CLINICAL SCIENCE
Multicenter Cohort Study of Diabetes Mellitus and Impaired Fasting Glucose in HIV-Infected Patients in China Chengda Zhang, MD,* Felicia C. Chow, MD,† Yang Han, PhD,* Jing Xie, PhD,* Zhifeng Qiu, PhD,* Fuping Guo, MD, PhD,* Yanling Li, MD,* Huanling Wang, MD, PhD,* and Taisheng Li, MD, PhD*
Background: As life expectancy increases, HIV-infected patients are facing a wide array of metabolic complications, including diabetes mellitus (DM) and impaired fasting glucose (IFG). However, little is known about the incidence of and risk factors for glycemic disorders in Chinese HIV-infected patients.
Methods: Longitudinal data were pooled from a multicenter clinical trial of combination antiretroviral regimens between 2009 and 2010 across Mainland China. DM was defined as fasting glucose level $7.0 mmol/L and IFG as between 5.6 and 6.9 mmol/L on 2 separate measurements. We calculated the incidence densities of DM and IFG. Risk factors for DM and IFG were also identified.
Results: Four hundred fifteen patients contributed 457.35 personyears of follow-up. The incidence densities of DM and IFG were 2.62 and 35.64 per 100 person-years, respectively. In a multivariate analysis, advanced age [adjusted hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.01 to 1.04], hepatitis B virus coinfection (adjusted HR: 1.59, 95% CI: 1.06 to 2.38), and baseline fasting glucose (adjusted HR: 1.28, 95% CI: 1.00 to 1.63) were associated with DM and IFG.
Conclusions: A high incidence of DM and IFG was detected in Chinese HIV-infected patients receiving combination antiretroviral therapy. Clinicians should be aware of the potential for an increased risk of glycemic disorders in Chinese HIV-infected patients, particularly those of advanced age, with hepatitis B virus coinfection or high baseline fasting glucose.
Received for publication February 16, 2014; accepted November 5, 2014. From the *Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; and †Department of Neurology, University of California San Francisco, San Francisco, CA. Supported by the National Natural Science Foundation of China (grant 81071372 to T.L.), National Key Technologies R&D Program for the 12th Five-year Plan (grant 2012ZX10001003-001), and Key Clinical Program of the Ministry of Health (2010–2012). J.X. was supported by the grant of Chinese Ministry of Human Resources and Social Security (2011). The authors have no conflicts of interest to disclose. C.Z. and T.L. designed the study. T.L. and F.C.C. provided critical review of this article. Y.H., J.X., Z.Q., F.G., Y.L., and H.W. preserved the sample and collected the data. Y.H. did the laboratory test. C.Z. and F.C.C. analyzed the data and wrote the article. Correspondence to: Taisheng Li, MD, PhD, Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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Key Words: DM and IFG, HIV, antiretroviral therapy, diabetes mellitus (J Acquir Immune Defic Syndr 2015;68:298–303)
INTRODUCTION Long-term viral suppression achieved by combination antiretroviral therapy (cART) has enabled HIV-infected patients to lead a longer and healthier life. As life expectancy rises, however, and duration of exposure to cART lengthens, age-related complications, including diabetes mellitus (DM) and impaired fasting glucose (IFG), are growing in importance.1–3 DM is of particular concern in HIV infection given its association with myocardial infarction and stroke,4,5 rates of which are elevated in HIV-infected individuals.6–9 Although the risk of DM and IFG in ART-naive HIVinfected individuals may be similar to or slightly higher than the general population,10–13 studies have found an increased incidence of DM and IFG in HIV-infected individuals on cART,14–17 although most of these have focused on predominantly non-Hispanic White and Black cohorts in the United States and Europe.16–20 Few studies have focused on DM in HIV infection in Asia, despite the rising prevalence of DM in Asia and the unique presentation of DM among Asians at a younger age and lower body mass index (BMI).21–23 We tested the hypothesis that the incidence of DM and IFG would be higher in cART-treated Chinese HIV-infected individuals compared with a general Chinese reference population. We also identified risk factors associated with DM and IFG among the Chinese HIV-infected cohort.
METHODS Study Population All subjects enrolled in a multicenter clinical trial led by the Department of Infectious Diseases of Peking Union Medical College Hospital evaluating 3 different cART regimens were eligible for the study. Subjects were between 18 and 65 years of age, ART naive, and were recruited from 12 clinical trial units across China between November 2008 and January 2010. Exclusion criteria included (1) pregnancy or breast-feeding, (2) AIDS-defining illness within 2 weeks of entry, (3) white blood cell count less than 2.0 · 109/L, (4) hemoglobin level less than 90 g/dL, (5) platelet count less than 75 · 109/L, (6) alanine aminotransferase level 3 times higher than the upper limit of normal (ULN), (7) total bilirubin level
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DM and IFG in HIV-Infected Patients in China
2.5 times higher than ULN, and (8) serum creatinine level 1.5 times higher than ULN. Specific to this DM substudy, subjects were excluded if they were currently using corticosteroids or antidiabetic therapy, including insulin or if they had evidence by fasting glucose of DM or IFG at enrollment. As part of the clinical trial, patients were randomly assigned to 3 study groups. Group A received zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP) for 96 weeks. Group B received stavudine (d4T) + 3TC + NVP for 96 weeks. Group C received d4T + 3TC + NVP for the first 24 weeks and changed to AZT + 3TC + NVP for the rest of 72 weeks. Antiretroviral drug dosage was consistent with current Chinese guidelines. FIGURE 1. Patient flow chart.
Outcome After the baseline visit, we measured fasting plasma glucose at each subsequent interval visit for the clinical trial (weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, and 96). DM and IFG were defined as fasting glucose level $7.0 mmol/L or between 5.6 and 6.9 mmol/L at 2 different time points, respectively, based on definitions derived from the American Diabetes Association.24 The observation period started at the enrollment visit for each patient and ended with the development of DM or the last encounter for those who did not develop DM, with a maximum observation period of 96 weeks.
