ritonavir and Hyperlipidemias

People with HIV infection have metabolic abnormalities that resemble metabolic syndrome (hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance), which is known to predict increased risk of cardiovascular disease (CVD). However, there is not one underlying cause for these abnormalities and they are not linked to each other. Rather, individual abnormalities can be affected by the host response to HIV itself, specific HIV drugs, classes of HIV drugs, HIV-associated lipoatrophy, or restoration to health. Furthermore, one component of metabolic syndrome, increased waist circumference, occurs less frequently in HIV infection. Thus, HIV infection supports the concept that metabolic syndrome does not represent a syndrome based on a common underlying pathophysiology. As might be predicted from these findings, the prevalence of CVD is higher in people with HIV infection. It remains to be determined whether CVD rates in HIV infection are higher than might be predicted from traditional risk factors, including smoking.

Topics: Adipose Tissue; Atherosclerosis; Cardiovascular Diseases; Cholesterol, HDL; Comorbidity; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperlipidemias; Hypertriglyceridemia; Indinavir; Metabolic Syndrome; Prevalence; Risk Factors; Ritonavir; Terminology as Topic

Ritonavir-boosted protease inhibitor (PI) regimens have provided substantial benefits in the treatment of HIV/AIDS, resulting in improved clinical outcomes. However, treatment toxicities often affect adherence and may influence outcomes. Dyslipidemia is highly prevalent in many patients who receive a boosted PI regimen. The mechanism underlying dyslipidemia is probably multifactorial and may differ among the individual PIs. The prevalence of cardiovascular disease and events appears to be higher in patients treated with boosted PIs, and as long-term survival increases in HIV-infected persons, the long-term effect of dyslipidemia becomes a growing concern. The practitioner must consider the possibility of these adverse effects when choosing the antiretroviral regimen that best suits each patient. Until future studies define the optimal approach, an evaluation of cardiovascular risk factors and treatment of those risk factors according to evidence-based guidelines are warranted.

Topics: Coronary Disease; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Metabolic Syndrome; Middle Aged; Risk Factors; Ritonavir

To assess the correlation between antiretroviral treatment and dyslipidaemia in HIV-infected patients, and the role of bezafibrate as a lipid-lowering agent.. We retrospectively compared serum lipid levels of five groups of 40 patients, each of them treated with either saquinavir hard gel, indinavir, or ritonavir (associated with two nucleoside analogues), or dual nucleoside reverse transcriptase inhibitors (NRTI) with or without a non-nucleoside reverse transcriptase inhibitor (NNRTI), or not treated with antiretrovirals, randomly selected from nearly 1000 HIV-infected patients followed-up for >or= 12 months, while on the relevant therapy. Hypertriglyceridaemia was defined by triglyceride levels >or= 172 mg/dl, and hypercholesterolaemia by cholesterol levels >or= 200 mg/dl. All patients with triglyceridaemia > 300 mg/dl and cholesterolaemia > 220 mg/dl for at least 6 months, and unresponsive to a >or= 3-month diet, started bezafibrate (400 mg/day), and were prospectively followed-up at a

Topics: Bezafibrate; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Hypolipidemic Agents; Indinavir; Lipids; Retrospective Studies; Ritonavir; Saquinavir

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 assess the 48-week efficacy, safety, pharmacokinetics, and resistance of double boosted protease inhibitors (PI), saquinavir (SQV), and lopinavir/ritonavir (LPV/r), in children who have failed nucleoside reverse transcription inhibitors /non-nucleoside reverse transcription inhibitors-based regimens.. Fifty children at 2 sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4, HIV-RNA viral load (VL), plasma drug concentrations and safety laboratory evaluations were monitored. Virologic failure was defined as having 2 consecutive VL >400 copies/mL after week 12 of therapy. Intention to treat analysis was performed.. Baseline data were a median age of 9.3 years (interquartile range [IQR]: 7.1-11.2), Center for Disease Control and Prevention (CDC) classification N:A:B:C 4%:14%:68%:14%, VL 4.8 log10 (IQR: 4.5-5.1), CD4 7% (IQR: 3-9.5). At 48 weeks, 3 had died of bacterial infection but no cases had progressed CDC classification. Median CD4% rise was 9 (IQR: 5-16) and median HIV RNA reduction was -2.8 log10 (IQR: -3.2 to -1.4), both P < 0.001. Thirty-nine (78%) and 32 (64%) children had VL <400 and <50 with significant differences between the 2 sites. Five children (10%) had VL failure as a result of poor adherence to the drug regimen but no one had major PI mutations. Median serum cholesterol and triglyceride increased significantly (+35 mg/dL, +37 mg/dL, respectively, both P < 0.001). Mean minimum plasma concentrations (Cmin) of LPV and SQV were 4.6 and 1.24 mg/L, respectively.. Double boosted SQV/LPV/r resulted in significant CD4 rise and VL decline at 48 weeks. Hyperlipidemia was common. Cmin of both PIs exceeded therapeutic concentrations. Poor adherence caused failure in 10%. No major PI mutations were found.

