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Association between HLA-B*4001 and Lipodystrophy among HIV-Infected Patients from Thailand Who Received a Stavudine-Containing Antiretroviral Regimen

  1. Wittaya Wangsomboonsiri1,
  2. Surakameth Mahasirimongkol4,5,
  3. Soranun Chantarangsu2,6,
  4. Sasisopin Kiertiburanakul1,
  5. Angkana Charoenyingwattana3,
  6. Surat Komindr1,
  7. Chupong Thongnak3,
  8. Taisei Mushiroda6,
  9. Yusuke Nakamura6,7,
  10. Wasun Chantratita2, and
  11. Somnuek Sungkanuparph1
  1. 1Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Bangkok
  2. 2Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Bangkok
  3. 3Pharmacogenomics project under collaboration between Thailand Center of Excellence for Life Sciences, Mahidol University, Bangkok
  4. 4Center for International Cooperation, Nonthaburi, Thailand
  5. 5Medical Genetic Section, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
  6. 6Research Group for Pharmacogenomic, RIKEN, Center for Genomic Medicine, Tokyo, Japan
  7. 7Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
  1. Reprints or correspondence: Dr Somnuek Sungkanuparph, Div of Infectious Diseases, Dept of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand (rasuy{at}mahidol.ac.th).
 
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Abstract

Background. Stavudine-containing antiretroviral regimens are widely used in developing countries. Stavudine-associated lipodystrophy commonly occurs, without a clear predictable pattern owing to the unknown interaction between stavudine and the host, among patients who received this regimen. The aim of this study was to determine the clinical risk factors and human leukocyte antigen (HLA) alleles associated with stavudine-associated lipodystrophy.

Methods. A case-control, cross-sectional study was conducted for HIV-infected patients receiving stavudine-containing antiretroviral regimens. Clinical assessments for lipodystrophy by physical examination, anthropometry, and dual-energy X-ray absorptiometry were obtained. On the basis of their clinical assessment, the patients were classified into 2 groups: the case group (moderated to severe lipodystrophy) and the control group (absent to mild lipodystrophy). The clinical characteristics and allelic distribution of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 were compared between the case group and the control group, to determine the possible association with stavudine-associated lipodystrophy.

Results. There were 103 patients; 55 patients were in the case group, and 48 patients were in the control group. By use of forward stepwise logistic regression, the presence of HLA-B*4001 (odds ratio [OR], 14.05; 95% confidence interval [CI], 2.57–76.59; P=.002) and a longer duration of stavudine treatment (OR, 1.02; 95% CI, 1.00–1.04; P=.02) were significantly associated with stavudine-associated lipodystrophy, whereas a higher body mass index during treatment (OR, 0.73; 95% CI, 0.61–0.86; P<.001) was associated with a lower risk for lipodystrophy. HLA-B*4001 has a high specificity (95.8%) and a positive predictive value (88.9%) for lipodystrophy.

Conclusions. HLA-B*4001 is a strong genetic risk factor for stavudine-associated lipodystrophy in HIV-infected patients in Thailand. HLA-B*4001 may be used as a genetic marker to predict which patients will develop stavudine-associated lipodystrophy, to avoid or shorten the duration of stavudine use. This finding needs to be confirmed in further replication studies.

Stavudine is a nucleoside analogue reverse-transcriptase inhibitor that has been approved since 1994 by the US Food and Drug Administration [1]. A generic, fixed-dose combination of stavudine, lamivudine, and nevirapine has been available and widely used in Thailand and other developing countries since 2002 [2]. This stavudine-containing regimen has been proven in terms of efficacy and safety for human immunodeficiency virus (HIV) treatment in resource-limited settings [3–5]. Nucleoside reverse-transcriptase inhibitors (NRTIs), especially stavudine, have several adverse effects that are associated with mitochondrial toxicity [6–9], such as lactic acidosis [10–12], neuropathy [13, 14], pancreatitis [15, 16], and lipodystrophy [17–19]. However, the pathogenesis and mechanisms of stavudine-associated lipodystrophy are not well understood, even though some advances have been made in molecular and genetic studies of lipodystrophy [20–23]. Stavudine-associated lipodystrophy could be considered an inflammation syndrome, according to previous studies that demonstrated increased plasma levels of proinflammatory and inflammatory cytokines [24–27], or it could be considered the apoptosis of adipocytes, as evidenced by decreased adipogenic factors [21, 28, 29].

