Few patients enrolled in the Staccato study examining CD4 cell count-guided treatment interruptions had evidence of resistance mutations in their HIV, according to a poster presentation earlier this month at the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver.
In contrast to the SMART study, which suggested that treatment interruptions guided by CD4 cell counts are dangerous, Staccato showed similar rates of treatment failure and complications in patients randomised to continuous therapy and intermittent treatment guided by CD4 cell count.
A number of differences between SMART and Staccato could explain their opposite conclusions, including the criteria for starting and stopping HIV treatment in the intermittent treatment groups, the nature of the study populations, prior treatment exposure, and the choice of drug regimens. Eighty per cent of the 430 patients in Staccato were from Thailand.
Overall, 80% of the patients in Staccato took ritonavir (Norvir)-boosted saquinavir (Invirase) along with two nucleoside reverse transcriptase inhibitors (NRTIs). These were either d4T (stavudine, Zerit) and ddI (didanosine, VidexEC) or tenofovir (Viread) and 3TC (lamivudine, Epivir).
The rest of the patients took treatment combinations based on other protease inhibitors (4%) or non-nucleoside reverse transcriptase inhibitors (NNRTIs; 14%), or they took triple NRTI treatment (2%).
In Denver, researchers from Staccato revealed the results of a genetic analysis of HIV isolated from 139 patients. All were judged to be at risk of developing resistance mutations, since they had had two or more treatment interruptions or their viral load was above 500 copies/ml despite being on treatment.
In 128 (92%) of the patients, no resistance mutations were seen in the protease or reverse transcriptase genes.
Among the 111 patients who had had two or more treatment interruptions, seven (6%) of the samples analysed contained resistance mutations. All of these included the MI84V mutation in the gene for reverse transcriptase. This confers resistance to 3TC (lamivudine, Epivir).
Of the 28 samples from patients with viral loads above 500 copies/ml, four (14%) contained resistance mutations. Three of these were M184V, one of which also had the K103N mutation, which results in resistance to NNRTIs. The fourth resistant virus contained two mutations in the protease gene (M36I and M46I), which would result in resistance to the protease inhibitor indinavir (Crixivan).
No details on the drugs taken by each individual patient with detectable resistance were presented. However, the investigators did show results of an analysis that failed to detect any significant differences in the risk of resistance mutations between patients taking NNRTIs and those taking ritonavir-boosted saquinavir. Confirming previous studies, patients taking triple NRTI treatment were more likely to develop resistance to their HIV drugs.
“Few resistance mutations occurred during structured treatment interruptions,” the researchers concluded. “In contrast to other studies, where resistance was more frequently observed, most patients in Staccato were treated with a boosted protease inhibitor, and highly active antiretroviral therapy duration before structured treatment interruptions was relatively short.”
The low incidence of resistance mutations may be linked to the high barrier for resistance seen with boosted protease inhibitor-based HIV treatment. A similar trend was seen in another poster presentation in Denver, showing that patients with poor adherence may be less likely to experience treatment failure if a boosted protease inhibitor is part of their HIV treatment combination.
Ananworanich J et al. CD4-guided scheduled treatment interruptions: low incidence of resistance mutations in the Staccato trial. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 622b, 2006.