In the present study, we found that PRT consistently increased muscle strength in HIV-infected men (). Although subjects receiving creatine supplementation had a greater increase in LBM 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 
and indices of short-term high intensity exercise performance, including muscle strength and power output 
as well as intramuscular PCr levels assessed by both 31
and biopsy 
. Chronic use of creatine (up to 12 months) has been associated with increases in total body weight 
. In contrast, other studies have failed to demonstrate a positive effect of creatine supplementation on strength, body composition or muscle energy metabolism 
. The responses to creatine supplementation in patients with chronic diseases have been similarly mixed, with some studies showing positive effects 
and others showing no benefit 
The pre-treatment PCr concentrations observed in the current study are consistent with those in the same muscle in healthy young and older adults 
, 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 
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 
. In view of the potential role of carbohydrate availability and insulin in stimulating the transport of creatine into muscle cells 
, 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 
. Nonetheless, we saw no change in intramuscular PCr concentration 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 
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 
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 
. 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 individuals with HIV infection, as has been reported previously in smaller studies 
. In addition, the rate of PCr recovery following a 15-second MVC improved in the group as a whole. At baseline, average PCr recovery rate (T1/2
) was 29 seconds, which is approximately 24% slower than those of healthy young and old adults studied with the same apparatus and using comparable methodology 
. Following training, PCr recovery rates approached those in healthy untrained adults (T½
). Because PCr recovery under the conditions applied in the present study reflects the capacity for oxidative phosphorylation, these data suggest that PRT improved mitochondrial energy metabolism in patients with HIV infection. Overall, these benefits provide further evidence that persons with HIV infection can adapt to a demanding exercise-training program.
Because HIV-infected persons on ART are at risk of developing metabolic and morphologic abnormalities, including peripheral lipoatrophy 
, we examined the effects of creatine supplementation and PRT on fat distribution and fasting lipids and glucose homeostasis. The observed preservation of subcutaneous fat during PRT suggests that this type of exercise did not promote or exacerbate lipoatrophy. Overall, we saw no evidence of improvement in metabolic and morphologic outcomes with either creatine supplementation or exercise. Because renal function is impaired in some patients with HIV infection 
, clinicians should be aware of the possibility that elevations in serum creatinine may occur in patients using creatine supplementation.
In summary, in this randomized, placebo-controlled trial of the effects of progressive resistance training with and without creatine supplementation in HIV-positive subjects, significant gains in strength were achieved with 12 weeks of PRT with no further benefit from creatine. The medical use of creatine supplementation in this population may be limited to aesthetic purposes, rather than to improve functional capacity. However, the efficacy and safety of PRT demonstrates its potential therapeutic benefit in preventing or reversing muscle weakness.