Statistical Analyses Unadjusted incidence density rates of DM and IFG per 100 person-years (PYs) of observation time were calculated. Chi-square test and Kruskal–Wallis test were used to compare characteristics between those who developed DM or IFG and those who did not. We used stepwise Cox regression analysis to model the time from cART initiation to the development of DM or IFG, which was defined as the midpoint between the last normal glucose level and the first elevated glucose level. Covariates analyzed included gender, race, age, alcohol use, BMI, hepatitis B surface antigen serostatus, hepatitis C virus (HCV) antibody serostatus, baseline fasting glucose, baseline CD4+ cell count, baseline HIV viral load, and cART regimen. Covariates included in the multivariate model were determined by forward stepwise selection, for which the P values for entry and exclusion were prespecified at 0.10 and 0.05, respectively. Forward stepwise selection is a widely used technique to construct a regression model in cases where there are a large number of potential clinically relevant explanatory variables. We also used the model to compare the incidence of DM and IFG among 3 cART groups. Analysis was done by SAS v 9.13. P values for all hypothesis testing ,0.05 were considered statistically significant.
(21.8 vs. 20.9 kg/m2, P = 0.01) and higher triglyceride level (1.29 vs. 1.21 mmol/L, P = 0.02) at baseline compared with the 415 analyzed patients. Of the 415 patients included in the study, 333 (74%) were males, and median age was 34 years [interquartile range (IQR), 27–41 years]. Median baseline CD4+ cell count was 182/mL (IQR, 87–254/mL), and median log baseline viral load was 4.59 (IQR, 4.04–4.99). Fifty-four (13%) patients were coinfected with hepatitis B virus (HBV), and 53 (13%) were coinfected with HCV. Fifty-seven patients discontinued the trial early because of a variety of reasons, including immigration, incarceration, pregnancy, treatment failure, nonadherence, and severe adverse events. None of the patients terminated the trial early because of DM- or IFG-related complications or death.
Incidence of DM and IFG
Four hundred fifteen patients contributed 457.35 PYs during the observation period. DM developed in 12 patients, resulting in an incidence density of 2.62 per 100 PYs. IFG was diagnosed in 163 patients, resulting in an incidence density of 35.64 per 100 PYs (Fig. 2).
Risk Factors for DM and IFG Patients who developed DM or IFG were older, had lower baseline CD4+ cell count, higher baseline triglyceride
RESULTS From 2008 to 2010, 552 HIV-infected patients were enrolled in the multicenter clinical trial. One hundred thirtyseven patients were excluded, 99 of whom had DM or IFG at baseline and 38 of whom only completed the initial evaluation, resulting in 415 ART-naive patients free of DM or IFG (Fig. 1). Excluded patients tended to have higher BMI Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 2. Proportions of participants free of DM or IFG. www.jaids.com |
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level, and were more likely to be coinfected with HBV compared with patients who did not develop DM or IFG (Table 1). In a multivariate model, for every 1-year increase in age, the adjusted hazard of DM or IFG rose by 3% [adjusted hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.01 to 1.04]. HBV coinfection was associated with an increased hazard of DM or IFG (adjusted HR: 1.59, 95% CI: 1.06 to 2.38), as was a higher baseline fasting glucose (adjusted HR: 1.28 for every 1 mmol/L, 95% CI: 1.00 to 1.63) (Table 2). To investigate whether the association between HBV coinfection and DM and IFG could be explained in part by a change in BMI, we calculated the mean change in BMI between those with and without HBV coinfection. We did not find a statistically significant difference between the mean change in BMI after 96 weeks of ART in HBV-negative patients (decrease of 2.72 kg/m2) compared with HBV coinfected patients (decrease of 2.19 kg/m2, P = 0.627). Furthermore, overall BMI, baseline triglyceride level, CD4+ cell count, and HIV viral load were not predictive of DM or IFG. Cox regression did not show a significant difference in the incidence of DM and IFG among the 3 study groups receiving different cART regimens (P = 0.37).
DISCUSSION In our study of HIV-infected Chinese individuals from a multicenter clinical trial, the incidence of DM was 2.62 per 100 PYs and of IFG was 35.64 per 100 PYs. Certain risk factors, such as advanced age, predictive of DM and IFG in previously studied HIV cohorts were associated with DM and IFG in our cohort, whereas other risk factors, including BMI, were not. Moreover, we demonstrate the novel finding that HBV coinfection may actually increase the risk of DM or IFG in HIV-infected patients.
TABLE 1. Baseline Characteristics of Patients Patients With DM or IFG (n = 175)*
Patients Without DM or IFG (n = 240)*
P
36 (29–43)
32 (26–39)
0.0005
93† 75† 21.1 (19.1–23.1) 167 (73–249)
95† 73† 20.9 (19.4–22.9) 195 (114–259)
0.32 0.65 0.83 0.043
4.60 (4.14–5.13)
4.56 (3.97–4.93) 0.10
5.00 (4.70–5.30)
4.56 (3.97–4.93) 0.0002
2.19 (1.85–2.62) 1.36 (0.91–1.88)
2.15 (1.74–2.65) 0.52 1.15 (0.84–1.73) 0.041
Age (yrs), median (IQR) Han race (%) Male (%) BMI (kg/m2) CD4+ count (cells per microliter) HIV viral load (log, copies per milliliter) Fasting glucose (mmol/L) LDL-C (mmol/L) Triglyceride (mmol/L) HBsAg (+) (%) HCV antibody (+) (%)
17† 13†
10† 13†
0.0343 0.8705
*Median and IQR unless otherwise specified. †Percentage. HBsAg, hepatitis B surface antigen; LDL-C, low-density lipoprotein cholesterol.
