Approach to the human immunodeficiency virus-infected patient with lipodystrophy

Subcutaneous atrophy and central fat accumulation are common among HIV-infected patients receiving highly active antiretroviral therapy, and may be accompanied by dyslipidemia and insulin resistance. These fat changes, although commonly referred to together as lipodystrophy, are best considered as separate disorders, with distinct pathogeneses and treatment approaches. These morphological and metabolic abnormalities first appeared after introduction of protease inhibitors more than 10 yr ago, but research has demonstrated that their pathogenesis is multifactorial, with contributions from other antiretroviral medications, patient-related factors, and HIV itself. Switching to a less toxic highly active antiretroviral therapy regimen has shown partial effectiveness for the management of fat atrophy and lipid abnormalities. Lifestyle modification or surgical approaches are the treatment of choice for lipohypertrophy, although novel therapies targeting the GH axis show promise. HIV-related dyslipidemia may be difficult to treat, and can be complicated by drug-drug interactions between some lipid-lowering medications and antiretroviral medications. Treatment of diabetes in HIV-infected patients should generally follow established guidelines, but thiazolidinediones, rather than metformin, may be considered first-line treatment in a patient with lipoatrophy, given their potential to increase sc fat. The contribution of body fat changes and metabolic abnormalities to cardiovascular risk and the changing risk profiles of newer antiretroviral regimens are under intense investigation.     

Hyperandrogenemia in human immunodeficiency virus-infected women with the lipodystrophy syndrome

A novel lipodystrophy syndrome characterized by insulin resistance, hypertriglyceridemia, and fat redistribution has recently been described in human immunodeficiency virus (HIV)-infected men and women. Women with the HIV lipodystrophy syndrome exhibit a marked increase in waist-to-hip ratio and truncal adiposity; however, it is unknown whether androgen levels are increased in these patients. In this study, we assessed androgen levels in female patients with clinical lipodystrophy based on evidence of significant fat redistribution in the trunk, extremities, neck and/or face (LIPO: n = 9; age, 35.7+/-1.7 yr; BMI, 24.7+/-0.8 kg/m2) in comparison with age- and BMI-matched nonlipodystrophic HIV-infected females (NONLIPO: n = 14; age, 37.6+/-1.1 yr; BMI, 23.4+/-0.6 kg/m2) and healthy non-HIV-infected control subjects (C: n = 16; age, 35.8+/-0.9 yr; BMI, 23.1+/-0.4 kg/m2). Fasting insulin, lipid levels, virologic parameters, and regional body composition using dual energy x-ray absorptiometry were also assessed. Total testosterone [ LIPO, 33+/-6 ng/dL (1.1+/-0.2 nmol/L); NONLIPO, 17+/-2 ng/dL (0.6+/-0.1 nmol/L); C, 23+/-2 ng/dL (0.8+/-0.1 nmol/L); P < 0.05 LIPO vs. C and LIPO vs. NONLIPO] and free testosterone determined by equilibrium dialysis [LIPO, 4.5+/-0.9 pg/mL (16+/-3 pmol/L); NONLIPO, 1.7+/-0.2 pg/mL (6+/-1 pmol/L); C, 2.4+/-0.2 pg/mL (8+/-1 pmol/L); P < 0.05 LIPO vs. C and LIPO vs. NONLIPO] were increased in the lipodystrophic patients. Sex hormone-binding globulin levels were not significantly different between LIPO and C, but were significantly lower in the LIPO vs. NONLIPO patients (LIPO 84+/-7 vs. NONLIPO 149+/-17 nmol/L, P < 0.05). The LH/FSH ratio was significantly increased in the LIPO group compared with the NONLIPO and C subjects (LIPO, 2.0+/-0.6; NONLIPO, 1.1+/-0.1; C, 0.8+/-0.1; P < 0.05 LIPO vs. NONLIPO and LIPO vs. C). Body fat distribution was significantly different between LIPO and C subjects. Trunk to extremity fat ratio (1.46+/-0.17 vs. 0.75+/-0.05, LIPO vs. C, P < 0.05) was increased and extremity to total fat ratio decreased (0.40+/-0.03 vs. 0.55+/-0.01, LIPO vs. C, P < 0.05). In contrast, fat distribution was not different in the NONLIPO group vs. control subjects. Among the HIV-infected patients, free testosterone correlated with percent truncal fat (trunk fat/trunk mass) (r = 0.43, P = 0.04). These data suggest that hyperandrogenemia is another potentially important feature of the HIV-lipodystrophy syndrome in women. Additional studies are necessary to determine the clinical significance of increased androgen levels and the relationship of hyperandrogenism to fat redistribution and insulin resistance in this population of patients.     

