Withdrawal of non-nucleoside reverse transcriptase inhibitors (NNRTIs) from the antiretroviral drug combination of patients with resistance to this drug class does not lead to viral rebound or more rapid loss of CD4 T-cells, according to a research letter published in the July 2nd edition of AIDS. This suggests that NNRTIs do not have any residual antiretroviral activity in the presence of NNRTI mutations.
In contrast to protease inhibitors, which usually require a number of mutations for the emergence of drug resistance, a single key mutation can bring about resistance to all available NNRTIs. Despite this, treatment-experienced patients with resistance to all classes of antiretroviral drug and few remaining options for therapy are often maintained on an NNRTI-containing combination. This study suggests that this strategy is unnecessary, since NNRTIs offer no additional clinical benefit when NNRTI resistance mutations are present.
“NNRTI resistance mutations are not associated with a deep reduction in the capacity of viral replication,” argue the authors. “NNRTI may be withdrawn with no risk of viral rebound in patients with virological failure and resistance to drugs from this class.”
The investigators, from five hospitals in Paris, recruited 53 patients as part of the ANRS 107 (Puzzle) study, which was designed to assess the efficacy of a switch to ritonavir (Norvir)-boosted atazanavir (Reyataz) in patients having failed previous drug combinations including protease inhibitors and NNRTIs.
Nineteen of these patients were receiving an NNRTI at enrolment, including 13 (66%) receiving efavirenz (Sustiva) and six (32%) nevirapine (Viramune). Two weeks before being randomised to receive atazanavir or remain on their current drug regimen, these patients stopped taking their NNRTI, to avoid any potential interactions with atazanavir.
At two weeks before NNRTI withdrawal, these patients’ median viral load was 79,400 copies/ml and their median CD4 cell count was 237 cells/mm3. All of the patients had one or more NNRTI resistance mutations.
Two weeks after NNRTI withdrawal, the mean change in viral load was 0.0 log10 copies/ml (95% confidence interval [CI]: -0.17 – 0.15), and the mean change in CD$ cell count was –13 cells/mm3 (95% CI: -29 – 4). Over the same time period, there was a decrease in NNRTI trough drug concentrations from within the therapeutic range (1 – 5 µg/ml for efavirenz and 3 – 8 µg/ml for nevirapine) to below the limit of detection in all 19 patients.
The remaining 34 patients who were not receiving NNRTIs at enrolment showed a similar maintenance of viral load (mean change: 0.0 log10 copies/ml; 95% CI: -0.09 – 0.09) and CD4 cell count (mean change: -2 cells/mm3; 95% CI: -19 – 16) over the same two-week period, suggesting that removal of the NNRTI had no significant effect on viral replication or disease progression.
By 28 weeks, only three (16%) of the 19 patients who stopped NNRTIs showed a reversion to the wild-type NNRTI resistance mutation pattern. Similarly, of the remaining 34 patients in the study, who had stopped NNRTIs for a median of 21 months before inclusion in the trial, NNRTI resistance mutations were absent in only nine (26%). The authors conclude that “the delay in observing NNRTI mutations disappearance is relatively long.”
Further information on this website
Resistance - factsheet
Resistance - patient information booklet
Reference
Piketty C et al. Virological and immunological impact of non-nucleoside reverse transcriptase inhibitor withdrawal in HIV-infected patients with multiple treatment failures. AIDS 18: 1469-1471, 2004.