Integrase inhibitors: a novel class of antiretroviral agents.

OBJECTIVE: To review the pharmacology, efficacy, safety, and resistance profiles of the integrase inhibitors raltegravir and elvitegravir.

DATA SOURCES: A search of PubMed was conducted (2000-August 2009) using the following key words: raltegravir, MK-0518, elvitegravir, and GS-9137. Articles were evaluated for content and bibliographies were reviewed. Data available exclusively in abstracts from major infectious diseases and HIV conferences were also evaluated for inclusion.

STUDY SELECTION AND DATA EXTRACTION: Studies included were in vitro investigations; Phase 1, 2, and 3 clinical trials; retrospective analyses including case reports; and pharmacokinetic and pharmacodynamic evaluations.

DATA SYNTHESIS: Raltegravir is currently approved by the Food and Drug Administration for the management of HIV-1 infection in treatment-naïve or-experienced adults as part of an optimized combination regimen. When combined with other active agents, it has demonstrated similar virologic efficacy after 96 weeks to the combination of efavirenz, tenofovir, and emtricitabine in treatment-naïve patients. Unlike many antiretrovirals, raltegravir does not enter cytochrome P450 metabolism and instead undergoes glucuronidation. Elvitegravir is in the late stages of clinical development. A Phase 2 study has demonstrated virologic efficacy in treatment-experienced patients comparable to protease inhibitor-based regimens after 24 weeks. Boosting of elvitegravir through inhibition of CYP3A4 metabolism has been investigated and suggests a pharmacokinetic profile conducive to once-daily-dosing. Phase 2 and 3 clinical trials evaluating boosted elvitegravir are in process. The Phase 2 trial combines elvitegravir with a non-ritonavir boosting agent plus tenofovir/emtricitabine given once daily as a "quad-pill" formulation. The Phase 3 trial compares once-daily ritonavir-boosted elvitegravir with twice-daily raltegravir, each given with an optimized background regimen. Both integrase inhibitors are well tolerated and raltegravir has few drug-drug interactions. Resistance mutations have been identified in patients experiencing virologic failure and cross resistance between raltegravir and elvitegravir has been confirmed.

CONCLUSIONS: The integrase inhibitors provide a novel target for antiretroviral therapy and provide an option for patients harboring resistance to other antiretrovirals.