Hepatitis B or C virus coinfection in and risks for transaminitis in human immunodeficiency virus - infected Thais on combined antiretroviral therapy

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Abstract

Background

The impact of hepatitis B or C virus (HBV or HCV) coinfection on the progression of liver diseases in patients infected with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) has not been fully studied in resource-limited settings.

Objectives

To examine the seroprevalence of HBV or HCV coinfection and its effect on hepatic function in HIV-infected Thai patients receiving HAART.

Methods

A single-center cross-sectional study was conducted from October 2011 to January 2013 in Thai patients infected with HIV (n = 211). Combination ART was received by 94.3% of the patients (median duration, 32.1 (range, 0–95.3) months). The patients were screened for HBV and HCV infection and examined for transaminitis, defined as levels of aspartate aminotransferases (AST) and/or alanine aminotransferase (ALT) increased above the upper normal limits, and ARV-associated hepatotoxicity. Regression analyses were performed to determine risks for transaminitis in the studied group.

Results

Prevalence of HBV or HCV coinfection in the HIV-infected patients was 11.4% and 7.6%, respectively and the rate of transaminitis was 26.5%, with only one patient developing severe grade 3 hepaticity. Univariate and multivariate analyses indicated that predictive risk factors for transaminitis in this study group were seropositivity for HCV (OR 12.3, 95% CI 3.0-50.1, P < 0.001), but not for HBV, together with age difference, sex, and CD4+ cell count.

Conclusions

Coinfection with HCV is a potentially more important risk for transaminitis than coinfection with HBV, leading to chronic liver diseases in HIV-infected Thai patients with ongoing HAART.

Introduction

The introduction of combination highly active antiretroviral therapy (HAART), also termed highly active antiretroviral therapy (HAART), has decreased the morbidity and mortality of patients infected with human immunodeficiency virus (HIV) with an increased evidence of liver-related diseases. Hepatitis B or C virus (HBV or HCV) coinfection has been a major cause of progression to severe liver damage adding complexity to the setting of HIV infection [1-3]. Patients with HIV who are coinfected with HBV or HCV are at high risk of antiretroviral (ARV)associated hepatotoxicity and long-term liver damage [4-7]. Coinfection of HBV or HCV with HIV is linked to the development of hepatocellular carcinoma and liver disease-related mortality in patients coinfected with HBV or HCV and HIV is increasingly reported [8,9].

HBV or HCV coinfection with HIV is commonly found because of the shared routes of transmission. The prevalence of HBV or HCV coinfection with HIV varies widely depending on the risk factors in different populations studied [10]. In the Asia-Pacific region, an observational cohort study in 1,731 HIV patients found a high prevalence of approximately 10% coinfection with HBV or HCV. While a studies of Thai patients reported coinfection in 7%–10% [4, 11-13]. However, only 40%–50% of HIV-seropositive patients are sceened for HBV and HCV infections in resource-limited settings, including Thailand [11,13].

In Thailand, HAART was initiated in 2000, and became national in 2004. During 2000–2007, 92.4% of HIV-infected patients received nevirapine and 2 nonnucleoside reverse transcriptase inhibitors (NNRTIs) as an initial regimen. Currently, most patients in resource-limited settings rely on this regimen [14-16]. Although several guidelines recommend screening for HBV and HCV infection in HIV-infected patients before starting HAART and switching patients coinfected with HBV to different regimens, HBV and HCV coinfections, and the prevalence of liver-related diseases in the HIV patients, especially in resource-limited areas, have not been well-monitored [17, 18]. A previous study in HIV-infected Thai patients indicated that HBV or HCV coinfection increased the mortality of HAART-naïve patients [19]. Coinfection has been well established as a major predictor for liver enzyme elevation in ARV-naïveHIV patients, and for acute severe ARV hepatotoxicity when HAART is initiated [4, 5, 7]. However, the effect of coinfection with HBV or HCV on hepatic function of HIV patients, who are on long-term suppressive ART, is less clear.

This cross-sectional study aimed to examine the prevalence of HBV or HCV coinfection with HIV and its effect on the liver function of patients attending the ART clinic of a secondary care level hospital in Thailand. The prevalence of HBV or HCV coinfection with HIV was examined and its association with transaminitis and ARV-associated hepatotoxicity was determined. Risk factors for an increased level of liver enzymes were investigated.

