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Raltegravir Treatment for Antiretroviral-resistant HIV Infection
Abstract and Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University, School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Synopsis: In HIV patients with three-drug, class-resistant (3DCR) virus, raltegravir plus optimized background therapy (OBT) provided better viral suppression than OBT alone. Virologic failures did occur in some patients and were associated with the emergence of amino acid substitutions at positions 148, 155, or 143 in integrase.
Sources: Steigbegel RT, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339-354; Cooper DA, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008;359:355-365.
The Merck integrase inhibitor, raltegravir, was studied in two identical trials in different geographic locations to evaluate its safety and efficacy vs placebo in combination with optimized background therapy in patients infected with 3-drug class-resistant (3DCR) HIV-1. Patients were randomized to receive raltegravir or placebo in a 2:1 ratio; 699 randomized patients received the study drug. At week 16, 61.8% of raltegravir patients vs 34.7% of placebo recipients achieved HIV RNA < 50 copies/mL. Overall frequencies of drug-related adverse events (AEs) were similar in the raltegravir and placebo groups. At 48 weeks, 105 of the 462 raltegravir recipients experienced virologic failure, and genotyping was performed in 94. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Of the 64 patients, 48 had two or more resistance-associated substitutions. Raltegravir was superior to placebo in all clinically relevant subgroups of patients, including those that normally predict a poor response to ARV therapy: high baseline HIV RNA, low CD4 count, and low genotypic or phenotypic sensitivity score.
Merck's antiviral discovery group (originally led by Dr. Emilio Emini and John Condra) began looking at HIV integrase as a therapeutic target in the early 1990s. The team was (and is still) headed by Dr. Daria Hazuda. Integrase (the 3' gene product encoded by the pol gene) performs two major functions during the replication cycle of HIV: 3' processing of the double-stranded cDNA followed by DNA strand transfer, which results in integration of the cDNA into the host cell chromosome. Merck's original diketo compounds were discovered to inhibit this latter strand transfer reaction. Several earlier lead compounds fell out of development due to either poor bioavailability or toxicity; however, Merck tenaciously persisted, and raltegravir (MK-0518) is the fruit of this labor.
The BENCHMARK 1 and 2 studies reported in these two papers are the two pivotal, controlled trials on which FDA approval of raltegravir was based. In addition to dramatic efficacy demonstrated in this patient population of 3DCR virus-infected patients, the agent was extremely well tolerated and no side effects in excess of placebo were observed. Raltegravir is metabolized by glucuronidation (rather than acting as either a substrate or inhibitor of the cytochrome P450 system), so ritonavir boosting is not needed, and significant drug interactions are largely absent. We have personally used raltegravir as a component of salvage therapy regimens for patients with highly resistant virus at our HIV Clinic at the County Hospital. It is extremely well-tolerated, and has resulted in being able to suppress HIV replication to undetectable levels in patients who have not had undetectable viral loads for years. The recovery of CD4+ lymphocyte counts in many of these patients with advanced disease who have experienced virologic suppression on raltegravir-containing salvage therapy regimens has been dramatic. Depending on the specific findings seen on HIV-1 genotyping, we often combine raltegravir with etravirine, tenofovir/FTC, and ritonavir-boosted darunavir.
The data presented in this paper (along with the experience gained with clinical use of raltegravir) do raise concern that effort must be taken to construct the best optimized background antiretroviral regimen to prevent emergence of resistance to raltegravir on therapy. Amino acid substitutions (mainly at amino acid residues 148, 155, or 143) have arisen on therapy with raltegravir and correlate with phenotypic resistance in vitro and virologic failure in vivo. Unfortunately it appears that Gilead's candidate integrase inhibitor, elvitegravir, develops resistance through the same set of amino acid substitutions, making it very unlikely that one will be able to successfully salvage virologic failure of one integrase inhibitor with the other.