Lipodystrophy syndrome among HIV infected children on highly active antiretroviral therapy in northern India

Background

It is estimated that about 2.5 million people are living with HIV infection in India. Although antiretroviral drugs have been able to reduce the mortality, these drugs have serious side effects one of which is lipodystrophy syndrome. Most of the drugs used in HAART viz, protease inhibitors, stavudine and nevirapine are associated with lipodystrophy. Hence we conducted this study to assess the prevalence of lipodystrophy in HIV infected children on HAART and its associated risk factors.

Materials and methods

A cross sectional study was conducted on 80 HIV infected children aged 2–18 years of age who were on stavudine based HAART for ≥2 years. These children were assessed for presence of lipodystrophy, its metabolic complications and associated risk factors.

Results

Lipodystrophy was observed in 33.7% of children with lipoatrophy being the commonest subtype followed by lipohypertrophy. Older age, increased duration of treatment and dyslipidaemia were found to be associated in patients with lipodystrophy than those without. On further multivariate analysis of independent risk factors only increased duration of treatment was significantly associated with lipodystrophy. No association was found with insulin resistance.

Conclusion

We observed that lipodystrophy is a common finding in HIV patients treated with HAART for long duration.     

Another emerging event occurring during HIV infection treated with any antiretroviral therapy: frequency and role of gynecomastia

To identify HIV-associated episodes of gynecomastia occurred during antiretroviral therapy in a cohort of around 1,000 patients, and to investigate potential correlations with demographic and epidemiological variables, clinical-laboratory markers of HIV disease, metabolic disturbances, and antiretroviral treatment, a cross-sectional survey of 1.007 patients treated for at least 12 months (669 males: 66.4%), identified all subjects with true (ultrasonography-confirmed) gynecomastia, after exclusion of all other predisposing conditions. Special attention was paid to eventual metabolic alterations, including lipodystrophy syndrome, dyslipidemia, and hyperglycemia, and administered antiretrovirals. Fifteen of the 516 evaluable male subjects (2.9%), developed gynecomastia when aged 12-58 years. A concurrent lipodystrophy was present in all cases, while hypertriglyceridemia, hypercholesterolemia, and hyperglycemia were found in 11, 6, and 3 patients, respectively. Duration of seropositivity and time from start of antiretroviral therapy varied significantly, and no correlation was found with HIV disease progression, but 5 patients never received protease inhibitors, while an efavirenz-based treatment apparently prompted gynecomastia in 4 protease inhibitor-naive patients, and worsened this sign in other 4 patients switching from a protease inhibitor-based HAART. One patient developed gynecomastia while on isolated nucleoside analogue therapy. In the whole patient group, stavudine proved the nucleoside analogue administered more frequently and for a more prolonged time. During the follow-up, no significant ameliorament of gynecomastia was observed despite eventual therapeutic changes. Gynecomastia, as an emerging untoward event of treated HIV infection, deserves further investigation, from an epidemiological, clinical, and especially pathogenetic point of view. The frequent association with metabolic abnormalities suggests some common ethiologic pathway with other HAART-related disturbances.     

Coronary heart disease in HIV-infected patients

Increased risk of coronary heart disease has emerged as a long-term concern among HIV-infected patients receiving antiretroviral therapy. HIV-infected patients may have modifiable risk factors for heart disease that are associated with HIV itself, antiretroviral therapy, or factors unrelated to HIV. Dyslipidemia, insulin resistance, and diabetes mellitus are often multifactorial in origin. Patients with lipodystrophy frequently have a constellation of metabolic changes that may predispose them to accelerated atherosclerosis. There is also concern about contributions of chronic inflammation and prothrombotic tendencies in the pathogenesis of coronary heart disease in the HIV-infected population. Several epidemiological studies support an increased relative risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy. Although absolute risk appears low in the short term, patients may accrue significant risk over time. Clinicians are advised to assess coronary heart disease risk in HIV-infected patients and to intervene to reduce the impact of modifiable risk factors.     