Topics: Anti-HIV Agents; Blood Chemical Analysis; CD4 Lymphocyte Count; Child; Cholesterol; Drug Resistance, Viral; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Saquinavir; Thailand; Treatment Refusal; Triglycerides; Viral Load

The aim of this study was to assess the long-term efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs).. A total of 272 antiretroviral-naive patients with a CD4+ T-cell count of 200-350 cells/mm3 were treated with two NRTIs and saquinavir/ritonavir 1,600/100 mg per day for > 24 weeks. Patients were followed up every 12 weeks for CD4+ T-cell counts, HIV RNA levels, clinical and laboratory toxicities. Intention-to-treat analyses were used for the first 24 weeks of treatment and as-treated analysis after week 24.. The median baseline CD4+ T-cell count was 269 cells/mm3 and HIV RNA was 4.7 log10 copies/ml. At a median follow-up time of 56 (interquartile range [IQR] 25-113) weeks, 262/272 (96.3%) had HIV RNA < 400 copies/ml, with a median HIV RNA decline of -2.89 (IQR 3.31--2.37) log10 copies/ml (P < 0.001) and a median rise in CD4+ T-cell count of 192 (IQR 117-317) cells (P < 0.001). At weeks 24, 48, 72 and 96, 249/272 (91.5%), 157/164 (95.7%), 113/126 (89.7%) and 84/90 (93.3%) had HIV RNA < 400 copies/ml, respectively; at the same time points, 83.8%, 92.7%, 85.7% and 85.6% had HIV RNA < 50 copies/ml. Drug-related adverse events were reported in 6.30%. Significant rises in total cholesterol, triglyceride, low-density lipoprotein and high-density lipoprotein were seen.. First-line highly active antiretroviral therapy with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Combinations; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Thailand; Time Factors; Treatment Outcome; Viral Load

Lopinavir/ritonavir (LPV/r) has been the gold standard in first line rescue treatment for many years. No other boosted protease inhibitor (PI/r) has managed to demonstrate that it is superior to LPV/r. In this regard, the TITAN study compared the efficacy and safety of darunavir (DRV/r) in 595 patients, at a dose of 600/100 mg two times a day against the normal LPV/r dose, combined with at least 2 other optimised antiretroviral drugs. The efficacy of the treatment at 48 weeks (VL<400 copies/mL) was significantly higher in the DRV/r goup compared to the LPV/r group, both in the analysis by protocol (77% vs. 68%), the non-inferiority of DRV/r being demonstrated (estimated difference +9%, 95% CI 2-16), and by intention to treat (77% vs. 67%), the superiority of DRV/r being demonstrated (estimated difference 10%, 95% CI 2-17%). The incidence of diarrhoea and increase in triglycerides was higher in the LPV/r group. The differences in efficacy of both treatments in favour of DRV/r started to be seen from a basal primary mutation in the protease, with these differences increasing as the number of these mutations increased. In patients with virological failure, DRV/r protected the protease and reverse transcriptase against mutations, thus preserving future therapeutic options. We have some theoretical and clinical data available that enables us to consider the possibility of administering DRV/r once a day in some patients with a few mutations in the protease and in those where this dosing regime is considered important. With the results of the TITAN study, DRV/r must be considered the new gold standard in first line rescue, at least in those patients with a primary mutation in the protease.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Darunavir; Diarrhea; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prognosis; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy; Sulfonamides

The aim of this study was to evaluate the frequency, characteristics and risk factors of lipid changes associated with lopinavir/ritonavir treatment in antiretroviral-naive patients.. A prospective cohort of 107 antiretroviral-naive HIV-infected patients was followed for 12 months after starting lopinavir/ritonavir-based highly active antiretroviral therapy.. At 12 months, percentages of patients with hypercholesterolaemia and hypertriglyceridaemia were 17.4% and 40%, respectively. Mean increases in total cholesterol and triglycerides were 40.7 and 73.3 mg/dL. There was a significant increase in both low-density and high-density (HDL) cholesterol, and no increase in the total cholesterol/HDL ratio (from 4.16 at baseline to 4.49 after 12 months). Baseline cholesterol > 200 mg/dL and triglycerides > 150 mg/dL were independent risk factors for dyslipidaemia, while hepatitis C coinfection appeared to be protective.. Patients with elevated lipid values at baseline have the greatest risk of developing hypercholesterolaemia and hypertriglyceridaemia after starting lopinavir/ritonavir. Antiretroviral-naive patients coinfected with hepatitis C have a low risk of developing hyperlipidaemia after starting lopinavir/ritonavir.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Cholesterol, HDL; Cholesterol, LDL; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Risk Factors; Ritonavir; Triglycerides

Blood lipid abnormalities in patients on highly active antiretroviral therapy (HAART) have been associated with exposure to protease inhibitors (PIs), particularly ritonavir. First therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) leads to relatively favourable lipid profiles. We report on medium-term lipid profiles (up to 5 years) for antiretroviral-naive patients starting NNRTI- and PI-based HAART in the Swiss HIV Cohort Study.. Since April 2000, blood samples taken at visits scheduled every 6 months have been analysed for cholesterol and triglyceride concentrations. For 1065 antiretroviral-naive patients starting HAART after April 2000, we estimated changes in concentration over time using multivariate linear regression with adjustment for baseline covariates, use of lipid-lowering drugs and whether the sample was taken in a fasting state.. Non-high density lipoprotein (HDL) cholesterol levels increase with increasing exposure to either PI- or NNRTI-based therapy, HDL cholesterol levels increase and triglyceride levels decrease with increasing exposure to NNRTI-based therapy, whereas triglyceride levels increase with increasing exposure to PI-based therapy. Between NNRTI-based therapies, there is a slight difference in triglyceride levels, which tend to increase with increasing exposure to efavirenz and to decrease with increasing exposure to nevirapine. Of the three common PI-based therapies, nelfinavir appears to have a relatively favourable lipid profile, with little change with increasing exposure. Of the other two PI therapies, lopinavir with ritonavir has a more favourable profile than indinavir with ritonavir, with smaller increases in both non-HDL cholesterol and triglycerides and an increase in HDL cholesterol. Increasing exposure to abacavir is associated with a decrease in the level of triglycerides.. In general, NNRTI-based therapy is associated with a more favourable lipid profile than PI-based therapy, but different PI-based therapies are associated with very different lipid profiles. Nelfinavir appears to have a relatively favourable lipid profile. Of the two boosted PI therapies, lopinavir appears to have a more favourable lipid profile than indinavir.