Factors influencing the development of lipodystrophy in human immunodeficiency virus-infected patients

238 human immunodeficiency virus-infected patients on highly active antiretroviral therapy (HAART) were studied, 67 of whom (28.2%) developed lipodystrophy. The presence of hyperlipidaemia (p = 0.002) and of hepatitis C virus coinfection (p = 0.014) were associated with lipodystrophy, but only the duration of HAART was significantly predictive of lipodystrophy (p < 0.0001) in the multivariate analysis.     

Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy.

Multidrug antiretroviral regimens that include human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and deposition of visceral abdominal adipose tissue. To determine whether these findings are related to abnormalities of adrenal function, we compared the hypothalamic-pituitary-adrenal axes of HIV-positive patients who had evidence of protease inhibitor-associated lipodystrophy (PIAL), control volunteers (CON), and patients with Cushing's syndrome (CS). To elucidate the metabolic consequences of the observed lipodystrophy, we measured basal serum lipids and compared glucose and insulin concentrations during an oral glucose tolerance test. Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean +/- SD, 76 +/- 51 nmol/day) was significant lower than those in CON (165 +/- 64 nmol/day; P < 0.001) and CS (1715 +/- 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 +/- 23 micromol/day) than in CON (17 +/- 8 micromol/day; P < 0.001), although lower than that in CS (74 +/- 47 micromol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 +/- 5.63 mmol/L) than in CS (1.78 +/- 0.83 mmol/L; P < 0.001) or CON (1.36 +/- 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min. We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.     

Exocrine pancreatic function and fat malabsorption in human immunodeficiency virus-infected patients.

BACKGROUND: Nutrients malabsorption frequently occurs in human immunodeficiency virus (HIV)-infected patients, but very few studies have investigated exocrine pancreatic digestive capacity in these patients. We therefore evaluated the frequency of exocrine pancreatic impairment and its eventual relation with fat malabsorption in HIV-infected patients. METHODS: Thirty-five HIV-infected patients (30 male, 5 female: mean age +/- standard deviation, 33.6 +/- 7.2 years) and 51 sex- and age-matched controls without gastroenterologic diseases were studied. In all subjects fecal elastase 1 (EL-1) was assayed, and fecal fat excretion was evaluated with the steatocrit test. RESULTS: Nineteen of 35 (54%) HIV-infected patients showed subnormal EL-1 values, whereas all the controls had normal values; furthermore, EL-1 values were significantly lower in patients than in controls: mean (95% confidence intervals), 207 ( 164-251 ) microg/g versus 312 (291-332) microg/g (P < 0.0001). Increased fecal fat excretion was observed in almost all (25 of 35) HIV-infected patients, and an inverse but not significant correlation was found between fecal EL-1 and steatocrit values. No association was found between reduced fecal EL-1 and the severity of HIV disease or nutritional and immunologic status. Opportunistic infections and drug administration had no influence on EL-1 concentrations in stools. CONCLUSIONS: Reduced exopancreatic function is frequent in HIV-infected patients but does not seem to be a major factor contributing to fat malabsorption.     

The burden of liver disease in human immunodeficiency virus-infected patients

Introduction of effective combined antiretroviral therapy has made human immunodeficiency virus (HIV) infection a chronic illness. Substantial reductions in the number of acquired immunodeficiency syndrome- (AIDS-) related deaths have been accompanied by an increase in liver-related morbidity and mortality. Liver diseases rank in the first three most-common causes of death in HIV-infected persons. Mortality is mainly due to cirrhosis and hepatocellular carcinoma induced by hepatitis C virus and hepatitis B virus coinfection. However, antiretroviral drugs toxicity also plays a role. Nonalcoholic fatty liver disease is a common cause of liver injury as well. Nevertheless, alcohol consumption probably plays a pivotal role. Noncirrhotic portal hypertension, an uncommon condition observed in less than 1% of patients, is increasingly described. Finally, acute hepatitis A virus (HAV) and acute and even chronic hepatitis E virus infection have also been reported as causes of liver damage in HIV. Anti-HAV vaccination is thus recommended in persons at risk living with HIV.     