Methods

Study population

A cross-sectional study was undertaken among patients infected with HIV attending the ART clinic in Nakhon Nayok Hospital, Thailand, from October 2011 to January 2013. A total of 211 patients, 92 male (43.6%) and 119 female (56.4%), were recruited in this study. The mean age of these patients was 40.1 ± 10.6 years. One hundred ninety-nine (199) of 211 patients (94.3%) were on combined ARV drugs, 103/ 211 (48.8%) on lamivudine/zidovudine/nevirapine, 24/ 211 (11.4%) on lopinavir/ritonavir or atazanavir, 23/ 211 (10.9%) on lamivudine/stavudine/nevirapine, and 49/211 (23.2%) on other combined regimens including efavirenz- (40/211, 19.0%) and tenofovir-containing regimens (28/211,13.3 %). Median duration of the ART was 32.1 (range, 0–95.3) months. Patients were older than 15 years, documented as HIV-infected, provided written informed consent and had no record of HBV or HCV screening. Patients who consumed alcohol, herbal medicines, and steroid drugs, and patients with opportunistic infections (OIs) including tuberculosis were excluded from this study [1, 20, 21]. The study protocol was reviewed and approved by the Human Research Ethics Committees of Thammasat University (No.005/2555) and Nakhon Nayok hospital, Thailand.

Clinical data and laboratory investigations

Data collected from the patient's medical records were age, sex, body mass index (BMI), opportunistic infections, baseline levels of aspartate and alanine aminotransferases (AST and ALT) before starting ART, duration of ART, and currently used ARV drug regimens. Other data collected from a standardized questionnaire included transmission routes, alcohol consumption, herbal medicine use, and steroid drug intake. EDTAblood and serum samples collected from the patients were subjected to testing of HIV viral loads (Roche Diagnostics, Indianapolis, IN, USA) and CD4+ cell count (BD Biosciences, San Jose, CA, USA). Serum samples were also routinely tested for the levels of AST and ALT (Roche Diagnostics). The cut-off levels of AST and ALT were >40 U/L. The remaining samples were tested by electrochemilu-minescence immunoassay for anti-HCV and HBV surface antigen (HBsAg). The HBsAg-positive samples were further examined for the extracellular form of HBV core antigen (HBeAg) (Roche Diagnostics).

Evaluation for transaminitis and ARV-associated hepatotoxicity

In this study, transaminitis was defined as an increased level from the normal upper limit (ULNs) of either AST or ALT (>40 U/L) [22]. The hepatotoxicity was classified into grades 1–4 based on the standard approach proposed by the AIDS Clinical Trials Group (ACTG) [7]. The elevation of AST or ALT level detected at the date of enrollment relative to the upper normal limit (ULN) was considered as baseline and the hepatotoxicity was classified as normal (ULN), grade 0 (<1.25 × ULN), grade 1 (1.25–2.5 × ULN), grade 2 (2.6-5 × ULN), grade 3 (5.1–10 × ULN) and grade 4 (>10 × ULN). To avoid a selection bias favoring inclusion of patients with very high pretreatment AST and ALT levels (higher than ULN), the toxicity was graded based on changes relative to the baseline values detected before starting the ARV treatment rather than ULN; grade 0 (<1.25x baseline), grade 1 (1.25–2.5X baseline), grade 2 (2.6–3.5 × baseline), grade 3 (3.6–5 × baseline) and grade 4 (>5 × baseline). The grade 3–4 aminotransferase elevations were evaluated as ARV-associated hepatotoxicity.

Statistical analysis

Prevalence of the hepatitis B and C virus coinfections in the HIV-infected patients was analyzed by descriptive statistics and presented as percentages. Chi-square and Fisher exact tests were used to determine the association of HBV or HCV coinfections with categorical variables, while a Mann-Whitney U test was used to analyze that with continuous variables. The level of statistical significance was set at P < 0.05. Univariate and multivariate analyses for a risk of transaminitis were analyzed by logistic regression. Odds ratio (OR) with 95% confidence interval (CI) and P were calculated. The level of significance was set at P < 0.05.