Topics: Antiretroviral Therapy, Highly Active; Cohort Studies; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Male; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Switzerland; Triglycerides

Ritonavir (RTV) at doses of 400 mg twice a day (bid) or higher adversely affects serum lipids. However, the effect of RTV 100 mg bid on serum lipids is unknown. We conducted a study to evaluate the effect of RTV 100 mg bid on fasting serum lipid profiles in HIV-negative healthy volunteers.. Ritonavir 100 mg bid was administered for 14 days to 20 healthy HIV-seronegative adults with normal serum lipids. After a 7-day washout, lopinavir/ritonavir (LPV/RTV) 400/100 mg bid was administered for 14 days. Fasting serum lipid parameters were measured twice at baseline, after 14 days of RTV, and after 14 days of LPV/RTV, and comparisons were made at each time-point for levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, the total/HDL cholesterol ratio and triglycerides.. After 14 days of RTV 100 mg bid, total cholesterol level increased by 10.2% (P<0.001), LDL cholesterol level increased by 16.2% (P<0.001), triglyceride levels increased by 26.5% (P<0.001), HDL cholesterol level decreased by 5.4% (P<0.01) and the total/HDL cholesterol ratio increased by 17.3% (P<0.001). The addition of LPV 400 mg bid to RTV 100 mg bid resulted in no significant further changes in LDL cholesterol or triglyceride level or total/HDL cholesterol ratio, but there were significant increases in both total cholesterol (8.0% increase; P=0.007) and HDL cholesterol levels (6.7% increase; P=0.008).. Ritonavir dosed at 100 mg bid significantly increased the concentration of total cholesterol, LDL cholesterol, total/HDL cholesterol ratio and triglycerides and reduced HDL cholesterol concentration. The addition of LPV 400 mg bid to RTV 100 mg bid further increased both total and HDL cholesterol levels without affecting the total/HDL ratio.

Topics: Adolescent; Adult; Cholesterol, HDL; Cholesterol, LDL; Drug Combinations; Fasting; Female; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Triglycerides

Two hundred and twelve HIV-positive patients who started a new protease inhibitor (PI)-based antiretroviral regimen between January 1998 and December 2000 in our tertiary care centre were prospectively followed-up during a 12-month study period, in order to assess the incidence of hyperlipidaemia and related clinical adverse events. At the end of 1-year follow-up, PI-containing antiretroviral treatment led to a statistically significant increase in serum triglyceride levels (P<0.005) and total and LDL-cholesterol levels (P<0.05). The overall incidence of hypertriglyceridaemia and hypercholesterolaemia was 38.2 and 25%, respectively. The incidence of increased serum triglyceride levels was significantly higher in patients treated with ritonavir (66.6%) or lopinavir/ritonavir (60.7%), compared with other PIs (P<0.04). Clinical adverse events possibly related to the hyperlipidaemia (such as cardiovascular diseases or acute pancreatitis) were not observed during the entire 12 months study period. In conformity with other previously published studies, the very high incidence of hyperlipidaemia during a PI-based therapy recognised in our work raises a big concern about its potential clinico-pathological consequences and the most convenient pharmacological management of these metabolic imbalances.

Topics: Adult; Antiretroviral Therapy, Highly Active; Cholesterol; Cholesterol, LDL; Cohort Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Triglycerides

To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in lipid levels.. A prospective, nonrandomized study.. HIV-infected subjects with virologic failure on protease inhibitor-containing regimens. Twenty-two consecutive patients were enrolled, 19 completed 24 weeks of treatment, and 16 completed the full 48-week study period. INTERVENTION Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. Subjects were evaluated at baseline and weeks 4, 8, 12, 24, 36, and 48. LPV trough plasma concentrations and lipid levels were measured.. LPV trough concentrations were higher in patients experiencing grade 3 or higher lipid elevations (mean [SD]: 9.71 microg/mL (5.62) vs. 6.09 microg/mL (3.83); P = 0.002) and in those developing grade 2 or higher hypercholesterolemia (mean [SD]: 8.48 microg/mL [4.64] vs. 5.71 microg/mL [3.94]; P = 0.003). All patients developing grade 2 or higher cholesterol elevation had an LPV trough concentration at week 4 greater than 8 microg/mL. Significant positive correlations were found between LPV trough concentrations and changes in triglyceride and cholesterol levels.. In patients receiving salvage therapy with LPV/r, there is an association between LPV plasma concentrations and lipid changes. Patients achieving higher LPV trough concentrations may be at greater risk of experiencing dyslipidemia. Further investigations are warranted to support a direct cause and effect relationship.

