Nonalcoholic fatty liver disease and HIV infection.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome that includes a range of disorders associated with fatty liver from steatosis to cirrhosis and hepatocellular carcinoma, defined by the presence of liver fat accumulation exceeding 5% of hepatocytes in the absence of other causes of liver disease such as alcohol consumption, viral hepatitis, or any other specific etiology. Half the patients with human immunodeficiency virus (HIV) who undergo additional testing for unexplained liver test abnormalities may suffer from NAFLD, which is the hepatic manifestation of the metabolic syndrome. In HIV-infected patients, NAFLD can result from the HIV itself, highly active antiretroviral therapy (HAART), and/or lipodystrophy. Evaluation of the liver impact of NAFLD remains mainly based on liver biopsy, but numerous noninvasive procedures are under evaluation. In HIV/hepatitis C virus (HCV-) coinfected patients, steatosis seems more frequent and severe by comparison with HCV-monoinfected patients, and is associated with significant liver fibrosis, which may contribute to the more rapid progression of liver disease. First-line treatment of NAFLD is mainly based on the adequate management of the metabolic syndrome, including lifestyle changes. Specific therapeutic approaches are under investigation.

Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin.

BACKGROUND: Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue (VAT) by 15%-20% over 6-12 months in individuals with human immunodeficiency virus (HIV)-associated abdominal adiposity, but it is unknown whether VAT reduction is directly associated with endocrine and metabolic changes. METHODS: In 2 phase III, randomized, double-blind studies, men and women with HIV-associated abdominal fat accumulation were randomly assigned (ratio, 2:1) to receive tesamorelin or placebo for 26 weeks. At week 26, patients initially receiving tesamorelin were randomly assigned to continue receiving tesamorelin or to receive placebo for an additional 26 weeks. In per-protocol analysis of 402 subjects initially randomly assigned to receive tesamorelin, those with ≥8% reduction in VAT were defined a priori as responders per the statistical analysis plan. Post hoc analyses were performed to assess differences between responders and nonresponders. RESULTS: Compared with tesamorelin nonresponders, responders experienced greater mean (±SD) reduction in triglyceride levels (26 weeks: -0.6 ± 1.7 mmol/L vs -0.1 ± 1.2 mmol/L [P = .005]; 52 weeks: -0.8 ± 1.8 mmol/L vs 0.0 ± 1.1 mmol/L [P = .003]) and attenuated changes in fasting glucose levels (26 weeks: 1 ± 16 mg/dL vs 5 ± 14 mg/dL [P = .01]; 52 weeks: -1 ± 14 mg/dL vs 8 ± 17 mg/dL [P < .001]), hemoglobin A1c levels (26 weeks: 0.1 ± 0.3% vs 0.3 ± 0.4% [P < .001]; 52 weeks: 0.0 ± 0.3% vs 0.2 ± 0.5% [P = .003]), and other parameters of glucose homeostasis. Similar patterns were seen for adiponectin levels, with significant improvement in responders vs nonresponders. Changes in lipid levels and glucose homeostasis were significantly associated with percentage change in VAT. CONCLUSIONS: In contrast to nonresponders, HIV-infected patients receiving tesamorelin with ≥8% reduction in VAT have significantly improved triglyceride levels, adiponectin levels, and preservation of glucose homeostasis over 52 weeks of treatment. CLINICALTRIALS.GOV REGISTRATION: NCT00123253, NCT00435136, NCT00608023.

Impact of a nutritional counseling program on prevention of HAART-related metabolic and morphologic abnormalities.

The advent of highly active antiretroviral therapy (HAART) improved HIV infection prognosis. However, adverse metabolic and morphologic effects emerged, highlighting a lack of investigation into the role of nutritional interventions among this population. The present study evaluated the impact of a nutritional counseling program on prevention of morphologic and metabolic changes in patients living with HIV/AIDS receiving HAART. A 12-month randomized clinical trial was conducted with 53 adults of both genders in use of HAART. Subjects were allocated to either an intervention group (IG) or a control group (CG). Nutritional counseling was based on the promotion of a healthy diet pattern. Anthropometrical, biochemical, blood pressure, and food intake variables were assessed on four separate occasions. Sub scapular skin-fold results showed a significant tendency for increase between time 1 (Mean IG = 14.9 mm; CG = 13.6 mm), time 3 (Mean IG = 16.7 mm; CG = 18.2 mm), and time 4 (Mean IG = 16.4 mm; CG = 17.7 mm). Lipid percentage intake presented a greater increase among controls (time 1 mean = 26.3%, time 4 mean = 29.6%) than among IG subjects (time 1 mean = 29.1%, time 4 mean = 28.9%). Moreover, participants allocated to the IG presented an increase in dietetic fiber intake of almost 10 grams. The proposed nutritional counseling program proved to be effective in improving diet by reducing fat consumption and increasing fiber intake.