The development of pharmacogenomics has provided the medical community with the novel predictive capability to determine a drug's response and susceptibility to toxicities or adverse effects on the basis of a patient's genotype information [30, 31]. Recently, HLA-B*5701 [32, 33] and HLA-B*3505 [34], variants of a gene within the major histocompatibility complex (MHC), had been shown to be useful for predicting abacavir hypersensitivity and nevirapine-induced rash, respectively. Stavudine is the strongest antiviral agent among its class that is associated with lipodystrophy [18, 35, 36]. Previous studies implicated the role of tumor necrosis factor (TNF)–α, a gene in the MHC class III, as a risk factor for lipodystrophy associated with antiretroviral therapy [37]. Because of the close proximity of these human leukocyte antigen (HLA) genes with TNF-α, the implication of immune-related genes in drug-induced lipodystrophy, it is likely that variations within MHC regions play an important role in determining the courses of stavudine-associated lipodystrophy. To our knowledge, there is no study on the association between stavudine-associated lipodystrophy and HLA genes in MHC class I and MHC class II. The aims of the present study were to determine clinical risk factors for stavudine-associated lipodystrophy and to assess the association between HLA alleles and stavudine-associated lipodystrophy among HIV-infected patients in Thailand.

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Methods

Study population. A case-control, cross-sectional study of HIV-infected patients who attended the infectious diseases clinic, Ramathibodi Hospital (an 800-bed university hospital), Mahidol University, Bangkok, Thailand, was conducted. The patients were from a previous study [34, 38]; enrollment began in March 2006 and ended in February 2007. Inclusion criteria for this study were that the patients had to be adult (⩾15 years old) HIV-infected patients who have been exposed to stavudine and maintained the stavudine-containing antiretroviral regimen. The patients were invited to participate for evaluation and physical examination for lipodystrophy. The study period of this study was between November 2008 and March 2009. For all patients, baseline data included demographics, time since first positive HIV-antibody test, a previous AIDS-defining illness, CD4 cell count, HIV RNA, past and current antiretroviral therapy, duration of antiretroviral therapy, and duration of treatment with stavudine-containing regimens.

Evaluation of lipodystrophy syndrome. The presence of lipodystrophy was independently assessed by the patients and the investigator. Patients had completed a lipodystrophy-specific questionnaire and underwent a standardized, lipodystrophy-specific physical examination by the same infectious disease physician throughout the study (data collection form available from investigator). Both assessments recorded independently any lipoatrophy or diffuse fat accumulation in each of face, neck, dorsocervical area, arms, breasts, abdomen, buttocks, and legs, as well as the presence and site. The degree of lipoatrophy and diffuse fat accumulation at each region was rated as absent (score of 0), mild (noticeable on close inspection; score of 1), moderate (readily noticeable by patient and/or physician; score of 2) or severe (readily noticeable to casual observer; score of 3) [39, 40].

To reduce the influence of a mild physical manifestation incorrectly being attributed to the syndrome, we defined a lipodystrophy group, which we call “moderate to severe lipodystrophy,” on the basis of the number and severity of the 3 body areas affected (signs): sunken cheeks, thinning extremities, and thinning hips or buttocks. Patients with any “severe” signs were included in the group. Patients whose most severe sign was “moderated” were only included if they had at least 1 additional sign (mild or moderate). Patients with a single moderate sign but no additional signs and patients with 1, 2, or 3 mild signs were assigned to the control (absent to mild lipodystrophy) group. However, the presence of moderate or severe isolated abdominal obesity was a reason for exclusion, because we would like to minimize the misclassification bias that would occur if we included patients with age-related central obesity. We combined patients with no sign of lipodystrophy together with patients whose signs were too mild for the “moderate to severe” group. Mild lipodystrophy might have a less cosmetic and clinical effect on patients' compliance to stavudine; thus, we separated patients into a “moderate to severe” group and an “absent to mild” group for further association analysis [39, 40]. We defined “moderate to severe lipodystrophy” as the “case group” and “absent to mild lipodystrophy” as the “control group.”

