Creatine Fails to Augment the Benefits from Resistance Training in Patients with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Study Giorgos K. Sakkas1,2,3, Kathleen Mulligan1,2, Makani DaSilva2, Julie W. Doyle4, Hootan Khatami2, Thomas Schleich5, Jane A. Kent-Braun 6 , Morris Schambelan1,2* 1 Department of Medicine, University of California San Francisco, San Francisco, California, United States of America, 2 Division of Endocrinology, San Francisco General Hospital, San Francisco, California, United States of America, 3 Department of Medicine, University of Thessaly, Thessaly, Greece, 4 Northern California Institute for Research and Education, San Francisco, California, United States of America, 5 Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz, California, United States of America, 6 Department of Exercise Science, University of Massachusetts, Amherst, Massachusetts, United States of America Abstract Background: Progressive resistance exercise training (PRT) improves physical functioning in patients with HIV infection. Creatine supplementation can augment the benefits derived from training in athletes and improve muscle function in patients with muscle wasting. The objective of this study was to determine whether creatine supplementation augments the effects of PRT on muscle strength, energetics, and body composition in HIV-infected patients. Methodology/Principal Findings: This is a randomized, double blind, placebo-controlled, clinical research center-based, outpatient study in San Francisco. 40 HIV–positive men (20 creatine, 20 placebo) enrolled in a 14-week study. Subjects were randomly assigned to receive creatine monohydrate or placebo for 14 weeks. Treatment began with a loading dose of 20 g/ day or an equivalent number of placebo capsules for 5 days, followed by maintenance dosing of 4.8 g/day or placebo. Beginning at week 2 and continuing to week 14, all subjects underwent thrice-weekly supervised resistance exercise while continuing on the assigned study medication (with repeated 6-week cycles of loading and maintenance). The main outcome measurements included muscle strength (one repetition maximum), energetics (31P magnetic resonance spectroscopy), composition and size (magnetic resonance imaging), as well as total body composition (dual-energy X-ray absorptiometry). Thirty-three subjects completed the study (17 creatine, 16 placebo). Strength increased in all 8 muscle groups studied following PRT, but this increase was not augmented by creatine supplementation (average increase 44 vs. 42%, difference 2%, 95% CI 29.5% to 13.9%) in creatine and placebo, respectively). There were no differences between groups in changes in muscle energetics. Thigh muscle cross-sectional area increased following resistance exercise, with no additive effect of creatine. Lean body mass (LBM) increased to a significantly greater extent with creatine. Conclusions / Significance: Resistance exercise improved muscle size, strength and function in HIV-infected men. While creatine supplementation produced a greater increase in LBM, it did not augment the robust increase in strength derived from PRT. Trial Registration: ClinicalTrials.gov NCT00484627 Citation: Sakkas GK, Mulligan K, DaSilva M, Doyle JW, Khatami H, et al. (2009) Creatine Fails to Augment the Benefits from Resistance Training in Patients with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Study. PLoS ONE 4(2): e4605. doi:10.1371/journal.pone.0004605 Editor: Gianni Parise, McMaster University, Canada Received June 30, 2008; Accepted January 2, 2009; Published February 26, 2009 Copyright: 2009 Sakkas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was performed under a grant from the National Center for Complementary and Alternative Medicine of the National Institutes of Health (AT00491, DK45833, DK54615, RR-00083). Creatine monohydrate and placebo were donated by Jarrow Universal Herbs, Inc., but they provided neither funds for this study nor any input on data analysis. Competing Interests: The authors have declared that no competing interests exist. * E-mail: morrie@sfghgcrc.ucsf.edu Introduction In people with HIV infection and other chronic diseases, maintenance or augmentation of muscle mass is important for preserving functional status and forestalling disease progression [1]. Progressive resistance exercise training (PRT), either alone or in combination with aerobic exercise training, can increase muscle mass and improve physical performance in persons with HIV infection [2– 10]. Many individuals employ so-called ergogenic aids, including substances such as anabolic steroids and growth hormone, to facilitate muscle accrual, and to enhance the anabolic effect of PRT on body composition with a view to both functional and aesthetic improve- ments [11,12]. Creatine monohydrate is a nutritional supplement that has been shown to enhance short-term energy availability during intense exercise and to improve recovery between intense exercise bouts [13,14]. Based on such findings, it is being used by competitive and recreational athletes as an ergogenic aid to improve their training efficiency. Although in some populations creatine supplementation has been shown to improve isotonic strength [15], torque [16] and power [17] other studies have failed to show any such effects [18–21]. To date, there have been no specific studies of the efficacy of the medical use of creatine supplementation in people with HIV PLoS ONE | www.plosone.org 1 February 2009 | Volume 4 | Issue 2 | e4605