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Only one study of hyperglycemia in Mainland Chinese HIV-infected patients has been performed,25 although it was a cross-sectional study of newly diagnosed patients who were not on ART. Other studies of East and South Asian HIVinfected cohorts have focused on metabolic syndrome, which includes IFG as one criterion but can be diagnosed in its absence.26,27 Our study represents the first to evaluate the incidence of DM and IFG in a longitudinal cohort of Mainland Chinese HIV-infected patients followed from cART initiation, who may differ genetically and socioculturally from both non-Asian and other Asian HIV cohorts. The incidence of DM in our cohort was higher than the published incidence density rates of DM for the general Chinese population, ranging from 0.43 to 1.55 per 100 PYs.28,29 Including patients with baseline DM or IFG who were excluded from our main analysis, the prevalence by the end of the observation period of DM or IFG in our cohort was 39.7%, more than twice as high as other estimates of prevalence of DM and prediabetes in the general Chinese population.30 Furthermore, the incidence of DM in our cohort, like that observed in a Chinese HIV-infected cohort in Taiwan,31 was higher than that reported in other studies of DM in HIV-infected cohorts.32,33 In light of the current HIV epidemic in China, with an estimated 780,000 HIV-infected patients, a growing proportion of newly diagnosed infections in individuals older than 50 years,34 and the increasing availability of cART in China, our findings suggest that the burden of HIV-associated DM and IFG in China may be on the rise and warrants additional studies on optimal prevention and management. Few studies have focused on DM in HIV infection in Asia, despite the rapidly rising prevalence of DM in Asia, especially in China,35,36 and the fact that Asians are an established risk group for DM may have unique genetic and lifestyle susceptibilities to DM and develop DM at a younger age and lower BMI.22,23,37–41 Several single nucleoside polymorphisms in FADS gene cluster, which plays an important role in the development of DM,42 were different between White and Asian adults.43 New variants in the ADIPOR1 gene were also found in a Chinese population to be associated with DM.44 Lifestyle factors, including high rice, noodle,45 and cigarette46,47 consumption, may place Chinese populations at particularly increased risk of DM. In the Swiss HIV Cohort study, the only study of DM in HIV infection that included Asian as a separate race/ethnicity group, the incidence of DM in Asians was nearly 5 times that of their White counterparts, whereas the rate ratio was only twice as high comparing Blacks and Whites.20 Given the unique epidemiology of DM in China, DM and IFG may be associated with distinct risk factors in Chinese HIV-infected individuals compared with other populations. Although DM has been reported at younger ages in Asian studies,21,22 advanced age, a commonly recognized risk factor for DM both in the general population and in HIVinfected patients,30,32,36,48 remained a significant predictor of DM and IFG in our cohort. We also found a novel association between HBV coinfection and DM and IFG in our cohort. Although an association between HCV coinfection and DM in HIV-infected patients has been reported,11,49 to the best of Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
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TABLE 2. HRs for Risk Factors Associated With DM and IFG Variable Female Race (Han vs. non-Han) Age Alcohol use BMI HBsAg (+) HCV antibody (+) Baseline CD4 Viral load Baseline fasting glucose (mmol/L) LDL-C (mmol/L) Triglyceride (mmol/L) cART regimen 1 vs. 2, 3 2 vs. 1, 3 3 vs. 1, 2
Crude HR 1.07 1.43 1.02 0.76 0.999 1.51 1.21 0.84 1.27 1.32 0.99 0.99
(0.77–1.49) (0.80–2.58) (1.01–1.04) (0.51–1.12) (0.95–1.05) (1.02–2.24) (0.66–1.60) (0.60–1.19) (1.03–1.56) (1.05–1.65) (0.71–1.38) (0.75–1.31)
1.21 (0.89–1.66) 1.21 (0.89–1.64) 1.01 (0.72–1.42)
P
Adjusted HR
P
0.69 0.23 0.002 0.16 0.97 0.040 0.90 0.33 0.026 0.017 0.95 0.92
NA NA 1.03 (1.01–1.04) NA NA 1.59 (1.06–2.38) NA NA NA 1.28 (1.00–1.63) NA NA
NA NA 0.0007 NA NA 0.025 NA NA NA 0.046 NA NA
0.23 0.23 0.95
NA NA NA
NA NA NA
Regimen 1: d4T + 3TC + NVP. Regimen 2: AZT + 3TC + NVP. Regimen 3: d4T + 3TC + NVP for the first 24 weeks, followed by AZT + 3TC + NVP for the remainder of the trial. HBsAg, hepatitis B surface antigen; LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
our knowledge, an association between HBV coinfection and DM has not been reported before in HIV-infected patients. The high prevalence of HBV coinfection in our Chinese cohort may have enabled us to identify this association. The effect of HBV infection on DM in the general population is unclear. Hepatitis B surface antigen carrier status has been shown to be an independent risk factor for gestational diabetes.50 Furthermore, the odds ratio of HBV infection for DM in one study was 3.17 (95% CI: 1.58 to 6.35) among Asian Americans and Pacific Islanders.51 However, other studies have not consistently demonstrated an association between chronic HBV infection and DM in the general population.52,53 Liver disease and inflammation may result in insulin resistance, leading to an association between HBV and the development of DM, although further investigation specifically in HIV-infected patients is required. We also specifically evaluated for differences in the mean change in BMI between those with and without HBV coinfection and did not find any statistically significant difference that may have mediated the association between HBV and DM. Among our cohort of HIV-infected individuals, no difference in DM incidence was found among those on d4T vs. AZT, both of which are still commonly used in resourcelimited settings.54–56 There are ample data supporting d4T and AZT as a risk factor for DM31,57,58; however, few studies have compared the incidence of DM between individuals on AZT and d4T. Early mitochondrial depletion has been observed among patients receiving low and standard doses of d4T.59 The defect in mitochondrial oxidative phosphorylation may lead to DM.60 AZT is said to have less mitochondrial toxicity than d4T,61 which might result in lower risk of DM. Our small cohort of patients and relatively short duration of follow-up may have precluded us from detecting a difference in incidence of DM between the 2 Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
treatment groups. Adequately powered studies to evaluate differential effects of individual antiretrovirals or classes of antiretrovirals on the incidence of DM and IFG in Chinese HIV-infected patients are needed. Unlike previous studies,18,20,48,62,63 we did not find an association between BMI, CD4+ cell count, or HIV viral load and rates of DM. Our study population had lower BMI and baseline CD4+ count (Table 1), which may have limited our ability to detect an association between these variables and DM or IFG. Although BMI is an established risk factor for DM in the general population,30 the DM epidemic in Asia has affected individuals at lower BMI than Western populations, which further weakens the risk of higher BMI in Asians and may also explain why BMI was not associated with DM in our Chinese HIV-infected cohort.39 Although some studies have reported CD4+ cell count as a risk factor for DM or IFG,48,62 others have not.11 Our study has several strengths. Data were prospectively collected enabling us to determine the incidence of IFG and DM and confirm the diagnoses. The data were derived from a multicenter clinical trial that included a broad representation of the Chinese HIV-infected population, thereby enhancing external validity. However, oral glucose tolerance testing, the gold standard for diagnosis of DM as recommended by the American Diabetes Association, was not available, which may have resulted in an underestimate of incidence. We were also not able to directly evaluate insulin resistance, which might have also led to an underestimate of the incidence of glycemic disorders, although fasting glucose has been shown to be an adequate screening tool for DM and IFG in HIV-infected patients.64 Additionally, our sample size was relatively small, which may have limited our ability to detect associations between various risk factors and DM or IFG. Furthermore, some of the metabolic problems observed www.jaids.com |
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in this cohort may be because of the older nucleoside reverse transcriptase inhibitors used, so that evaluations using more contemporary cART regimens are needed in China to sort out the role of thymidine analogs in mitochondrial toxicity and impaired glucose metabolism. Lastly, we did not have an HIV-uninfected control group derived from the same study population with which to compare the incidence of DM/IFG in our HIV cohort. In conclusion, we demonstrated the novel finding that the incidence of DM and IFG among Chinese HIV-infected patients receiving cART was increased compared with estimates from the general Chinese population and estimates from previously described HIV cohorts. Large prospective studies are warranted to further evaluate the burden of DM and IFG in Chinese HIV-infected patients, as a first step in the management of a chronic HIV-associated condition. Medical providers should monitor Chinese HIV-infected patients regularly for evidence of impaired glucose metabolism, including patients with lower BMI who may still be at risk for DM and IFG. Particular attention may also need to be paid to patients with HBV coinfection, advanced age, and elevated fasting glucose.