Current therapy of HIV.

Antiretroviral therapy has improved continuously. Almost every year a new drug has been approved. Nucleoside analogs still build the backbone of antiretroviral therapy. They inhibit reverse transcriptase and thus the transcription of RNA to DNA. They are combined with non-nucleoside reverse transcriptase inhibitors or protease inhibitors. New therapeutic approaches are attachment or entry inhibitors, integrase inhibitors and maturation inhibitors. Multiple prospective multicenter studies have proven the life prolonging effect of antiretroviral therapy. With the optimal therapy life expectancy of HIV patients is only slightly reduced, similar to that of those with chronic diseases such as diabetes mellitus. One result of the higher age of HIV patients is an increase in concomitant diseases and medications. Drug interactions have to be considered and avoided. There has been a long discussion about the best time point to start antiretroviral therapy. In the late 1990s, every infected patient was treated hoping to eliminate the virus, ignoring the CD4+ cell count and viral load. This caused multiple (long-term) side effects and a rising resistance problem. The guidelines now recommend starting therapy at about 350/microl CD4 lymphocytes. Due to its complexity antiretroviral therapy should be initiated and monitored in specialized centers.

Pathogenesis and treatment of lipodystrophy: what clinicians need to know.

The pathogenesis of lipodystrophy in HIV-infected patients is likely multifactorial, involving effects of antiretroviral medications, HIV itself, as well as genetic and other host factors. Protease inhibitors have been associated with fat accumulation, and the nucleoside analogue reverse transcriptase inhibitors (nRTIs) stavudine, didanosine, and zidovudine have been associated with fat loss (lipoatrophy). Strategies that have met with some success in reducing central fat accumulation include treatment with growth hormone or growth hormone-releasing hormone. Strategies that have met with some success for lipoatrophy include switching from nRTIs associated with lipoatrophy or starting treatment with regimens that include drugs associated with lower risk of lipoatrophy (tenofovir, abacavir, lamivudine, emtricitabine). This article summarizes a presentation on lipodystrophy made by Fred R. Sattler, MD, at an International AIDS Society--USA Continuing Medical Education course in Washington, DC, in May 2008. The original presentation is available as a Webcast at www.iasusa.org.

Use of diet, nutritional supplements and exercise in HIV-infected patients receiving combination antiretroviral therapies: a systematic review.

BACKGROUND: The use of combination antiretroviral therapy (cART) has improved the prognosis of HIV infection, but it has also been linked to a spectrum of body composition changes and metabolic alterations known as the lipodystrophy syndrome. Nutritional status could influence body composition changes. METHODS: We performed a systematic search of published peer-reviewed data on the effects of diet, nutrition support and exercise on body composition and metabolic complications in patients receiving cART. RESULTS: Few controlled studies, most of them with small sample size, were found. Oral nutritional support increases protein and energy intake, and results in body weight and fat mass gains. Resistance exercise, with or without an aerobic component, increases lean mass and can improve insulin resistance. Low-fat diets or exercise can result in loss of fat mass, and they should be used with caution in subjects with lipoatrophy. CONCLUSIONS: Nutritional support and exercise result in small but significant body composition changes and can be used as complementary interventions. There is a need for further research on nutritional interventions in HIV-infected patients receiving cART.

Current perspectives on the management and prevention of antiretroviral-associated lipoatrophy.

Lipoatrophy (LA) is a common and now well-recognized complication of highly active antiretroviral therapy (HAART). Over the last decade as knowledge of the mechanisms behind LA has developed, several antiretroviral drugs, in particular, have emerged as the likely agents responsible for this complication. This has been supported by studies comparing alternative HAART regimens and by those in which HAART regimens have been modified with a resulting impact on LA. In this article, we review the evidence underlying the current perspectives on the development of LA and the strategies employed to manage or avoid it.

HIV-associated dyslipidaemia: pathogenesis and treatment.

Dyslipidaemia, consisting of hypertriglyceridaemia together with depressed concentrations of high-density lipoprotein cholesterol and elevated low-density lipoprotein cholesterol, is being observed with increasing frequency among HIV patients. Pathogenic mechanisms include effects of the virus itself, effects of the antiretroviral drugs on key metabolic pathways, and drug-associated adipose repartitioning with subsequent development of insulin resistance and associated metabolic derangements. Diagnostic methods include a fasting lipoprotein profile and assessment of secondary factors. Treatment strategies include non-pharmacological approaches such as changes to diet and lifestyle, as well as switching to a less metabolically active antiretroviral regimen without compromising antiretroviral efficacy. Pharmacological treatment may include statin drugs, fibrates, niacin, or cholesterol absorption inhibitors, in addition to management of comorbidities such as increased global cardiometabolic risk and insulin resistance.

