Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production.

OBJECTIVE: The purpose of this study was to investigate the mechanism by which the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) increases high-density lipoprotein cholesterol (HDLc) in treatment-experienced human immunodeficiency virus-1 (HIV-1)-infected patients. METHODS AND RESULTS: Twelve HIV-1 infected patients, with stably suppressed HIV-1 viral load using AZT/3TC/abacavir for > or =6 months, added NVP to their current antiretroviral regimen. Patients received a primed bolus infusion of the stable isotope L-[1-(13)C]-valine for 12 hours before, as well as 6 and 24 weeks after, the addition of NVP to study apolipoprotein A-I (apoA-I) kinetics. Absolute production rate (APR) and fractional catabolic rate (FCR) of apoA-I were calculated using SAAM-II modeling. Major HDLc-modulating enzymes were assessed. Plasma apoA-I and HDLc levels increased significantly after 24 weeks of treatment by, respectively, 13+/-4% (P=0.01) and 16+/-6% (P=0.015). Concomitantly, apoA-I production rate at 24 weeks increased by 17+/-7% (P=0.04). ApoA-I catabolism did not change. A modest increase of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity was observed. CONCLUSIONS: NVP increases apoA-I production, which contributes to the HDLc increase after introduction of NVP-containing regimens. In view of the potent antiatherogenic effects of apoA-I, the observed increase may contribute to the favorable cardiovascular profile of NVP.

Increased carotid intima-media thickness in HIV patients treated with protease inhibitors as compared to non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Prolonged exposure to protease inhibitor (PI)-, but not non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing combination antiretroviral therapy (CART) has been associated with an increased cardiovascular risk, partly explained by the different effects of these drugs on plasma lipids. Most markedly, NNRTIs have been associated with increases in high density lipoprotein cholesterol (HDL-C), which may be atheroprotective. METHODS: In a cross-sectional study we investigated the impact of PI- vs. NNRTI-based CART in 130 HIV-1-infected patients with plasma virus suppressed to below the limit of detection, whom had been continuously exposed for at least 2 years to either one of such regimens, but not both. Carotid intima-media thickness (C-IMT) and fasting metabolic parameters were measured. RESULTS: Mean (+/-S.D.) C-IMT in patients treated with PI-based CART was 0.81 (+/-0.17) mm as compared to 0.71 (+/-0.14)mm in NNRTI treated patients (p=0.0003). HDL-C and apolipoprotein A-I (apoA-I) levels were higher in the NNRTI than in the PI group (1.39 mmol/L vs. 1.03 mmol/L; p<0.0001, and 1.44 mmol/L vs. 1.33 mmol/L; p=0.0008, respectively). Framingham Risk Score, body mass index, duration of CART, and use of PI-based CART were positively correlated with C-IMT whereas HDL-C and apoA-I were inversely correlated with C-IMT. CONCLUSIONS: Treatment of HIV-1-infected patients for 2 years or more with PI-based compared to NNRTI-based CART is associated with greater C-IMT, consistent with the reported higher risk of CVD in patients using PI. However, this difference seems not fully explained by a more favorable impact of NNRTI-based CART on HDL-C and apoA-I levels.

Effects of nevirapine, compared with lamivudine, on lipids and lipoproteins in HIV-1-uninfected newborns: the stopping infection from mother-to-child via breast-feeding in Africa lipid substudy.

BACKGROUND: The objective of the present study was to assess whether the high-density lipoprotein cholesterol (HDL-c)-increasing effect of nevirapine (NVP), as observed in human immunodeficiency virus type 1 (HIV-1)-infected subjects, at least in part may relate to intrinsic properties of NVP. METHODS: At 2, 6, and 12 weeks after birth, complete lipid profiles as well as plasma apolipoproteins levels were assessed in 80 HIV-uninfected newborns, half of whom received NVP and half lamivudine (3TC), respectively. Newborns were randomly selected from a randomized trial in which NVP or 3TC had been administered to HIV-uninfected infants born to HIV-infected mothers to try and prevent HIV-1 transmission from occurring during breast-feeding. RESULTS: After 6 weeks of therapy, the expected physiological decline in HDL-c levels in the newborns was attenuated in infants treated with NVP, compared with levels in those treated with 3TC. Apolipoprotein A-I (apoA-I) levels were higher at all time points in the NVP arm than they were in the 3TC arm (P=.02), reaching peak levels at 6 weeks. The difference in HDL-c was no longer significant at 12 weeks. CONCLUSIONS: apoA-I levels and HDL-c were elevated in HIV-1-uninfected newborns receiving NVP, compared with those receiving 3TC. These data support that NVP may indeed have intrinsic apoA-I and HDL-c elevating properties in humans.