Anthropometric measurements were performed by the same dietician throughout the study. The height, the body weight, the circumference of neck, chest, midarm, midthigh, waist, and hip, and the skinfold thickness at 4 sites (scapular, biceps, triceps, and suprailiac) were measured according to the World Health Organization recommendations [41]. Skinfold thickness and circumference were measured by using skinfold caliper and anthropometric tape, respectively. Body mass indices (BMIs) and waist-hip ratios were calculated from anthropometric data.

Whole-body dual-energy X-ray absorptiometry (DEXA) scans (Hologic Discovery A, version 12.6.1; Hologic) were conducted by a single operator. Scans were performed to access body fat mass, fat-free mass, and bone mass, as described in the Lipodystrophy Case Definition Study [42]. Bioelectrical impedance analysis was performed with a multifrequency impedance analyzer by using the InBody 720 body composition analyzer (Biospace), as described in the manufacturer's manual. This analyzer was used to determine the body fat mass and the visceral fat area.

Blood samples were analyzed for serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, and fasting blood glucose. The processes used for evaluating lipodystrophy syndrome for individual patients were done completely within 1 day, except for the DEXA scans, which were performed on another day for some patients but within 2 weeks from clinical assessment. The study was approved by the institutional review board. Informed consent was obtained from all study patients.

DNA isolation. Genomic DNA was isolated with a standard phenol-chloroform extraction protocol and resuspended in Tris-HCL buffer (pH 8.5) [34]. Their concentration was quantified by using a UV spectrophotometer ND-1000 (NanoDrop Technologies). The purity was determined by calculating the ratio of absorbance at 260–280 nm.

HLA genotyping. Genotypes in HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 were determined by sequence-based typing using the AlleleSEQR Sequence-Based Typing Kits (Atria Genetics), according to the manufacturer's instructions [34]. Briefly, the primary amplification reaction consists of a polymerase chain reaction (PCR) premix reagent, AmpliTaq Gold, and 20 ng/µL of genomic DNA. The PCR products were purified by using ExoSAP-IT and sequenced in the forward and reverse orientations. Finally, the reaction products were reconstituted with 15 µL of Hi-Di formamide (Applied Biosystems) and run on the ABI 3730xl DNA Analyzer (Applied Biosystems), and genotype calling was made by Assign SBT 3.2.7 software (Conexio Genomics).

Statistical analysis. Gene-wise comparisons of allele frequencies between the case and control groups for each gene were made using the CLUMP program [43]. Individual allelic association tests for a gene that shows evidence of an association (from analysis using the CLUMP program) were further clarified by use of the Fisher exact test. All P values <.05 were considered to indicate possible statistical significance. The corrected P (Pc) values were adjusted by applying a gene-wise multiple correction for each gene (14 for HLA-A, 20 for HLA-B, 16 for HLA-C, 18 for HLA-DRB1, 12 for HLA-DQB1, and 13 for HLA-DPB1) to account for the number of alleles observed in more than 1% of the total number of case and control patients [34].

Continuous data with a normal distribution are shown as mean values (± standard deviation [SD]), and those with a nonnormal distribution are shown as median values (interquartile range [IQR]). Categorical data are shown as frequency and percentage. Continuous data were compared between the 2 groups using an independent t test or the Mann-Whitney U test. The χ2 test or the Fisher exact test was used for categorical data analysis, where appropriate. Multivariate analysis was performed to determine factors associated with lipodystrophy by using multivariate logistic regression models with P<.1 for entry into the model and P<.05 for remaining in the model. The Pearson product-moment correlation coefficients were used to quantify the pair-wise correlations between variables' entry into the model. Step-wise forward regression analysis was used to measure the contribution of variables to the value of independent variables in a multivariate logistic regression. The odds ratio (OR) and its 95% confidence interval (CI) were estimated. All analyses were performed using SPSS, version 14.0 (SPSS). A P value of <.05 was considered to be statistical significance.

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Results

Characteristics of patients. One-hundred and three patients from a previous cohort could be reached by mail or telephone; all had accepted to participate in this study. All of the patients had completed the process of evaluation of lipodystrophy syndrome, except for 2 patients who refused a DEXA scan because of claustrophobia. All patients had already had genotype data in HLA genes from the previous study [34].

