a Centre for Excellence in HIV/AIDS.
b Canadian HIV Trials Network.
c Departments of Health Care and Epidemiology,
d Pathology and Laboratory Medicine,
e Department of Medicine, Faculty of Medicine, University of British Columbia.
Katherine Heath, BC Centre for Excellence in HIV/AIDS, 6081081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada. E-mail: kheath{at}hiunet.ubc.ca
Abstract
Objective To provide population-based incidence estimates for constituent symptoms of human immundeficiency virus (HIV)-related lipodystrophy syndrome and to identify possible independent predictors of accrued cases.
Design Prospective population-based cohort.
Methods Study subjects were antiretroviral-naïve individuals who initiated treatment between October 1998 and May 2001 and provided completed self-reported data regarding the occurrence of lipoatrophy, lipohypertrophy and increased triglyceride and cholesterol levels. Possible predictors of incident lipoatrophy, lipohypertrophy, dyslipidaemia and mixed lipodystrophy (symptoms of both lipoatrophy and lipohypertrophy) were identified using logistic regression modelling. A sub-analysis restricted to subjects retaining original treatment at study completion was conducted using similar methods.
Results Among the 366 study subjects, cumulative incidence was 29% for lipoatrophy, 23% for lipohypertrophy, 9% for dyslipidaemia, and 13% for mixed lipodystrophy after a median duration of 12 months of antiretroviral therapy. In an intentto-treat analysis incident lipoatrophy and lipohypertrophy were independently associated with initiation of protease inhibitor (PI)-containing regimens, (adjusted odds ratio [AOR] = 1.94; 95% CI: 1.253.03 and AOR = 1.76; 95% CI: 1.092.85, respectively) and female gender (AOR = 2.06; 95% CI: 1.034.12 and AOR = 2.36; 95% CI: 1.174.74, respectively). Both mixed lipodystrophy and reported dyslipidaemia were associated only with PI inclusion in the initial regimen (AOR = 2.27; 95% CI: 1.144.53 and AOR = 2.14; 95% CI: 1.263.65, respectively). Similar results were obtained in analysis of individuals retained in initial treatment groups throughout follow-up.
Conclusion Incident morphological and lipid abnormalities are common among individuals initiating first-time antiretroviral therapy. Use of PI was consistently associated with all lipodystrophy-related abnormalities after adjustment for a broad range of patient personal, clinical and treatment characteristics.
Keywords Lipodystrophy, dyslipidaemia, antiretrovirals, protease inhibitors
Accepted 12 June 2002
Standard care with highly active triple combination antiretroviral therapy for human immunodeficiency virus (HIV) infection has been linked to the emergence of morphological and lipid abnormalities often appearing in constellation as a syndrome of HIV-associated lipodystrophy.1 Morphological changes include localized lipohypertrophy of the abdomen, breasts and dorso-cervical region, and peripheral lipoatrophy of the face, buttocks, arms and legs.13 Metabolic changes include increased cholesterol and triglyceride levels.1,3
Cross-sectional and retrospective analyses indicate prevalence rates ranging from <10% to >80% for these abnormalities (for a review see ref. 4). While the aetiology of these abnormalities remains obscure, reports have identified increased risk associated with exposure to protease inhibitors (PI)1,2,58 and nucleoside analogue reverse transcriptase inhibitors (NRTI)7,911 among other factors.
Inconsistencies in study findings may be due to variations in diagnostic criteria or outcomes assessment. While objective methods such as dual energy X-ray absorptiometry (DEXA), computed tomography (CT), and magnetic resonance imaging (MRI) have been used, the resulting data is not well standardized in the context of HIV-associated lipodystrophy. These techniques can also be prohibitively costly and difficult to access. Therefore, many larger studies have relied on patient self-report and subjective/semi-qualitative clinical exam.6,1118 Patient self-report, while subject to misclassification, has been shown to be highly concordant with clinical findings of morphological abnormalities.5 Variability may also be due to differences in study design. Many aetiological investigations have relied on cross-sectional,10,13,16,19 and/or retrospective17,18,20 analyses or have included highly selected study subjects.15,18,20
Neither the incidence of lipodystrophy-associated abnormalities nor the possible predictors of emerging symptoms subsequent to first initiation of standard therapy have been well described. Here we report the cumulative incidence and possible predictors of lipodystrophy-associated symptoms and lipid abnormalities based on prospective self-report data from an observational cohort of people initiating a variety of antiretroviral regimens.
