Comorbidities among the HIV-Infected Patients Aged 40 Years or Older in Taiwan

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Comorbidities among the HIV-Infected

Patients Aged 40

Years or Older in Taiwan

Pei-Ying Wu

1

, Mao-Yuan Chen

2

, Szu-Min Hsieh

2

, Hsin-Yun Sun

2

, Mao-Song Tsai

3

,

Kuan-Yeh Lee

4

,

Wen-Chun Liu

2

, Shan-Ping Yang

1

, Yu-Zhen Luo

1

, Jun-Yu Zhang

1

, Wang-Huei Sheng

1,2

*,

Chien-Ching Hung

2,5,6

*

1 Center of Infection Control, National Taiwan University Hospital, Taipei, Taiwan, 2 Department of Internal Medicine, National Taiwan University Hospital and National

Taiwan University College of Medicine, Taipei, Taiwan, 3 Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan, 4 Department of

Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan, 5 Department of Medical Research, China Medical University Hospital,

Taichung, Taiwan, 6 China Medical University, Taichung, Taiwan

Abstract

Background: With the widespread use of combination antiretroviral therapy (cART), life expectancy of HIV-infected patients

has significantly prolonged. An increasing number of HIV-infected patients are aging and concurrent use of medications are

not uncommon for management of metabolic complications and cardiovascular diseases related to aging and prolonged

exposure to cART.

Methods: We reviewed medical records of all HIV-infected patients aged 40 years or older who had been followed at a

university hospital for HIV care in Taiwan between January and December 2013. A standardized case record form was used

to collect information on demographics and clinical characteristics, comorbidity, cART, and concurrent medications.

Results: During the study period, 610 patients aged 40 to 49 years (mean, 44.1) and 310 aged 50 years or older (mean, 58.8)

sought HIV care at this hospital. Compared with patients aged 40 to 49 years, those aged 50 years or older were significantly

more likely to be female (15.9% vs 3.8%); to have received cART (97.7% vs 94.8%) and a lower plasma HIV RNA load (1.6 vs

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1.7 log10 _{copies/ml); and to have diabetes mellitus (18.4% vs 4.6%), hypertension (31.0%} vs 10.8%), hyperlipidemia (29.4% vs

11.6%), coronary artery disease (6.8% vs 0.5%), and an estimated glomerular filtration rate ,60 ml/min/1.73 m2 _{(11.5% vs}

2.7%); and were significantly less likely to have syphilis. Other than HIV infection, patients aged 50 years or older were more

likely to have been receiving two or more concurrent medications than those aged 40 to 49 years (22.9% vs 6.4%).

Conclusions: Our findings show a significant proportion of the HIV-infected patients aged 50 years or older have multiple

comorbidities that may increase the risk for cardiovascular and renal complications. Issues of poly-pharmacy among the HIVinfected

patients who are aging should be addressed to ensure adherence and minimize drug-drug interactions.

Citation: Wu P-Y, Chen M-Y, Hsieh S-M, Sun H-Y, Tsai M-S, et al. (2014) Comorbidities among the HIV-Infected Patients Aged 40 Years or Older in Taiwan. PLoS

ONE 9(8): e104945. doi:10.1371/journal.pone.0104945

Editor: Li-Min Huang, National Taiwan University Hospital, Taiwan

Received March 12, 2014; Accepted July 11, 2014; Published August 13, 2014

Copyright: _ 2014 Wu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted

use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. A de-identified data set is

available after approval from the Research Ethics Committee. Requests for the data may be sent to the corresponding author who will proceed with the

application for approval.

Funding: Taiwan Centers for Disease Control (DOH-102-DC-1401). The funders had no role in study design, data collection and analysis, decision to publish, or

preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist. * Email: whsheng@ntu.edu.tw (W-HS); hcc0401@ntu.edu.tw (C-CH)

Introduction

The widespread use of combination antiretroviral therapy (cART) has markedly improved the survival of HIV-1-infected patients [1,2]. According to the multinational cohort study, the life expectancy of HIV-infected patients aged 20 years is projected to increase from 36.1 years to 49.4 years [1]. As a result of reduction

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in AIDS-related mortality, the number of elderly people living with HIV will continue to increase; furthermore, the number of cases of newly diagnosed HIV infection among the elderly people is increasing in many countries [3–5], which will have considerable impact on the future delivery of care in the developed as well as developing countries where cART coverage is increasing.