Therapy insight: Body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy.

Increasingly effective therapies for HIV infection are now available. These treatments, referred to collectively as highly active antiretroviral therapy, comprise various combinations of anti-HIV drugs from different drug classes. Recently, a range of metabolic complications have emerged as important toxicities in treated patients. Complications present as abnormalities of body-fat mass distribution in association with an often significant dyslipidemia and glucose homeostasis dysregulation. The body-shape changes, manifesting as peripheral lipoatrophy or central lipohypertrophy, can have a negative impact on quality of life and consequently on adherence to treatment. The combination of central lipohypertrophy, dyslipidemia and insulin resistance is associated with accelerated rates of atherosclerosis and other potentially significant long-term effects. The pathogenesis of these effects is complex and is still being actively investigated. Possible contributing factors relate to host characteristics, HIV viral parameters and specific effects of anti-HIV drugs on adipose-tissue biology and on intermediary metabolism. Management of these complications involves manipulation of the anti-HIV drugs using an understanding of their particular effects on lipid and glucose metabolism, in association with standard therapeutic interventions. Individualized approaches, taking into consideration quality-of-life issues, and assessment of potential cardiovascular risks, are now an important component of effective care of HIV-infected patients.

Leisure time physical activity prevents accumulation of central fat in HIV/AIDS subjects on highly active antiretroviral therapy.

The aim of this study was to verify the relationship between habitual physical activity and body fat in HIV/AIDS subjects on highly active antiretroviral therapy. This was a cross-sectional study covering 169 men and 51 women. It was conducted at the AIDS Clinic of the School of Medicine, University of São Paulo. The dependent variables analysed were central subcutaneous fat (CSF) and waist-to-hip-ratio (WHR). The independent variable was the score for leisure time physical activity (LTPA). The control variables were sex, age, education, energy intake, body mass index, smoking, diagnosis of AIDS, T-CD4+ lymphocyte levels and duration of use of protease inhibitors. Multiple linear regressions were used for statistical analysis. After controls, there was significant negative correlation for LTPA with CSF (beta=-2.849; Pvariable=0.013; r2(adjusted)=0.65; Pmodel<0.001), and LTPA was in the limit of the significance with WHR (beta=-0.005; Pvariable=0.073; r2(adjusted)=0.41; Pmodel<0.001). Physical activity contributed towards preventing fat accumulation in HIV/AIDS subjects.

Complications of HIV disease and antiretroviral therapy.

As antiretroviral treatment regimens become more potent and easier to administer, differences in the rates of adverse events and complications associated with treatment will increasingly drive decisions regarding the selection of therapy. This year's Conference on Retroviruses and Opportunistic Infections featured a wide range of research directed toward understanding the pathogenesis, treatment, and long-term consequences of complications associated with HIV infection and the use of antiretroviral therapy in both resource-limited settings and in the developed world. This review will summarize information on complications of antiretroviral therapy in resource-limited settings, hepatitis C virus, tuberculosis, and discussion of metabolic, cardiovascular, and renal complications.

Management of dyslipidemia and other cardiovascular risk factors in HIV-infected patients: case-based review.

Many HIV-infected patients have dyslipidemia and other cardiovascular risk factors prior to acquiring infection. Both HIV infection itself and antiretroviral therapy can cause or worsen lipid abnormalities. Management of dyslipidemia in the HIV-infected patient requires awareness of the effects of antiretroviral agents on lipid profiles, including potential sex- and race-related effects, and interactions between lipid-modifying agents and antiretroviral agents. This article uses individual case histories to illustrate the decisions encountered in treating HIV infection and dyslipidemia. The article is based on a presentation on management of dyslipidemia and other cardiovascular risk factors in HIV infection made by Judith A. Aberg, MD, at the International AIDS Society-USA Los Angeles CME program in February 2006.

Coronary heart disease risks and lifestyle behaviors in persons with HIV infection.