Methods
In British Columbia, Canada, the distribution of antiretrovirals free of charge to all eligible province residents is centralized in a provincial HIV/AIDS drug treatment programme. All patients are registered in the programme when first prescribed any antiretroviral agent. A complete prospective record of all therapies prescribed is maintained in addition to demographic and clinical data. Consenting patients provide additional information, including the occurrence of known or suspected adverse drug effects, through annual voluntary self-administered questionnaires. Since October of 1998, these have included symptoms and laboratory abnormalities associated with lipodystrophy syndrome including lipoatrophy of the face, arms or legs, lipohypertrophy (weight gain in the abdomen or breasts and/or buffalo hump) and increased cholesterol and triglycerides. All data is, therefore, based on patient self-report which may be particularly problematic for accuracy of reported lipid abnormalities. To assess the accuracy of self-reported dyslipidaemia survey responses were compared to actual laboratory values for 134 individuals with laboratory data available within 3 months prior to survey. Of those reporting high cholesterol or high triglycerides 94% and 84% had laboratory values indicating high cholesterol (defined as >5.2 mm/dl) or triglycerides (defined as >2.3 mm/dl), respectively. These findings indicate a low rate of false positives for self-reported dyslipidaemia in this study.
The study population for the present analysis included antiretroviral-naïve individuals who initiated treatment between October 1998 and May 2001 and provided completed data regarding the occurrence of adverse drug effects at least 3 months and no more than 24 months after therapy initiation.
A broad range of socio-demographic and clinical characteristics were investigated in preliminary bivariate analyses. These included patient age, ethnicity, gender, employment status, education level, transmission risk group, plasma viral load (pVL) and CD4 cell count at baseline, and change in pVL and CD4 over follow-up. Treatment variables assessed included initial prescription of therapy by regimen makeup, therapy class inclusion (PI, NRTI and non-nucleoside analogue reverse transcriptase inhibitors [NNRTI]) and total duration by class and by agent for each of four PI, five NRTI and three NNRTI. Variables significant at the P < 0.05 level were offered for inclusion in logistic modelling to assess independent contributions to each of four incidence outcomes: lipoatrophy; lipohypertrophy; dyslipidaemia; and mixed lipodystrophy (defined as having both peripheral lipoatrophy and one or more areas of lipohypertrophy).
Initial models followed the intent-to-treat principal, retaining all subjects grouped for analysis by initial treatment regimen. This approach has been used to gain information on lipodystrophy-associated abnormalities in clinical trials and is useful in comparing the results of these trials to those obtained by other methods. A sub-analysis was restricted to those people who remained on the initial treatment regimen throughout follow-up. This approach ensures that confounding or other complex treatment-related phenomena that may arise as a result of multiple therapy switches or temporary therapy cessation are minimized.
Results
Table 1 summarizes initial prescribed regimens, the proportion of subjects remaining on initially prescribed therapy and duration of follow-up for the 366 subjects eligible for analysis. Thirty per cent of individuals initiated antiretroviral treatment with regimens including two or three NRTI and one NNRTI, 49% with two or three NRTI plus a PI, 10% used two PI including Ritonavir as a boosting agent, and 11% were restricted to dual NRTI therapy. Overall, 59% of subjects initiated therapy with PI-containing regimens, 30% with NNRTI, and 100% utilized NRTI inclusive regimens. In terms of non-treatment characteristics median age was 38 years, 68% were Caucasian, 89% male, 52% had greater than a high school education and 47% were employed. Median CD4 count at entry was 320 cells/mm3 (interquartile range: 100430), median pVL was 66 500 copies/ml and 16% had been diagnosed as having AIDS. Over the course of follow-up the median decline in pVL was 66 298 copies/ml and CD4 cell counts increased by 120 cells/mm3.
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After a median duration of therapy of 12 months (range: 323 months) the cumulative incidence was 29% for lipohypertrophy, 23% for lipoatrophy, 9% for increased cholesterol or triglycerides and 13% for mixed syndrome. The occurrence of lipid abnormalities and of morphological changes appear to be independent, with those having morphological abnormalities at no greater risk of concomitant lipid disturbances (2 P = 0.299).
Table 2 summarizes the findings of multivariate analysis for each of lipohypertrophy, lipoatrophy, dyslipidaemia and mixed lipodystrophy in the cohort overall. Both incident lipoatrophy and lipohypertrophy were independently associated with use of PI containing regimens (adjusted odds ratio [AOR] = 1.94; 95% CI: 1.253.03 and AOR = 1.76; 95% CI: 1.092.85, respectively). Risk of lipoatrophy and lipohypertrophy were also significantly greater for women (AOR = 2.06; 95% CI: 1.034.12 and AOR = 2.36; 95% CI: 1.174.74, respectively). Mixed lipodystrophy was associated only with PI inclusion in the treatment regimen (AOR = 2.27; 95% CI: 1.144.53) as was the occurrence of dyslipidaemia (AOR = 2.14; 95% CI: 1.263.65).
