For patients who develop adverse reactions or have significant drug-drug interactions on antiretroviral (ARV) therapy, clinicians often replace the problematic ARV with a comparable one, if such an option exists. Increasingly, the integrase inhibitor raltegravir is considered a possible substitute for other ARVs because it is well tolerated, has few significant drug-drug interactions, is potent, and has no cross-resistance with agents in other ARV classes. Several small studies have shown that using raltegravir to replace enfuvirtide in virologically suppressed individuals on potent ARV regimens is likely to maintain virologic control (see, for example, Raltegravir Substitution for Enfuvirtide in the Spring 2008 installment of HIV Meds Quarterly). However, raltegravir substitution has not been studied in other contexts. Jointly presented at the 16th Conference on Retroviruses and Opportunistic Infections in Montreal in February, the results from two studies in which raltegravir was substituted for lopinavir/ritonavir (LPV/r) demonstrate the importance of careful patient selection for this strategy.(1)
These were parallel randomized, controlled, double-blind noninferiority studies of patients with HIV RNA suppression on stable regimens consisting of LPV/r plus 2 or more nucleoside reverse transcriptase inhibitors (NRTIs). A total of 702 patients were randomized to substitute raltegravir for LPV/r or to continue LPV/r (twice daily), and all continued receiving their NRTIs. At 24 weeks, by intention-to-treat analysis, the raltegravir groups had lower rates of virologic suppression: In combined analysis, 89% of raltegravir vs 94% of LPV/r recipients had HIV RNA viral loads of <50 copies/mL (the criterion of noninferiority was not met). Integrase resistance mutations (as well as reverse transcriptase mutations) were detected in most patients with virologic failure.
The increase in virologic failure after substitution of raltegravir for LPV/r probably is explained by baseline NRTI resistance in many of the study patients, as well as by raltegravir's comparatively low genetic barrier to resistance. The study protocols did not exclude patients who had a history of ARV resistance or virologic failure on previous regimens, and study subjects had substantial previous exposure to ARVs [a median of 3-4 years (and up to 22 years)] and had used a median of 5-6 (maximum 16) ARVs. In fact, of the patients with virologic failure on raltegravir, 84% were not on their first ARV regimen, and of these, two thirds reported a history of virologic failure on a previous regimen. In many of these patients, the raltegravir may have been functioning as monotherapy.
| Clinical Bottom Line|
In substitution strategies, it is crucial to consider the potency of the overall ARV regimen, particularly when using raltegravir to replace an ARV with a higher genetic barrier to resistance. If raltegravir is used as a substitute for another ARV, it must be combined with other fully active agents.
- Eron J, Andrade J, Zajdenverg R, et al. Switching from stable lopinavir/ritonavir-based to raltegravir-based combination ART resulted in a superior lipid profile at week 12 but did not demonstrate non-inferior virologic efficacy at week 24. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal. Abstract 70aLB.