ritonavir and Lipodystrophy

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Topics: Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Lipodystrophy; Nelfinavir; Ritonavir; Saquinavir

To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy.. Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status.. 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (-5.4% [-0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference -0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment.. In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks.. This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463 http://clinicaltrials.gov/ ct2/show/NCT00931463?term = NCT00931463&rank = 1.

Topics: Adult; Anti-HIV Agents; Body Fat Distribution; Body Mass Index; Cardiovascular Diseases; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipodystrophy; Logistic Models; Lopinavir; Male; Metabolic Syndrome; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; RNA, Viral; Viral Load; Virus Replication

Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery.. This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007).. Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)].. In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.

Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Atrophy; Body Composition; Chemistry, Pharmaceutical; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; Humans; Intention to Treat Analysis; Lamivudine; Lipids; Lipodystrophy; Lopinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure

To compare information on body fat changes from questionnaire and clinical examination and to study lipoatrophy in HIV-1 patients on highly active antiretroviral therapy (HAART).. The study was cross-sectional within a randomized trial. One hundred and sixty-eight male HIV-1 patients were examined by questionnaire and clinical examination. Clinical lipoatrophy was studied and defined as fat wasting in the face, legs and/or arms. Fasting blood samples reflecting lipid and glucose metabolism were taken and the role of indinavir, ritonavir (RTV) and RTV/saquinavir (SQV) on lipoatrophy was investigated.. After a median of 17 months on HAART, concordance rates between information on changes in body fat from questionnaire and clinical examination were significant and varied from 70 to 96%. With a positive criteria of lipoatrophy in both assessments, 14% of patients had lipoatrophy. These patients had lower weight (P = 0.0007), weight loss from baseline (P = 0.003), lower circumferences at all measurements (P < 0.01), lower plasma triglycerides and low-density lipoprotein (LDL) (P < 0.05) and longer treatment with stavudine (P = 0.0009). Homeostasis model assessment (HOMA) estimates for insulin resistance and beta-cell function were comparable. Plasma cholesterol, triglycerides and very low-density lipoprotein (VLDL) were higher in patients receiving RTV or RTV/SQV (P < 0.03).. Questionnaire and clinical assessment provide concordant information on changes in body fat. Lipoatrophic patients on HAART with neither increase in abdominal circumference, nor hyperlipidaemia nor glucose intolerance may have side-effects to protease inhibitor treatment, to nucleoside reverse transcriptase inhibitor treatment (stavudine) or suffer from a drug-independent condition.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Cross-Sectional Studies; Drug Therapy, Combination; Glucose Intolerance; HIV Infections; HIV Protease Inhibitors; HIV Wasting Syndrome; Humans; Hyperlipidemias; Indinavir; Lipodystrophy; Male; Middle Aged; Ritonavir; Saquinavir; Stavudine; Surveys and Questionnaires

The molecular basis of lipodystrophy, a syndrome associated with HIV antiretroviral (ARV) therapy, remains unknown.. To examine whether ARV therapy might inhibit the expression of CD36, which is known to play an important role in fatty acid and glucose metabolism, and if this might contribute to the metabolic alterations associated with lipodystrophy.. The effects of ARV therapy on CD36 levels was examined in vivo in a prospective cohort of individuals treated with ARV therapy and in vitro in assays of human cell lines exposed to ARV drugs.. Monocyte CD36 levels were assessed by flow cytometry at baseline and after 7 days of therapy in five healthy volunteers and 10 treatment-naive HIV-1-infected individuals. ARV therapy included protease inhibitors (ritonavir, nelfinavir or lopinavir/ritonavir). In addition, human cell lines (THP-1 and C32) were assessed for CD36 levels pre and post-ritonavir treatment.. Three of four healthy controls (one withdrew because of adverse effects) and 6 of 10 HIV-1-infected individuals had a 50 to > 90% decrease in monocyte CD36 levels after 7 days of therapy. One of ten HIV-infected subjects had a 30% decrease, and the remaining individuals had no change or an increase in CD36 levels. CD36 levels decreased significantly in human cell lines treated with ritonavir but not in those treated with zidovudine.. ARV therapy resulted in a marked decrease in CD36 in approximately 70% of our participants. Sustained ARV therapy-induced CD36 deficiency may contribute to insulin resistance and other metabolic complications of lipodystrophy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD36 Antigens; Cell Line; Cohort Studies; HIV Infections; HIV-1; Humans; In Vitro Techniques; Insulin Resistance; Lipodystrophy; Monocytes; Prospective Studies; Ritonavir; Zidovudine