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Discussion
Our results indicate a high incidence of morphological and lipid abnormalities among those initiating first-time antiretroviral therapy. Few comparable estimates of incidence are available, although reported figures are in agreement with the data presented here. A similar study of therapy-naïve patients initiating triple drug regimens reported a prevalence of morphological changes identified subjectively by both physician and patient of 17% after a median of 18 months of therapy.14 Similarly, a study of 121 people treated with triple therapy for primary HIV infection reported a cumulative incidence of morphological changes of 18% at 24 months based on clinical exam.12 Studies conducted among non-naïve subjects utilizing PI inclusive therapy report comparable rates of incidence.15,18
Multivariate analyses indicate PI class exposure in each of the symptom groups examined here. While some studies have not implicated treatment-related factors in the occurrence of morphological abnormalities,10,19 the majority have identified specific PI or PI use in general as possible predictors of prevalent symptoms.1,5,7,8,17,21 Studies utilizing symptom-specific analyses have also noted associations between duration of PI exposure in both lipoatrophy and abdominal obesity,9 and PI-containing highly active antiretroviral therapy (HAART) duration and any lipodystrophy and lipoatrophy.14 One study of HAART-exposed individuals has reported significantly increased risk of lipohypertrophy with PI class therapy.6
Reported dyslipidaemia in our cohort was also independently associated only with use of PI-inclusive regimens. These findings are consistent with the known effects of PI on lipid profiles and prior reports describing lipid abnormalities among those with treatment-related lipodsytrophy.5,22,23
The occurrence and differential rates of presentation of lipodystrophy symptoms among women have been well described,24,25 unfortunately, many aetiological studies have not included substantial numbers of female subjects or have not assessed gender as an independent variable. Despite restricted power in our study (n = 40), we noted a greater than twofold increased risk of both lipoatrophy and lipohypertrophy among women. Martinez et al. have similarly reported a relative hazard of 1.87 among women for lipodystrophy overall among naive subjects exposed to PI inclusive triple therapy.14 Three other studies that have included analysis by gender noted no increased risk among women, however, these studies were also limited by power constraints.11,13,18 While reporting bias is a possible explanation for our findings, no increased risk of mixed lipodystrophy among women was noted suggesting that simple over-reporting is not likely to have occurred.
The data presented here do not indicate a role of immune reconstitution as indicated by improvements in pVL and/or CD4 cell count in the development of symptoms as has been suggested in some reports.13,16 It is important to note that such previously published results were not adjusted for treatment adherence and that our findings are consistent with those of further studies.17,18
The data reported here is based on patient self-report, and therefore subject to the limitations of this methodology. However, identification of morphological abnormalities in clinical practice and large cohort studies is likely to remain reliant on relatively subjective measures. Moreover, patient assessment of morphological abnormalities has been shown to correspond well to the findings of physical exam. It should be noted, however, that under-reporting of abnormal lipids may be problematic if physicians do not communicate these findings to patients or if recall among patients is poor.
The data presented here indicate a high incidence of lipodystrophy-associated abnormalities among those initiating antiretroviral therapy. Increased risk associated with initiation of PI-inclusive regimens and among women is cause for concern. The long-term clinical consequences of these disorders are not clear at this time. However, morphologically defined lipodystrophy has been associated with cardiovascular risk factors such as increased fasting insulin levels and diastolic blood pressure, impaired glucose tolerance, diabetes and hypertriglyceridaemia among HIV positive subjects.26 Moreover, there is some evidence that women may be more susceptible to the adverse metabolic effects of PI-containing regimens.27 Clearly, large prospective studies of women need to be undertaken to determine whether the traditional consideration of female gender as a protective factor in terms of cardiovascular risk applies equally to those receiving PI-inclusive antiretroviral therapy for HIV infection.
KEY MESSAGES
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Acknowledgments
Ms Heath is supported by a Walton Killam Memorial Pre-doctoral Fellowship and Dr Hogg is supported by an Career Investigator Award through the Michael Smith Foundation for Health Research and an Investigator Award through the Canadian Institutes of Health Research. We thank Bonnie Devlin, Diane Campbell, Elizabeth Ferris, Nada Gataric, Kelly Hsu, Myrna Reginaldo, and Peter Vann for their research and administrative assistance.
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