A total 103 patients with a mean (±SD) age of 41.5±7.1 years were included in the study. Forty-nine patients (47.6%) were male. The mean (±SD) body weight was 56.8±10.9 kg, and the mean (±SD) height was 162.1±7.7 cm. Fifty patients (48.5%) had previous AIDS-defining illness prior to the initiation of antiretroviral therapy. The median duration of known HIV infection was 93.1 months (IQR, 71.5–117.8 months). The median duration of antiretroviral therapy was 57.7 months (IQR, 47.1–71.6 months), and the median duration of stavudine treatment was 47.1 months (IQR, 26.3–65.4 months). The median CD4 cell count at baseline of study was 478 cells/mm3 (IQR, 378–612 cells/mm3). The number of patients who had an undetectable viral load at baseline of study was 96 (93.2%). There were 55 patients in the case group and 48 patients in the control group. The case group consisted of 45 patients with moderate lipodystrophy and 10 patients with severe lipodystrophy. The control group consisted of 31 patients without lipodystrophy and 17 patients with mild lipodystrophy.

Lipoatrophy was a predominate feature of lipodystrophy, and lipohypertrophy was rare. table 1 shows the comparison of baseline characteristics between case and control groups. In the case group, there were higher proportions of patients with a history of AIDS-defining illness (P=.036), an undetecta-ble viral load at baseline of study (P=.013), and HLA-B*4001 (P=.001). Other baseline characteristics were not significant-ly different between the 2 groups.

Table 1
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Table 1

Clinical Characteristics of 103 Study Patients

Body composition. table 2 shows anthropometric data, body composition data, and metabolic data. In anthropometric measurements, patients in the case group had statistically significant lower body weight at baseline of study, BMI, body circumferences and skinfold thickness than those in the control group. Height, body weight at the initiation of antiretroviral therapy, neck circumference, and waist/hip ratio between the 2 groups did not differ significantly. In bioelectrical impedance analysis, the case group had significantly lower body fat mass and visceral fat than did the control group. In DEXA scans, the case group had statistically significant lower arm, leg, limb, and trunk fat, lower total mass, and lower total fat than did the control group. Fasting plasma glucose and lipid profiles were not different between the 2 groups.

Table 2
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Table 2

Anthropometric, Body Composition, and Metabolic Parameters at Baseline of Study

Association between HLA-B*4001 and moderate to severe lipodystrophy. With existing data on DNA sequences [34], we determined genotypes at the HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 loci in the set of 55 patients in the case group and in the set of 48 patients in the control group. HLA-B*4001 allele was observed at a significantly higher frequency in the case group than in the control group. After the gene-wise multiple testing correction, HLA-B*4001 remained significantly different between case and control groups (Pc=.02). The HLA-B*4001 was present in a total of 18 patients (17.5%): 16 (29.1%) from the case group and only 2 (4.2%) from the control group (table 3). The high effect size of HLA-B*4001, incorporated with convincing statistical evidence after gene-wise multiple testing correction, supported this allele or those in high linkage disequilibrium with this allele as the causative genetic variation.

Table 3
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Table 3

Status of HLA-B*4001 between Case Group and Control Group

Risk factors for stavudine-associated lipodystrophy. In the multivariate logistic regression model, the BMI at baseline of study (OR, 0.73; 95% CI, 0.61–0.86; P<.001), the duration of stavudine treatment (OR, 1.02; 95% CI, 1.00–1.04; P=.020), and the HLA-B*4001 status (OR, 14.05; 95% CI, 2.57–76.59; P=.002) were identified to be significantly associated with stavudine-associated moderate to severe lipodystrophy (table 4). HLA-B*4001 had a sensitivity of 29.1%, a specificity of 95.8%, a positive predictive value of 88.9%, and a negative predictive value of 54.1%.

Table 4
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Table 4

Multivariate Analysis of Risk Factors Associated with Stavudine-Associated Lipodystrophy

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Discussion

To the best of our knowledge, this is the first report that shows how the HLA allele HLA-B*4001 influences stavudine-associated lipodystrophy. The results of the HLA-B*4001 association provide statistical support of the role that MHC class I locus plays for this phenotype. Interestingly, when we combined this genetic factor together with clinical factors in the regression model, we found that HLA-B*4001 was the strongest risk factor of stavudine-associated lipodystrophy in the present study.