Changes in body fat distribution are an adverse effect of therapy with HIV protease inhibitors (PI). It has been suggested that nucleoside analogue reverse transcriptase inhibitors (NRTI) may also contribute to this so-called lipodystrophy syndrome, but the relative contribution of the two drug classes is unclear as they are usually administered concomitantly.. The occurrence of lipodystrophy, as reported by physicians using no standardized criteria, was followed in patients randomly assigned to treatment with either a PI alone or a PI combined with an NRTI. The patients were part of a multicenter, open-label, randomized comparison of ritonavir (RTV)/saquinavir (SQV) with or without the addition of stavudine (d4T) in HIV-1-infected patients without prior PI and d4T experience (the Prometheus study).. Lipodystrophy was reported in 29 of 175 (17%) patients during 96 weeks of follow up. Overall, it was reported significantly more frequently in patients who were randomized to RTV/SQV/d4T (22/88; 25%), than in patients randomized to RTV/SQV alone (7/87; 8%) (P = 0.003). When the analysis was limited to patients without any prior antiretroviral experience, lipodystrophy likewise was significantly more frequent in patients randomized to RTV/SQV/d4T (12/50; 24%) than in those randomized to RTV/SQV (2/44; 5%) (P = 0.008).. This randomized clinical trial, in spite of not having been blinded, supports a contributory role of NRTI in the development of antiretroviral therapy-associated lipodystrophy. The low incidence of lipodystrophy in patients with no or limited NRTI exposure supports further evaluation of NRTI-sparing regimens as alternatives to current antiretroviral regimens.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lipodystrophy; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Time Factors

HIV patients on antiretroviral therapy have shown elevated incidence of dyslipidemia, lipodystrophy, and cardiovascular disease (CVD). Most studies, however, focus on cohorts from developed countries, with less data available for these co-morbidities in Ethiopia and sub-Saharan Africa.. Adult HIV-negative (n = 36), treatment naïve (n = 51), efavirenz (EFV)-treated (n = 91), nevirapine (NVP)-treated (n = 95), or ritonavir-boosted lopinavir (LPV/r)-treated (n=44) subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Aortic pressure, augmentation pressure, and pulse wave velocity (PWV) were measured via applanation tonometry and carotid intima-media thickness (cIMT) and carotid arterial stiffness, and brachial artery flow-mediated dilation (FMD) were measured via non-invasive ultrasound. Body mass index, waist-to-hip circumference ratio (WHR), skinfold thickness, and self-reported fat redistribution were used to quantify lipodystrophy. CD4+ cell count, plasma HIV RNA levels, fasting glucose, total-, HDL-, and LDL-cholesterol, triglycerides, hsCRP, sVCAM-1, sICAM-1, leptin and complete blood count were measured.. PWV and normalized cIMT were elevate and FMD impaired in EFV- and LPV/r-treated subjects compared to NVP-treated subjects; normalized cIMT was also elevated and FMD impaired in the EFV- and LPV/r-treated subjects compared to treatment-naïve subjects. cIMT was not statistically different across groups. Treated subjects exhibited elevated markers of dyslipidemia, inflammation, and lipodystrophy. PWV was associated with age, current EFV and LPV/r used, heart rate, blood pressure, triglycerides, LDL, and hsCRP, FMD with age, HIV duration, WHR, and glucose, and cIMT with age, current EFV use, skinfold thickness, and blood pressure.. Current EFV- or LPV/r-treatment, but not NVP-treatment, correlated with elevated markers of atherosclerosis, which may involve mechanisms distinct from traditional risk factors.