Metabolic complications such as HIV-associated lipodystrophy syndrome are common in patients with HIV-1 infection who are taking highly active antiretroviral therapy. HIV-associated lipodystrophy syndrome is characterized by dyslipidemia, fat redistribution, and altered glucose metabolism; however, there has been little study of relationships between these risk factors for coronary heart disease (CHD) and lifestyle risks. The aims of this study were to (a) describe the physical activity levels, nutrition habits, and smoking behaviors of persons with HIV-1 infection; (b) describe their CHD risks and estimate 10-year risk for CHD outcomes; and (c) examine the relationship between potentially modifiable lifestyle behaviors and risk factors for atherosclerotic cardiovascular disease in persons with HIV-1 infection receiving highly active antiretroviral therapy. Variables included lipid profile and other metabolic indices, body fat distribution, body mass index, blood pressure, and lifestyle behaviors (physical activity, dietary habits, smoking). A cross-sectional design and convenience sampling (n = 95) was used. Participants had multiple modifiable risk factors: 20% had a 10-year risk of 10% or higher of developing CHD. Results underscore the need for health promotion interventions to target lifestyle risks in persons with HIV-1 infection taking highly active retroviral therapy.

Changes in body fat measured by DEXA in patients taking different formulations of stavudine.

BACKGROUND: Lipoatrophy is a frequent complication of chronic stavudine therapy. Stavudine extended release formulation (stavudine ER) gives lower peak and higher trough levels than the immediate release formulation (stavudine IR), and we hypothesized that the lower peak might result in less lipoatrophy. OBJECTIVE: To compare the rate of peripheral lipoatrophy between patients taking stavudine ER and stavudine IR. METHOD: Body composition was measured by dual energy X-ray absorptiometry (DEXA) every 6 months for 18 months in 29 patients taking either stavudine ER or IR as part of a randomized controlled clinical trial. RESULTS: DEXA fat measurements did not differ between the ER and IR groups at baseline, after a median of 32 months on stavudine-containing treatment. Over the 18 months of follow-up in the whole cohort limb fat decreased by a mean of 0.29 +/- 0.50 kg (p = .01) and leg fat percent decreased by a mean of 1.23% +/- 1.92% (p = .001), whereas trunk fat and trunk-to-limb fat percent ratio did not change significantly. There was no significant difference between the ER and IR groups in the rate of change of any of the fat parameters. At study completion, the proportion of patients with clinical lipodystrophy was similar in the stavudine ER and stavudine IR groups (67% and 64%, respectively; p = .893). CONCLUSION: Stavudine ER does not appear to cause less peripheral lipoatrophy.

Do non-nucleoside reverse transcriptase inhibitors contribute to lipodystrophy?

Lipodystrophy complications, including lipoatrophy (pathological fat loss) and metabolic complications, have emerged as important long-term toxicities associated with antiretroviral therapy in the current era. The wealth of data that has accumulated over the past 6 years has now clarified the contribution of specific antiretroviral drugs to the risk of these clinical endpoints, with evidence that lipoatrophy is strongly associated with the choice of nucleoside reverse transcriptase inhibitor therapy (specifically, stavudine and to a lesser extent zidovudine). The aetiological basis of metabolic complications of antiretroviral therapy has proven to be complex, in that the risk appears to be modulated by a number of lifestyle factors that have made the metabolic syndrome highly prevalent in the general population, with additional contributions from HIV disease status itself, as well as from individual drugs within the HIV protease inhibitor class. The currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, efavirenz and nevirapine, have been proven to have a favourable safety profile in terms of lipodystrophy complications. However, it must be noted that NNRTI drugs also have individual toxicity profiles that must be accounted for when considering and/or monitoring their use in the treatment of HIV infection.

Lipid metabolism and lipodystrophy in HIV-1-infected patients: the role played by nonnucleoside reverse transcriptase inhibitors.

Dyslipidemia and lipodystrophy represent significant healthcare concerns in HIV-infected patients due to their association with diabetes mellitus and increased cardiovascular disease risk. Since the lipid effects of the nonnucleoside reverse transcriptase inhibitors are not well characterized, we systematically summarized the effects of nonnucleoside reverse transcriptase inhibitor treatment on dyslipidemia and lipodystrophy in HIV-1 infection. As with other classes of antiretroviral agents, the nonnucleoside reverse transcriptase inhibitors are associated with lipid changes, although individual agents exhibit differing effects on lipid profiles. Comparative trials have shown that the risk for hypertriglyceridemia is lower with efavirenz than with the use of ritonavir-boosted lopinavir, but there is a greater likelihood of hypercholesterolemia compared to ritonavir-boosted atazanavir. Data also suggest that efavirenz results in greater increases in plasma lipid levels than integrase inhibitors and CC-chemokine-receptor-5 antagonists. Lipid disturbances are less frequent with the newer nonnucleoside reverse transcriptase inhibitors than with efavirenz. However, in most cases, no change in the total:high-density lipoprotein-cholesterol ratio was seen between the efavirenz and comparator groups. Switching from efavirenz to etravirine or rilpivirine, or the integrase inhibitors raltegravir or elvitegravir, resulted in significant reductions in lipid levels. There appears to be minimal potential for efavirenz or rilpivirine to result in development of lipodystrophy. Overall, nonnucleoside reverse transcriptase inhibitors have a smaller impact on plasma lipids than ritonavir-boosted protease inhibitors, with the newer agents exhibiting more favorable lipid profiles than efavirenz. When considering antiretroviral regimens, awareness of the different lipid effect profiles of the third agent is important, without forgetting the critical contribution of the background antiretrovirals.