Disorders of glucose metabolism in patients infected with human immunodeficiency virus.

New-onset diabetes mellitus, clinically similar to type 2 diabetes, will affect a small proportion (1%-6%) of patients infected with human immunodeficiency virus (HIV) who are treated with HIV-1 protease inhibitors (PIs). However, insulin resistance and impaired glucose tolerance will develop during PI treatment in a considerable proportion of patients. Dyslipidemia, abdominal obesity, and loss of peripheral fat frequently coexist with insulin resistance, but it is not clear whether all of these result from a common pathogenic mechanism. Recent data suggest that insulin resistance may also be associated with HIV infection in patients not receiving PI therapy. The long-term consequences of insulin resistance in this population are not known. The effect of switching to other antiretroviral therapies has not been fully determined. Treatment of established diabetes mellitus should generally follow existing guidelines. There is no clinically useful screening test that will determine the existence and degree of insulin resistance in individual patients. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as weight reduction for obese persons and regular aerobic exercise.     

Cardiovascular manifestations in human immunodeficiency virus-infected patients

Human immunodeficiency virus (HIV) is now a pandemic. It afflicts multiple organs, including the cardiovascular system. This occurs by direct invasion as well as opportunistic infections complicating acquired immunodeficiency syndrome. The presence of newer highly active antiretroviral therapy has led to longer survival of patients infected with HIV, but the cardiac abnormalities related to HIV have remained less well characterized. It is now evident that cardiac involvement in patients with acquired immunodeficiency syndrome is relatively common. This includes coronary artery disease, dilated cardiomyopathy, pericardial effusion, pulmonary hypertension, and ill effects of highly active antiretroviral therapy in the form of lipodystrophy, lipoatrophy, and dyslipidemia. In fact, HIV can now be viewed as a potential risk factor for coronary artery disease, and the dilemma facing clinicians is how to quantify this risk. Awareness of accelerated coronary artery disease and dilated cardiomyopathy is critical to implement preventive measures early in the course of HIV. However, better guidelines are still needed on the basis of prospective randomized controlled studies involving large populations. In conclusion, this review describes cardiac abnormalities associated with HIV, including possible molecular mechanisms. The co-morbid sequelae, their presentation, and pharmacologic management are also discussed.     

Anorectal lesions in human immunodeficiency virus-infected patients

In a prospective study, we analysed the anorectal lesions observed in 148 human immunodeficiency virus-infected patients and compared the data with those reported in the literature. The majority of the patients (97.3%) were homosexual or bisexual men. The mean age of the population was 34.2 years. A history of previous sexually transmitted diseases was found in 79.7% of the male patients. The stage of HIV-related disease, according to the Centers for Disease Control classification, could be determined in 141 patients: 54.6% were stage II, 3.5% stage III and 41.8% stage IV. Anal condylomata were the most frequent manifestation, affecting 29.7% of the patients, 7.1% of whom showed moderate to severe dysplasia. The types were mainly 6, 11, 16 and 18, but types 31, 35 and 39 were also observed. Ulcerations were the most frequent non-condylomatous lesions, occurring in 41 patients; most (60%) were due to herpes viruses, and a large minority (21%) to cytomegalovirus. The etiology could not be determined in five cases. Anal sepsis was present in 11.4%, haemorrhoidal disease in 16.8% and fissures in 6%. Six patients developed Kaposi's sarcoma and seven, non-Hodgkin's lymphoma. No anal cancers were observed. Finally, wound healing was slowed in the patients operated on for haemorrhoids, fissures and suppuration. No statistical analysis could be performed because of the small number of patients.