ACKNOWLEDGMENTS The authors thank the study participants for their cooperation. The following clinical institutions or hospitals participated in this study: Peking Union Medical College Hospital, Beijing Youan Hospital, Beijing Ditan Hospital, Zhengzhou Sixth People’s Hospital, Tangdu Hospital, Guangzhou Eighth People’s Hospital, Shanghai Public Health Clinical Center, Shenzhen Third People’s Hospital, Fuzhou Infectious Diseases Hospital, Yunnan AIDS Care Center, Kunming Third People’s Hospital, and Honghe First People’s Hospital. The authors are grateful to Weidong Zhang, MD PhD, Director of the Department of Epidemiology, School of Public Health, Zhengzhou University, for his kind assistance in data analysis. REFERENCES 1. Kiertiburanakul S, Luengroongroj P, Sungkanuparph S. Clinical characteristics of HIV-infected patients who survive after the diagnosis of HIV infection for more than 10 years in a resource-limited setting. J Int Assoc Physicians AIDS Care (Chic). 2012;11:361–365. 2. Mocroft A, Reiss P, Gasiorowski J, et al. Serious fatal and nonfatal nonAIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr. 2010; 55:262–270. 3. Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIVinfected persons: the Swiss HIV cohort study. Clin Infect Dis. 2011;53: 1130–1139. 4. Worm SW, De Wit S, Weber R, et al. Diabetes mellitus, preexisting coronary heart disease, and the risk of subsequent coronary heart disease events in patients infected with human immunodeficiency virus: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D Study). Circulation. 2009;119:805–811. 5. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349: 1993–2003. 6. Triant VA, Lee H, Hadigan C, et al. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007; 92:2506–2512.
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41. 42. 43. 44.
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subjects aged over 40 years in Shanghai Huayang community. Chin J Endocrinol Metab. 2004;20:392–395. Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med. 2010;362:1090–1101. Lo Y, Chen M, Sheng W, et al. Risk factors for incident diabetes mellitus among HIV-infected patients receiving combination antiretroviral therapy in Taiwan: a case-control study. HIV Med. 2009;10:302–309. Tien PC, Schneider MF, Cox C, et al. Association of HIV infection with incident diabetes mellitus: impact of using hemoglobin A1C as a criterion for diabetes. J Acquir Immune Defic Syndr. 2012;61:334–340. Petoumenos K, Worm SW, Fontas E, et al. Predicting the short-term risk of diabetes in HIV-positive patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. J Int AIDS Soc. 2012;15: 17426. Liu H, Lin X, Xu Y, et al. Emerging HIV epidemic among older adults in Nanning, China. AIDS Patient Care STDS. 2012;26:565–567. Zhong XL. Diabetes mellitus survey in China. Chin Med J (Engl). 1982; 95:423–430. Xu Y, Wang L, He J, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310:948–959. Cho YS, Lee JY, Park KS, et al. Genetics of type 2 diabetes in East Asian populations. Curr Diab Rep. 2012;12:686–696. Bertoni AG, Burke GL, Owusu JA, et al. Inflammation and the incidence of type 2 diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2010;33:804–810. Nyamdorj R, Pitkaniemi J, Tuomilehto J, et al. Ethnic comparison of the association of undiagnosed diabetes with obesity. Int J Obes (Lond). 2010;34:332–339. Villegas R, Liu S, Gao YT, et al. Prospective study of dietary carbohydrates, glycemic index, glycemic load, and incidence of type 2 diabetes mellitus in middle-aged Chinese women. Arch Intern Med. 2007;167:2310–2316. Dickinson S, Colagiuri S, Faramus E, et al. Postprandial hyperglycemia and insulin sensitivity differ among lean young adults of different ethnicities. J Nutr. 2002;132:2574–2579. Huang T, Sun J, Chen Y, et al. Genetic variants in desaturase gene, erythrocyte fatty acids, and risk for type 2 diabetes in Chinese Hans. Nutrition. 2014;30:897–902. Merino DM, Johnston H, Clarke S, et al. Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults. Mol Genet Metab. 2011;103:171–178. Jin Z, Pu L, Sun L, et al. Identification of susceptibility variants in ADIPOR1 gene associated with type 2 diabetes, coronary artery disease and the comorbidity of type 2 diabetes and coronary artery disease. PLoS One. 2014;9:e100339. Zuniga YL, Rebello SA, Oi PL, et al. Rice and noodle consumption is associated with insulin resistance and hyperglycaemia in an Asian population. Br J Nutr. 2014;111:1118–1128. Shi L, Shu XO, Li H, et al. Physical activity, smoking, and alcohol consumption in association with incidence of type 2 diabetes among middle-aged and elderly Chinese men. PLoS One. 2013;8:e77919. Au WW, Su D, Yuan J. Cigarette smoking in China: public health, science, and policy. Rev Environ Health. 2012;27:43–49.
