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Raltegravir (Isentress)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of raltegravir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for raltegravir treatment
References
Related Resources
DHHS Guidelines
Characteristics of Integrase Inhibitors
Drug Interactions with Integrase Inhibitors
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Raltegravir (Isentress)
Class

Integrase inhibitor

Background
U.S. Manufacturer

Merck

Approval

Raltegravir received accelerated approval from the U.S. Food and Drug Administration (FDA) in October 2007 and traditional approval in 2009 for use by adults with HIV strains that are resistant to multiple antiretroviral agents and by those who have ongoing viral replication while receiving antiretroviral therapy. In July 2009, raltegravir was approved for use in initial therapy in adults. In 2012, it was approved for use in children 2 years of age and older, and in 2013, it was approved for use in children aged 4 weeks and older. It is intended for use as part of combination therapy. Raltegravir is the first agent in the class of integrase inhibitors to be approved by the FDA. It inhibits integration of reverse-transcribed HIV DNA into the chromosomes of host cells.

FDA approval was based on 24-week results from 2 randomized, placebo-controlled Phase III studies in patients with resistance to at least 1 agent in each of the protease inhibitor, nucleoside analogue, and nonnucleoside reverse transcriptase inhibitor classes. Patients received either raltegravir or placebo, plus a background regimen selected on the basis of resistance profiles. At 24 weeks, the raltegravir groups had greater decreases in HIV RNA and higher rates of viral suppression to <400 copies/mL and to <50 copies/mL than did the comparator group; these differences were statistically significant.(1,2)

Formulation and Dosing

Raltegravir is available in film-coated tablets, and in chewable tablets for pediatric administration. A formulation for oral suspension has been approved and is expected to be available in 2014. Recommended dosing is twice daily.

Dosing of Raltegravir
Adult400 mg BID
PediatricAge <4 weeksNot FDA approved
Age ≥4 weeks (and weight ≥3 kg)

Weight:

3 to <4 kgOral suspension 20 mg (1 mL) BID
4 to <6 kgOral suspension 30 mg (1.5 mL) BID
6 to <8 kgOral suspension 40 mg (2 mL) BID
8 to <11 kgOral suspension 60 mg (3 mL) BID
11 to <14 kgOral suspension 80 mg (4 mL) BID or chewable tablet 75 mg BID
14 to <20 kgOral suspension 100 mg (5 mL) BID or chewable tablet 100 mg BID
20 to <25 kgChewable tablet 150 mg BID
25 to <28 kgFilm-coated tablet 400 mg BID or chewable tablet 150 mg BID
28 to <40 kgFilm-coated tablet 400 mg BID or chewable tablet 200 mg BID
≥40 kgFilm-coated tablet 400 mg BID or chewable tablet 300 mg BID

Abbreviations: BID = twice daily

Note: The oral suspension is approved for pediatric patients weighing <20 kg; the chewable tablet is approved for pediatric patients weighing ≥11 kg. These formulations and the film-coated tablet formulation are not bioequivalent; follow specific dosing instructions for each formulation. The maximum dosage of oral suspension is 100 mg BID; the maximum dosage of chewable tablets is 300 mg BID.

There are no food restrictions.
Raltegravir interacts with other medications; dosage adjustments may be required and certain combinations are contraindicated. For more information about drug interactions, see Combinations below and refer to the Database of Antiretroviral Drug Interactions.
No dosage adjustment is necessary for patients with renal insufficiency.
Consult product labeling for detailed dosing information.
FDA Pregnancy Category C.

Clinical Use
Combinations

Raltegravir must be used in combination with other antiretroviral medications.

Raltegravir interacts with several medications, including other antiretroviral agents. Raltegravir does not interact with the hepatic cytochrome P450 enzyme system. It is metabolized primarily by glucuronidation, particularly by uridine diphosphate glucuronosyltransferase (UGT) 1A1. Inducers or inhibitors of UGT 1A1 may affect serum levels of raltegravir. For example, rifampin induces raltegravir glucuronidation and substantially decreases raltegravir concentrations; rifampin should not be given concomitantly with raltegravir. The nonnucleoside analogues efavirenz and etravirine and the protease inhibitor combination of tipranavir + ritonavir also lower raltegravir concentrations by this mechanism; however, the therapeutic significance of these interactions has not been defined. Other strong UGT 1A1 inducers such as phenobarbital and phenytoin have not been studied in combination with raltegravir.(3,4)

