Andrew Carr

A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving Hiv protease inhibitors

Objective: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. Design:Cross-sectional study. Setting:Outpatient clinic of a university teaching hospital. Patients:HIV-infected patients either receiving at least one protease inhibitor (n = 116) or protease inhibitor-naive (n = 32), and healthy men (n = 47). Interventions and main outcome measures: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. Results: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. Conclusion:A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndromes pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.

Adverse effects of antiretroviral therapy

Antiretroviral toxicity is an increasingly important issue in the management of HIV-infected patients. With the sustained major declines in opportunistic complications, HIV infection is a more chronic disease, and so more drugs are being used in more patients for longer periods. This review focuses on the pathogenesis, clinical features, and management of the principal toxicities of the 15 licensed antiretroviral drugs, including mitochondrial toxicity, hypersensitivity, and lipodystrophy, as well as more drug-specific adverse effects and special clinical settings.

A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome.

BackgroundLipodystrophy (LD; peripheral lipoatrophy, central adiposity) hyperlipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. Lipoatrophy and abdominal distension were observed in protease inhibitor-naive nucleoside analogue reverse transcriptase inhibitor (NRTI) recipients with lactic acidaemia and hepatic impairment, which are known NRTI-induced mitochondrial toxicities. Design and settingCase-control study in a university-based outpatient clinic. Patients and methodsThe patients studied included 14 NRTI recipients with lipoatrophy, 32 antiretroviral-naive patients without LD, 28 NRTI recipients without LD, 44 combined NRTI-protease inhibitor recipients without LD, and 102 NRTI-protease inhibitor recipients with LD. Data was obtained on body composition (questionnaire, physical examination, dual-energy x-ray absorptiometry and abdominal computerized tomography), with biochemical, lipid and glycaemic parameters. ResultsThe NRTI-LD syndrome was characterized by recent onset fatigue and nausea, peripheral lipoatrophy (6 kg loss over 4 months), abdominal distension (ascites ± hepatomegaly) and elevated lactate (4.6, 1.1, 1.2, 1.4 and 1.7 mmol/l, respectively; P  < 0.0001) and liver enzymes. Cases without hepatic involvement also had lower body fat and greater lactate than unaffected controls. Metabolic disturbances and weight improved after cessation. The NRTI-LD syndrome differed from protease inhibitor-related LD syndrome by the presence of recent onset symptoms and weight loss, higher lactate and alanine aminotransferase, and lower albumin, cholesterol, triglycerides, glucose and insulin. In treated controls, current stavudine therapy, protease inhibitor duration, and lactic acidaemia were independently associated with both lipoatrophy and abdominal obesity; total NRTI duration was also associated with lipoatrophy, and lamivudine and protease inhibitor duration with buffalo hump. ConclusionsA syndrome of lipoatrophy, constitutional illness, lactic acidaemia and hepatic dysfunction can complicate NRTI therapy. Both protease inhibitor and NRTI therapies, particularly if associated with lactic acidaemia, contribute to LD syndrome, but have some distinguishable clinical and metabolic effects.

A SHORT-TERM STUDY OF THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF RITONAVIR, AN INHIBITOR OF HIV-1 PROTEASE

BACKGROUND Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability. METHODS We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. RESULTS During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. CONCLUSIONS In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established.

An objective case definition of lipodystrophy in HIV-infected adults: a case-control study

BACKGROUND Lipodystrophy (peripheral lipoatrophy, central fat accumulation, and lipomatosis) is a common and disfiguring problem in adult patients with HIV-1 infection on antiretrovirals. However, an objective, validated definition of the disorder does not exist. We aimed to develop an objective, sensitive, specific, and broadly applicable case definition of HIV lipodystrophy. METHODS In a case-control study, 1081 consecutive, HIV-infected, adult outpatients (261 [15%] women) without active AIDS were recruited from 32 sites worldwide. We classed patients with at least one moderate or severe subjective lipodystrophic feature, identified by lipodystrophy-specific physical examination and patient questionnaire, and apparent to both doctor and patient as cases (n=417). We classed patients with no such feature as controls (n=371), and patients without a clear diagnosis as non-assigned. We used objective clinical, metabolic, and body composition measurements to construct a logistic regression model with a subset of randomly selected cases and controls. The model was validated in the remaining patients. FINDINGS A model including age, sex, duration of HIV infection, HIV disease stage, waist to hip ratio, anion gap, serum HDL cholesterol concentration, trunk to peripheral fat ratio, percentage leg fat, and intra-abdominal to extra-abdominal fat ratio had 79% (95% CI 70-85) sensitivity and 80% (95% CI 71-87) specificity for diagnosis of lipodystrophy. Models that incorporated only clinical, or only clinical and metabolic variables had lower sensitivity and specificity than the inclusive model. Models for lipoatrophy, fat accumulation, and lipomatosis could not be developed since pure phenotypes occurred in fewer than 10% of patients with clinical diagnoses of these disorders. INTERPRETATION Our objective case definition of HIV-associated lipodystrophy should improve assessment of lipodystrophy prevalence, risk factors, and pathogenesis; prevention and treatment approaches; and assist in diagnosis.

Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.

Objective: Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV‐1 infection and potent antiretroviral therapy, but limited data ate available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. Participants: A 12‐member panel representing international expertise in HIV‐1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society‐USA, a not‐for‐profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society‐USA; the panel members are not compensated for their participation. Evidence: The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. Process: For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. Conclusions: Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV‐1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long‐term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long‐term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the riskbenefit ratio of antiretroviral therapies.

Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy

BACKGROUND Enterocytozoon bieneusi and Cryptosporidium parvum cause chronic antimicrobial-resistant gastrointestinal infections in HIV-1-infected individuals. HIV-1 reverse transcriptase inhibitors delay the onset of opportunistic infections, but are not known to reverse established infections. HIV-1 protease inhibitors are more effective across a broader range of HIV-1-infected immune cells. Combination antiretroviral therapy that includes a protease inhibitor could improve immunity to E bieneusi and C parvum. METHODS HIV-1 infected patients with chronic microsporidiosis (five), cryptosporidiosis (three), or dual infection (one), were treated with combination therapy that included at least one HIV-1 protease inhibitor. Outcome measures were symptoms, weight, use of antidiarrhoeal and antimicrobial drugs, T-lymphocyte subsets, HIV-1 viraemia, stool microscopy, and biopsy by endoscopy. FINDINGS All patients had complete clinical responses, gained a median 15 kg in weight, and ceased all antidiarrhoeal and antimicrobial therapies. Biliary cryptosporidiosis responded in both affected patients. Neither pathogen was detected in follow-up stool microscopy (eight of eight patients) or in biopsy samples by endoscopy (five of five). Intestinal architecture returned to normal in three patients. There was a dense CD8 lymphocyte and macrophage infiltrate and staining of intraepithelial E bieneusi with interferon-gamma before and after treatment, but little staining for CD4 or B lymphocytes, interleukin 10, or HIV-1 gp41. Five patients remained symptom-free after a median 13 months follow-up. Four patients had recurrent diarrhoea at 7-13 months (one with positive stool microscopy), associated with declining CD4 counts. INTERPRETATION Combination antiretroviral therapy that includes a protease inhibitor can restore immunity to E bieneusi or C parvum in HIV-1 infected individuals, and result in complete clinical, microbiological, and histological responses. The persistent CD8 cell and macrophage infiltrate, and the rapid time to relapse in patients with declining CD4 lymphocyte counts, suggest that neither infection was eradicated.

A controlled trial of zidovudine in primary human immunodeficiency virus infection.

BACKGROUND It is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis. METHODS To assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months. RESULTS The mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (+/- SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P = 0.009 by the log-rank test). After adjustment for the base-line CD4 cell count, the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, -1.4 to 19.1) during the first six months of the study, whereas those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 percent confidence interval, 5.2 to 18.7), for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P = 0.001). CONCLUSIONS Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

Epidemiological Evidence for Cardiovascular Disease in HIV-Infected Patients and Relationship to Highly Active Antiretroviral Therapy

In the mid-1990s, case reports of myocardial infarction (MI) in young patients infected with human immunodeficiency virus (HIV) sparked interest in the relationship between HIV infection and cardiovascular disease (CVD).1,2 Although the initial focus was primarily on the relationship between dyslipidemia associated with antiretroviral therapy (ART) and cardiovascular risk, a broader appreciation of the complex interplay between traditional risk factors for CVD and HIV infection has emerged more recently. Several groups of investigators have designed studies to examine various aspects of the relationship between HIV infection, traditional cardiovascular risk factors, ART, and short- and longer-term cardiovascular risk3–11 (see also Working Group 1). Studies have included both clinical end points (MI, hospitalization for MI or angina, and revascularization) and surrogate markers of atherosclerosis (endothelial function or carotid intima-media thickness). Successive studies have generally improved in quality, with inclusion of data on traditional risk factors, longer follow-up, and more diverse patient populations. HIV and ART can contribute to an altered risk of CVD in 3 principal ways: (1) HIV may serve as a marker to identify a subgroup of the general population with an altered prevalence of traditional cardiovascular risk factors, unrelated to HIV or ART (eg, HIV-infected patients may have higher smoking rates); (2) HIV or ART may affect the risk of developing a traditional cardiovascular risk factor (eg, HIV or ART may worsen dyslipidemia); and (3) HIV or ART may affect the pathogenetic process that leads to CVD in ways other than via an effect on traditional risk factors (eg, through effects on inflammation or endothelial function). Importantly, there is substantial evidence to suggest that all 3 mechanisms are in operation and affect the risk of CVD in patients infected with HIV. All 3 factors should be considered in epidemiological studies assessing the relationship between CVD and HIV …