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Résumé Dans une étude prospective, nous avons analysé les lésions anorectales observés chez 148 malades atteints d'immunodéficience virale et comparés ces faits avec ceux rapportés dans la littérature. La majorité des malades (97,3%) étaient des hommes homo ou bi-sexuels. La moyenne d'âge de la population était de 34,2 ans. Un antécedent de maladie sexuellement transmissible antérieur fut retrouvé dans 79,7% des patients mâles. Le stade de la maladie en relation avec le virus HIV, selon la classification des centres de contrôle, a pû être déterminé chez 141 patients: 54,6 étaient du stade II, 3,5 du stade III et 41,8 du stade IV. Une condylomatose anale était la manifestation la plus fréquente affectant 29,7% des patients, 7,1 % d'entre elles montrant des lésions de dysplasie modérée à sévère. Les types étaient principalement 6, 11, 16 et 18 mais les types 31, 35 et 39 étaient aussobservés. Des ulcérations étaient la lésion la plus fréquente non condylomateuse, survenant chez 41% des patients. La plupart (60%) étaient dû au virus de l'herpès et une large minorité (21 %) au cytomégalovirus. L'étiologie n'a pas pu être déterminée chez 5 malades. Une suppuration anale était présente chez 11,4%, une maladie hémorroidaire chez 16,8% et des fissures chez 6%. 6 malades ont developpés un syndrome de Kaposi et 7 un lymphome non Hodgkinien. Aucun cancer anal n'a été observé. Enfin, la guérison des plaies était ralentie chez les patients opérés pour fissure, hémorroides ou suppuration. Aucune analyse statistique n'a pu être effectuée en raison du petit nombre de malades.

     

Anorectal surgery in human immunodeficiency virus-infected patients

PURPOSE: Anorectal disease is commonly found in human immunodeficiency virus (HIV)-infected patients. The aim of this study was to determine the spectrum of anorectal disease, its surgical treatment, clinical outcome, and its relation to immune status. METHODS: Medical records of all HIV-infected patients with anorectal pathology that required surgical treatment from January 1984 to January 1994 were retrospectively reviewed. Patients were divided into five different groups: common anorectal pathology (hemorrhoids, polyps, Group A); condylomata acuminata (Group B); perianal sepsis (abscesses, fistulas, Group C); anorectal ulcers (Group D); malignancies (Group E). RESULTS: Eighty-three patients needed 204 surgical consultations (13 percent conservative, 87 percent operative) for 170 anorectal diseases. Fifty-one patients had multiple anorectal pathology. Operative intervention resulted in adequate wound healing and symptom relief in 59 percent of patients, adequate wound healing without relief of symptoms in 24 percent of patients, and disturbed wound healing in 17 percent of patients. Disturbed wound healing was related to type of anorectal disease (P <0.001) and to preoperative CD4 ⁺-lymphocyte counts (P <0.01). Disturbed wound healing and most insufficient immune status were encountered in Groups C, D, and E. Within these groups low CD4 ⁺-lymphocyte counts were a risk factor for disturbed wound healing (P=0.004). Median postoperative survival was highest (4.7 years) in Group A, lowest (0.6 years) in Groups D and E, and related to type of anorectal disease (P=0.0001). CONCLUSIONS: The spectrum of anorectal disease is complex. Type of anorectal disease is strongly related to immune status, wound healing, and postoperative survival.     

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic, human immunodeficiency virus (HIV)-infected patients with and without lipodystrophy. We studied 18 HIV-infected patients with lipodystrophy (LIPO) on antiretroviral therapy and 25 HIV-infected patients without lipodystrophy (controls) of whom 18 were on antiretroviral therapy and 7 were not. Posthepatic insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU.m-2 .min-1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting insulin (130%, P < .001), impaired insulin sensitivity index (M value, -29%, P < .001), and reduced MCRi (-17%, P < .01). Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P < .02 and r = -0.68, P < .002) and positively with M value (r = 0.63, P < .01 and r = 0.65, P < .004). In controls, MCRi correlated inversely with fasting insulin (r = -0.47, P < .02) and positively with M value (r = 0.57, P < .004); however, the correlations between HEXi and these parameters were insignificant (P > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy.     

Intestinal absorption and permeability in human immunodeficiency virus-infected patients

BACKGROUND: Impaired intestinal function could account for diarrhoea and weight loss, which are common features of advanced human immunodeficiency virus (HIV) infection. METHODS: We assessed intestinal permeability to lactulose and mannitol and absorption of D-xylose in 96 HIV-infected patients (group I: asymptomatic subjects (CDC-A); group II: symptomatic subjects (CDC-B or C) without body weight loss and/or diarrhoea; group III: 25 acquired immunodeficiency syndrome (AIDS) patients (CDC-C) with severe body weight loss and/or diarrhoea) and 10 healthy subjects as controls. RESULTS: An incremental decrease in urinary D-xylose recoveries was observed, with all groups statistically different from each other. Impaired intestinal permeability was only found in patients of group III (statistically different from all other groups). CONCLUSIONS: These findings suggest a loss of intestinal functional absorptive surface as HIV disease progresses. This process may be present at the early stage of infection. Impaired intestinal permeability is observed later in AIDS patients when digestive signs are present, particularly diarrhoea.     