Inhibitors of UGT 1A1, including atazanavir, may increase raltegravir levels; the interaction with atazanavir does not appear to be clinically significant. By an unknown mechanism, coadministration of raltegravir with the nucleotide analogue tenofovir increases raltegravir levels and modestly decreases tenofovir levels.(3)

It appears that polyvalent cations (such as magnesium, calcium, and iron) bind integrase inhibitors and interfere with their activity against integrase. A pharmacokinetic study showed that administration of antacids containing divalent cations at the same time as elvitegravir (an investigational integrase inhibitor) lowered serum elvitegravir concentration by more than 40%. This effect was minimal if antacids were taken 4 hours apart from the integrase inhibitor.(5) The interaction of raltegravir and antacids has not been studied; pending further investigation, antacid medications and other agents with polyvalent cations should be used cautiously with (and taken separately from) raltegravir. There is no effect of proton pump inhibitors on integrase inhibitor concentrations.

Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

Use in Initial vs Subsequent Therapy

Current adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services state that the combination of raltegravir plus tenofovir/emtricitabine is a "preferred" regimen for initial treatment of HIV infection, and raltegravir plus abacavir/lamivudine is an "alternative" regimen.

In initial therapy, a randomized double-blind noninferiority comparison of raltegravir and efavirenz, each in combination with tenofovir + emtricitabine, found similar rates of virologic suppression to <50 copies/mL at 48 weeks: 86% in the raltegravir arm and 82% in the efavirenz group.(6) CD4 increases also were similar in the two groups: 189 cells/µL and 163 cells/µL, respectively.

An earlier randomized double-blind study also showed raltegravir to be effective in initial therapy. Raltegravir (given at 100 mg, 200 mg, 400 mg, or 600 mg twice daily) was compared with efavirenz, each in combination with lamivudine + tenofovir. Although the study was not powered for formal efficacy analyses, it found similar virologic and CD4 responses in all treatment groups. At 48 weeks, the proportion of patients with HIV RNA levels of <50 copies/mL was 83-88% in the 4 raltegravir groups and 87% in the efavirenz group. The CD4 count increases were 144-221 cells/µL in the raltegravir groups and 170 cells/µL in the efavirenz group.(7)

In treatment-experienced patients with resistance to 3 classes of antiretrovirals (nucleoside analogues, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors) and ongoing viral replication, 2 Phase III studies (described above in "Approval") compared raltegravir with placebo, each given in combination with an optimized background regimen. In combined analysis, the groups that received raltegravir had higher rates of virologic suppression at 24 weeks than the groups that received placebo (HIV RNA level of <400 copies/mL in 75% of raltegravir recipients vs 40% of placebo recipients, and <50 copies/mL in 65% vs 35%, respectively). These differences were statistically significant (p < .001). Virologic suppression was closely correlated with having at least 1 active agent in the background antiretroviral regimen, and the inclusion of enfuvirtide or darunavir in the regimen of those without previous exposure to these drugs substantially improved the rates of virologic response. In the raltegravir treatment groups, the mean increase in CD4 count was higher than in the placebo group (84 cells/µL vs 37 cells/µL; p < .001).(1,2,3,8)

A smaller Phase II randomized controlled trial, also involving patients with advanced HIV disease, extensive treatment experience, and resistance to at least 1 agent in each of 3 classes, compared 3 dosages of raltegravir (200 mg, 400 mg, and 600 mg, administered twice daily) with placebo. All participants were also given an optimized background regimen (tipranavir and darunavir were not available for use). At 24 weeks, by intention-to-treat analysis, the proportion of patients with HIV RNA levels of <50 copies/mL was 56-67% in the raltegravir groups and 13% in the placebo group (p < .0001 for comparison of each raltegravir dose with placebo). All participants were continued on open-label raltegravir (at the 400 mg twice daily dosage) to 48 weeks; at this time point, the proportion with HIV RNA levels of <50 copies/mL was 46-64%. As in the Phase III studies, the presence of other active antiretroviral agents (including enfuvirtide) in the background regimen substantially increased the rates of virologic suppression. The raltegravir groups had greater increases in CD4 cell counts at 24 weeks (60-102 cells/µL) than the placebo group (8 cells/µL).(9,10)

It is not known whether the superior virologic and CD4 cell count responses seen in the raltegravir recipients in these studies will result in improved clinical outcomes.