Topics: Adult; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipid Metabolism; Lipids; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Time Factors; Triglycerides

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

Topics: Adult; Anticholesteremic Agents; Drug Tolerance; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Hyperlipidemias; Indinavir; Male; Nelfinavir; Pilot Projects; Pravastatin; Ritonavir; Saquinavir; Treatment Outcome

This research work was planned to determine whether Naringin (NG) had any protective effects against lopinavir/ritonavir (LR)-induced alterations in blood lipid levels, hepatotoxicity, and testicular toxicity.. Four groups of six rats each were used for the study: Control (1% ethanol), naringin (80 mg/kg), lopinavir (80 mg/kg)/ritonavir (20 mg/kg), and lopinavir (80 mg/kg)/ritonavir (20 mg/kg) + naringin (80 mg/kg). The drug treatment was continued for 30 days. On the last day, the serum lipid fractions, liver biochemical parameters, testicular antioxidants (enzymatic and non-enzymatic), and the histopathology of the liver and testis tissue were assessed for all rats.. Treatment with NG decreased significantly (p<0.05), the baseline serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C). But these parameters were significantly (p<0.05) increased in LR-treated animals. Naringin, co-administered with LR, restored the liver and testicular biochemical, morphological, and histological balance.. This study shows that NG can be used as a treatment for LR-induced biochemical and histological changes in the liver and testes and changes in serum lipid levels.

Topics: Animals; Cholesterol, LDL; Hyperlipidemias; Lipids; Lopinavir; Male; Rats; Ritonavir; Triglycerides

An observational, prospective, cohort study was performed to compare efficacy and safety of a switch from ritonavir-boosted protease inhibitor (PI/r) to nevirapine or raltegravir with that of rosuvastatin addition to current antiretroviral therapy in HIV-infected patients with hyperlipidaemia.. All HIV-infected patients receiving a stable PI/r-based antiretroviral regimen, with persistently suppressed viremia, naïve to non-nucleoside analogues and to integrase strand transfer inhibitors, with mixed hyperlipidaemia, and who underwent a switch from PI/r to nevirapine (Group A) or raltegravir (Group B) or who started rosuvastatin at 10 mg daily (group C) with unchanged antiretroviral regimen were enrolled into the study.. Overall, 136 patients were enrolled: 43 patients were included in the group A, 46 in the group B, and 47 in the group C. The mean age was 46.6 years, and 108 (79.4%) were males. After 48 weeks of follow-up, a significantly greater reduction in the mean low-density lipoprotein (LDL) cholesterol level was reported in group C (-28.2%) than in group A (-10.2%; p < .001) and B (-12.4%; p = .021), while a significantly greater reduction in the mean concentration of triglycerides was observed in group A (-31.2%) and B (-35.5%) than in group C (-11.9%; p = .034 and p = .004, respectively). The incidence of adverse events was <10% and comparable across the three groups.. In HIV-positive subjects receiving a PI/r, the initiation of rosuvastatin treatment after 48 weeks yielded a greater decline in LDL cholesterol, while the switch from PI/r to nevirapine or raltegravir led to a greater decline in triglycerides.

Topics: Adult; Anti-HIV Agents; Anticholesteremic Agents; Antiretroviral Therapy, Highly Active; Cholesterol, LDL; Cohort Studies; Drug Substitution; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Hyperlipidemias; Male; Middle Aged; Nevirapine; Prospective Studies; Raltegravir Potassium; Ritonavir; Rosuvastatin Calcium; Viral Load; Viremia

Cardiovascular disease (CVD) is an emerging concern for HIV-infected patients. Hyperlipidaemia is a risk factor for CVD and a complication of protease-inhibitor-based antiretroviral therapy, but little is known about its incidence and risk factors in treated patients in resource-limited settings (RLS).. We conducted a secondary analysis of ACTG A5230 trial in which HIV-infected adults from India, Malawi, Tanzania, Thailand and South Africa, with virological relapse on first-line therapy were initiated on lopinavir/ritonavir (LPV/r) monotherapy. Hyperlipidaemia was a grade 2+ elevated fasting total cholesterol (FTC≥240 mg/dl) or fasting triglycerides (FTG≥500 mg/dl) or calculated low-density lipoprotein cholesterol (LDL≥160 mg/dl) based on measurements at weeks 12, 24, 48, 68 and 104. We evaluated factors potentially associated with quantitative lipid changes from baseline to week 12. These were age, sex, race, site and baseline body mass index, CD4. 106 participants without hyperlipidaemia at baseline started LPV/r; median age 39 years, 68% Black African, 55% female. The cumulative incidence of hyperlipidaemia at week 104 was 48% (95% CI 36, 58%). At week 12, there were significant mean increases from baseline in FTC (17 mg/dl, P<0.001) and FTG (104 mg/dl, P<0.001). In multivariable analysis, higher baseline FTC (P=0.044), FTG (P=0.025), Thai (P<0.001) or Indian sites (P=0.020) versus African sites were associated with increased risk of hyperlipidaemia.. In HIV-infected adults in RLS initiating LPV/r, hyperlipidaemia was common. Baseline lipid measurements and routine monitoring should be recommended in individuals starting LPV/r-based treatments with borderline high lipids.

