RAPID COMMUNICATIONRapid and Durable Antiretroviral Effect of the HIV-1Integrase Inhibitor Raltegravir as Part of CombinationTherapy in Treatment-Naive Patients With HIV-1 InfectionResults of a 48-Week Controlled StudyMartin Markowitz, MD,* Bach-Yen Nguyen, MD,† Eduardo Gotuzzo, MD,‡ Fernando Mendo, MD,§Winai Ratanasuwan, MD,kColin Kovacs, MD,¶ Guillermo Prada, MD,#Javier O. Morales-Ramirez, MD,** Clyde S. Crumpacker, MD,†† Robin D. Isaacs, MD,†Lucinda R. Gilde, BS,† Hong Wan, MS,† Michael D. Miller, PhD,† Larissa A. Wenning, PhD,†Hedy Teppler, MD,† and the Protocol 004 Part II Study TeamBackground: Raltegravir is an HIV-1 integrase strand-transferinhibitor with potent in vitro activity. This study explored theantiretroviral activity and safety of raltegravir in treatment-naivepatients with plasma HIV-1 RNA levels $5000 copies/mL and CD4+T-cell counts $100 cells/mm3.Methods: Multicenter, double-blind, randomized, controlled studyof raltegravir at doses of 100, 200, 400, and 600 mg twice dailyversus efavirenz at a dose of 600 mg/d, all in combination withtenofovir at a dose of 300 mg/d and lamivudine at a dose of 300 mg/d(clinicaltrials.gov identifier: NCT00100048).Results: In the 198 patients treated (160 on raltegravir and 38 onefavirenz), the mean HIV-1 RNA level ranged from 4.6 to 4.8 log10copies/mL at baseline. At weeks 2, 4, and 8, the proportion of patientsachieving an HIV-1 RNA level ,50 copies/mL was greater in each ofthe raltegravir treatment groups than in the efavirenz group. By week24, all treatment groups appeared similar, with plasma HIV-1 RNAlevels ,400 copies/mL in 85% to 98% of patients and ,50copies/mL in 85% to 95% of patients. These reductions weremaintained through week 48 in 85% to 98% of patients and in 83% to88% of patients, respectively. Five (3%) patients on raltegravir and 1(3%) on efavirenz experienced virologic failure before week 48.Drug-related clinical adverse events were less common withraltegravir than with efavirenz. After 24 and 48 weeks of treatment,raltegravir did not result in increased serum levels of total cholesterol,low-density lipoprotein cholesterol, or triglycerides.Conclusions: Raltegravir at all doses studied was generally welltolerated in combination with tenofovir and lamivudine. Raltegravirexhibited potent and durable antiretroviral activity similar to that ofefavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels belowdetection at a more rapid rate.Key Words: antiretroviral therapy, HIV-1, integrase inhibitor,MK-0518, raltegravir(J Acquir Immune Defic Syndr 2007;46:125–133)Despite the success of highly active antiretroviral therapyin reducing HIV-1–related mortality and morbidity,current treatment regimens may be limited by the emergenceof drug resistance and short- and long-term toxicities. Up to88% of patients with detectable viremia despite treatment withantiretroviral therapy harbor virus with reduced susceptibilityto at least 1 therapeutic class, with more than 50% resistant tomultiple classes.1Furthermore, transmission of drug-resistantHIV-1 has been well documented: the prevalence of drug-resistant HIV-1 mutations in untreated individuals ranges from8% to 27% and includes resistance to more than 1 drug class inup to 13%.2–7Transmitted drug-resistant mutations can persistfor years8–10and may be associated with a less favorableresponse to antiretroviral therapy.5,6,11Clearly, new drugsdirected against novel targets are needed for treatment-naiveand treatment-experienced patients. Raltegravir (formerlyknown as MK-0518) is a strand-transfer inhibitor of HIV-1integrase, which is essential for viral replication and thereforeprovides a unique and specific target for antiretroviral drugdevelopment.12In treatment-experienced patients with multidrug-re-sistant HIV, raltegravir with optimized background therapy(OBT) has been shown to be generally well tolerated, witha safety profile comparable to that of placebo plus OBT, and toprovide significantly better viral suppression than placebo plusReceived for publication April 12, 2007; accepted July 31, 2007.From the *Aaron Diamond AIDS Research Center, Rockefeller University,New York, NY; †Merck Research Laboratories, West Point, PA; ‡HospitalNacionale Cayetano Heredia, Lima, Peru; §Hospital Nacionale EdgardoRebagliati, Lima, Peru;kSiriraj Hospital, Bangkok, Thailand; {CanadianImmunodeficiency Research Collaborative, Toronto, Ontario, Canada;#Fundacio´n Santafe de Bogota University Hospital, Bogota´, Colombia;**Clinical Research Puerto Rico, Inc., San Juan, PR; and ††Beth IsraelDeaconess Medical Center, Boston, MA.All funding for this study was provided by Merck and Co., Inc.Preliminary (week 24) results of this study were presented at the 16th BiennialWorld Congress of the International AIDS Conference, Toronto, Ontario,Canada, August 13–18, 2006.Correspondence to: Hedy Teppler, MD, Merck Research Laboratories, POBox 1000, North W ales , PA 19454-1099 (e-mail: [email protected]).Copyright Ó 2007 by Lippincott Williams & WilkinsJ Acquir Immune Defic SyndrVolume 46, Number 2, October 1, 2007 125JOBNAME: joa 46#2 2007 PAGE: 1 OUTPUT: Thursday August 23 10:13:54 2007tsp/joa/145820/QAI200830Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.OBT at 16 and 24 weeks.13–15In treatment-naive patients, 10days of monotherapy with raltegravir (100, 200, 400, or 600mg twice daily) resulted in an approximately 2.0 log10reduction in plasma HIV-1 RNA levels.16Here, we presentthe results of the second part of that study, which evaluated thesafety and efficacy of raltegravir after 48 weeks of com-bination therapy with tenofovir and lamivudine in treatment-naive HIV-1–infected patients. The control regimen selectedfor this study, efavirenz plus tenofovir and lamivudine, is apotent and durable antiretroviral treatment regimen17recom-mended as initial therapy in current Department of Health andHuman Services (DHHS) guidelines.18Preliminary data fromdrug-drug interaction studies demonstrated satisfactory ralte-gravir levels and tolerability when used in combination withtenofovir and suggested no need for dosage adjustments.19METHODSStudy DesignProtocol 004 was a double-blind, randomized, dose-ranging study in treatment-naive HIV-1–infected patients. PartI consisted of 10 days of raltegravir monotherapy in 35patients.16Part II examined the safety, tolerability, and efficacyof raltegravir versus