Soluble Urokinase Plasminogen Activator Receptor (suPAR) is Associated with Metabolic Changes in HIV-1-Infected Africans: A Prospective Study

Soluble urokinase plasminogen activator receptor (suPAR) is associated with inflammation and may predict lipodystrophy and dysmetabolism in human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy. We aimed to assess firstly, whether suPAR levels are elevated in treated and untreated HIV-1-infected Africans compared to uninfected controls at baseline and at a 3-year follow-up, and secondly whether suPAR levels are correlated with cardiovascular and/or metabolic changes. SuPAR, cardiovascular, and metabolic variables were assessed and the percentage change was determined. HIV-1-infected black South Africans had significantly higher suPAR levels than uninfected controls at baseline and at follow-up 3 years later. However, only the treated HIV-1-infected participants showed an increase in suPAR levels at follow-up. The treated group also showed signs of lipodystrophy and their baseline suPAR levels correlated positively with an increased waist circumference. This study indicates that suPAR levels increase and that baseline suPAR is associated with an increase in abdominal fat distribution in HIV-infected black Africans on antiretroviral therapy.     

Recombinant Human Growth Hormone

The role of hormonal and metabolic alterations in HIV-associated lipodystrophy syndrome is not yet clear. In patients with HIV-1 undergoing antiretroviral treatment, lipodystrophy is associated with peripheral fat wasting and central adiposity, dyslipidemia, insulin resistance, and increased intramuscular fat accumulation.In HIV lipodystrophy, changes in fat distribution are heterogeneous and can include reduced subcutaneous fat as well as increased visceral fat. In the literature, there is evidence showing that overnight growth hormone (GH) secretion and pulse amplitude decrease in patients with HIV lipodystrophy, with rates of response to standardized GH stimulation being abnormal in at least 20% of these patients.Excess accumulation of visceral fat, central obesity, and increased intra-abdominal adiposity are also typical features of patients with GH deficiency. Recombinant human GH (rhGH) is a potential treatment to diminish excess visceral fat. Our group recently demonstrated that GH therapy in HIV-infected patients with syndromes of fat accumulation produced a significant decrease in body fat and a gain in lean tissue. In this article, we discuss the origin of lipodystrophy in HIV patients, and the use of rhGH treatment (benefits and adverse effects) in HIV-related lipodystrophy.     

Metabolic effects of protease inhibitor therapy

Fat redistribution (lipodystrophy) and metabolic anomalies are reported increasingly in HIV-infected patients being treated with protease inhibitors. The incidence of these side effects ranges from 5% to 75% in such patients, who often complain of spontaneous fat wasting in the face, arms, or legs, with or without central obesity. Hyperlipidemia and insulin resistance are almost always associated with lipodystrophy. We review the metabolic complications of antiretroviral therapies and discuss possible therapeutic interventions.     

Impact of metabolic complications on antiretroviral treatment adherence: Clinical and public health implications

Antiretroviral therapy (ART) is an effective strategy for preventing disease progression of HIV infection, particularly when patients adhere closely to the treatment regimen. However, ART medications can cause side effects, including metabolic complications that can impact patients’ adherence levels. Selected chronic complications associated with ART include lipodystrophy, hyperlipidemia, insulin resistance and diabetes, peripheral neuropathy, and bone disorders such as osteopenia/osteoporosis. In this article, we review the effects of these metabolic complications on ART adherence and approaches to prevent or reverse them     

Psychosocial impact of the lipodystrophy syndrome in HIV infection

Lipodystrophy is a poorly understood condition associated with antiretroviral therapy in HIV infection. The symptoms may include some combination of central fat accumulation, peripheral fat depletion, and metabolic disturbance. A qualitative survey of 33 HIV-infected heterosexual women and gay men with lipodystrophy assessed psychosocial impact and effect on quality of life. Dominant themes included erosion of self-image and self-esteem, problems in social and sexual relations, threats to locus of control, forced HIV disclosure, and demoralization and depression. Another theme was clinicians' minimization of the importance of lipodystrophy. Further research is required to fully understand the psychosocial impact of lipodystrophy and to develop strategies that help individuals cope.     

Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients

This study tested the hypothesis that in patients with HIV-associated lipodystrophy, adiponectin levels were related to insulin resistance, TNF-alpha and IL-6 and treatment with nucleoside analogues. HIV seropositive men undergoing highly active antiretroviral treatment were enrolled into three predetermined clinical groups: lipodystrophy with central fat accumulation (n = 12); lipodystrophy without central fat accumulation (n = 15); no lipodystrophy (n = 15). HIV-negative healthy men served as controls (n = 12). Both lipodystrophic groups had a low percentage of limb fat compared to the two control groups. Patients with lipodystrophy with fat accumulation had increased truncal fat compared with controls. Levels of adiponectin did not correlate with either TNF-alpha or IL-6. Low levels of adiponectin were found in both lipodystrophic groups and were associated with current or previous treatment with stavudine. Furthermore, the adiponectin level correlated with the percentage of limb fat. Patients with lipodystrophy with fat accumulation were more insulin resistant, measured by HOMA-IR, compared with controls. However, HOMA-IR did no correlate to adiponectin or other cytokines. In conclusion, the finding of no difference between the two lipodystrophic groups with regard to adiponectin, indicates that low levels of adiponectin reflects fat atrophy, whereas the insulin resistance was best explained by increased truncal fat mass.     

Disease progression among HIV-infected children who receive perinatal zidovudine prophylaxis

BACKGROUND: Studies of perinatal HIV infection have reported mixed results regarding the prognosis of HIV-infected infants exposed to perinatal zidovudine prophylaxis (PZP). METHODS: We have followed a population-based cohort of children with perinatal HIV infection to evaluate whether early HIV disease progression was more common among those who received PZP and whether subsequent antiretroviral therapy (ART) was less effective in preventing early disease progression. RESULTS: We identified 73 children with perinatal HIV infection born between 1994 and 2001 with at least 3 years of follow-up and with information concerning PZP administration. Children who received PZP started subsequent ART at an earlier age than those who did not receive PZP (median age at starting treatment: 2 months for PZP vs. 6 months for no PZP; P = 0.0002). PZP was associated with decreased early HIV progression: 21% (7 of 33) of children who received PZP progressed to a category C diagnosis by 3 years compared with 45% (18 of 40) of children who did not receive PZP (P = 0.047). Children who did not receive PZP progressed to a category C diagnosis at a younger age than children who received PZP (median: 4 vs. 11 months; P = 0.061). ART was as effective in preventing early HIV progression in children who received PZP as in children who did not receive PZP. CONCLUSIONS: In our population-based cohort of perinatally HIV-infected children, those who received PZP started ART at a significantly earlier age than those who did not receive PZP and also demonstrated decreased HIV disease progression by the age of 3 years.     

Leptin and adipose tissue maldistribution in HIV-infected male patients with predominant fat loss treated with antiretroviral therapy.

BACKGROUND: Metabolic disturbances and fat maldistribution are main features of the antiretroviral-related lipodystrophy syndrome (LDS). Different phenotypes of fat distribution abnormalities can be observed: fat loss, fat accumulation, or a mixed pattern. In patients with predominant loss of fat, the roles of leptin, lipids, and glucose homeostasis disturbances have not yet been clearly established. METHODS: The study comprised 34 HIV-infected male patients receiving antiretroviral treatment that included protease inhibitors. A lipoatrophic phenotype, defined as fat loss in face or extremities, both normal weight and waist:hip ratio, and absence of fat accumulation elsewhere, was present in all cases. Fat distribution disturbances were confirmed by abdominal and midthigh computed tomography-calculated adipose tissue content. Fasting plasma glucose, insulin, proinsulin, total leptin, testosterone, and lipid profiles were measured. After 2 hours, 75-g oral glucose tolerance test (OGTT), glucose, insulin, and proinsulin levels were also obtained. Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA-r) method. Both healthy study subjects ( n = 385) and antiretroviral-naive HIV-positive patients ( n = 13) were used as controls. RESULTS: Of these LDS patients, 5.8% showed diagnostic criteria for diabetes and 17.8% for impaired glucose tolerance. A lipid pattern characterized by high total cholesterol and high low density lipoprotein (LDL) plasma levels, hypertriglyceridemia, and normal high density lipoprotein (HDL) levels was observed. Fasting insulin and 2-hour post OGTT insulin levels, and insulin resistance index were significantly higher in LDS patients than in antiretroviral-naive HIV-positive patients. Plasma leptin levels were significantly lower in lipoatrophic patients than in healthy control individuals. Patients with LDS presented with significant midthigh fat reduction and visceral fat accumulation compared with findings in antiretroviral-naive HIV-positive patients. A significant correlation was found between plasma leptin levels and midthigh fat content. CONCLUSION: Peripheral fat loss in extremities in LDS patients with lipoatrophic phenotype is also associated with low plasma leptin levels, visceral fat accumulation, and metabolic disturbances related to an increased cardiovascular risk. In LDS patients, plasma leptin levels could be a marker of subcutaneous adipose tissue content.     