Results

Characteristics of the study population

We recruited 211 HIV-infected patients for HBV and HCV testing. Twenty-four patients were positive for HBsAg and 4 of these were also positive for HBeAg. Sixteen patients were positive for anti-HCV antibodies, but triple infection was not observed in this group. Prevalence of HBV and HCV coinfection in this HIV-infected group was 11.4% (24/211) and 7.6% (16/211), respectively, and that of HIV monoinfection was 81.0% (171/211). The characteristics of these 3 groups of patients were similar, except for sex and transaminitis(P = 0.013 and P < 0.001, respectively) as shown in (Table 1. In this study, 83.9% (177/211) of the 211 patients received ART for longer than 6 months. ARV regimens currently used and duration of the ART in the HIV monoinfected and, HBV- or HCV-coinfected groups were not statistically significantly different (Table 1).

Notably, there was no significant difference between the median ART duration in HIV monoinfected and, HBV- or HCV-coinfected patients (32.1 months [range, 0–95.3]), 31.4 months [range, 0–63.8]), and 44.9 months [range, 7.8–54.9]), respectively) (P > 0.05)) (data not shown).

Table 1

Characteristics of patients infected with human immunodeficiency virus (HIV) recruited in this study

CharacteristicsAll HIV+ n(%)HBsAg-/ anti-HCV- n(%)HBsAg+/ anti-HCV- n(%)HBsAgV-/ anti-HCV+ n(%)P
Patients (%)211(100)171(81.0)24(11.4)16(7.6)
Age (years)
 <3034(16.1)31(18.1)3 (12.5)0(0.0)
 31–4082(38.9)62(36.3)12(50.0)8(50.0)
 41-5053(25.1)45(26.3)4(16.7)4(25.0)
 >5042(19.9)33(19.3)5 (20.8)4(25.0)0.41
Sex
  Male92(43.6)67(39.2)13 (54.2)12(75.0)
  Female119(56.4)104(60.8)11(45.8)4(25.0)0.013*
BMI(kg/m2)
 Normal143 (67.8)119(69.6)12(50.0)12(75.0)
 Underweight34(16.1)24(14.0)7(29.2)3 (18.8)
 Overweight/obese34(16.1)28(16.4)5 (20.8)1(6.3)0.21
Transmission routes
 Sex with a spouse133 (63.0)111(64.9)15(62.5)7(43.8)
 Sex with others59(28.0)45 (26.3)6(25.0)8(50.0)
 Men who have sex with men9(4.3)7(4.1)2(8.3)0(0.0)
 Others10(4.8)8(4.7)1(4.2)1(6.3)0.36
ARV drugs
 Naive to ARV treatment12(5.7)11(6.4)1(4.2)0(0.0)
 Lamivudine/stavudine/nevirapine23 (10.9)19(11.1)2(8.3)2(12.5)
 Lamivudine/zidovudine/nevirapine103 (48.8)86(50.3)10(41.7)7(43.8)
 Lopinavir/ritonavir or atazanavir24(11.4)17(9.9)3 (12.5)4 (25.0)
 Others49(23.2)38(22.2)8(33.3)3 (18.8)0.71
Duration of ARV treatment
 <3 months27(12.8)26(15.2)1(4.2)0(0)
 3-6 months7(3.3)7(4.1)0(0)0(0)
 >6 months177(83.9)138(80.7)23 (95.8)16(100)0.22
CD4+(cells/μL)
 <20053 (25.2)41 (24.0)9(37.5)3 (18.8)
 200–349.952(24.6)38(22.2)7(29.2)7(43.8)
 >350106(50.2)92(53.8)8(33.3)6(37.5)0.13
Transaminitis
 AST and/or ALT≤ULN (40 U/L)155 (73.5)136(79.5)16(66.7)3 (18.8)
 AST and/or ALT>ULN (40 U/L)56(26.5)35 (20.5)8(33.3)13(81.3)0.001*

Liver enzyme levels and CD4+ cell counts in patients infected with HIV, and patients coinfected with HIV and HBV or HCV

The medians of AST, ALT, and CD4+ Τ cell count in three groups of HIV patients were analyzed for 199 patients who were currently on combination ART (Table 2). The data showed that AST levels in the patients coinfected with HBV or HCV were significantly higher than those in HIV-monoinfected patients (P = 0.001 and P < 0.001, respectively). When compared with the HIV-monoinfected patients, the level of ALT in the patients coinfected with HBV was similar (P = 0.137), whereas that in patients coinfected with HCV was significantly higher (P < 0.001). These data correlated with a significant association between HCV- or HBV-coinfection and transaminitis as shown in Table 1.

