Metabolic abnormalities are common in patients with human immunodeficiency virus (HIV) infection and range from protein catabolism to lipodystrophy and dyslipidemia associated with the use of highly active antiretroviral therapy. One abnormality is increased resting energy expenditure, which even occurs in clinically stable HIV-infected patients. Increased resting energy expenditure may aggravate the tendency towards weight loss and wasting, which are independent predictors of mortality. Despite much investigation, the factors associated with altered resting energy expenditure remain unclear; viral load, CD4 cell count, use of antiretroviral drugs, body composition, hormones, and proinflammatory cytokines have been imputed. Mechanisms that could explain increased resting energy expenditure include the HIV accessory protein viral protein R, antiretroviral drugs that affect mitochondrial function, and futile cycling within adipocytes. Other components of energy expenditure are also important to overall energy balance and may also be affected. Identifying unifying mechanisms will be an important step to finding effective treatments for HIV-related alterations in energy expenditure and to reversing metabolic risks in patients with HIV infection.

Introduction Plasma triglycerides (TG) and HDL-C are inversely related in Metabolic Syndrome (MetS), due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein (CETP). We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug (HAART)-treated HIV patients. Methods Fasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV/HAART patients and 71 HIV-negative persons (31 normotriglyceridemic (NL) and 40 hypertriglyceridemic due to type IV hyperlipidemia (HTG)). CETP mass and activity were compared in 19 NL and 87 HIV/HAART subjects. Results Among the three groups, a plot of HDL-C vs. TG gave similar slopes but significantly different y-intercepts (9.24 ± 0.45, 8.16 ± 0.54, 6.70 ± 0.65, sqrt(HDL-C) for NL, HIV and HTG respectively; P<0.001); this difference persisted after adjusting HDL-C for TG, age, BMI, gender, glucose, CD4 count, viral load and HAART strata (7.18 ± 0.20, 6.20 ± 0.05 and 4.55 ± 0.15 sqrt(HDL-C) for NL, HIV and HTG, respectively, P <0.001). CETP activity was not different between NL and HIV, but CETP mass was significantly higher in HIV (1.47 ± 0.53 compared to 0.93 ± 0.27 μg/mL, P<0.0001), hence CETP specific activity was lower in HIV (22.67 ± 13.46 compared to 28.46 ± 8.24 nmol/μg/h, P=0.001). Conclusions Dyslipidemic HIV/HAART patients have a distinctive HDL-C plasma concentration adjusted for TG. The weak inverse relationship between HDL-C and TG is not explained by altered total CETP activity; it could result from a non-CETP-dependent mechanism or a decrease in CETP function due to inhibitors of CETP activity in HIV patients’ plasma.

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