Relative Effects of Insulin Resistance and Protease Inhibitor Treatment on Lipid and Lipoprotein Metabolism in HIV-Infected Patients

Abstract

Background: The relationship between insulin resistance, dyslipidemia, HIV infection, and antiretroviral therapy remains unclear, and the atherogenic nature of lipid and lipoprotein profiles in HIV-infected patients has not been fully characterized. Method: We measured plasma lipid and lipoprotein subfractions using Vertical Auto Profile-II methodology and directly measured insulin-mediated glucose disposal in 45 protease inhibitor (PI)-treated and non-PI-treated HIV-infected patients. Results: PI-treated patients had higher total, LDL, and narrow-density LDL cholesterol (p < .05) and a trend toward higher triglycerides, whereas HDL cholesterol and LDL particle characteristics were unrelated to PI use or history of lipodystrophy. Insulin sensitivity did not differ on the basis of PI therapy, but decreased insulin sensitivity was associated with lower HDL and HDL-3 cholesterol (p < .01); elevated triglyceride (p < .01), VLDL 1+2, and VLDL 3a+3b lipoproteins (p < .01); and smaller, denser (more atherogenic) LDL particle characteristics (p < .01). Thus, the lipoprotein abnormality associated with PI use was increased LDL cholesterol, whereas changes in TG and HDL metabolism were associated with insulin resistance, independent of PI use. Conclusion: The variables of PI-treatment, dyslipidemia, lipodsytrophy, and insulin resistance do not always cluster together in HIV-infected patients, which suggests that the metabolic phenotype emerging in treated patients results from a complex interplay of drug effects, immune restoration, and baseline insulin sensitivity.     

Fat redistribution syndromes associated with HIV-1 infection and combination antiretroviral therapy

More than 15 years after the introduction of highly active antiretroviral therapy, HIV/HAART-associated lipodystrophy syndrome still shadows the indisputable efficacy of antiretroviral therapy. Several issues related to this complication (prevalence, diagnosis, pathogenesis, prevention, or clinical management) have not been completely clarified. However, in the last years, substantial progress has been made in elucidating some of these basic aspects. This includes a better knowledge of the pathogenic mechanisms underlying HIV/HAART-associated lipodystrophy syndrome such as genetic host determinants, the impact of HIV infection per se, as well as the contribution of antiretroviral therapy. In regard to treatment, we have learned that certain drugs are especially prone to cause HIV/HAART-associated lipodystrophy syndrome (i.e. thymidine analogues). Pharmacological interventions to treat this condition have yielded mostly disappointing results, and the only intervention which offers an immediate aesthetical improvement for patients with HIV/HAART-associated lipodystrophy syndrome is plastic surgery. Even under the most favorable conditions (ideal host genetic make-up, and the timely initiation of HIV therapy with less toxic drugs), current data show that HIV/HAART-associated lipodystrophy syndrome is a complication of HIV infection and/or antiretroviral treatment that we are unable to avoid. In the context of HIV-1-infected patients under long-term antiretroviral therapy, fat toxicity is still the dark side of the rainbow.     