Atherosclerotic vascular disease in HIV: it is not just antiretroviral therapy that hurts the heart!

PURPOSE OF REVIEW: Although potent combination antiretroviral therapy has heralded an unparalleled improvement in the treatment of HIV-1-infected patients, the now well known metabolic complications of treatment, which include dyslipidemia, insulin resistance and changes in body fat distribution, are thought to contribute to an increased risk of atherosclerotic (cardio)vascular disease. Atherogenic changes in plasma lipids as well as some evidence of increased atherogenesis, however, had already been described in HIV-1-infected patients prior to the availability of combination antiretroviral therapy and even prior to that of suboptimal antiretroviral therapy. In this review, we will summarize the various possible factors and mechanisms involved in atherogenesis in HIV-1-infected individuals, with a focus on those mechanisms related to the infection itself and its immunological consequences. RECENT FINDINGS: Recent data suggest that a treatment strategy involving repeated cycles of CD4-cell-guided combination antiretroviral therapy interruption is associated with a higher risk of (cardio)vascular disease than continuous treatment aimed at optimal viral suppression. SUMMARY: Apart from the effects of combination antiretroviral therapy-associated metabolic derangements, HIV-1 infection, directly or indirectly, for instance by being associated with a state of chronic immune activation, may contribute to atherogenesis.

Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia.

OBJECTIVE: Individuals with familial hypobetalipoproteinemia (FHBL) have been reported to be prone to fatty liver disease (FLD). Conversely, the profound reduction of low-density lipoprotein (LDL) cholesterol in this disorder might decrease cardiovascular risk. In the present study, we assessed hepatic steatosis as well as noninvasive surrogate markers for cardiovascular disease (CVD) in subjects with FHBL and in matched controls. METHODS AND RESULTS: Hepatic steatosis was assessed by abdominal ultrasonography. Carotid intima-media thickness (IMT) and distal common carotid arterial wall stiffness as surrogate markers for CVD risk were measured using high-resolution B-mode ultrasonography. Whereas transaminase levels were only modestly elevated, both prevalence (54% versus 29%; P=0.01) and severity of steatosis were significantly higher in FHBL individuals compared with controls. Despite similar IMT measurements, arterial stiffness was significantly lower in FHBL (P=0.04) compared with controls. Additionally, the increase in arterial stiffness as seen in the presence of traditional risk factors was attenuated, suggesting that very low levels of apoB-containing lipoproteins can negate the adverse effects of other risk factors on the vasculature. CONCLUSIONS: FHBL is characterized by an increased prevalence and severity of fatty liver disease. The observed decreased level of arterial wall stiffness, most pronounced in the presence of nonlipid risk factors, is indicative of cardiovascular protection in these subjects.

Surrogate markers for atherosclerotic disease.

PURPOSE OF REVIEW: Novel treatment modalities for cardiovascular prevention are emerging rapidly. Since it is virtually impossible to evaluate all these new compounds in long-term trials using clinical end points, there is an urgent need for validated surrogate markers of atherosclerosis to save both time and costs. Over the last decade, the use of imaging markers has been widely introduced into drug-development strategies. Here we will discuss the most commonly used techniques. RECENT FINDINGS: Whereas both testing of endothelial function, assessed as flow-mediated dilation, and assessment of carotid intima-media thickness have been shown to predict future cardiovascular events, predominantly intima-media thickness has been used successfully as a surrogate marker in intervention studies. More recently, standardization of intravascular ultrasound has also enabled reproducible assessment of coronary atheroma volume. Multidetector computed tomography and electron-beam computed tomography have proven useful in providing quantitative information on plaque burden and coronary calcium content, respectively. Although cardiovascular magnetic resonance (CMR) is improving continuously, additional technical improvements will be mandatory before this technique can be implemented in multicenter clinical studies. SUMMARY: The imaging modalities reviewed here all provide specific information on either functionality or morphology of the vasculature. The value of carotid intima-media thickness for cardiovascular risk prediction has been studied most extensively. Whereas assessment of plaque burden using intravascular ultrasound appears to be the most direct way to quantify coronary changes, its predictive value for future cardiovascular events remains to be established. Awaiting further technical improvements, CMR is expected to provide the most valuable information for the evaluation of atherosclerosis in the near future.