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48. Galli L, Salpietro S, Pellicciotta G, et al. Risk of type 2 diabetes among HIVinfected and healthy subjects in Italy. Eur J Epidemiol. 2012;27:657–665. 49. Hejazi N, Rajikan R, Choong CL, et al. Metabolic abnormalities in adult HIV infected population on antiretroviral medication in Malaysia: a cross-sectional survey. BMC Public Health. 2013;13:758. 50. Lao TT, Tse KY, Chan LY, et al. HBsAg carrier status and the association between gestational diabetes with increased serum ferritin concentration in Chinese women. Diabetes Care. 2003;26:3011–3016. 51. Li-Ng M, Tropp S, Danoff A, et al. Association between chronic hepatitis B virus infection and diabetes among Asian Americans and Pacific Islanders. Dig Liver Dis. 2007;39:549–556. 52. Spradling PR, Simons B, Narayanan M, et al. Incidence of diabetes mellitus in a population-based cohort of persons with chronic hepatitis B virus infection. J Viral Hepat. 2013;20:510–513. 53. Huang ZS, Huang TS, Wu TH, et al. Asymptomatic chronic hepatitis B virus infection does not increase the risk of diabetes mellitus: a ten-year observation. J Gastroenterol Hepatol. 2010;25:1420–1425. 54. Phanuphak N, Ananworanich J, Teeratakulpisarn N, et al. A 72-week randomized study of the safety and efficacy of a stavudine to zidovudine switch at 24 weeks compared to zidovudine or tenofovir disoproxil fumarate when given with lamivudine and nevirapine. Antivir Ther. 2012;17:1521–1531. 55. Thuppal SV, Karthik R, Abraham OC, et al. Cost Estimation of First-Line Antiretroviral Therapy with Zidovudine/Stavudine as the Nucleoside Backbone in India: A Pilot Study. J Int Assoc Provid AIDS Care. 2013. [Epub ahead of print]. 56. Nouhin J, Madec Y, Ngo-Giang-Huong N, et al. Increased risk of Q151M and K65R mutations in patients failing stavudine-containing first-line antiretroviral therapy in Cambodia. PLoS One. 2013;8:e73744. 57. Nightingale SL. From the Food and Drug Administration. JAMA. 1997; 278:1728. 58. Brown TT, Li X, Cole SR, et al. Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS. 2005; 19:1375–1383. 59. Menezes C, Duarte R, Dickens C, et al. The early effects of stavudine compared with tenofovir on adipocyte gene expression, mitochondrial DNA copy number and metabolic parameters in South African HIVinfected patients: a randomized trial. HIV Med. 2013;14:217–225. 60. Petersen KF, Dufour S, Befroy D, et al. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350:664–671. 61. White AJ. Mitochondrial toxicity and HIV therapy. Sex Transm Infect. 2001;77:158–173. 62. Gianotti N, Visco F, Galli L, et al. Detecting impaired glucose tolerance or type 2 diabetes mellitus by means of an oral glucose tolerance test in HIV-infected patients. HIV Med. 2011;12:109–117. 63. El-Sadr WM, Mullin CM, Carr A, et al. Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naive cohort. HIV Med. 2005;6:114–121. 64. Wohl DA, McComsey G, Tebas P, et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis. 2006;43:645–653.
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Multicenter Cohort Study of Diabetes Mellitus and Impaired Fasting Glucose in HIV-Infected Patients in China Chengda Zhang, MD,* Felicia C. Chow, MD,† Yang Han, PhD,* Jing Xie, PhD,* Zhifeng Qiu, PhD,* Fuping Guo, MD, PhD,* Yanling Li, MD,* Huanling Wang, MD, PhD,* and Taisheng Li, MD, PhD*
Background: As life expectancy increases, HIV-infected patients are facing a wide array of metabolic complications, including diabetes mellitus (DM) and impaired fasting glucose (IFG). However, little is known about the incidence of and risk factors for glycemic disorders in Chinese HIV-infected patients.
Methods: Longitudinal data were pooled from a multicenter clinical trial of combination antiretroviral regimens between 2009 and 2010 across Mainland China. DM was defined as fasting glucose level $7.0 mmol/L and IFG as between 5.6 and 6.9 mmol/L on 2 separate measurements. We calculated the incidence densities of DM and IFG. Risk factors for DM and IFG were also identified.
Results: Four hundred fifteen patients contributed 457.35 personyears of follow-up. The incidence densities of DM and IFG were 2.62 and 35.64 per 100 person-years, respectively. In a multivariate analysis, advanced age [adjusted hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.01 to 1.04], hepatitis B virus coinfection (adjusted HR: 1.59, 95% CI: 1.06 to 2.38), and baseline fasting glucose (adjusted HR: 1.28, 95% CI: 1.00 to 1.63) were associated with DM and IFG.
Conclusions: A high incidence of DM and IFG was detected in Chinese HIV-infected patients receiving combination antiretroviral therapy. Clinicians should be aware of the potential for an increased risk of glycemic disorders in Chinese HIV-infected patients, particularly those of advanced age, with hepatitis B virus coinfection or high baseline fasting glucose.
Received for publication February 16, 2014; accepted November 5, 2014. From the *Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; and †Department of Neurology, University of California San Francisco, San Francisco, CA. Supported by the National Natural Science Foundation of China (grant 81071372 to T.L.), National Key Technologies R&D Program for the 12th Five-year Plan (grant 2012ZX10001003-001), and Key Clinical Program of the Ministry of Health (2010–2012). J.X. was supported by the grant of Chinese Ministry of Human Resources and Social Security (2011). The authors have no conflicts of interest to disclose. C.Z. and T.L. designed the study. T.L. and F.C.C. provided critical review of this article. Y.H., J.X., Z.Q., F.G., Y.L., and H.W. preserved the sample and collected the data. Y.H. did the laboratory test. C.Z. and F.C.C. analyzed the data and wrote the article. Correspondence to: Taisheng Li, MD, PhD, Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730 China (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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Key Words: DM and IFG, HIV, antiretroviral therapy, diabetes mellitus (J Acquir Immune Defic Syndr 2015;68:298–303)
INTRODUCTION Long-term viral suppression achieved by combination antiretroviral therapy (cART) has enabled HIV-infected patients to lead a longer and healthier life. As life expectancy rises, however, and duration of exposure to cART lengthens, age-related complications, including diabetes mellitus (DM) and impaired fasting glucose (IFG), are growing in importance.1–3 DM is of particular concern in HIV infection given its association with myocardial infarction and stroke,4,5 rates of which are elevated in HIV-infected individuals.6–9 Although the risk of DM and IFG in ART-naive HIVinfected individuals may be similar to or slightly higher than the general population,10–13 studies have found an increased incidence of DM and IFG in HIV-infected individuals on cART,14–17 although most of these have focused on predominantly non-Hispanic White and Black cohorts in the United States and Europe.16–20 Few studies have focused on DM in HIV infection in Asia, despite the rising prevalence of DM in Asia and the unique presentation of DM among Asians at a younger age and lower body mass index (BMI).21–23 We tested the hypothesis that the incidence of DM and IFG would be higher in cART-treated Chinese HIV-infected individuals compared with a general Chinese reference population. We also identified risk factors associated with DM and IFG among the Chinese HIV-infected cohort.
