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.
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
“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
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
A team of US
investigators hypothesised that developments in HIV treatment –
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.
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.
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.
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
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.
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.
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
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.”