KT et al. HIV salvage therapy does not require nucleoside reverse transcriptase inhibitors. Ann Intern Med, 163: 908-17, 2015.