METHODS Study Population All subjects enrolled in a multicenter clinical trial led by the Department of Infectious Diseases of Peking Union Medical College Hospital evaluating 3 different cART regimens were eligible for the study. Subjects were between 18 and 65 years of age, ART naive, and were recruited from 12 clinical trial units across China between November 2008 and January 2010. Exclusion criteria included (1) pregnancy or breast-feeding, (2) AIDS-defining illness within 2 weeks of entry, (3) white blood cell count less than 2.0 · 109/L, (4) hemoglobin level less than 90 g/dL, (5) platelet count less than 75 · 109/L, (6) alanine aminotransferase level 3 times higher than the upper limit of normal (ULN), (7) total bilirubin level
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2.5 times higher than ULN, and (8) serum creatinine level 1.5 times higher than ULN. Specific to this DM substudy, subjects were excluded if they were currently using corticosteroids or antidiabetic therapy, including insulin or if they had evidence by fasting glucose of DM or IFG at enrollment. As part of the clinical trial, patients were randomly assigned to 3 study groups. Group A received zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP) for 96 weeks. Group B received stavudine (d4T) + 3TC + NVP for 96 weeks. Group C received d4T + 3TC + NVP for the first 24 weeks and changed to AZT + 3TC + NVP for the rest of 72 weeks. Antiretroviral drug dosage was consistent with current Chinese guidelines. FIGURE 1. Patient flow chart.
Outcome After the baseline visit, we measured fasting plasma glucose at each subsequent interval visit for the clinical trial (weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, and 96). DM and IFG were defined as fasting glucose level $7.0 mmol/L or between 5.6 and 6.9 mmol/L at 2 different time points, respectively, based on definitions derived from the American Diabetes Association.24 The observation period started at the enrollment visit for each patient and ended with the development of DM or the last encounter for those who did not develop DM, with a maximum observation period of 96 weeks.
Statistical Analyses Unadjusted incidence density rates of DM and IFG per 100 person-years (PYs) of observation time were calculated. Chi-square test and Kruskal–Wallis test were used to compare characteristics between those who developed DM or IFG and those who did not. We used stepwise Cox regression analysis to model the time from cART initiation to the development of DM or IFG, which was defined as the midpoint between the last normal glucose level and the first elevated glucose level. Covariates analyzed included gender, race, age, alcohol use, BMI, hepatitis B surface antigen serostatus, hepatitis C virus (HCV) antibody serostatus, baseline fasting glucose, baseline CD4+ cell count, baseline HIV viral load, and cART regimen. Covariates included in the multivariate model were determined by forward stepwise selection, for which the P values for entry and exclusion were prespecified at 0.10 and 0.05, respectively. Forward stepwise selection is a widely used technique to construct a regression model in cases where there are a large number of potential clinically relevant explanatory variables. We also used the model to compare the incidence of DM and IFG among 3 cART groups. Analysis was done by SAS v 9.13. P values for all hypothesis testing ,0.05 were considered statistically significant.
(21.8 vs. 20.9 kg/m2, P = 0.01) and higher triglyceride level (1.29 vs. 1.21 mmol/L, P = 0.02) at baseline compared with the 415 analyzed patients. Of the 415 patients included in the study, 333 (74%) were males, and median age was 34 years [interquartile range (IQR), 27–41 years]. Median baseline CD4+ cell count was 182/mL (IQR, 87–254/mL), and median log baseline viral load was 4.59 (IQR, 4.04–4.99). Fifty-four (13%) patients were coinfected with hepatitis B virus (HBV), and 53 (13%) were coinfected with HCV. Fifty-seven patients discontinued the trial early because of a variety of reasons, including immigration, incarceration, pregnancy, treatment failure, nonadherence, and severe adverse events. None of the patients terminated the trial early because of DM- or IFG-related complications or death.
Incidence of DM and IFG
Four hundred fifteen patients contributed 457.35 PYs during the observation period. DM developed in 12 patients, resulting in an incidence density of 2.62 per 100 PYs. IFG was diagnosed in 163 patients, resulting in an incidence density of 35.64 per 100 PYs (Fig. 2).
Risk Factors for DM and IFG Patients who developed DM or IFG were older, had lower baseline CD4+ cell count, higher baseline triglyceride
RESULTS From 2008 to 2010, 552 HIV-infected patients were enrolled in the multicenter clinical trial. One hundred thirtyseven patients were excluded, 99 of whom had DM or IFG at baseline and 38 of whom only completed the initial evaluation, resulting in 415 ART-naive patients free of DM or IFG (Fig. 1). Excluded patients tended to have higher BMI Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 2. Proportions of participants free of DM or IFG. www.jaids.com |
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level, and were more likely to be coinfected with HBV compared with patients who did not develop DM or IFG (Table 1). In a multivariate model, for every 1-year increase in age, the adjusted hazard of DM or IFG rose by 3% [adjusted hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.01 to 1.04]. HBV coinfection was associated with an increased hazard of DM or IFG (adjusted HR: 1.59, 95% CI: 1.06 to 2.38), as was a higher baseline fasting glucose (adjusted HR: 1.28 for every 1 mmol/L, 95% CI: 1.00 to 1.63) (Table 2). To investigate whether the association between HBV coinfection and DM and IFG could be explained in part by a change in BMI, we calculated the mean change in BMI between those with and without HBV coinfection. We did not find a statistically significant difference between the mean change in BMI after 96 weeks of ART in HBV-negative patients (decrease of 2.72 kg/m2) compared with HBV coinfected patients (decrease of 2.19 kg/m2, P = 0.627). Furthermore, overall BMI, baseline triglyceride level, CD4+ cell count, and HIV viral load were not predictive of DM or IFG. Cox regression did not show a significant difference in the incidence of DM and IFG among the 3 study groups receiving different cART regimens (P = 0.37).