Prolonged exposure to antiretroviral therapy along with aging may increase risk of developing metabolic complications and cardiovascular diseases among HIV-infected patients. Several studies have provided evidence that comorbidities such as diabetes mellitus [6–11], hypertension [6,8,9,12], coronary artery disease [11], hyperlipidemia [13,14], renal disease [7,11,15], and reduced bone mineral density [16–18] are more common among HIVinfected elderly patients than HIV-uninfected controls. Other than

cART, medications for management of metabolic complications and cardiovascular diseases will be needed, which will increase the pill burden and potential for drug-drug interactions in the elderly patients [19,20].

PLOS ONE | www.plosone.org 1 August 2014 | Volume 9 | Issue 8 | e104945

The prevalence of HIV-1 infection continues to increase with improvement of accessibility to HIV testing and care in Taiwan [21,22]. However, the information on comorbidities among the HIV-infected patients has been lacking. The purpose of this study aimed to describe the comorbidity profile and concurrent

medications used among the elderly patients with HIV-1 infection who sought care at a referral medical center in Taiwan.

Methods

Study setting and population

After the first case of HIV-1 infection and AIDS was reported in Taiwan in 1984, the number of patients diagnosed as having HIV infection through sexual contacts continued to increase steadily over the next two decades [23]. The outbreak of HIV infection among injecting drug users (IDUs) between 2003 and 2007 had caused a significant change of the landscape of HIV infection in Taiwan, with the proportion of IDUs increasing from less than 2% before 2003 to 27.6% of total cases reported as of 2013. At the end of 2013, a total of 26,457 cases of HIV infection were reported to the Taiwan Centers for Disease Control and 4,171 (15.8%)

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patients had died. After control of the outbreak of HIV infection among IDUs through harm reduction program, sexual contacts,

especially among men who have sex with men (MSM), have reemerged as the most common route of HIV transmission. As of

December 2013, MSM have accounted for 53% of all reported cases of HIV infection and patients aged 50 years or older accounted for 13.6% [21,22].

HIV-infected patients in Taiwan are provided with free medical care at designated hospitals around Taiwan by the government of Taiwan, including cART that was introduced in April 1997, and monitoring of CD4 lymphocyte count and plasma HIV RNA load. As of December 2012, it was estimated that 60% of HIV-infected patients sought HIV-related care and initiated cART after the diagnosis of HIV infection was made.

Study design

This was a cross-sectional study that enrolled HIV-infected patients who were aged 40 years or older and sought HIV care at the HIV clinics of the National Taiwan University Hospital from 1 January, 2013 to 31 December, 2013. Two age groups were identified: patients aged 40–49 years and those aged §50 years. We collected information on their baseline demographics, clinical characteristics, and medications including antiretroviral therapy, antihypertensives, lipid-lowering agents, and insulin and oral

hypoglycemics. Data on comorbid conditions, including hypertension, diabetes mellitus, chronic viral hepatitis, cardiovascular

disease, hyperlipidemia, fracture, malignancy, and osteoporosis and information on smoking status and alcohol use were also collected by interview, which were confirmed by review of medical records. The study was approved by the Research Ethics

Committee of the National Taiwan University Hospital (registration number: 200904020R) and participants gave written

informed consent.

Clinical measurements

Systolic and diastolic blood pressure was measured after the subjects were seated and rested for at least five minutes. Height was determined without shoes by the same machine. Weight was measured by a digital scale, and patients were fully dressed but without shoes or heavy clothing. Body mass index (BMI) was

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calculated as weight in kilograms divided by the square of the height in meters. Because diabetes mellitus is considered coronary artery disease-equivalent, we examined the status of diabetes mellitus control by retrospectively collecting laboratory data of fasting glucose, glycosylated hemoglobin (HbA1C) among those who received a diagnosis of diabetes mellitus from 1 January, 2012 to 31 December, 2013.

