Elsevier

The Lancet

Volume 357, Issue 9256, 24 February 2001, Pages 592-598
The Lancet

Articles
Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study

https://doi.org/10.1016/S0140-6736(00)04056-3Get rights and content

Summary

Background

Risk factors for lipodystrophy in patients infected with HIV-1 treated with highly active antiretroviral therapy (HAART) containing HIV-1 protease inhibitors are poorly understood. We aimed to identify the risk factors for lipodystrophy in antiretroviral-naïve HIV-1-infected adults on HAART.

Methods

Moderate or severe body-fat changes were clinically assessed and categorised as subcutaneous lipoatrophy, central obesity, or both, in all consecutive antiretroviral-naïve HIV-1-infected adults who began HAART with two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor from October, 1996, to September, 1999. A person-years analysis was used to calculate the incidence of types of lipodystrophy, and Cox proportional hazards models were used to describe the univariate and multivariate factors associated with progression to any lipodystrophy.

Findings

After a median follow-up of 18 months, 85 (17%) of the 494 patients developed some type of lipodystrophy. The incidences of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and lipodystrophy with central obesity were 11·7 (95% CI 9·2–14·2), 9·2 (7·0–11·4), and 7·7 (5·7–9·7) per 100 patient-years. An increased risk for any lipodystrophy was found among women as compared with men (relative hazard 1·87 [1·07–3·28]), heterosexuals (2·86 [1·50–5·48]), and homosexuals (2·17 [1·07–4·42]) as compared with intravenous drug users, with increasing age (1·33 per 10 years older [1·08–1·62]), and with the duration of exposure to antiretroviral therapy (1·57 per 6 months extra [1·30–1·88]) but not with any individual antiretroviral agent. The factors associated with an increased risk for lipodystrophy with subcutaneous lipoatrophy or lipodystrophy with central obesity were very similar to those associated with any lipodystrophy. The duration of indinavir use may represent an additional contribution for the development of lipodystrophy with central obesity (1·26 per 6 months extra [0·99–1·60]); p=0·064).

Interpretation

Risk factors associated with development of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and lipodystrophy with central obesity in patients infected with HIV-1 who were receiving HAART containing protease inhibitors are multifactorial and overlapping, and cannot be exclusively ascribed to the duration of exposure to an particular antiretroviral agent.

Introduction

After the publication of several case reports, abnormal fat distribution in HIV-1-infected patients receiving antiretroviral therapy was formally described as a clinical entity in 1998, under the name of lipodystrophy syndrome.1 Soon after lipodystrophy was recognised as one of the major limiting factors for long-term antiretroviral therapy. Initially described as a single entity, at least two different syndromes were found to exist: lipoatrophy or loss of subcutaneous fat;2 and central or visceral fat accumulation.3 Despite the difficulties in defining lipodystrophy, a high level of concordance has been seen between the doctor and patient diagnosis of moderate or severe lipodystrophy and the results of dual-energy X-ray absorptiometry (DEXA)4 or sonography.5

Lipodystrophy was initially considered to be only due to HIV-1 protease inhibitors.6 However, lipodystrophy does not invariably develop in all patients treated with protease inhibitors and it has been also described in patients who had never received protease inhibitors. Moreover, reversion of lipodystrophy does not occur after withdrawal of protease inhibitors.7, 8 More recently, several studies have linked the development of lipodystrophy with specific nucleoside reverse transcriptase inhibitors (NRTI).9, 10, 11, 12, 13 Interference with the lipid metabolism and mitochondrial toxicity associated with protease inhibitors6 and NRTI,14 respectively, are postulated to be involved in the pathogenesis of lipodystrophy.

Current studies on risk factors for lipodystrophy have important design limitations.4, 9, 10, 11, 12, 13 Small and sometimes biased population samples have been included, or cross-sectional analysis of mixed retrospective and prospectively followed cohort have been done. In addition, antiretroviral agents have usually been included in the analysis either as the initial prescribed drugs or as the current drugs when the analysis was undertaken.

We report on a prospective cohort study specifically designed to identify risk factors for moderate or severe lipoatrophy and fat accumulation including total exposition to individual antiretroviral agents in a large, unselected sample of antiretroviral-naive patients who were started on highly active antiretroviral therapy (HAART) including two NRTI plus at least one protease inhibitor.

Section snippets

Patients

All consecutive antiretroviral-naive HIV-1-infected adults who started triple therapy with two NRTIs plus at least one protease inhibitor from October, 1996, to September, 1999, were eligible if they granted oral informed consent to be assessed for clinical lipodystrophy at baseline and in subsequent routine medical visits. Data on body changes were prospectively collected as part of a protocol addressed to analyse the incidence of increased abdominal girth or fat accumulation since the

Study group

During the period of study, 494 antiretroviral-naive adults started HAART containing protease inhibitors. The median CD4-lymphocyte count at baseline was 204 cells per mm3 (IQR 96–342) and median viral load was 4·9 log copies/mL (4·4–5·4). Median known duration of HIV-1 infection was 33 months (3–87), and the median date of starting HAART was December, 1997 (May, 1997, to July, 1998). During a median follow-up of 18 months (10–24), 85 (17%) of the patients developed lipodystrophy. There were

Discussion

The patterns of antiretroviral drugs used were representative of those used in other more-developed countries at that time.16, 17 Previous cross-sectional epidemiological studies have reported a wide variable prevalence ranging from 2% to 84%.6 The incidence of any lipodystrophy in the present study was very similar to the prevalence rates of moderate or severe lipodystrophy in two mixed cross-sectional and longitudinal studies.4, 18

We found a high proportion of patients with overlapping

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