DISCUSSION In our study of HIV-infected Chinese individuals from a multicenter clinical trial, the incidence of DM was 2.62 per 100 PYs and of IFG was 35.64 per 100 PYs. Certain risk factors, such as advanced age, predictive of DM and IFG in previously studied HIV cohorts were associated with DM and IFG in our cohort, whereas other risk factors, including BMI, were not. Moreover, we demonstrate the novel finding that HBV coinfection may actually increase the risk of DM or IFG in HIV-infected patients.
TABLE 1. Baseline Characteristics of Patients Patients With DM or IFG (n = 175)*
Patients Without DM or IFG (n = 240)*
P
36 (29–43)
32 (26–39)
0.0005
93† 75† 21.1 (19.1–23.1) 167 (73–249)
95† 73† 20.9 (19.4–22.9) 195 (114–259)
0.32 0.65 0.83 0.043
4.60 (4.14–5.13)
4.56 (3.97–4.93) 0.10
5.00 (4.70–5.30)
4.56 (3.97–4.93) 0.0002
2.19 (1.85–2.62) 1.36 (0.91–1.88)
2.15 (1.74–2.65) 0.52 1.15 (0.84–1.73) 0.041
Age (yrs), median (IQR) Han race (%) Male (%) BMI (kg/m2) CD4+ count (cells per microliter) HIV viral load (log, copies per milliliter) Fasting glucose (mmol/L) LDL-C (mmol/L) Triglyceride (mmol/L) HBsAg (+) (%) HCV antibody (+) (%)
17† 13†
10† 13†
0.0343 0.8705
*Median and IQR unless otherwise specified. †Percentage. HBsAg, hepatitis B surface antigen; LDL-C, low-density lipoprotein cholesterol.
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Only one study of hyperglycemia in Mainland Chinese HIV-infected patients has been performed,25 although it was a cross-sectional study of newly diagnosed patients who were not on ART. Other studies of East and South Asian HIVinfected cohorts have focused on metabolic syndrome, which includes IFG as one criterion but can be diagnosed in its absence.26,27 Our study represents the first to evaluate the incidence of DM and IFG in a longitudinal cohort of Mainland Chinese HIV-infected patients followed from cART initiation, who may differ genetically and socioculturally from both non-Asian and other Asian HIV cohorts. The incidence of DM in our cohort was higher than the published incidence density rates of DM for the general Chinese population, ranging from 0.43 to 1.55 per 100 PYs.28,29 Including patients with baseline DM or IFG who were excluded from our main analysis, the prevalence by the end of the observation period of DM or IFG in our cohort was 39.7%, more than twice as high as other estimates of prevalence of DM and prediabetes in the general Chinese population.30 Furthermore, the incidence of DM in our cohort, like that observed in a Chinese HIV-infected cohort in Taiwan,31 was higher than that reported in other studies of DM in HIV-infected cohorts.32,33 In light of the current HIV epidemic in China, with an estimated 780,000 HIV-infected patients, a growing proportion of newly diagnosed infections in individuals older than 50 years,34 and the increasing availability of cART in China, our findings suggest that the burden of HIV-associated DM and IFG in China may be on the rise and warrants additional studies on optimal prevention and management. Few studies have focused on DM in HIV infection in Asia, despite the rapidly rising prevalence of DM in Asia, especially in China,35,36 and the fact that Asians are an established risk group for DM may have unique genetic and lifestyle susceptibilities to DM and develop DM at a younger age and lower BMI.22,23,37–41 Several single nucleoside polymorphisms in FADS gene cluster, which plays an important role in the development of DM,42 were different between White and Asian adults.43 New variants in the ADIPOR1 gene were also found in a Chinese population to be associated with DM.44 Lifestyle factors, including high rice, noodle,45 and cigarette46,47 consumption, may place Chinese populations at particularly increased risk of DM. In the Swiss HIV Cohort study, the only study of DM in HIV infection that included Asian as a separate race/ethnicity group, the incidence of DM in Asians was nearly 5 times that of their White counterparts, whereas the rate ratio was only twice as high comparing Blacks and Whites.20 Given the unique epidemiology of DM in China, DM and IFG may be associated with distinct risk factors in Chinese HIV-infected individuals compared with other populations. Although DM has been reported at younger ages in Asian studies,21,22 advanced age, a commonly recognized risk factor for DM both in the general population and in HIVinfected patients,30,32,36,48 remained a significant predictor of DM and IFG in our cohort. We also found a novel association between HBV coinfection and DM and IFG in our cohort. Although an association between HCV coinfection and DM in HIV-infected patients has been reported,11,49 to the best of Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
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TABLE 2. HRs for Risk Factors Associated With DM and IFG Variable Female Race (Han vs. non-Han) Age Alcohol use BMI HBsAg (+) HCV antibody (+) Baseline CD4 Viral load Baseline fasting glucose (mmol/L) LDL-C (mmol/L) Triglyceride (mmol/L) cART regimen 1 vs. 2, 3 2 vs. 1, 3 3 vs. 1, 2
Crude HR 1.07 1.43 1.02 0.76 0.999 1.51 1.21 0.84 1.27 1.32 0.99 0.99
(0.77–1.49) (0.80–2.58) (1.01–1.04) (0.51–1.12) (0.95–1.05) (1.02–2.24) (0.66–1.60) (0.60–1.19) (1.03–1.56) (1.05–1.65) (0.71–1.38) (0.75–1.31)
1.21 (0.89–1.66) 1.21 (0.89–1.64) 1.01 (0.72–1.42)
P
Adjusted HR
P
0.69 0.23 0.002 0.16 0.97 0.040 0.90 0.33 0.026 0.017 0.95 0.92
NA NA 1.03 (1.01–1.04) NA NA 1.59 (1.06–2.38) NA NA NA 1.28 (1.00–1.63) NA NA
NA NA 0.0007 NA NA 0.025 NA NA NA 0.046 NA NA
0.23 0.23 0.95
NA NA NA
NA NA NA
Regimen 1: d4T + 3TC + NVP. Regimen 2: AZT + 3TC + NVP. Regimen 3: d4T + 3TC + NVP for the first 24 weeks, followed by AZT + 3TC + NVP for the remainder of the trial. HBsAg, hepatitis B surface antigen; LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