Laboratory and radiologic investigations

Total cholesterol, triglyceride, glucose, HbA1C, high-density

lipoprotein cholesterol (HDL-C), and low-density lipoproteincholesterol (LDL-C) levels were determined after at least an 8-hour

fast. The data of most recent plasma HIV RNA load, CD4 lymphocyte count, blood urea nitrogen, serum creatinine, estimated glomerular filtration rate (eGFR) that was calculated with the use of the abbreviated Modification of Diet in Renal Disease (MDRD) equation [24], hemoglobin, and rapid plasma reagin (RPR) (within 6 months of survey) were collected using a standardized case record form. Plasma HIV RNA load was quantified using the Cobas Amplicor HIV-1 Monitor test (Cobas Amplicor version 1.5, Roche Diagnostics Corporation, IN, USA) with a lower detection limit of 20 copies/mL, and CD4 count was determined using FACFlow (BD FACS Calibur, Becton Dickinson, CA, USA). Bone mineral density (BMD) was measured with the use of dual-energy X-ray absorptiometry scan (Lunar Prodigy; GE Healthcare, Belgium) [17].

Definitions

Comorbid conditions were defined by the ICD-9 diagnostic codes or in those who took antihypertensives, hypoglycemics, or lipid-lowering agents. Chronic hepatitis B virus (HBV) infection was defined as presence of HBV surface antigen for 6 months or longer. Hepatitis C virus (HCV) infection was defined as presence of HCV antibody. Osteopenia and osteoporosis were defined on the basis of World Health Organization (WHO) criteria [25]. Patients with a BMD T-score between 21.0 and 22.5 were

categorized as having osteopenia, and patients with a BMD Tscore less than or equal to 22.5 were categorized as having

osteoporosis.

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classes of antiretroviral agents according to the national treatment guidelines for adults with HIV infection. The most commonly prescribed antiretroviral combinations in antiretroviral-naive patients were 2 nucleoside reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI), 2 NRTIs plus ritonavir-boosted

protease inhibitor (PI), unboosted atazanavir or raltegravir, while triple NRTIs or combination of 3 classes were only infrequently prescribed. Ritonavir was available only in capsule form.

Statistical analysis

Categorical variables were analyzed by using X2 _{tests for} continuous variables were compared using Student’s t test. Baseline and comorbid conditions were compared with two groups. A P-value of ,0.05 was considered statistically significant. All P value was two-tailed. Analyses were performed using SAS software (Version 9.3).

Results

During the 12-month study period, 920 patients who were aged 40 years or greater were enrolled, among whom 310 (33.7%) and 610 (66.3%) were aged §50 years (elderly group) and 40–49 years (younger group), respectively (Figure 1). Clinical characteristics of the participants, stratified by age, are shown in Table 1. Of the 815 patients with available data, 304 (37.3%) were classified as overweight with a BMI .24 according to the criteria of the National Bureau of Health Promotion, Ministry of Health and

HIV Infection and Aging

Welfare, Taiwan; 31.0% (231/745) had fasting glucose levels §100 mg/dl, 51.5% (456/885) triglyceride levels §150 mg/dl, 20.0% (112/561) HbA1C levels§6.0%, and 5.7% (49/854) eGFR levels ,60 mL/min/1.73 m2_.