Table 2

Medians of liver enzyme levels, AST and ALT, and CD4+ cell count in HIV monoinfected, and patients coinfected with HIV and HBV or HCV currently on combination ART (n= 199)

HBsAg-/anti-HCV- (n = 160)HBsAg/anti-HCV- (n = 23)HBsAg-/anti-HCV+ (n = 16)P


P
MedianRangeMedianRangeMedianRange
AST(U/L)23.0(9-1338)33.0a(16-124)0.001*44.5b(21-208)<0.001*
ALT(U/L)22.5(6-765)22.012-99)0.28051.5b(13-149)<0.001*
CD4+cells (cells/μL)388.5(4-1601)279.0(1-810)0.091311.0(1291238)0.46

AST = aspartate aminotransferase, ALT = alanine aminotransferase, HIV= human immunodeficiency virus, HBsAg = hepatitis B virus (HBV) surface antigen, HCV = hepatitis C virus

The levels of HIV RNA and CD4+ Τ cell counts in these patients were monitored. Most of the 211 HIV-infected patients had undetectable levels of HIV RNA (<20 copies/mL) (data not shown) and CD4+ cell counts with median of 385.0 cells/μL (range, 41 to 601). Data analysis showed that the coinfection with either HBV or HCV was not associated with the levels of CD4+ Τ cells (Table 1) and the median levels of CD4+ cell counts in patients coinfected with HBV or HCV were not significantly different from that in the HIV-monoinfected patients (Table 2).Interestingly, among the HBsAg -positive patients, there were four HBeAg-positive patients having higher median levels of AST and ALT, 57.0 U/L (range, 43-471) and 46.0 U/L (range, 20–138), respectively, than those with HBeAg negative. The median CD4+ Τ cell number of the HBeAg-positive patients was dramatically decreased (192.0 cells/μL; range, 5–269) (data not shown).

Hepatotoxicity rates and risk factors for transaminitis in Thai patients infected with HIV

Based on the standard approach to ACTG, 35 of 211 patients (16.6%) developed hepatotoxicity. Of these 35 patients, 94% (33/35) were assessed as having grade 1 hepatotoxicity, and 3% (1/35) were assessed as having grade 2 hepatotoxicity. Only one patient coinfected with HBV (3%) were assessed as having drug-induced hepatotoxicity (grade 3). In this study, 56 of 211 (26.5%) participants were assessed as having transaminitis. Of note, 48 of 56 (86%) patients with transaminitis had been on combined ARV treatment for more than 6 months including the patient who was assessed as having grade 3 hepatotoxicity. The median duration of ARV treatment of the patients having transaminitis was 31.2 months (range, 0–81.7).

As shown in Table 3, univariate analysis indicated that anti-HCV-positivity and the ages of 31–40 years were risk factors for developing transaminitis (OR 16.8, 95% CI 4.5-62.4, P < 0.001 and OR 5.9, 95% CI 1.7–21.2, P = 0.006, respectively). Female patients had a relatively lower risk than male patients (OR 0.3, 95% CI 0.2-0.6, P < 0.001). The HIV-positive patients having a CD4+ cell count >350 cells/μL had a lower risk for ULN levels of aminotransferases than those having a CD4+ cell count <200 cells/μL (OR 0.3, 95% CI 0.2–0.7, P = 0.005). In multivariate analysis, anti-HCV positivity as well as an age of 31-40 years remained predictive factors (OR 12.3. 95% CI 3.0-50.1, P < 0.001 and OR 4.6, 95% CI 1.2–17.5,P = 0.023, respectively), and being female and having CD4+ cell count >350 cells/ L were factors for not associated with transaminitis (OR 0.4,95% CI 0.2-0.8, P = 0.014 and OR 0.4, 95%CI 0.2-0.9, P = 0.040, respectively). The analysis did not show any significant association of currently used ARV regimens and HBsAg positivity with transaminitis in this group of HIV patients (P >0.05).

