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Data from clinical trials involving the HIV integrase inhibitor raltegravir have generally been very encouraging. The BENCHMRK studies established raltegravir as an important option for highly treatment-experienced patients (JW Infect Dis Jul 23 2008), and the STARTMRK studies demonstrated excellent activity for initial antiretroviral therapy (ART) that included raltegravir (JW AIDS Clin Care Aug 10 2009). Is this a drug that offers something for everyone? Recently published data suggest situations where raltegravir may not be a good option.
The SWITCHMRK studies were nearly identical manufacturer-sponsored trials in which patients with HIV suppression on lopinavir/ritonavir-based ART were randomized either to remain on their current regimens or to replace lopinavir/r with raltegravir in a double-blind, double-dummy fashion. The primary endpoints included changes in lipid parameters, given the relatively common problem of lipid abnormalities among patients on PIs.
A total of 702 patients received at least one dose of study treatment. Those who switched to raltegravir had significantly better lipid profiles at week 12 than those who remained on lopinavir/r, but they were also less likely to sustain virologic suppression — a result that led to early termination of the study. At week 24, the proportion of patients with viral loads <50 copies/mL by PCR was 84.4% among raltegravir recipients versus 90.6% among lopinavir/r recipients (treatment difference, –6.2%; 95% CI, –11.2% to –1.3%).
Eron JJ et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): Two multicentre, double-blind, randomised controlled trials. Lancet 2010 Jan 30; 375:396.
Comment
An exploratory analysis in this study suggested that a history of ART failure prior to study entry was associated with increased risk of virologic failure among patients who switched to raltegravir, perhaps a consequence of resistance to the nucleoside components of the treatment regimen. The apparent diminished genetic barrier to resistance for raltegravir compared with lopinavir/r then manifested itself with higher rates of virologic failure in this group after the switch. Clinicians should carefully assess all available information — including prior treatment history and results of resistance testing — before modifying successful antiretroviral regimens.