The two groups of patients differed significantly in many

characteristics examined (Table 1). Compared with patients in the younger group, HIV-infected patients in the elderly group were more likely to be female (15.9% vs 3.8%) and have a higher fasting glucose level (106 vs 97 mg/dl), HbA1C level (5.9 vs 5.6%) and systolic blood pressure (130 vs 126 mmHg), and have a lower eGFR (88.5 vs 98.9 ml/min/1.73 m2), plasma HIV RNA load (1.6 vs 1.7 log10 _{copies/ml) and BMI (22.9 vs 23.4 Kg/m}2₎

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(Table 1). Compared with the younger group, there was a

statistically significantly higher prevalence of comorbidities in the elderly patients (59.0 vs 36.4%) (Table 2), such as hypertension (31.0 vs 10.8%), hyperlipidemia (29.4 vs 11.6%), diabetes mellitus (18.4 vs 4.6%), and coronary artery disease (6.8 vs 0.5%);

furthermore, HIV-infected patients in the elderly group were more likely to have 2 or more comorbidities (30.6 vs. 8.7%). Of the 920 patients, 76 (8.3%) were taking oral hypoglycemic agents or receiving insulin replacement for control of diabetes

mellitus, 102 (11.1%) lipid-lowering agents, 142 (15.4%) antihypertensives, and 159 (17.3%) hypnotics drugs (Table 2). More than

95% of the patients (95.8%) were receiving cART during the study period. The antiretroviral agents to which the patients had been exposed and the cumulative exposure duration for each antiretroviral agent are shown in Table 3. Patients in the elderly group

had significantly longer exposure durations to PIs, nNRTIs, and NRTIs than those in the younger group (Table 3). The

antiretroviral agents and exposure durations for patients with at least 1 metabolic, cardiovascular, renal or hepatic comorbidity and those without any comorbidity are shown in Table 4.

Compared with those in the younger group, HIV-infected

patients in the elderly group were more likely to take medications for management of comorbidities: oral hypoglycemic agents or insulin replacement (16.5% vs 4.1%), lipid-lowering agents (19.4% vs 6.9%), and antihypertensives (26.5% vs 9.8%) (Table 2). Other than therapy for HIV infection, patients in the elderly group were more likely to have receiving 2 or more concurrent medications than those in the younger group (22.9% vs 6.4%). Patients in the younger group had a higher prevalence of syphilis (RPR titer §4) than those in the elderly group (26.3% vs. 11.4%).

The comparisons of clinical characteristics of 85 patients (9.2%) with diabetes mellitus and 835 patients (90.8%) without diabetes mellitus are shown in Table S1. Compared with those patients without diabetes mellitus, the patients with diabetes mellitus were more likely to be aged 50 years or greater (67.1 vs 30.3%) and to have a higher BMI (24.2 vs 23.2 Kg/m2_{), higher systolic blood} pressure (134 vs 127 mmHg), higher triglyceride level (260 vs 195 mg/dl), lower eGFR (82.7 vs 96.7 mL/min), and lower

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plasma HIV RNA load (1.5 vs 1.7 log10 _copies/ml).

Because diabetes mellitus is related to long-term metabolic, cardiovascular and renal complications, we examined the status of control by assessing the fasting glucose and HbA1C data of the patients with diabetes mellitus. All of the available results of blood sampling in fasting state (n= 270) of 85 patients with diabetes mellitus over the 12-month follow-up were stratified into 4 groups (Figure S1): group 1, HbA1C.6.5% and fasting glucose.

110 mg/dl (53.3%; 144/270); group 2, HbA1C.6.5% and fasting glucose,110 mg/dl (6.7%; 18/270); group 3, HbA1C,6.5% and fasting glucose.110 mg/dl (21.9%; 59/270) and group 4, HbA1C,6.5% and fasting glucose,110 mg/dl (18.1%; 49/270).

Discussion

In this cross-sectional study, we found that HIV-1-infected Taiwanese patients who were aged 50 years or older had significantly more comorbidities than those who were aged 40–

Figure 1. Study flow.

doi:10.1371/journal.pone.0104945.g001 HIV Infection and Aging

49 years. Polypharmacy was not uncommon in that more than 20% of the elderly patients were taking 2 or more concurrent medications in addition to cART for HIV infection.