Topics: Adolescent; Adult; Aged; Biomarkers; CD4 Lymphocyte Count; Clinical Trials as Topic; Developing Countries; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Incidence; Lipids; Lopinavir; Male; Middle Aged; Multicenter Studies as Topic; Risk Factors; Ritonavir; Viral Load; Young Adult

Use of protease inhibitors (PI) in HIV patients is associated with hyperlipidemia and increased risk of coronary heart disease. Chronic systemic and cardiac effects of ritonavir (RTV), a universal PI booster, and Mg supplementation were examined. RTV was administered (75 mg·kg(-1)·day(-1) po) to Lewis × Brown-Norway hybrid (LBNF1) rats for up to 8 wk; significant increases in plasma triglyceride and cholesterol occurred from 8 days to 8 wk. At 5 wk, the expression of selected hepatic genes (CYP7A1, CITED2, G6PC, and ME-1), which are key to lipid catabolism/synthesis, were altered toward lipogenesis. Dietary Mg supplementation (six-fold higher) completely reversed the altered expression of these genes and attenuated both hypertriglyceridemia and hypercholesterolemia. Neutrophils isolated from the RTV-treated rats displayed a three-fold higher basal and a twofold higher stimulated superoxide production; plasma isoprostane and red blood cell (RBC) GSSG levels were elevated two- to three-fold. All oxidative indices were normalized by Mg supplementation. After 5 wk, RTV caused significant decreases in cardiac left ventricular (LV) shortening fraction and LV ejection fraction; mitral valve early/late atrial ventricular filling (E/A) ratio was reduced accompanied by LV posterior wall thinning. Immunohistochemical staining revealed significant white blood cell (WBC) infiltration (5 wk) and prominent fibrosis (8 wk) in the RTV hearts. Mg supplementation attenuated RTV-induced declines in systolic and diastolic (improved mitral valve E/A ratio) function (>70%), lessened LV posterior wall thinning (by 75%), and substantially decreased the pathological markers. The known clinical hyperlipidemia effects of RTV can be mimicked in the LBNF1 rats; in association, systemic oxidative stress and progressive cardiac dysfunction occurred. Remarkably, Mg supplementation alone suppressed RTV-mediated hyperlipidemia, oxidative stress, and cardiac dysfunction.

Topics: Animal Feed; Animals; Diet; Dietary Supplements; Gene Expression Regulation; Heart Diseases; HIV Protease Inhibitors; Hyperlipidemias; Magnesium; Male; Oxidative Stress; Rats; Ritonavir; Weight Gain

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

The relationship between plasma protease inhibitor (PI) trough concentrations and hyperlipidemic effects were evaluated retrospectively using data from 2 pilot clinical trials of a double-boosted PI regimen (saquinavir/lopinavir/ritonavir) in 25 HIV patients. The patients' median age was 39 years (range, 25-60). At baseline, PI-naive patients had a median viral load of 53 500 copies/mL and median CD4 of 296 cells/mm(3), while PI-experienced patients had 37 750 copies/mL and 214 cells/mm(3). Plasma PI trough concentrations of saquinavir, lopinavir, and ritonavir at week 12 were 520, 4482, and 153 ng/mL, respectively. At week 12, median fasting lipids increased significantly from baseline: total cholesterol increased from 165 to 189 mg/dL (P = .0005) and the triglyceride increased from 113 to 159 mg/dL (P = .001). There were no associations between PI trough concentrations at week 12 and the percent total cholesterol change at week 12. No associations were found between PI trough concentrations and lipid changes in HIV patients on a double-boosted PI regimen (saquinavir/lopinavir/ritonavir). Factors other than systemic exposure to PIs (such as host or genetic factors) may modulate the hyperlipidemic effect of PIs.

Topics: Adult; Clinical Trials as Topic; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Lopinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrimidinones; Retrospective Studies; Ritonavir; Saquinavir

Patients treated with highly active antiretroviral therapy may develop metabolic side effects such as hyperlipidemia, insulin resistance, lipoatrophy and lactic acidosis. The pathophysiology of these metabolic abnormalities is unknown, although some, e.g., lactic acidosis and lipoatrophy, are more associated with nucleoside use while protease inhibitors (PIs) have been shown to contribute to hyperlipidemia and insulin resistance. Identifying new PIs that are not associated with dyslipidemia has been hindered by the lack of mechanistic information and the unavailability of relevant animal models. In order to understand the molecular mechanism behind the hyperlipidemia associated with other protease inhibitors, and to develop a more effective, faster screen for compounds with this liability, we have analyzed expression profiles from PI-treated animals. Previously, we have shown that treatment of rats with ritonavir results in increases in the expression of proteasomal subunit genes in the liver. We show this increase is similar in rats treated with bortezomib, a proteasome inhibitor. In addition, we have treated rats with additional protease inhibitors, including atazanavir, which is associated with lower rates of lipid elevations in the clinic when administered in the absence of ritonavir. Our results indicate a strong correlation between proteasomal induction and lipid elevations, and have allowed us to develop a rapid screen for identifying novel PIs that do not induce the proteasome.

