ICAAC: In NNRTI-based regimens, stepwise discontinuation minimises risk of antiretroviral resistance

Stopping NNRTI treatment seven to ten days before stopping the nucleoside analogue backbone does minimise the risk of developing NNRTI resistance, a Thai study has confirmed.

The findings were presented as a poster this week at the 47^th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.

Since NNRTIs persist in the bloodstream for much longer than NRTIs, simultaneous discontinuation of all drugs in an NNRTI/NRTI regimen effectively results in a period of NNRTI monotherapy which could lead to NNRTI resistance.

Antiretroviral treatment (ART) interruptions and discontinuations are now widely discouraged due to the unfavourable findings of the SMART study and other clinical trials of treatment interruptions.

However, before the SMART results were available, a group of researchers in Thailand initiated a prospective clinical trial of discontinuation strategies for NNRTI-based regimens. All patients were on an initial regimen of dual NRTIs plus either efavirenz (Sustiva) or nevirapine (Viramune), were virologically controlled with HIV viral loads of less than 50 copies/ml, had CD4 cells counts above 350 cells/mm³, and were willing to discontinue their antiretrovirals.

This was a CD4-guided treatment interruption trial in which treatment was resumed if CD4 counts fell below 250 cells/mm³, or if HIV-related symptoms manifested. The study ran between September 2005 and December 2006; when the SMART study results became available in November 2006, patients either resumed ART within the study protocol, or discontinued study follow-up.

On treatment interruption, all patients first discontinued their NNRTI, and continued their dual NRTIs for a further seven or ten days for nevirapine- or efavirenz-based regimens, respectively. HIV-1 genotypic assays were performed before re-initiating therapy.

There were 43 patients who interrupted and re-initiated ART, with a mean of 5.6 months after treatment. Efavirenz and nevirapine were almost equally used. Patients had a mean age of 43 years, were 44% male, had a median CD4 cell count of 178 cells/mm³ and median viral load of 5.78 log₁₀ copies/ml at the time of re-initiation.

Genotypic testing performed in 21 of the patients found no NRTI- or NNRTI-associated resistance mutations. By six months after re-initiation, all patients had achieved viral loads 3.

The researchers concluded that “continuation of dual NRTIs for 7-10 days after treatment interruption of NNRTI-based regimens can minimise the risk of acquired NNRTI resistance. With this strategy, the same regimen can be used for re-initiation and yields good short-term virological and immunological outcomes.” Although such treatment interruptions are now strongly discouraged, this strategy may serve to guide situations in which treatment must be discontinued for reasons other than simple patient preference.