Topics: Adult; Alkynes; Anti-HIV Agents; Atherosclerosis; Benzoxazines; Biomarkers; Blood Pressure; C-Reactive Protein; Carotid Intima-Media Thickness; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Cyclopropanes; Ethiopia; Female; Heart Rate; HIV Infections; HIV-1; Humans; Lipodystrophy; Lopinavir; Male; Middle Aged; Nevirapine; Pulse Wave Analysis; Ritonavir; Triglycerides

Lipodystrophy is a common complication in HIV-infected patients taking highly active antiretroviral therapy. Its early diagnosis is crucial for timely modification of antiretroviral therapy. We hypothesize that mitochondrial DNA in plasma may be a potential marker of LD in HIV-infected individuals. In this study, we compared plasma mitochondrial DNA levels in HIV-infected individuals and non-HIV-infected individuals to investigate its potential diagnostic value. Total plasma DNA was extracted from 67 HIV-infected patients at baseline and 12, 24 and 30 months after initiating antiretroviral therapy. Real-time quantitative PCR was used to determine the mitochondrial DNA levels in plasma. Lipodystrophy was defined by the physician-assessed presence of lipoatrophy or lipohypertrophy in one or more body regions. The mitochondrial DNA levels in plasma were significantly higher at baseline in HIV-infected individuals than in non-HIV-infected individuals (p<0.05). At month 30, 33 out of 67 patients (49.2%) showed at least one sign of lipodystrophy. The mean plasma mitochondrial DNA levels in lipodystrophy patients were significantly higher compared to those without lipodystrophy at month 24 (p<0.001). The receiver operating curve analysis demonstrated that using plasma mitochondrial DNA level (with cut-off value <5.09 log10 copies/ml) as a molecular marker allowed identification of patients with lipodystrophy with a sensitivity of 64.2% and a specificity of 73.0%. Our data suggest that mitochondrial DNA levels may help to guide therapy selection with regards to HIV lipodystrophy risk.

Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Biomarkers; Case-Control Studies; Cyclopropanes; DNA, Mitochondrial; Drug Combinations; Female; HIV; HIV Infections; Humans; Lamivudine; Lipodystrophy; Lopinavir; Male; Middle Aged; Mitochondria; Nelfinavir; Predictive Value of Tests; Ritonavir; ROC Curve; Stavudine; Zidovudine

The complex interplay between viral infection and virus-activated inflammatory pathways with protease inhibitors (PIs) contributes to the increased risk of developing atherosclerosis and coronary artery disease in HIV-infected patients. Leflunomide is an antirheumatic drug whose administration to HIV-1-infected persons effectively decreases T-cell turnover and activation. In this study we have investigated the effects of leflunomide on dyslipidaemia and lipodistrophy induced by ritonavir in rodents.. Mice were administered ritonavir (5 mg/kg/day) alone or in combination with leflunomide (40 mg/kg/day) for 12 days. Expression of nuclear receptor and lipidogenetic genes was measured in liver and adipose tissues.. Administration of the HIV PI ritonavir to mice increased plasma triacylglycerols, free fatty acids and cholesterol levels, and this effect was reverted by cotreatment with leflunomide. Ritonavir administration was associated with reduced epididymal fat/body weight ratio and increased liver content of triacylglycerols content. These effects were reverted by leuflunomide. Histopathology analysis shows that exposure to ritonavir causes inflammation of epididymal fat as demonstrated by dense leukocytes infiltration as well as by increased levels of proinflammatory mediators and reduced expression and activity of peroxisome proliferator-activated receptor-γ (PPAR-γ). Leflunomide reduced epididymal fat inflammatory-metabolic alteration induced by ritonavir and restored PPAR-γ expression in the epididymal fat.. We have shown that the anti-inflammatory drug leflunomide protects against ritonavir-induced inflammation and dysmetabolism in adipose tissue and might be a promising strategy in the setting of HIV-infected patients at risk for HIV-induced dyslipidaemia.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dyslipidemias; Epididymis; Fatty Liver; HIV Protease Inhibitors; Isoxazoles; Leflunomide; Lipodystrophy; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Ritonavir

