A New Class of Antiretrovirals: Isentress® (Raltegravir)

Abstract & Commentary

By Lian Chang, PharmD Candidate, Jessica C. Song, MA, PharmD, and John O'Brien, PharmD, Lian Chang is PharmD Candidate, University of the Pacific, Jessica C. Song is Pharmacy Residency Coordinator, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert, and John O'Brien is Clinical Pharmacist Specialist, Santa Clara Valley Health and Hospital System

Lian Chang, Jessica C. Song, and John O'Brien report no financial relationships relevant to this field of study.

Over the past decade, tremendous progress has been made to increase the tolerability of treatment regimens and to reduce the pill burden for HIV-1 infected patients. However, many potential areas for improvement exist for optimizing the treatment of HIV-1 infected patients. These areas include the development of new agents with activity against highly-resistant HIV strains, and new agents that are not associated with the adverse events seen in established regimens (ie, lipoatrophy, dyslipidemia, insulin resistance, renal and liver toxicities, and central nervous system effects).1

In September 2007, maraviroc (Selzentry), the first CCR5 co-receptor antagonist, was approved by the FDA.1 Shortly thereafter, in October 2007, approval was granted for the first HIV-1 integrase inhibitor raltegravir (Isentress).1,2 With the approval of these new agents, highly treatment-experienced HIV-1 patients now have access to novel classes of drugs, with minimal propensity towards conferring HIV resistance. This article will review the pharmacology of raltegravir and discuss the resistance patterns and pivotal clinical studies highlighting this new antiretroviral agent.

Management of Treatment-Experienced Patients

According to the 2008 DHHS (US Department of Health and Human Services), HIV treatment guidelines for adults and adolescents should contain at least two, preferably three, fully active agents.3 The two most common types of combination therapy in treatment-naïve patients are NNRTI (nonnucleoside reverse transcriptase inhibitor)-based (1 NNRTI + 2 NRTI [nucleoside reverse transcriptase inhibitor]) and PI (protease inhibitor)-based (1 or 2 PI + 2 NRTI) regimens.3 Table 1 shows the DHHS-recommended agents for initial therapy in treatment-naïve patients. The goal of treatment is to achieve an undetectable viral load of HIV-1 RNA < 50 copies/mL (goal at Santa Clara Valley Medical Center (SCVMC, San Jose, CA) is < 75 copies/mL).

Antiretroviral (ARV) treatment failure is not uncommon, and is defined as a viral load of > 400 copies/mL after 24 weeks, > 50 copies/mL after 48 weeks, or a repeated detected viral load after prior virologic suppression.3 Healthcare providers should evaluate adherence history, medication intolerance, suboptimal pharmacokinetics, and drug resistance, all of which may contribute to treatment failure.3

A new treatment regimen should be designed for the treatment-experienced patient based on treatment history and resistance testing results. Ideally, a genotypic drug resistance test should be obtained while the patient is taking the failing ARV regimen (or within four weeks of treatment discontinuation).3 A coreceptor tropism assay should also be performed to determine whether a CCR5 inhibitor (maraviroc) may be added to raltegravir in order to maintain at least two fully active drugs in the new regimen.1

While adding a singly, fully active agent in a new regimen is not recommended to prevent the risk of rapidly developing resistance, it may be done in some clinically deteriorating patients, because even transient decreases in HIV RNA and/or transient increases in CD4 T-cell count have been shown to provide clinical benefits.3 Discontinuing or briefly interrupting therapy (even with ongoing viremia) may quickly lead to drug resistance and treatment failure; therefore, it is not recommended.

Table 2 summarizes the ARV classes with newly approved drugs in treatment-experienced patients.