Dietary habits and their association with metabolic abnormalities in human immunodeficiency virus-related lipodystrophy.

Relatively little is known about the influence of dietary habits on the metabolic complications associated with human immunodeficiency virus (HIV) infection and lipodystrophy. Although recommendations to modify diet and exercise remain a first-line approach to the management of HIV-infected patients with dyslipidemia and glucose intolerance, it is important to determine to what extent, if any, these metabolic abnormalities may be attributed to or modified by dietary behaviors. I review previous work evaluating dietary behaviors and their relationship to lipid levels and insulin resistance in HIV-infected patients with and without lipodystrophy and discuss the implications of possible dietary interventions and results of preliminary studies of the effects of diet on dyslipidemia. Sound dietary guidelines based on investigational research among HIV-infected patients are clearly needed to help face the challenges of the emerging problems of hyperlipidemia, insulin resistance, and the possible increased risk of cardiovascular disease among patients with HIV infection and lipodystrophy.

Fat distribution and metabolic abnormalities in HIV-infected patients on first combination antiretroviral therapy including stavudine or zidovudine: role of physical activity as a protective factor.

OBJECTIVE: To compare body composition, serum lipid profile, parameters of insulin secretion and endocrine measurements in HIV-1-infected patients whose first combination antiretroviral regimen differed only in a nucleoside reverse transcriptase inhibitor (NRTI). DESIGN AND SETTING: Cross-sectional study in an AIDS clinic of a university hospital. PATIENTS: One-hundred-and-fifty HIV-infected patients on long-term first highly active antiretroviral therapy including stavudine (n=75) or zidovudine (n=75). MAIN OUTCOME MEASURE: Fat wasting was assessed by physical examination. Regional fat distribution was estimated using calliper measurements of skinfold thickness at four sites. Central adiposity was assessed by measurement of waist-hip ratio. Fasting glucose, insulin, triglyceride, cholesterol and its fractions, testosterone, follicle stimulating hormone, luteinizing hormone levels, CD4 cell count and HIV viral load were determined. Daily caloric intake and physical activity level were also calculated. RESULTS: Total body fat was significantly lower in patients taking stavudine, whereas the lean body mass was not statistically different amongst both groups. Ninety-four patients (62.7%; 95% CI: 54.9-70.4%) had fat redistribution, being isolated lipoatrophy in 20 (13.3%; 95% CI: 7.9-18.8%), isolated lipohypertrophy in 33 (22.0%; 95% CI: 15.4-28.6%) and mixed syndrome in 41 (27.3%; 95% CI: 20.2-34.5%). There were not statistically significant differences between stavudine- and zidovudine-treated patients with respect to the overall prevalence of fat redistribution syndromes (P=0.34). The prevalence of lipoatrophy (OR=1.86; 95% CI: 0.58-6.33, P=0.37), lipohypertrophy (OR=0.65; 95% CI: 0.25-1.69, P=0.45) and mixed syndromes (OR=1.05; 95% CI: 0.43-2.54, P=0.93) was not statistically different in both groups of patients. The only independent predictor for the appearance of mixed syndrome and lipoatrophy was sedentarism (OR=4.418; 95% CI: 1.565-12.472, P=0.005) and (OR=4.515; 95% CI: 1.148-17.761, P=0.03), respectively. Independent predictors of lipohypertrophy were age (OR=1.138; 95% CI: 1.061-1.220, P<0.0001) and prior AIDS (OR=0.305; 95% CI: 0.100-0.931, P=0.04). There were no statistically significant differences between stavudine and zidovudine-based groups with respect to metabolic and hormonal parameters. CONCLUSION: The use of stavudine or zidovudine in the context of the first combination antiretroviral therapy is not associated either with an increased likelihood of lipid or gonadal hormones abnormalities, and although there was a trend to a lesser body fat content in the stavudine group, there was no increase in the overall likelihood of fat redistribution syndromes with respect to zidovudine group. Physical activity is a protective factor for the development of fat redistribution syndromes.