The prevalence of the elderly group with 2 or more

comorbidities is higher than younger group in our study (30.6

vs. 8.6%), which is similar to what have been observed in HIVinfected elderly patients with access to cART in many Western

countries [6–9,13]. The types of comorbid diseases in our study are also similar to those reported among the HIV-infected elderly patients in Western countries, such as hypertension [7,9,12,13] and hyperlipidemia [13]. Previous studies comparing the prevalence of comorbidities between HIV-infected and HIV-uninfected

individuals showed discrepant results, however. The prospective cross-sectional study by Onen et al showed that HIV-infected patients in the US had a higher prevalence of hypertension and hypertriglyceridemia than HIV-uninfected individuals [18], while the VACS study by Oursler et al showed that HIV-uninfected

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populations according to age.

Variable §50 years, N= 310 40–49 years, N= 610 P Male, n (%) 262 (84.5) 587 (96.2) ,.0001

Age, mean (SD), years 58.8 (7.8) 44.1 (2.9) ,.0001 Risk behavior, n (%) ,.0001 MSM 152 (49.0) 521 (85.4) Heterosexual 139 (44.8) 64 (10.5) IDU 12 (3.9) 22 (3.6) Other 7 (2.3) 3 (2.3) Smoking status, n (%) (N = 290, 550) Never 149 (51.4) 269 (48.9) 0.50 Past 64 (22.1) 80 (14.6) ,.01 Current 77 (26.6) 201 (36.6) ,.01

Body mass index, mean (SD), Kg/m2 22.9 (3.3) 23.4 (3.4) 0.02 (N = 287, 552)

Systolic blood pressure, mean (SD), mm Hg (N = 286, 540) 130 (18.7) 126 (15.5) ,0.001 Diastolic blood pressure, mean (SD), mm Hg, 78 (11.9) 80 (11.4) 0.01

(N = 286, 540)

Plasma HIV RNA load, mean (SD), log10 copies/ml (N = 306, 603) 1.6 (0.7) 1.7 (1.0) 0.006 CD4, mean (SD), cells/ml, (N = 308, 602) 525 (273) 552 (278) 0.2 TG, mean (SD), mg/dl (N = 300, 585) 199 (148.2) 203 (177.8) 0.73 TG§150 mg/dl, n (%) 162 (54.0) 294 (50.3) 0.29 T-cholesterol, mean(SD), mg/dl (N = 300, 579) 180 (39.7) 178 (37.0) 0.34 T-cholesterol§220 mg/dl, n (%) 54 (18.0) 75 (13.0) 0.05 HDL, mean (SD), mg/dl (N = 26, 87) 44 (15.2) 40 (10.1) 0.24 HDL,40 mg/dl, n (%) 12 (46.2) 46 (52.9) 0.55 LDL, mean (SD), mg/dl (N = 38, 74) 105 (40.7) 104 (31.9) 0.85

Fasting glucose, mean (SD), mg/dl (N = 261, 484) 106 (32.8) 97 (25.3) ,.001 Fasting glucose§100 mg/dl, n (%) 116 (44.4) 115 (23.8) ,.0001

Fasting glucose§110 mg/dl, n (%) 59 (22.6) 51 (10.5) ,.0001 HbA1C, mean (SD) (N = 215, 346) 5.9 (1.0) 5.6 (0.9) ,.0001 HbA1C§6.5%, n (%) 32 (14.9) 18 (5.2) ,.0001

BUN, mean (SD) (N = 214, 395) 18.1 (13.2) 14.5 (6.7) ,.001 Serum creatinine, mean (SD) (N = 297, 553) 1.1 (1.2) 0.9 (0.8) 0.12

eGFR, mean (SD), ml/min/1.73 m2 (N = 297, 557) 88.5 (27.4) 98.9 (24.9) ,.0001 eGFR ,60 ml/min/1.73 m2, n (%) 34 (11.5) 15 (2.7) ,.0001

On cART, n (%) 303 (97.7) 578 (94.8) 0.03 Current exposure to PI 185 (59.7) 325 (53.3) 0.06

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Current exposure to TDF 92 (29.7) 246 (40.3) 0.002

Note: The numbers in the parenthesis presented after each variable indicate the number of patients with data for the elderly and younger groups of patients,

respectively.