克罗恩病的糖、脂类和蛋白质代谢异常

炎症性肠病(inflammatory bowel diseases,IBD)包括克罗恩病(Crohn's disease,CD)和溃疡性结肠炎(ulcerative colitis,UC),其威胁着人类的健康.他起因不适当的免疫应答、遗传易感个体及共生的微生物抗原,并可被特定的环境因素所诱发.本文主要综述了CD的糖、脂类及蛋白质代谢异常及代谢组学平台在揭示CD生物学标志和发病机制中的意义.     

Acute myocardial infarction in human immunodeficiency virus-infected patients

BACKGROUND: Patients infected with human immunodeficiency virus (HIV) are at an increased risk for premature coronary artery disease. However, the clinical outcome of HIV-infected patients who have had an acute myocardial infarction (AMI) is unknown. METHODS: We studied 24 consecutive HIV-infected patients admitted because of AMI. During the hospital phase, the patients were examined for recurrent ischemia, congestive heart failure, arrhythmia, and death. Patients were followed up for an average of 15 months after discharge for reinfarction; recurrent angina; the need for any angioplasty, bypass surgery, or target vessel revascularization for restenosis and stent thrombosis; HIV-related complications; and death. For comparison, we included a matched control group of non-HIV-infected patients. RESULTS: The HIV-infected patients with AMI were predominantly male (21 [88%]), 47 +/- 9 years of age. Twenty-two (92%) were receiving antiretroviral treatment; 17 (71%), protease inhibitors; and 13 (54%), lipid-lowering therapy. With aggressive therapy, the lipid profile was similar in HIV-infected patients treated with protease inhibitors and those who were not. Twenty-one (88%) of 24 patients underwent immediate angiography and 20 (83%) had angioplasty or bypass surgery. The HIV-infected patients with AMI had a benign in-hospital course, with no deaths or reinfarction. The admission characteristics, treatment strategy, and in-hospital outcome were similar in the matched uninfected patients with AMI. After discharge, HIV-infected patients had a higher incidence of reinfarction (4/20 [20%] vs 2/45 [4%]; P =.07), and 6 (43%) of 14 HIV-infected patients who had successful percutaneous coronary intervention and were available for follow-up required target vessel revascularization compared with 4 (11%) of 38 uninfected patients who had successful percutaneous coronary intervention and were available for follow-up (P =.02). CONCLUSIONS: Patients infected with HIV sustain AMI at a young age and have a benign in-hospital course. Although HIV-infected patients have a higher incidence of postdischarge ischemic events, restenosis, and stent thrombosis, the intermediate-term mortality is low.     

Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients

The safety and efficacy of a once-daily regimen that combines emtricitabine, didanosine, and efavirenz was studied among 40 previously untreated human immunodeficiency virus (HIV)-infected patients. The median plasma HIV RNA level was 4.77 log(10) copies/mL at baseline and decreased by a median of 3.5 log(10) copies/mL at 24 weeks, with 98% and 93% of patients achieving plasma HIV RNA levels <400 and <50 copies/mL, respectively. The median CD4 cell count was 373 cells/microL at baseline and increased by a median of 159 cells/microL at week 24. The most common treatment-related adverse events were mild to moderate central nervous system symptoms (73% of patients), diarrhea (33%), rashes (10%), and biochemical abnormalities. Adverse reactions led to permanent drug discontinuation in only 1 patient. The once-daily combination therapy of emtricitabine, didanosine, and efavirenz was safe and demonstrated strong antiviral and immunologic effects that lasted for the 24-week period of the study.     

Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients

Pneumocystis carinii has taken on new importance with the emergence of the human immunodeficiency virus. It is the most common life-threatening opportunistic infection in the acquired immunodeficiency syndrome and eventually develops in 80% or more of those not receiving primary prophylaxis. This review focuses on the clinical presentation, diagnosis, treatment, and prophylaxis of P carinii pneumonia in patients with human immunodeficiency virus infection.