HIV-associated neurocognitive disorders (HAND) remain prevalent even with widespread use of combination antiretroviral therapy (ART), suggesting a potential role for co-morbidities in neurologic decline. Indeed, it is well established that ART drugs, particularly HIV protease inhibitors, can induce hyperlipidemia, lipodystrophy, and insulin resistance; all of which are associated with neurologic impairment. This study was designed to determine how metabolic dysfunction might contribute to cognitive impairment and to reveal specific metabolic co-morbidities that could be targeted to preserve brain function. Adult male C57BL/6 mice were thus treated with clinically relevant doses of lopinavir/ritonavir for 4 weeks, and subjected to thorough metabolic, neurobehavioral, and biochemical analyses. Data show that lopinavir/ritonavir resulted in manifestations of lipodystrophy, insulin resistance, and hyperlipidemia. Evaluation of neurologic function revealed cognitive impairment and increased learned helplessness, but not motor impairment following treatment with lopinavir/ritonavir. Further analyses revealed a significant linear relationship between cognitive performance and specific markers of lipodystrophy and insulin resistance. Finally, analysis of brain injury indicated that lopinavir/ritonavir treatment resulted in cerebrovascular injury associated with decreased synaptic markers and increased inflammation, and that the cerebral cortex was more vulnerable than the cerebellum or hippocampus. Collectively, these data reveal an intimate link between metabolic co-morbidities and cognitive impairment, and suggest that remediation of selective aspects of metabolic syndrome could potentially reduce the prevalence or severity HIV-associated neurocognitive disorders.

Topics: Animals; Brain Injuries; Cerebral Cortex; Hippocampus; HIV Protease Inhibitors; Hyperlipidemias; Insulin Resistance; Lipodystrophy; Lopinavir; Male; Mice; Mice, Inbred C57BL; Ritonavir

Lipodystrophy with high nonesterified fatty acid (FA) efflux is reported in humans receiving highly active antiretroviral therapy (HAART) to treat HIV infection. Ritonavir, a common component of HAART, alters adipocyte FA efflux, but the mechanism for this effect is not established. To investigate ritonavir-induced changes in FA flux and recycling through acylglycerols, we exposed differentiated murine 3T3-L1 adipocytes to ritonavir for 14 d. FA efflux, uptake, and incorporation into acylglycerols were measured. To identify a mediator of FA efflux, we measured adipocyte triacylglycerol lipase (ATGL) transcript and protein. To determine whether ritonavir-treated adipocytes increased glycerol backbone synthesis for FA reesterification, we measured labeled glycerol and pyruvate incorporation into triacylglycerol (TAG). Ritonavir-treated cells had increased FA efflux, uptake, and incorporation into TAG (all P < 0.01). Ritonavir increased FA efflux without consistently increasing glycerol release or changing TAG mass, suggesting increased partial TAG hydrolysis. Ritonavir-treated adipocytes expressed significantly more ATGL mRNA (P < 0.05) and protein (P < 0.05). Ritonavir increased glycerol (P < 0.01) but not pyruvate (P = 0.41), utilization for TAG backbone synthesis. Consistent with this substrate utilization, glycerol kinase transcript (required for glycerol incorporation into TAG backbone) was up-regulated (P < 0.01), whereas phosphoenolpyruvate carboxykinase transcript (required for pyruvate utilization) was down-regulated (P < 0.001). In 3T3-L1 adipocytes, long-term ritonavir exposure perturbs FA metabolism by increasing ATGL-mediated partial TAG hydrolysis, thus increasing FA efflux, and leads to compensatory increases in FA reesterification with glycerol and acylglycerols. These changes in FA metabolism may, in part, explain the increased FA efflux observed in ritonavir-associated lipodystrophy.

Topics: 3T3-L1 Cells; Adipocytes; Adrenergic beta-Agonists; Animals; Enzyme Inhibitors; Fatty Acids; Gene Expression; Glycerol; HIV Protease Inhibitors; Humans; Hydrolysis; Immunoblotting; Isoproterenol; Lipase; Lipodystrophy; Mice; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Time Factors; Triazenes; Triglycerides

HIV protease inhibitors (HIV-PIs) are key components of highly active antiretroviral therapy, but they have been associated with adverse side effects, including partial lipodystrophy and metabolic syndrome. We recently demonstrated that a commonly used HIV-PI, lopinavir, inhibits ZMPSTE24, thereby blocking lamin A biogenesis and leading to an accumulation of prelamin A. ZMPSTE24 deficiency in humans causes an accumulation of prelamin A and leads to lipodystrophy and other disease phenotypes. Thus, an accumulation of prelamin A in the setting of HIV-PIs represents a plausible mechanism for some drug side effects. Here we show, with metabolic labeling studies, that lopinavir leads to the accumulation of the farnesylated form of prelamin A. We also tested whether a new and chemically distinct HIV-PI, darunavir, inhibits ZMPSTE24. We found that darunavir does not inhibit the biochemical activity of ZMPSTE24, nor does it lead to an accumulation of farnesyl-prelamin A in cells. This property of darunavir is potentially attractive. However, all HIV-PIs, including darunavir, are generally administered with ritonavir, an HIV-PI that is used to block the metabolism of other HIV-PIs. Ritonavir, like lopinavir, inhibits ZMPSTE24 and leads to an accumulation of prelamin A.