Table 3

Univariate and multivariate analysis of risks for the transaminitis in patients infected with human immunodeficiency vims (HIV) (n = 211 )

CharacteristicsEnrolled patientsPatients with transaminitis n(%)Crude OR (95%CI)PAdjusted OR (95%CI)P
Age (years)
 <30343(5)11
 31–408230(54)5.9(1.7-21.2)0.006*4.6(1.2-17.5)0.023*
 41-505312(21)3.0(0.8-11.6)0.112.2(0.5-8.9)0.28
 >504211(20)3.7(0.9-14.4)0.062.6(0.6–10.9)0.20
Sex
 Male9236(64)11
 Female11920(36)0.3 (0.2–0.6)<0.001*0.4(0.2-0.8)0.014*
CD4+(cells/μL)
 <2005320(36)11
 200–349.95218(32)0.9(0.4–1.9)0.740.9(0.4–2.4)0.91
 >35010618(32)0.3 (0.2–0.7)0.005*0.4(0.2-0.9)0.04*
ARV treatment3(5)10.29
 Naive to ARV treatment1210(18)2.3 (0.5-10.8)0.65
 Lamivudine/stavudine/nevirapine2320(36)0.7(0.2-2.9)1.000
 Lamivudine/zidovudine/nevirapine1036(11)1.0(0.2–4.9)0.52
 Lopinavir/ritonavir or atazanavir2417(30)1.6(0.4–6.7)
 Others49
HBV and HCV serological status
 HBsAg anti-HCV-17135(63)11
 HBsAg+anti-HCV-248(14)1.9(0.8–4.9)0.171.3(0.5-3.5)0.64
 HBsAg-anti-HCV+1613 (23)16.8(4.5–62.4)<0.001*12.3(3.0–50.1)<0.001*

Data was adjusted for age, sex, CD4+ cell count, antiretroviral (ARV) treatment, hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection in the model.

Discussion

Accumulating evidence establishes several major risks for liver abnormality in patients with HIV including ARV treatment and coinfection with hepatitis viruses [1]. This cross-sectional study has demonstrated a relatively high seroprevalence of 11.4% HBV and 7.6% HCV coinfection, and a high rate of 26.5% of transaminitis in HIV-infected Thai patients mostly receiving combined ARV drugs. However, ARV drugs currently used in these patients were not significantly associated with elevated liver enzymes. Rather, positivity for HCV, but not HBV infection, together with age, sex, and CD4+ cell count were factors predictive of transaminitis.

ARV treatment usually causes liver enzyme elevation in HIV patients. Patients treated with NNRTI-containing regimens, in particular nevirapine, are at high risk of development of severe grades (3–4) of hepatotoxicity. The hepatotoxicity is usually observed within days to weeks and is frequently present as a second peak reaction approximately 4-6 months [7]. In the present study, 94.3% of the participants had currently ongoing ART, with 59.7% receiving nevirapine-containing regimens. Although previous reports indicated the NNRTI-induced liver enzyme elevation in HIV patients [4, 7], no currently used ARV regimen in the present study group was significantly associated with transaminitis (Table 3). In the present study, the low frequency of severe grade (3–4) hepatotoxicity observed and a lack of association of the ARV regimens used with transaminitis were possibly because most of our patients (83.9%) had been treated with ARV drugs for longer than those reported in previous studies (median: 32.1 [range up to 95.3] months) [4, 7]. Our present data also indicated that up to 85% of the patients with transaminitis had been on ART for longer than 6 months with a median duration of 31.2 months (range, 0–81.7); suggesting that early ARV-associated hepatotoxicity may not contribute to transaminitis observed in this HIV-infected group. However, long-term effects of some ARV drugs on liver function cannot be excluded [6]. Notably, to determine currently used ARV regimens may not reflect the effect of particular ARV drugs on hepatic abnormality in this group because the patients may have been switched from the other regimens because of complications.