Abbreviations: BUN, blood urea nitrogen; cART, combination antiretroviral therapy; eGFR, estimated glomerular filtration rate; HbA1C, glycosylated hemoglobin, HDL,

high-density lipoprotein cholesterol; IDU, injecting drug use; LDL, low-density lipoprotein cholesterol; MSM, men who have sex with men; PI, protease inhibitor; SD,

standard deviation; TDF, tenofovir disoproxil fumarate; TG, triglyceride. doi:10.1371/journal.pone.0104945.t001

individuals in the US had a higher prevalence of hypertension and diabetes mellitus than HIV-infected patients [12].

With the increasing prevalence of comorbidities, it is not

surprising that, other than antiretroviral therapy, use of concomitant medications for management of comorbid diseases were

common in our patients. It is therefore important to note some of the negative consequences as a result of polypharmacy. The patients taking multiple drugs for many chronic medical conditions are at potentially increased risk of drug-drug interactions and adverse drug events [20,26]. Consistent with findings reported in the literature (range, 82–96%) [20,26,27], 52.3% of our patients aged §50 years and 29.2% of the patients aged 40–49 years in this study were receiving 1 or more concurrent medications. Table 2. Comorbid conditions of the two study populations. Variable §50 years, N= 310 (%) 40–49 years, N= 610 (%) P

At least one comorbidity, n (%) 183 (59.0) 222 (36.4) ,.0001 Diabetes mellitus 57 (18.4) 28 (4.6) ,.0001 Hypertension 96 (31.0) 66 (10.8) ,.0001 Anti-HCV-positivity 18 (5.8) 46 (7.6) 0.33 Chronic HBV infection 21 (6.8) 63 (10.3) 0.08 Hyperlidemia 91 (29.4) 71 (11.6) ,.0001 Cancer 12 (3.9) 13 (2.1) 0.12 CAD 21 (6.8) 3 (0.5) ,.0001 Fracture 3 (1.0) 1 (0.2) 0.08 Osteoporosis (N = 99, 99) 7 (7.1) 2 (2.0) 0.09 Active drinking (N = 288, 551) 13 (4.5) 18 (3.3) 0.36

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RPR§4, n (%) 31 (11.4) 148 (26.3) ,.0001 Concurrent medications, n (%) Lipid-lowering agent 60 (19.4) 42 (6.9) ,.0001 Hypoglycemic agent 51 (16.5) 25 (4.1) ,.0001 Anti-hypertensives 82 (26.5) 60 (9.8) ,.0001 Hypnotics 59 (19.0) 100 (16.4) 0.31

Note: The numbers in the parenthesis presented after each variable indicate the number of patients with data for the elderly and younger groups of patients,

respectively.

Abbreviations: CAD, coronary artery disease; HBV, hepatitis B virus; HCV, hepatitis C virus; RPR, rapid plasma regain. doi:10.1371/journal.pone.0104945.t002

Table 3. The cumulative exposure durations of antiretroviral agents of the two study populations.

Drug class and duration §50 years, N= 310 40–49 years, N= 610 P PI, mean (SD), months 64.40 (46.6) 56.1 (40.8) 0.02

Lopinavir/ritonavir 50.26 (37.9) 46.10 (37.1) 0.41 Atazanavir 45.94 (29.7) 43.96 (29.9) 0.51 Darunavir 24.43 (24.5) 17.21 (15.8) 0.22 Indinavir 23.56 (25.9) 21.21 (19.6) 0.59 Saquinavir 19.10 (19.5) 17.48 (13.7) 0.74

NRTI, mean (SD), months 103.0 (57.7) 78.04 (55.1) ,.0001 Zidovudine 68.88 (53.8) 58.70 (48.8) 0.03

d4T/ddI/ddC 36.79 (41.1) 33.87 (37.7) 0.52 Abacavir/lamivudine 59.08 (37.1) 50.54 (32.6) 0.006 Tenofovir 21.29 (9.8) 18.60 (9.4) 0.02

nNRTI, mean (SD), months 71.35 (56.8) 54.88 (52.0) 0.0003 Efavirenz 75.73 (55.7) 56.17 (51.9) 0.0002