Topics: Animals; Atazanavir Sulfate; Carbamates; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Furans; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; HIV Protease Inhibitors; Hyperlipidemias; Male; Oligonucleotide Array Sequence Analysis; Oligopeptides; Proteasome Endopeptidase Complex; Pyridines; Rats; Rats, Sprague-Dawley; Ritonavir; Sulfonamides

Hyperlipidemia associated with the HIV protease inhibitor (PI), the major component of highly active antiretroviral treatment (HAART) for HIV infection, has stimulated interest in developing new agents that minimize these side effects in the clinic. HIV integrase inhibitor is a new class of anti-HIV agents. Raltegravir is a first-in-its-class oral integrase inhibitor and has potent inhibitory activity against HIV-1 strains that are resistant to other antiretroviral regimens. Our previous studies have demonstrated that HIV PI-induced endoplasmic reticulum (ER) stress links to dysregulation of lipid metabolism. However, little information is available as to whether raltegravir would have similar effects as the HIV PIs. In this study, we examined the effect of raltegravir on lipid metabolism both in primary rat hepatocytes and in in vivo mouse models, and we further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed development of dyslipidemia. The results indicated that raltegravir did not induce ER stress or disrupt lipid metabolism either in vitro or in vivo. However, HIV PI-induced ER stress and lipid accumulation were significantly inhibited by raltegravir both in in vitro primary rat hepatocytes and in in vivo mouse liver. High-performance liquid chromatography analysis further demonstrated that raltegravir did not affect the uptake and metabolism of HIV PIs in hepatocytes. Thus, raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of lipid metabolism by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the side effects associated with current HAART.

Topics: Animals; Apoptosis; Cells, Cultured; Drug Antagonism; Endoplasmic Reticulum; Hepatocytes; HIV Integrase Inhibitors; HIV Protease Inhibitors; Hyperlipidemias; Lipid Metabolism; Liver; Lopinavir; Male; Mice; Mice, Inbred C57BL; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Rats; Ritonavir; Signal Transduction

Ritonavir (RTV) and other protease inhibitors (PIs) used for the treatment of human immunodeficiency virus (HIV) infection are associated with elevated serum triglycerides (TG) and cholesterol in some patients. A rat strain (Sprague-Dawley or SD) commonly used in toxicology studies is not sensitive to RTV-induced hyperlipidemia, making mechanistic studies and the identification of novel, lipid-neutral PIs challenging. The objective of this study was to identify a rat strain that mirrors human PI-associated hyperlipidemia. RTV was administered at 100 mg/kg/day for 5 days to a panel of 14 rat strains estimated to cover approximately 86% of the known genetic variance in rats. Increased serum TG and cholesterol levels occurred only in two rat strains, including LEW x BN rats. Livers from LEW x BN (sensitive) and SD (resistant) rats were then evaluated using microarrays to investigate differences in the transcriptomic response to RTV. Several genes, including some involved in bile acid biosynthesis, gluconeogenesis, and carbohydrate metabolism, were differentially regulated between the two strains. In particular, cytochrome P450 7A1 (CYP7A1), a key enzyme for cholesterol metabolism, was down-regulated in the sensitive and up-regulated in resistant rats. Collectively, these results demonstrate the utility of a genetically diverse rat panel to identify strains with clinical relevance for a particular adverse effect. Furthermore, the genome-wide transcriptomic analysis suggests that RTV-induced hyperlipidemia is at least in part due to changes in hepatic lipid biosynthesis and metabolism. These findings will facilitate the discovery of novel, lipid-neutral HIV PIs and the identification of relevant biomarkers for this adverse event.

Topics: Animals; Gene Expression Profiling; Gene Expression Regulation; HIV Protease Inhibitors; Hyperlipidemias; Lipid Metabolism; Liver; Male; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Ritonavir

A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.

Topics: Animals; Binding Sites; Biological Availability; Caco-2 Cells; Carbamates; Cell Membrane Permeability; Crystallography, X-Ray; Dipeptides; Dogs; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Hyperbilirubinemia; Hyperlipidemias; In Vitro Techniques; Microsomes, Liver; Models, Molecular; Mutation; Putrescine; Pyridines; Rats; Rats, Gunn; Stereoisomerism; Structure-Activity Relationship

We report our experience on the impact of different fosamprenavir boosted regimens on plasma lipid levels in 48 naive monoinfectd- HIV-seropositive patients. Eighteen months after starting antiretroviral therapy (ART), all patients showed a good immuno-virological response, with no statistically significant differences among the three groups; no changes in ART regimens were necessary and no adverse events were reported. On the contrary, a statistically significant difference among the three groups of patients was observed in cholesterol and triglyceride levels, since higher levels of cholesterol (including LDLs) and triglycerides were observed in patients taking the higher dose of ritonavir. (www.actabiomedica.it)

Topics: Adult; Anti-HIV Agents; Carbamates; Drug Therapy, Combination; Female; Furans; HIV Protease Inhibitors; HIV Seropositivity; Humans; Hyperlipidemias; Male; Middle Aged; Organophosphates; Ritonavir; Sulfonamides; Triglycerides

The molecular mechanisms of action of a HIV protease inhibitor, ritonavir, on hepatic function were explored on a genomic scale using microarrays comprising genes expressed in the liver of Sprague-Dawley rats (Rattus norvegicus). Analyses of hepatic transcriptional fingerprints led to the identification of several key cellular pathways affected by ritonavir treatment. These effects were compared to a compendium of gene expression responses for 52 unrelated compounds and to other protease inhibitors, including atazanavir and two experimental compounds. We identified genes involved in cholesterol and fatty acid biosynthesis, as well as genes involved in fatty acid and cholesterol breakdown, whose expressions were regulated in opposite manners by ritonavir and bezafibrate, a hypolipidemic agonist of the peroxisome proliferator-activated receptor alpha. Ritonavir also upregulated multiple proteasomal subunit transcripts as well as genes involved in ubiquitination, consistent with its known inhibitory effect on proteasomal activity. We also tested three other protease inhibitors in addition to ritonavir. Atazanavir did not impact ubiquitin or proteasomal gene expression, although the two other experimental protease inhibitors impacted both proteasomal gene expression and sterol regulatory element-binding protein-activated genes, similar to ritonavir. Identification of key metabolic pathways that are affected by ritonavir and other protease inhibitors will enable us to understand better the downstream effects of protease inhibitors, thus leading to better drug design and an effective method to mitigate the side effects of this important class of HIV therapeutics.

