Creatine and HIV+ Patients Figure 2. Muscle strength before and after 14 weeks of study. Large rectangles represent the average values, while smaller rectangles individual data before and after creatine supplementation. Similarly, large circles represent the average values, while smaller circles individual data before and after placebo supplementation. Data are the sum of strength (1 RM) in 8 muscle groups in subjects randomized to receive creatine monohydrate or placebo. Strength increased significantly within each treatment group (P,0.01), but there was no significant difference between groups in the magnitude of the increase (average increase 44 and 42% (difference 2%, 95% CI 29.5% to 13.9%) in creatine and placebo, respectively, P = 0.58). doi:10.1371/journal.pone.0004605.g002 than those on placebo, our results provided no evidence that creatine augmented the increase in strength derived from PRT. Thus, the increase in LBM in the creatine group was of no measurable functional benefit. Moreover, using 31P-MRS, we found no difference between groups in skeletal muscle energy metabolism at rest, during or following muscle contractions, or in the fatigue profile. Overall, these data indicate that PRT is a highly effective means of increasing strength in individuals with HIV infection, but supplementation with creatine, though safe, confers no additional increase in strength in this population. Other studies of creatine supplementation have provided mixed results. In studies of healthy volunteers, short-term creatine supplementation (5–30 days) increased muscle size [30] and indices of short-term high intensity exercise performance, including muscle strength and power output [31,32] as well as intramuscular PCr levels assessed by both 31P-MRS [33] and biopsy [34]. Chronic use of creatine (up to 12 months) has been associated with increases in total body weight [35,36]. In contrast, other studies have failed to demonstrate a positive effect of creatine supplementation on strength, body composition or muscle energy metabolism [18–21]. The responses to creatine supplementation in patients with chronic diseases have been similarly mixed, with some studies showing positive effects [37–42] and others showing no benefit [43–46]. The pre-treatment PCr concentrations observed in the current study are consistent with those in the same muscle in healthy young and older adults [24], suggesting that no deficiency of PCr existed in this group of HIV-positive subjects. Although other studies have shown that creatine supplementation increased PCr levels in healthy adults with normal baseline levels [47] we saw no such increase in our subjects with HIV infection. We followed a protocol for creatine loading and maintenance that had been successfully applied in previous studies [13]. In view of the potential role of carbohydrate availability and insulin in stimulating the transport of creatine into muscle cells [22], we provided subjects with beverages containing 20 g of carbohydrate for consumption with each dose of study medication. Importantly, we raised plasma creatine to levels seen in previous studies [48]. Nonetheless, we saw no change in intramuscular PCr concentra- tion at rest or following exercise. It is possible that factors specific to HIV infection or its therapies may account for this failure. For example, some HIV protease inhibitors inhibit glucose uptake by skeletal muscle [49,50] and might have also interfered with creatine uptake into muscle. In addition use of another antiretroviral agent, zidovudine, has been associated with an accelerated rate of depletion of PCr during exercise in HIV- infected subjects [51] and may have had a similar effect in our population. An assessment of the effects of specific antiretroviral medications on outcome measures was not possible in view of the relatively small size of our study. In our study, administration of creatine for two weeks prior to the exercise intervention was associated with a modest increase in thigh CSA that approached a level of statistical significance (p = 0.06 vs. placebo). Likewise, subjects in the creatine group had a significantly greater increase in LBM following exercise training (p = 0.01 vs. placebo). Since these changes were not accompanied by increases in muscle strength or improvement in indices of muscle fatigue or mitochondrial energy metabolism, it is conceivable that the increases in CSA and LBM could be explained by increases in muscle water content, rather than functional muscle mass. Indeed, increases in muscle water content during creatine treatment have been reported in prior studies [52]. An increase in water content in muscle may precede increases in muscle protein synthesis, which may confer functional (fitness) and physiological (e.g. glucose disposal) benefits with a longer period of follow-up. Moreover, increasing muscle size may be considered to be desirable in persons using creatine and exercise for aesthetic purposes. All subjects showed robust increases in strength in eight important muscle groups following 12 weeks of PRT. These results provide further evidence of the beneficial effects of PRT in PLoS ONE | www.plosone.org 6 February 2009 | Volume 4 | Issue 2 | e4605