Nevirapine 45.79 (54.5) 35.36 (45.8) 0.17

Integrase inhibitor, mean (SD), months 27.65 (23.2) 17.93 (11.8) 0.07

Abbreviations: d4T, stavudine; ddI, didanosine; ddC, deoxycytidine; NRTI, nucleoside reverse-transcriptase inhibitors; nNRTI, non-nucleoside reverse-transcriptase

inhibitors; PI, protease inhibitor. doi:10.1371/journal.pone.0104945.t003

The prevalence and incidence of diabetes mellitus are increasing worldwide, especially in the elder patients regardless of the status of HIV infection [10,28–30]. Presence of diabetes mellitus is

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associated with a higher mortality rate among HIV-uninfected patients [31–34] because of increased risk of cardiovascular diseases, nephropathy, retinopathy, and neuropathy [35,36]. Whether the incidence of diabetes mellitus is higher in HIVinfected patients than HIV-uninfected individuals remains controversial. In the French study, Capeau et al found a markedly

higher incidence of diabetes mellitus in HIV-infected than HIVuninfected population (14.1 vs. 4-6/1000 person-years) [37]. In

the Denmark study, Rasmussen et al found HIV-infected

individuals did not have an increased risk of developing diabetes mellitus compared to HIV-uninfected population (3.70 vs. 3.87/ 1000 person-years) [38]. The discrepancy of incidence of DM in the published studies may be due to differences in demographic factors such as age, gender and race, exposure duration to cART and regimens of cART used [39,40].

Using Taiwan National Health Insurance data, Jiang et al have found that the prevalence of DM among women and men aged 40 to 59 years increased from 4.63% to 5.47% and from 4.97% to 7.56%, respectively, between 2000 and 2009 [33]; the prevalence of DM among women and men aged 60 to 79 years increased from 17.17 to 21.97% and from 13.60 to 13.97%, respectively, between 2000 and 2009. In this study that was conducted in 2013, we found that the prevalence of DM in HIV-infected males

(N = 749) and females (N= 41) aged 40–59 years was 7.48% and 7.32%, respectively; for the patients who were aged 60 years or older (N= 130), the prevalence of DM in males (N= 100) and females (N = 30) was 21.0% and 16.67%, respectively. However, given the small sample size of the patients in our study, the interpretation of the data should be cautious.

In our study, we found that diabetes mellitus was associated with older age and higher BMI, which are consistent with other studies [10,28,29]. The finding that more than 50% of the blood sampling among HIV-infected patients with diabetes mellitus showed HbA1C .6.5% and fasting glucose levels .110 mg/dl suggests that better strategies with multidisciplinary approach are urgently needed to improve the quality of care in terms of diabetic control to prevent the occurrence or delay the progression of metabolic, cardiovascular, and renal complications in the patients enrolled in

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this study.

Renal function in terms of eGFR usually decreases with age. The prevalence of eGFR,60 mL/min/1.73 m2 _{in our elderly} patients was 11.5%, which is higher than those in other studies among the HIV-infected population from Brazil (3.9%) [8] and Taiwan (7.03%) [41], but is lower than the studies from the UK (15.5%) [15] and Japan (15.4%) [42]. The difference between ours and other studies may be explained by the study populations. In our study population, the mean age was 49 years, which is greater than the other study from Taiwan (36.9 years). In the US study, Onen et al. found approximately 50% of the overall elderly study population had renal impairment with chronic kidney disease in 11% and 7% of HIV-infected persons and HIV-uninfected patients, respectively [18].

While most of patients in this study were receiving cART with good control of HIV infection, the finding of a high prevalence of syphilis is of particular concerns, especially in the patients aged 40 to 49 years [43,44]. Acquisition of syphilis indicates unprotected sex, which may increase the risk of HIV transmission to sexual partners or superinfection with HIV resistant to the regimens the

patients were receiving; furthermore, several studies have demonstrated that syphilis is associated with acquisition of other sexually

transmitted hepatotrophic virus infections such as hepatitis B, C and D virus [45–48].