Topics: Animals; Cluster Analysis; Female; Gene Expression Profiling; Gene Expression Regulation; HIV Protease Inhibitors; Hyperlipidemias; Lipid Metabolism; Liver; Male; Models, Biological; Oxidation-Reduction; Pregnane X Receptor; Proteasome Endopeptidase Complex; Rats; Rats, Sprague-Dawley; Receptors, Steroid; Ritonavir; Signal Transduction; Ubiquitination

We studied 382 multiexperienced HIV-infected patients followed up for > or =3 months after starting lopinavir/ritonavir (LPV/r) to identify the factors predicting hypertriglyceridemia and high non-HDL cholesterol levels (triglycerides > or =200 mg/dl and/or non-HDL cholesterol > or =190 mg/dl) after 6 and 12 months of LPV/r exposure. The predictors of hypertriglyceridemia were higher baseline triglyceride levels [OR: 2.28 (95% CI: 1.67-3.12) for each additional 100 mg/dl; p = 0.001], the total duration of antiretroviral treatment [OR: 1.26 (95% CI: 1.12-1.41) for each additional year; p = 0.01], CDC stage C (OR: 2.06; 95% CI: 1.24-3.88; p = 0.02), and male gender (OR: 2.52; 95% CI: 1.42-4.74; p = 0.02); intravenous drug abusers seem less likely to develop the event (OR: 0.52; 95% CI: 0.37-0.92; p = 0.03). The predictors of high non-HDL cholesterol levels were higher baseline levels [OR: 3.92 (95% CI: 1.92-6.24) for each additional 100 mg/dl; p = 0.001) and the combination of NRTIs and NNRTIs with LPV/r (OR: 1.83; 95% CI: 1.10-3.69; p = 0.03). The 75 patients stopping LPV/r showed a significant reduction in median triglyceride and non-HDL cholesterol levels after 3 months of 39 mg/dl and 20 mg/dl (p = 0.01 for both), respectively. Patients with high triglyceride and non- HDL cholesterol levels at the start of LPV/r treatment are at higher risk of developing hyperlipidemia.

Topics: Adult; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

To describe the evolution of the lipidic profile among LPV/r treated patients in a 'real life' situation.. Lipids measurements at LPV/r initiation time and every 3 months, and pharmacological measurements at M3 and M6 were collected retrospectively in 142 patients attending our clinic. Dyslipidaemia was defined as total cholesterol > or =6.2 mmol/l, HDL-cholesterol > or =1 mmol/l, total/HDL-cholesterol ratio > or =6.5 and triglycerides > or =2.3 mmol/l.. Eighty-nine percent of patients had previously received a regimen with protease inhibitors, 4% were treatment naive. At baseline, 17% of patients had high total cholesterol, 49% high triglycerides, 63% low HDL-cholesterol, 25% a high total/HDL-cholesterol ratio. At M12, the mean HDL-cholesterol increase per patient was 21%. Lipids levels significantly increased over the study period, as early as the 3rd month (6th month for ratio) and continuously until the 12th month. Among the patients with available LPV/r plasma determinations at M3, a higher lopinavir residual concentration was observed in those with high triglycerides (6.78 vs 3.02 mg/l, p = 0.05) as, at M6, in those with an elevated ratio (9.19 vs 0.96 mg/l, p = 0.02).. Those results suggest that LPV/r may induce a significant rise in the total/HDL-cholesterol ratio, despite an increase in HDL-cholesterol levels. The association between triglycerides and total/HDL-cholesterol ratio elevated levels and high residual concentrations of lopinavir may also argue for systematic drug monitoring.

Topics: Adult; Cholesterol; Cholesterol, HDL; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Ritonavir; Time Factors

Xanthomas most often occur in conjunction with a primary or secondary disorder of lipid metabolism. A range of metabolic disturbances has been described in association with protease inhibitors, including lipodystrophy, hyperglycemia, and hyperlipidemia. Ritonavir has been repeatedly shown to be the most common protease inhibitor to induce these metabolic abnormalities. This report highlights a case of both tuberous and tendinous xanthomata secondary to ritonavir-associated hyperlipidemia.

