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In this prospective cohort study, we determined the relationship between human immunodeficiency virus (HIV) RNA load and body weight in patients with HIV infection.Repeated-measures analysis was restricted to patients with ≥2 study visits, 4-9-month intervals between study visits, and complete data on virus load, resting energy expenditure (REE), and highly active antiretroviral therapy (HAART). The outcome was change in body weight across study intervals. The main predictor was virus load. Separate analyses were performed for weight change in patients receiving and patients not receiving HAART.The eligible sample consisted of 318 participants associated with 1886 study intervals. Sixty-one patients (19%) were women, and 173 (54%) were undergoing HAART at the time of enrollment. There was a significant interaction (P =.01) between virus load and HAART use. In the absence of HAART, each log10 increase in virus load was associated with a 0.92-kg decrease in body weight (P =.003), but during HAART, virus load was not significantly associated with weight change. During HAART, a CD4+ cell count decrease of 100 cells/mm3, rather than a change in the virus load, was associated with a 0.35-kg decrease in body weight (P <.001). REE was independently associated with weight change in both models (P <.001).Patients with HIV infection who are losing weight and are not taking HAART should be considered for HAART. Patients who are already receiving HAART and have unsuppressed virus loads may benefit virologically from an intensified regimen, because such a regimen may lead to complete suppression if there is an accompanying increase in CD4+ cell counts. Further research is needed to understand the strong independent effect of changes in REE among patients receiving and patients not receiving HAART.