There are several limitations of our study. First, it is a crosssectional survey of patients who sought HIV care at a university

hospital. The information examined is mainly from laboratory data that were accumulated during the clinical care. Many other comorbidities were not systematically examined, such as

osteopo-Table 4. The cumulative exposure durations of antiretroviral agents of the two study populations.

Drug class and duration Presence of any comorbidity (+),

N= 405 Without any comorbidity(-), N= 515 P PI, mean(SD) months 64.67 (45.9) 54.52 (40.2) 0.004 Lopinavir/ritonavir 50.63 (34.7) 45.51(38.9) 0.29 Atazanavir 46.78 (30.3) 42.78 (29.2) 0.16 Darunavir 22.24 (20.0) 16.27 (17.2) 0.17

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Indinavir 25.46 (27.9) 18.76 (14.8) 0.11 Saquinavir 19.46 (19.4) 16.19 (11.0) 0.45

NRTI, mean (SD), months 99.78 (59.1) 75.99 (53.4) ,.0001 Zidovudine 69.73 (52.4) 55.93 (48.5) 0.003

d4T/ddI/ddC 35.75 (40.6) 34.43 (37.6) 0.77 Abacavir/lamivudine 57.75 (36.5) 50.29 (32.7) 0.01 Tenofovir 20.07 (9.6) 18.83 (9.5) 0.23

nNRTI, mean (SD), months 71.27 (64.8) 51.90 (52.6) ,.0001 Efavirenz 73.36 (54.6) 54.0 (51.9) 0.0001

Nevirapine 45.33 (51.7) 34.50 (47.1) 0.15

Integrase inhibitor, mean (SD), months 24.97 (18.7) 16.93 (14.3) 0.06

Note: The comorbidities include hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, chronic kidney disease (eGFR,60 ml/min/1.73 m2),

malignancy, osteoporosis, and chronic viral hepatitis.

Abbreviations: d4T, stavudine; ddI, didanosine; ddC, deoxycytidine; NRTI, nucleoside reverse-transcriptase inhibitors; nNRTI, non-nucleoside reverse-transcriptase

inhibitors; PI, protease inhibitor. doi:10.1371/journal.pone.0104945.t004

rosis and malignancy. Second, the exposure duration to cART was not taken into consideration in comparisons made between the two age groups. Third, we did not have an HIV-uninfected population for comparison in terms of the frequency of comorbidity. Therefore, it is not known whether the frequency of any comorbidity examined in this study is higher in HIVinfected patients than in HIV-uninfected patients in Taiwan,

although several studies have suggested that cART and HIV infection may accelerate aging and increase risk of metabolic, cardiovascular and renal complications [10,14,15,39,40,42]. In conclusion, our findings show that a significant proportion of the HIV-infected elderly patients In Taiwan have multiple

comorbidities that may increase risk for cardiovascular and renal complications. Issues of poly-pharmacy among the elderly with HIV infection should be addressed to ensure adherence and minimize drug-drug interactions. Comprehensive approach to the management of metabolic, cardiovascular and renal comorbidities cannot be overemphasized in the long-term successful management

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of HIV-infected elderly population.

Supporting Information

Figure S1 The scattered plot of glycosylated hemoglobin

(HbA1C) and fasting glucose data collected from the 85 patients with diabetes mellitus during the 12-month study period. PI, protease inhibitor-containing regimens.

(TIF)

Table S1 Comparisons of demographic and clinical characteristics of the patients with and those without diabetes mellitus.

(DOCX)

Acknowledgments

Footnote: Preliminary analyses of these data were presented as abstract no. PE15/13 at the 14th European AIDS Conference, Brussels, Belgium, 16–19 October, 2013.

Author Contributions

Conceived and designed the experiments: WHS CCH PYW. Performed the experiments: PYW MYC SMH HYS MST KYL WCL SPY YZL JYZ. Analyzed the data: PYW MYC SMH HYS MST KYL. Contributed

reagents/materials/analysis tools: WCL SPY YZL JYZ. Contributed to the writing of the manuscript: CCH PYW WHS.

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