were performed in the evaluable subset, defined as the number of subjects assigned to each treatment in whom paired results (baseline to week 2, baseline to week 14) were available. The numbers of subjects in whom these results are available are indicated in each table. Within-group changes from baseline to week 2 and baseline to week 14 were evaluated using paired t-tests. Absolute changes (week 0 to week 2 and week 0 to week 14) in the creatine group were compared with those in the placebo group using unpaired t- tests, and the 95% confidence interval for the differences between mean changes calculated. All statistical analyses were performed using Statview (SAS Institute Inc. Cary, NC). Data are the mean and (SD). Two-tailed p-values ,0.05 were considered statistically significant. Non-parametric analyses were also performed and yielded similar results. Results Subjects Of the 40 subjects (20 creatine, 20 placebo) who underwent baseline testing and received at least one dose of study medication, 25% were African-American, 15% Hispanic, and 60% Caucasian. There were no differences between groups in age, racial distribution, BMI, CD4 count, years of known HIV infection, or in the classes of ART used (Table 1). Follow-up and Adherence to Study Treatments Thirty-three subjects (83%) completed the study. Seven subjects (3 creatine, 4 placebo) withdrew for the following reasons: hypersensitivity reaction (1 creatine), schedule conflicts (2 creatine), family emergency (1 placebo), and non-adherence (missing three consecutive PRT sessions [3 placebo]). Subjects who completed the study attended 95% of their training sessions. Adherence to the treatment regimen was evidenced by the fact that plasma creatine levels increased substantially in all subjects who were receiving creatine at week 14 (see below). Table 1. Baseline Characteristics of the Study Population. N Age (yrs) BMI (kg/m2) Total body fat (%) Testosterone (ng/dl) Yrs since HIV diagnosis CD4 (cells/ml) PI (%) NRTI (%) NNRTI (%) No Antiretroviral (%) Current antiretroviral therapy: Creatine 20 44 (9) 23.7 (2.6) 18.4 (6.7) 725 (295) 10 (7) 448 (310) 40 80 30 20 Placebo 20 44 (8) 23.7 (2.5) 16.0 (5.3) 597 (217) 10 (5) 460 (278) 35 75 30 35 Subject characteristics at baseline according to the assigned study medication. Data are mean (SD). Abbreviations: PI, protease inhibitor; NRTI, nucleoside analogue reverse transcriptase inhibitors; NNRTI, non-nucleoside analogue reverse transcriptase inhibitors. doi:10.1371/journal.pone.0004605.t001 Creatine and HIV+ Patients Effects on muscle strength At baseline, all measures of strength were similar in the two study groups (Table 2). At week 14, average 1RM strength increased in all muscle groups (Table 2, Fig. 2). Contrary to our hypothesis, the magnitude of the increase in strength was not greater with creatine (average increase 44% for creatine and 42% for placebo, difference 2%, 95% CI 29.5% to 13.9%; P = 0.58). In addition, the rate of strength gain did not differ between groups. Dorsiflexor muscle isometric strength (MVC) did not change significantly in either group (Table 2). Effects on muscle energetics and fatigue All measures of muscle energetics, including muscle oxidative capacity, were similar across groups at all time points, and were not significantly affected by creatine supplementation (Table 2). Likewise, the fatigue profile (the rate of force decline during the 6- minute exercise protocol) did not differ between or within the two groups at any time point (data not shown). Among subjects randomized to creatine, there was a weak association between changes in plasma creatine levels and changes in resting PCr (r = 0.53, P = 0.09) and no relationship with post-exercise PCr. In the two treatment groups combined, PCr recovery following 15- sec MVC improved significantly after PRT (T1/2 = 23.89 [20.04 to 27.74] seconds, P = 0.047). Effects on body composition Body weight and composition were similar at baseline (Table 3). By week 14, LBM had increased in both groups, with a greater increase in the creatine group (P = 0.01). Body weight increased only in the creatine group. No differences between groups were noted in total, trunk or limb fat content at any time point. Thigh muscle CSA increased in both groups at week 14, but the magnitude of the increase did not differ significantly between groups. There were no changes in calf CSA in either group. Likewise, no changes in muscle or subcutaneous fat were noted at any time point in either treatment group. Biochemical and safety measures There were no significant differences between groups in biochemical parameters at baseline (Table 4). Average plasma creatine levels increased significantly in the creatine group, with no change in those on placebo (P#0.001 vs. placebo). Serum creatinine concentrations increased more with creatine than placebo (P = 0.001 and 0.002 at weeks 2 and 14, respectively). Triglycerides increased with creatine at week 14 (P = 0.04 vs. placebo). Total cholesterol decreased significantly in the placebo group at week 14, but the difference between groups was not statistically significant. At week 2, both insulin and HOMA-IR decreased transiently in the creatine group (P = 0.04 and 0.05 vs. placebo, respectively). There were no differences in lactate, glucose or CK levels between or within groups at any time point. With regard to the pre-defined toxicity management guidelines, 4 subjects, all in the creatine group, experienced increases in serum creatinine levels to .1.8 mg/dL. In all four cases, creatinine levels had returned to ,1.8 mg/dL at week 14. CK levels increased to .450 U/liter 18 times in 14 subjects (10 on placebo and 4 on creatine). The increases were transient and likely related to exercise, and all had resolved by week 14. Discussion In the present study, we found that PRT consistently increased muscle strength in HIV-infected men (Fig. 2). Although subjects receiving creatine supplementation had a greater increase in LBM PLoS ONE | www.plosone.org 4 February 2009 | Volume 4 | Issue 2 | e4605