There is evidence of increased macrophages in adipose tissue in lipoatrophic fat [44] and evidence of an increase in gene expression and translation of proinflammatory and inflammatory cytokines, such as IL-6, IL-8, IL-18, and TNF-α [21, 24–26]. The MHC locus is located within the 6p21.3 region of human chromosome 6 and contains more than 220 genes of diverse function [45]. HLA-B is a ubiquitously expressed cell surface antigen presenting proteins for antigen presentation that are vital during the early steps of immune responses [46]. Variations within MHC class I are also important host factors that control disease progression in an HIV-infected population. Therefore, the association between HLA-B*4001 and stavudine-associated lipodystrophy could be explained by the role played by HLA-B*4001 in antigen presentation.

Given the high specificity of HLA-B*4001 in the results of the present study, if these findings are confirmed in future prospective studies, then it will be possible to use this allele to avoid a substantial portion of stavudine-associated lipodystrophy by using an alternative antiretroviral agent for patients with HLA-B*4001. In the settings where stavudine cannot be totally replaced with zidovudine or tenofovir because of limited resources, HLA-B*4001 may be used to select a subset of patients who are at higher risk of lipodystrophy and have priority to substitute stavudine with other NRTIs.

As with any genetic association study, false positives cannot be excluded at this stage. Because of the nature of multiple testing in genetic association studies, this finding can occur by chance alone as a result of multiple testing. Unless this finding is a false positive, the causative allele in this loci might not be the HLA-B*4001 itself but other, closely located genetic polymorphisms that correlated highly with HLA-B*4001, because of a linkage disequilibrium between HLA-B*4001 and nearby polymorphisms that were not genotyped in this study. Replication of this finding is needed in a novel set of samples before the clinical application of this genetic marker can be tested in a prospective manner.

In addition to the association between HLA-B*4001 and lipodystrophy, a longer duration of stavudine treatment was found to be a risk factor for stavudine-associated lipodystrophy. We found that, for each month of stavudine use, the risk of lipodystrophy increased by 2%. This finding is concordant with the results from previous studies [18, 47–49] and could be explained by the increased duration of mitochondria toxicity. Of note, the patients in the present study had received stavudine for ∼4 years, but some patients had never experienced lipodystrophy. This warrants the possibility that genetic susceptibility plays a role in stavudine-associated lipodystrophy.

The present study has several limitations. First, it is a cross-sectional study with a small sample size, owing to the nature of pilot studies, and there is sampling bias because the initial design was that of a case-control study that recruited patients on the basis of nevirapine-induced rash status, but we had excluded the effect of bias on this result by multivariate logistic analysis and proved that a nevirapine-induced rash is not associated with lipodystrophy. We could not establish the accurate onset of lipodystrophy. Future prospective studies with a larger sample size (to replicate this finding and to explore the nearby genetic markers that elucidate linkage disequilibrium patterns in this locus) are needed [50]. Second, all the study patients in the present study are Asian. Thus, the results from this study may not be applicable to other ethnicities until there is a validation from a prospective study involving other non-Asian patients.

In conclusion, HLA-B*4001 is a genetic marker significantly associated with stavudine-associated lipodystrophy. This genetic factor is indeed stronger than the factor of stavudine treatment duration. For individual patients, if this genetic risk is confirmed, the marker can be used to determine whether to create a personalized antiviral regimen long before the development of any symptoms of lipodystrophy. HLA-B*4001 may play a role in clinical use and should be further evaluated, to avoid stavudine-associated lipodystrophy.

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Acknowledgments

We thank all the attending staff and physicians in the Division of Infectious Disease, Department of Medicine, and Virology and Molecular Microbiology Unit, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, and Ministry of Public Health, Nonthaburi, Thailand, for their contribution to our study.

Financial support. This work was supported by a grant from the Thailand Center of Excellence for Life Sciences and the DMSc-RIKEN collaboration for genotyping support to researchers in Thailand.

Potential conflicts of interest. All authors: no conflicts.

  • Received July 22, 2009.
  • Accepted October 6, 2009.
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  1. Clin Infect Dis. (2010) 50 (4): 597-604. doi: 10.1086/650003
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