Skeletal Muscle Toxicity Associated With Raltegravir-Based Combination Antiretroviral Therapy in HIV-Infected Adults

Lee, Frederick J. BSc, MBBS, FRACP, FRCPA*; Amin, Janaki BSc, MPH, PhD; Bloch, Mark MBBS, MMed; Pett, Sarah L. BSc, MBBS, PhD, DTM&H, FRACP, FRCPE; Marriott, Debbie BSc, MBBS, FRACP, FRCPA, MASM§; Carr, Andrew MBBS, MD, FRACP, FRCPA*

JAIDS Journal of Acquired Immune Deficiency Syndromes: 15 April 2013 - Volume 62 - Issue 5 - p 525–533
doi: 10.1097/QAI.0b013e3182832578
Clinical Science

Objective/Design: Raltegravir is uncommonly associated with rhabdomyolysis and grade 3–4 creatine kinase (CK) elevation. In this cross-sectional study, we compared the prevalence of skeletal muscle toxicity in HIV-infected adults receiving raltegravir with that of a control group.

Methods: Adults receiving combination antiretroviral therapy were recruited consecutively. Assessments included physical examination, an exercise questionnaire, and blood testing for CK, troponin T, and raltegravir trough levels. The primary endpoint was the prevalence of skeletal muscle toxicity, defined as a composite of any of the following: (1) isolated CK elevation; (2) myalgia; (3) proximal myopathy on examination; or (4) rhabdomyolysis.

Results: A total of 318 participants (159 raltegravir, 159 control) were evaluated; 98% were male, 89% white, with median age 51 years, and 91% had HIV-1 RNA <50 copies per milliliter. Mean raltegravir exposure was 28 months. Skeletal muscle toxicity was present in 37% of the raltegravir vs. 19% of the control group (P < 0.001). By component, there were significant respective differences in myalgia (19% vs. 3%, P < 0.001) and proximal myopathy (4% vs. 0%, P = 0.030) but not CK elevation (14% vs. 16%, P = 0.639). No patient had rhabdomyolysis. In multivariate analysis, raltegravir therapy (P < 0.001) and strenuous exercise (P = 0.002) were independently associated with overall muscle toxicity. No component of muscle toxicity was associated with duration of raltegravir or the raltegravir level.

Conclusions: Raltegravir-based therapy is associated with a higher prevalence of symptomatic skeletal muscle toxicity, which does not seem to be concentration or time dependent, nor associated with elevated CK. Proximal myopathy may be an uncommon but significant side effect of raltegravir exposure.

*Clinical Research Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia

The Kirby Institute, Faculty of Medicine, University of New South Wales, Sydney, Australia

Holdsworth House Medical Practice, Sydney, Australia

§Department of Microbiology and Clinical Infectious Diseases, St. Vincent's Hospital, Sydney, Australia.

Preliminary findings from this study were presented at the 14th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV, Washington, DC, July 19–21, 2012.

F.J.L. receives research funding from the National Health and Medical Research Council of Australia (grant number 1017991); has received a Clinical Immunology Society Fellowship, travel sponsorships from the Australasian Society of Clinical Immunology and Allergy and the Australasian Society for HIV Medicine, and conference sponsorship from MSD. J.A. declares no conflict of interest. M.B. has received research funding from Abbott, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, MSD, and ViiV Healthcare; travel sponsorships from Janssen-Cilag, Gilead Sciences, MSD, and ViiV Healthcare; consultancy from MSD, and has served on advisory boards for Abbott, Bristol-Myers Squibb, Gilead Sciences, MSD, and ViiV Healthcare. S.L.P. has received travel and conference sponsorships from Boehringer-Ingelheim, Gilead Sciences, and MSD. D.M. declares no conflict of interest. A.C. has received research funding from Baxter, the Balnaves Foundation, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, MSD, and Pfizer; consultancy fees from Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, and MSD; lecture and travel sponsorships from Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, MSD, and Serono; and has served on advisory boards for Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, and MSD.

Correspondence to: Frederick J. Lee, BSc, MBBS (Hons), FRACP, FRCPA, St. Vincent's Centre for Applied Medical Research, Level 4, Xavier Building, St. Vincent's Hospital, 390 Victoria Street, Darlinghurst, NSW 2010, Australia (e-mail: flee3@stvincents.com.au).

Received September 11, 2012

Accepted December 13, 2012

© 2013 Lippincott Williams & Wilkins, Inc.