Disturbance of apolipoprotein B100 containing lipoprotein metabolism in severe hyperlipidemic and lipodystrophic HIV patients on combined antiretroviral therapy: evidences of insulin resistance effect

The aim was to study the mechanisms involved in the dyslipidemia associated with lipodystrophy in HIV infected patients on antiretroviral therapy (ART). We investigated the in vivo kinetics of apolipoprotein B100 (apoB) containing lipoproteins using a 14 h primed constant infusion of [5,5,5, (2)H(3)] leucine and compartmental modelling in normolipidemic without lipodystrophy (7 patients, NLD) or dyslipidemic with lipodystrophy (7 patients, LD) treated with ART. Subjects in group LD showed higher plasma triglycerides (5.73+/-3.58 vs 1.29+/-0.54 g/L, p<0.005), total cholesterol (2.98+/-0.95 vs 1.74+/-0.26 g/L, p<0.05), apoB (1.49+/-1.11 vs 0.51+/-0.11 g/L, p<0.005) and apolipoprotein CIII in apoB containing lipoproteins (117.7+/-42.2 vs 22.6+/-23.9 g/L, p<0.005). LD subjects exhibited an insulin resistant as observed by higher HOMA (3.44+/-1.62 vs 1.60+/-0.61, p<0.05). They exhibited an increase in VLDL (1.24+/-0.33 vs 0.80+/-0.21 mg/kg/h, p<0.05), decrease in IDL (0.20+/-0.10 vs 0.48+/-0.24 mg/kg/h, p<0.05) and no difference in LDL (0.38+/-0.19 vs 0.45+/-0.25 mg/kg/h) production rate. LD subject also showed a dramatic decrease in transformation of VLDL to IDL (0.013+/-0.010 vs 0.258+/-0.206 h(-1), p<0.005) and IDL to LDL (0.088+/-0.093 vs 0.366+/-0.189 h(-1), p<0.05) and a decrease in fractional catabolic rate (FCR) of VLDL (0.199+/-0.132 vs 0.555+/-0.398 h(-1), p<0.05), IDL (0.110+/-0.08 vs 0.523+/-0.275 h(-1), p<0.05) and LDL (0.010+/-0.005 vs 0.025+/-0.014 h(-1), p<0.05). These disturbances, overproduction and an overall delayed catabolism of apoB, are similar to those observed using the same protocol in insulin resistant subjects. Our study suggests that metabolic disturbance of apoB100 observed in lipodystrophic HIV in combined antiretroviral therapy are consecutive to insulin resistance induced by the treatment.     

Long-term exposure to lifelong therapies

Three categories of highly active antiretroviral therapy (HAART)-associated major toxic effects have been identified: nucleoside-related toxic effects (e.g., neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis, and possibly lipoatrophy), metabolic complications (e.g., fat redistribution, insulin resistance, and hyperlipidemia), and bone disease (e.g., osteopenia and/or osteoporosis). The toxic effects caused by nucleosides are hypothesized to be a result of mitochondrial injury and include myopathy, pancreatitis, liver failure, and lactic acidosis. Alterations in lactic acid metabolism range from common instances of asymptomatic lactic acidemia to rare occurrences of life-threatening lactic acidosis with hepatic steatosis. A metabolic syndrome consisting of lipodystrophy (i.e., fat redistribution), hyperlipidemia and insulin resistance has been observed, particularly with protease inhibitor treatment. Some additive interaction between protease inhibitors and nucleosides has also been described. The potential relationship of these metabolic abnormalities to increased risk of cardiovascular disease and diabetes has broad implications on long-term patient management. Lipodystrophy associated with HAART is generally accompanied by potentially serious abnormalities, including dyslipidemia (i.e., hypercholesterolemia and hypertriglyceridemia) and altered glucose metabolism (i.e., insulin resistance). Regimens of HAART may have adverse effects on bone metabolism, as indicated by emerging reports of osteopenia, osteoporosis, and avascular necrosis.