our knowledge, an association between HBV coinfection and DM has not been reported before in HIV-infected patients. The high prevalence of HBV coinfection in our Chinese cohort may have enabled us to identify this association. The effect of HBV infection on DM in the general population is unclear. Hepatitis B surface antigen carrier status has been shown to be an independent risk factor for gestational diabetes.50 Furthermore, the odds ratio of HBV infection for DM in one study was 3.17 (95% CI: 1.58 to 6.35) among Asian Americans and Pacific Islanders.51 However, other studies have not consistently demonstrated an association between chronic HBV infection and DM in the general population.52,53 Liver disease and inflammation may result in insulin resistance, leading to an association between HBV and the development of DM, although further investigation specifically in HIV-infected patients is required. We also specifically evaluated for differences in the mean change in BMI between those with and without HBV coinfection and did not find any statistically significant difference that may have mediated the association between HBV and DM. Among our cohort of HIV-infected individuals, no difference in DM incidence was found among those on d4T vs. AZT, both of which are still commonly used in resourcelimited settings.54–56 There are ample data supporting d4T and AZT as a risk factor for DM31,57,58; however, few studies have compared the incidence of DM between individuals on AZT and d4T. Early mitochondrial depletion has been observed among patients receiving low and standard doses of d4T.59 The defect in mitochondrial oxidative phosphorylation may lead to DM.60 AZT is said to have less mitochondrial toxicity than d4T,61 which might result in lower risk of DM. Our small cohort of patients and relatively short duration of follow-up may have precluded us from detecting a difference in incidence of DM between the 2 Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
treatment groups. Adequately powered studies to evaluate differential effects of individual antiretrovirals or classes of antiretrovirals on the incidence of DM and IFG in Chinese HIV-infected patients are needed. Unlike previous studies,18,20,48,62,63 we did not find an association between BMI, CD4+ cell count, or HIV viral load and rates of DM. Our study population had lower BMI and baseline CD4+ count (Table 1), which may have limited our ability to detect an association between these variables and DM or IFG. Although BMI is an established risk factor for DM in the general population,30 the DM epidemic in Asia has affected individuals at lower BMI than Western populations, which further weakens the risk of higher BMI in Asians and may also explain why BMI was not associated with DM in our Chinese HIV-infected cohort.39 Although some studies have reported CD4+ cell count as a risk factor for DM or IFG,48,62 others have not.11 Our study has several strengths. Data were prospectively collected enabling us to determine the incidence of IFG and DM and confirm the diagnoses. The data were derived from a multicenter clinical trial that included a broad representation of the Chinese HIV-infected population, thereby enhancing external validity. However, oral glucose tolerance testing, the gold standard for diagnosis of DM as recommended by the American Diabetes Association, was not available, which may have resulted in an underestimate of incidence. We were also not able to directly evaluate insulin resistance, which might have also led to an underestimate of the incidence of glycemic disorders, although fasting glucose has been shown to be an adequate screening tool for DM and IFG in HIV-infected patients.64 Additionally, our sample size was relatively small, which may have limited our ability to detect associations between various risk factors and DM or IFG. Furthermore, some of the metabolic problems observed www.jaids.com |
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in this cohort may be because of the older nucleoside reverse transcriptase inhibitors used, so that evaluations using more contemporary cART regimens are needed in China to sort out the role of thymidine analogs in mitochondrial toxicity and impaired glucose metabolism. Lastly, we did not have an HIV-uninfected control group derived from the same study population with which to compare the incidence of DM/IFG in our HIV cohort. In conclusion, we demonstrated the novel finding that the incidence of DM and IFG among Chinese HIV-infected patients receiving cART was increased compared with estimates from the general Chinese population and estimates from previously described HIV cohorts. Large prospective studies are warranted to further evaluate the burden of DM and IFG in Chinese HIV-infected patients, as a first step in the management of a chronic HIV-associated condition. Medical providers should monitor Chinese HIV-infected patients regularly for evidence of impaired glucose metabolism, including patients with lower BMI who may still be at risk for DM and IFG. Particular attention may also need to be paid to patients with HBV coinfection, advanced age, and elevated fasting glucose.
ACKNOWLEDGMENTS The authors thank the study participants for their cooperation. The following clinical institutions or hospitals participated in this study: Peking Union Medical College Hospital, Beijing Youan Hospital, Beijing Ditan Hospital, Zhengzhou Sixth People’s Hospital, Tangdu Hospital, Guangzhou Eighth People’s Hospital, Shanghai Public Health Clinical Center, Shenzhen Third People’s Hospital, Fuzhou Infectious Diseases Hospital, Yunnan AIDS Care Center, Kunming Third People’s Hospital, and Honghe First People’s Hospital. The authors are grateful to Weidong Zhang, MD PhD, Director of the Department of Epidemiology, School of Public Health, Zhengzhou University, for his kind assistance in data analysis. REFERENCES 1. Kiertiburanakul S, Luengroongroj P, Sungkanuparph S. Clinical characteristics of HIV-infected patients who survive after the diagnosis of HIV infection for more than 10 years in a resource-limited setting. J Int Assoc Physicians AIDS Care (Chic). 2012;11:361–365. 2. Mocroft A, Reiss P, Gasiorowski J, et al. Serious fatal and nonfatal nonAIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr. 2010; 55:262–270. 3. Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIVinfected persons: the Swiss HIV cohort study. Clin Infect Dis. 2011;53: 1130–1139. 4. Worm SW, De Wit S, Weber R, et al. Diabetes mellitus, preexisting coronary heart disease, and the risk of subsequent coronary heart disease events in patients infected with human immunodeficiency virus: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D Study). Circulation. 2009;119:805–811. 5. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349: 1993–2003. 6. Triant VA, Lee H, Hadigan C, et al. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007; 92:2506–2512.
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