Topics: Animals; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Lamin Type A; Lipodystrophy; Lopinavir; Membrane Proteins; Metabolic Syndrome; Metalloendopeptidases; Mice; Mice, Knockout; Nuclear Proteins; Protein Precursors; Protein Processing, Post-Translational; Pyrimidinones; Ritonavir; Sulfonamides

A major complication associated with the use of protease inhibitors (PIs) in treatment of HIV-infected patients is lipid abnormalities including dyslipidemia, lipodystrophy, and liver steatosis. Previous studies revealed that these abnormalities are associated with PI-induced accumulation of activated sterol regulatory element binding proteins (SREBPs) in the nucleus of liver and adipose tissues, resulting in constitutive activation of lipid metabolism genes. This study used the mouse model to determine the potential of polyunsaturated fatty acid (PUFA) diet or leptin replacement therapy to alleviate these PI-induced metabolic abnormalities. Results showed that feeding C57BL/6 mice with a PUFA-rich diet failed to normalize plasma cholesterol and triglyceride levels in ritonavir-treated mice. The PUFA-rich diet also had no effect on ritonavir-induced interscapular fat accumulation and liver steatosis. In contrast, daily administration of leptin significantly reversed the elevated plasma cholesterol level induced by ritonavir. Leptin replacement therapy also significantly reduced the ritonavir-induced interscapular fat mass and improved liver steatosis. Taken together, these data suggest that PI-induced lipid abnormalities, especially dyslipidemia, lipodystrophy, and liver steatosis, may be reduced with leptin replacement therapy.

Topics: Adipose Tissue; Animals; Azo Compounds; CCAAT-Enhancer-Binding Proteins; Cholesterol; Coloring Agents; Disease Models, Animal; DNA-Binding Proteins; Fat Necrosis; Fatty Acids, Unsaturated; HIV Protease Inhibitors; Hyperlipidemias; Leptin; Lipid Metabolism; Lipids; Lipodystrophy; Liver; Male; Mice; Mice, Inbred C57BL; Organ Size; Ritonavir; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Triglycerides

We investigated the effects of the HIV protease inhibitor ritonavir on body composition, serum lipids, and gene expression in C57BL/6 mice. Dual-energy X-ray absorptiometry measurements in ritonavir-treated male mice revealed whole-body lipoatrophy. In female mice fat reduction was restricted to the gonadal depot. A histopathological analysis showed no visible abnormalities in liver or adipose tissue from ritonavir-treated mice, although adipocytes were significantly smaller in diameter. Serum triglyceride levels were increased in ritonavir-treated male mice. Ritonavir was coadministered with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist gemfibrozil and the PPARgamma agonist rosiglitazone for 8 weeks. Neither drug alleviated the hypertriglyceridemia or lipoatrophy in ritonavir-treated male mice. Rather, gemfibrozil exacerbated the lipoatrophy. Ritonavir reduced basal expression of two PPARalpha target genes in liver, as well as the PPARgamma target gene phosphoenolpyruvate carboxykinase (PEPCK) in adipose tissues. Ritonavir partially inhibited induction of PPAR target genes by gemfibrozil and rosiglitazone. Gemfibrozil induced expression of fatty acid oxidation genes in liver, and this induction was less substantial when ritonavir was coadministered. Similarly, rosiglitazone induced expression of uncoupling protein-1, uncoupling protein-2, and PEPCK in adipose tissues, and this effect was partially inhibited by ritonavir. Thus, the effects of ritonavir on serum triglycerides and body composition may be due, at least in part, to an inhibition of PPAR function.

Topics: Animals; Fatty Acids; HIV Protease Inhibitors; Lipodystrophy; Liver; Male; Mice; Mice, Inbred C57BL; Ritonavir; Sterols

A 45-year-old man infected with human immunodeficiency virus (HIV) developed abnormal fat accumulations that initially were believed to be caused by HIV lipodystrophy. Further clinical evaluation revealed, however, that the patient had developed exogenous Cushing syndrome, which presumably was caused by the inhibition of CYP3A4's metabolism of inhaled fluticasone by the protease inhibitor ritonavir. Clinicians should be aware that clinical clues may indicate conditions other than lipodystrophy that may cause abnormal fat accumulation and that fluticasone should be cautiously administered to patients who are receiving ritonavir.