Factors Affecting Adherence

Symptomatic adverse effects of raltegravir include diarrhea, nausea, fatigue, and muscle aches. Laboratory abnormalities include increases in pancreatic amylase and hepatic transaminase levels.(3,7,9)

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with raltegravir is initiated.

Raltegravir has not been studied in patients taking the drug during pregnancy; it is classified as an FDA Pregnancy Category C drug.

Resistance

Resistance to raltegravir is associated with the selection of 1 or more of several resistance mutations; however, the resistance profile of raltegravir in human subjects has not been characterized fully. In vitro and in vivo studies of raltegravir show the emergence of a number of integrase mutations. In the limited clinical data currently available, two main genetic pathways to resistance have been identified. These involve Q148H/K/R plus additional mutations (E138K, G140A/S) or N155H plus additional mutations (L74M, T92Q, T97A, V151I, G163R). Increasing numbers of these mutations, as well as specific combinations, appear to be associated with greater degrees of reduced susceptibility to raltegravir.(7)

Implications of raltegravir resistance for treatment with other antiretrovirals

The degree to which resistance mutations selected by raltegravir confer resistance to other integrase inhibitors is not known. In limited in vitro data, raltegravir-resistant HIV strains exhibited cross-resistance to other investigational integrase inhibitors.(11,12)

Raltegravir mutations are not expected to affect sensitivity to other classes of antiretroviral agents.

Implications of resistance to other antiretrovirals for raltegravir treatment

Resistance mutations selected by other integrase inhibitors now in development appear to contribute to raltegravir resistance; however additional data from studies of raltegravir and other integrase inhibitors will be needed to define cross-resistance in this class of medications.(13)

Resistance mutations selected by other classes of antiretrovirals are not expected to contribute to raltegravir resistance.

References
1.  Cooper DA, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 105aLB.
2.  Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 105bLB.
3.  Isentress Prescribing Information. Whitehouse Station, New Jersey: Merck & Co; October 2007.
4.  Anderson MS, Kakuda TN, Miller JL, et al. Pharmacokinetic evaluation of non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125 and integrase inhibitor (InSTI) raltegravir (RAL) in healthy subjects. In: Program and abstract of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPDB02
5.  Ramanathan S et al. Pharmacokinetic evaluation of drug interactions with ritonavir-boosted HIV integrase inhibitor GS-9137 (elvitegravir) and acid-reducing agents. In: Program and abstracts of the 8th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2007; Budapest. Abstract 69.
6.  Lennox J, Dejesus E, Lazzarin A, et al. STARTMRK, A Phase III study of the safety and efficacy of raltegravir (RAL)-based vs efavirenz (EFV)-based combination therapy in treatment-naive HIV-infected patients. In: Program and abstracts of the 48th International Conference on Antimicrobial Agents and Chemotherapy; October 25-28, 2008; Washington, D.C. Abstract H-896a.
7.   Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33.
8.  Kumar P, Cooper D, Steigbigel R, et al. Efficacy of raltegravir, an HIV integrase inhibitor, in combination with regimens containing enfuvirtide, darunavir, or tipranavir in patients with triple-class resistant virus: combined results from Benchmrk-1 and Benchmrk-2. In: Program and abstracts of the European AIDS Conference; October 24-27, 2007; Madrid. Abstract P7.
9.   Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007 Apr 14;369(9569):1261-9.
10.  Grinsztejn B, Nguyen B, Katlama C, et al. 48 week efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago. Abstract H-713.
11.  Hazuda DJ, Miller MD, Nguyen BY, et al, Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a phase II study in patients with triple-class resistant HIV-1 infection. In: Program and abstracts of the XVI International HIV Drug Resistance Workshop; June 12-16, 2007; St. Michael, Barbados. Abstract 8.
12.  DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). In: Programs and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB032.
13.  McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a Phase II study of elvitegravir (GS-9137). In: Program and abstracts of the XVI International HIV Drug Resistance Workshop; June 12-16, 2007; St. Michael, Barbados. Abstract 9.