Topics: Histiocytes; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Middle Aged; Ritonavir; Skin; Tendons; Xanthomatosis

Topics: Anti-HIV Agents; Cardiovascular Diseases; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Insulin Resistance; Ritonavir

Although the clinical application of HIV protease inhibitors (PIs) has markedly reduced HIV-related morbidity and mortality, it is now recognized that PI-based therapy often causes serious metabolic disorders, including hyperlipidemia and premature atherosclerosis. The etiology of these adverse effects remains obscure. Here, we demonstrate that deficiency of the fat-derived hormone adiponectin might play a role. The steady-state mRNA levels of the adiponectin gene and secretion of this protein from 3T3-L1 adipocytes are significantly decreased after treatment with several PIs (indinavir, nelfinavir, and ritonavir), with ritonavir having the greatest effect. Intragastric administration of ritonavir into mice decreases plasma concentrations of adiponectin and concurrently increases the plasma levels of triglyceride, free fatty acids, and cholesterol. Adiponectin replacement therapy markedly ameliorates ritonavir-induced elevations of triglyceride and free fatty acids. These beneficial effects of adiponectin are partly due to its ability to decrease ritonavir-induced synthesis of fatty acids and triglyceride, and to increase fatty acid combustion in the liver tissue. In contrast, adiponectin has little effect on ritonavir-induced hypercholesterolemia and hepatic cholesterol synthesis. These results suggest that hypoadiponectinemia is partly responsible for the metabolic disorders induced by HIV PIs, and adiponectin or its agonists might be useful for the treatment of these disorders.

Topics: 3T3 Cells; Adipocytes; Adiponectin; Animals; Blotting, Northern; Blotting, Western; Cholesterol; Dose-Response Relationship, Drug; Fatty Acids; Fatty Acids, Nonesterified; Gene Expression; HIV Protease Inhibitors; Hormone Replacement Therapy; Hyperlipidemias; Intercellular Signaling Peptides and Proteins; Liver; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Proteins; Recombinant Proteins; Ritonavir; Triglycerides

Topics: Anti-HIV Agents; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperlipidemias; Lipids; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir

Topics: Adult; Antiretroviral Therapy, Highly Active; Arteriosclerosis; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Lipoproteins, LDL; Lopinavir; Pyrimidinones; Ritonavir

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

Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Oxazines; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Triglycerides

Topics: Adipose Tissue; Adult; Aged; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male; Middle Aged; Nelfinavir; Retrospective Studies; Ritonavir; Saquinavir; Triglycerides

Topics: Acquired Immunodeficiency Syndrome; Adult; Cholesterol; Delavirdine; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Retinal Diseases; Retinal Vessels; Ritonavir; Saquinavir; Triglycerides; Viral Load; Zalcitabine

Topics: Adult; Anti-HIV Agents; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male; Nelfinavir; Ritonavir; Saquinavir; Triglycerides

Hyperlipidemia may complicate the use of HIV protease inhibitors (PIs) in AIDS therapy. To determine the cause of hyperlipidemia, the effect of PIs on lipid metabolism was examined with HepG2 liver cells and AKR/J mice. In HepG2 cells, the PIs ABT-378, nelfinavir, ritonavir, and saquinavir stimulated triglyceride synthesis; ritonavir increased cholesterol synthesis; and amprenavir and indinavir had no effect. Moreover, nelfinavir increased mRNA expression of diacylglycerol acyltransferase and fatty acid synthase. The retinoid X receptor agonist LG100268, but not the antagonist LG100754, further increased PI-stimulated triglyceride synthesis and mRNA expression of fatty acid synthase in vitro. In fed mice, nelfinavir or ritonavir did not affect serum glucose and cholesterol, whereas triglyceride and fatty acids increased 57% to 108%. In fasted mice, ritonavir increased serum glucose by 29%, cholesterol by 40%, and triglyceride by 99%, whereas nelfinavir had no effect, suggesting these PIs have different effects on metabolism. Consistent with the in vitro results, nelfinavir and ritonavir increased triglyceride 2- to 3-fold in fasted mice injected with Triton WR-1339, an inhibitor of triglyceride clearance. We propose that PI-associated hyperlipidemia is due to increased hepatic triglyceride synthesis and suggest that retinoids or meal restriction influences the effects of select PIs on lipid metabolism.

Topics: Acyltransferases; Animals; Blood Glucose; Carbon Radioisotopes; Cholesterol; Diacylglycerol O-Acyltransferase; Fasting; Fatty Acid Synthases; Fatty Acids; HIV Protease Inhibitors; Hyperlipidemias; Liver; Male; Mice; Mice, Inbred AKR; Nelfinavir; Nicotinic Acids; Postprandial Period; Receptors, Retinoic Acid; Retinoid X Receptors; Ritonavir; RNA, Messenger; Saquinavir; Tetrahydronaphthalenes; Transcription Factors; Triglycerides; Tumor Cells, Cultured

Topics: Anti-HIV Agents; Humans; Hyperlipidemias; Ritonavir

Topics: Adult; Anticholesteremic Agents; Atorvastatin; Drug Therapy, Combination; Female; Heptanoic Acids; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Pyrroles; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir

Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir.. Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir.. Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established.

Topics: Adult; Anti-HIV Agents; Arteriosclerosis; Child; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Indinavir; Lipids; Lipoprotein(a); Lipoproteins; Logistic Models; Male; Nelfinavir; Risk Factors; Ritonavir; Saquinavir; Thyrotropin

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

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV-1; Humans; Hyperlipidemias; Protease Inhibitors; Ritonavir; Saquinavir; Triglycerides

Topics: Anti-HIV Agents; Coronary Artery Disease; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Pancreatic Pseudocyst; Pancreatitis; Risk Factors; Ritonavir; Saquinavir

Topics: Adult; Cholesterol; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hyperlipidemias; Male; Ritonavir; Triglycerides