Topics: Androstadienes; Cushing Syndrome; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Fluticasone; HIV; HIV Protease Inhibitors; Humans; Lipodystrophy; Male; Middle Aged; Mixed Function Oxygenases; Ritonavir

HIV protease inhibitor-related lipodystrophy is characterized by peripheral fat loss, hyperlipidemia, and insulin resistance. Increased availability of lipid to muscle may be one of the mechanisms that induce insulin resistance. Regional fat, intramyocellular lipid (by (1)H-magnetic resonance spectroscopy), serum lipids, and insulin-stimulated glucose disposal (by hyperinsulinemic-euglycemic clamp) were quantified in 10 men who had HIV-1 infection with moderate to severe lipodystrophy and a control group of 10 nonlipodystrophic men who had HIV-1 infection and were naïve to protease inhibitors to examine the effects of lipodystrophy on glucose and lipid metabolism. Lipodystrophic subjects showed lower insulin-stimulated glucose disposal than control subjects (P = 0.001) and had increased serum triglycerides (P = 0.03), less limb fat (P = 0.02), increased visceral fat as a proportion of total abdominal fat (P = 0.003), and increased intramyocellular lipid (1.90 +/- 0.15 vs. 1.23 +/- 0.16% of water resonance peak area; P = 0.007). In both groups combined, visceral fat related strongly to intramyocellular lipid (r = 0.83, P < 0.0001) and intramyocellular lipid related negatively to insulin-stimulated glucose disposal (r = -0.71, P = 0.0005). Fasting serum cholesterol and triglycerides related positively to intramyocellular lipid and visceral fat in lipodystrophic subjects only. The data indicate that lipodystrophy is associated with increased lipid content in muscle accompanying impaired insulin action. The results do not establish causation but emphasize the interrelationships among visceral fat, myocyte lipid, and insulin action.

Topics: Absorptiometry, Photon; Acquired Immunodeficiency Syndrome; Adipose Tissue; Adult; Anti-HIV Agents; Blood Glucose; Body Composition; HIV Protease Inhibitors; Homeostasis; Humans; Indinavir; Insulin; Leptin; Lipids; Lipodystrophy; Magnetic Resonance Imaging; Male; Middle Aged; Nelfinavir; Ritonavir; Saquinavir

Morphologic and metabolic changes associated with protease inhibitor (PI) therapy have been reported since the introduction of PIs for treatment of human immunodeficiency virus infection. These changes were measured 12-20 months after initiation of PI therapy in a cross-sectional study involving 614 patients from the Antiprotéases Cohorte (APROCO) Study (Agence Nationale de Recherches sur le Sida-EP11). The prevalence was 21% for isolated peripheral atrophy, 17% for isolated fat accumulation, 24% for mixed syndrome, 23% for glucose metabolism alterations, 28% for hypertriglyceridemia (triglyceride level, > or =2.2 mM), and 57% for hypercholesterolemia (cholesterol level, > or =5.5 mM). Age was significantly associated with different phenotypes of lipodystrophy and metabolic alterations, but body-mass index, CD4(+) cell count, and type of nucleoside reverse-transcriptase inhibitor or PI received were not constantly associated with these changes. Furthermore, in all models tested, exposure to stavudine was associated with lipoatrophy and exposure of ritonavir was associated with hypertriglyceridemia. Detection and management of these disorders should be implemented to prevent further complications.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; HIV Infections; Humans; Hypertriglyceridemia; Lipodystrophy; Ritonavir; Stavudine

To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy.. Cross-sectional study.. Outpatient clinic of a university teaching hospital.. HIV-infected patients either receiving at least one protease inhibitor (n=116) or protease inhibitor-naive (n=32), and healthy men (n=47).. Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholesterol, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed.. HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P=0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1(3%) protease inhibitor-naive patient (P=0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus.. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

Topics: Adult; Anti-HIV Agents; Body Composition; Cross-Sectional Studies; Diabetes Mellitus; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Insulin Resistance; Lipodystrophy; Male; Nelfinavir; Risk Factors; Ritonavir; Saquinavir; Syndrome