Pharmacologic Properties of Raltegravir

Raltegravir acts by inhibiting the strand transfer step (catalyzed by the integrase enzyme) that allows the insertion of reverse transcribed DNA into the host cell DNA.4,5 Inhibiting this essential step limits the ability of the virus to replicate and infect new host cells. Raltegravir is used in combination with other antiretrovirals for the treatment of HIV-1 in highly treatment-experienced adults who have evidence of viral progression and viral strains resistant to multiple antiretroviral agents.3 It is administered orally as a 400 mg tablet given twice daily with or without food and does not require boosting with ritonavir.1 In practice, PIs are boosted with ritonavir to achieve adequate plasma drug concentrations and to prevent resistance to PIs. Unfortunately, ritonavir has many drug-drug interactions, and it can induce significant medication intolerance in susceptible patients.

In studies, raltegravir was generally well tolerated. The most commonly reported adverse effects included diarrhea (16.6%), nausea (9.9%), headache (9.7%), and fever (4.9%).2 Grade 2-4 creatine kinase elevations were observed in patients receiving raltegravir (~2% , which is comparable to that of daptomycin6 and rosuvastatin7). Myopathy and rhabdomyolysis have been reported, although the causality is unknown.2 Healthcare providers should assess the risk factors for these two conditions, such as the co-administration of medications (ie, statins) also known to cause these conditions.

Raltegravir is metabolized by UGT1A1-mediated glucuronidation.2 It is neither a substrate, inhibitor, nor inducer of the CYP450 enzymes.2 Thus, it is expected to have no substantial interactions with drugs metabolized by the CYP450 system, including most PIs and NNRTIs. Concomitant usage of drugs that are strong inducers of UGT1A1 (eg, rifampin, efavirenz, tipranavir/ritonavir, rifabutin) may result in reduced plasma concentrations of raltegravir, and must be used with caution.2,3 However, data show that strong inhibitors of UGT1A1 (eg, atazanavir) may be co-administered with raltegravir without dose adjustment.2 Furthermore, no dose adjustment is required for renal and hepatic impairment.2

Table 3 summarizes the key pharmacologic properties of raltegravir.

Resistance Patterns/Clinical Studies of Raltegravir

The approval of raltegravir was based on 24-week data from two identical, randomized, double-blind, placebo-controlled, phase III BENCHMRK (I & II) studies. These studies included 699 treatment-experienced HIV-1 patients who were 16 years or older and had documented resistance to at least one drug in each of the three antiretroviral classes (NRTIs, NNRTIs, PIs).4,5 The results at 24 weeks showed that subjects who received raltegravir 400 mg twice daily plus optimized background therapy (OBT) were roughly twice as likely to achieve a viral load below 400 copies/mL and 50 copies/mL than those receiving OBT plus placebo (75.5% vs 39.3% and 62.6% vs 33.3%, respectively).4 The mean increase in CD4+ cell counts was also higher in the treatment arm than in the control arm (89 cells/mm2 vs 35 cells/mm2). These efficacy results were supported by 48-week analysis of a double-blind, phase II dose-ranging trial.8,9

As seen with the NNRTIs and many of the antimicrobial drug classes, development of resistance to one integrase inhibitor often confers cross-resistance within its own class. Limited data show that there are two distinct pathways that confer resistance in this class: N155H and Q148K/R/H.10 Elvitegravir, another HIV-1 integrase inhibitor, is in the late-stages of clinical development.11 One study analysis consisting of two patients who switched from elvitegravir/ritonavir to raltegravir after virologic failure showed no significant reductions in HIV-1 RNA, suggesting some cross-resistance between raltegravir and elvitegravir.11


As the first integrase inhibitor to be approved in its class, raltegravir offers much hope for current HIV-infected patients who have exhausted other treatment regimens. Since raltegravir does not undergo biotransformation by the CYP450 system and does not require to be boosted with ritonavir, this drug eliminates many of the issues concerning drug-drug interactions and current adverse drug reactions attributed to protease inhibitors. Furthermore, raltegravir has recently been approved by the AIDS Drug Assistance Program (ADAP) in November 2007, and no longer requires the SUPPORT program. As always, healthcare providers must enforce patient medication adherence to maintain efficacy with the current antiretroviral therapeutic options.


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