Previous studies demonstrated that HIV coinfection with HBV or HCV was associated with the elevation of baseline liver enzyme levels in ARV-naïve HIV patients and was a major predictor for ARV drug-induced aminotransferase elevation, and grade 3-4 hepatotoxicity, when HAART was initiated [4,5, 7, 23, 24]. Our data suggested that the coinfection with HBV or HCV was significantly associated with transaminitis (Table 1). Consistent with findings in previous studies [24, 25], patients coinfected with HIV and HBV had relatively higher medians of AST, but not ALT levels, than those infected with HIV alone (Table 2). Interestingly, 4 patients coinfected with HIV and HBV, who were potentially in an active stage of HBV infection (HBeAg+), showed considerably higher medians of both AST and ALT levels than HIV-monoinfected patients. However, univariate and multivariate analyses indicated that HBV infection was not significantly associated with transaminitis in this group of the patients (P > 0.05) (Table 3). [1]. In the present study, 71.1% of the participants received lamivudine- or tenofovir-containing ARV regimens that suppressed both HIV and HBV replication [3, 26]. The drug regimens may neutralize the influence of HBV infection in the development of transaminitis in this HIV patient group [26].

By contrast, like several previous studies [5, 23, 25], our present data showed significantly higher medians of AST and ALT levels in patients coinfected with HIV and HCV. We found that HCV-coinfection carries a 12.3 times higher risk of transaminitis than that in HCV seronegative patients (95% CI 3.0–use of the exclusion of patients with opportunistic infections including tuberculosis, alcohol consumers, and herbal and steroid drug users, coinfection with HCV was considered the major contributor to hepatic function abnormality as shown by the abnormal levels of liver enzymes. The elevation of liver enzymes, especially ALT, in HIV patients coinfected with HCV, is associated with hepatic steatosis, a common complication of HCV infection [27, 28]. Accumulating evidence suggests that coinfection of HCV accelerates the progression of HCV-related diseases including fibrosis, cirrhosis, and end-stage liver disease in HIV patients, and that treatment with HAART does not seem to improve prognosis of the liver diseases related to HCV infection [2, 29]. The current use of antiviral therapy against HCV infection in HCV–HIV coinfected patients seems to delay the progression to chronic liver disease [3]. However, it is important to note that there is still no specific treatment for HCV infection for our patients. Therefore, unlike HBV, HCV coinfection remains a risk for liver function abnormality in HIV patients.

Apart from HCV coinfection, we found other risk factors for transaminitis including age, sex, and CD4+ cell counts (Table 3). The ages of our patients varied from less than 30 to over 50 years, and the majority of the patients were aged between 31 and 40 years (38.9% [82/211]), which has been demonstrated to be predictive for the transaminitis. Being female was also found to be less associated than being male. This is consistent with our observation that HCV coinfection is a major factor involved in the abnormal levels of liver enzymes in the present study group and male sex is known to be a risk factor of HCV infection in HIV-infected Thai patients [12]. A CD4+ cell count higher than 350 cells/ L was identified as a protective factor for abnormal levels of liver enzymes, as consistent with a previous study demonstrating that a low number of CD4+ cells is an independent risk factor for cytolysis, a two-fold increase of AST and/or ALT levels in HBV–HIV coinfected patients [30]. The risk factors demonstrated in our present study are probably different from many previous studies because of differences in the study design, population characteristics, definition of liver enzyme elevation, ARV regimens used, and duration of ART [1, 4, 5, 31].

In the present study, the impact of HBV or HCV coinfection on the severity of HIV disease assessed by the number of CD4+ cells, may also be important. While other studies indicated a lower number of CD4+ Τ cells in HIV patients coinfected with HBV [32, 33], there was no significant difference between HIV patients coinfected with HBV or HCV, and HIV-monoinfected patients that were ARV-naïve [4, 5] Our data showed a relatively lower CD4+ cell count in HIV patients coinfected with HBV or HCV (Table 2), even though this was not significant. Possibly, effects of coinfection on the progression of HIV disease is lessened by current ARV treatment that helps maintaining CD4+ cell counts in this group of patients. However, it is likely that coinfection with HBV or HCV causes a poorer prognosis in these HIV-infected patients.

In conclusion, the present study demonstrated the relatively high prevalence of HBV and HCV coinfections in HIV-infected Thai patients. Our data indicated that the coinfection with HCV is a more important contributor to liver function abnormality assessed by transaminitis than coinfection with HBV and currently used ARV drugs. While several studies had demonstrated coinfection as the major risk factor for liver enzyme elevation in ARV-naïve HIV patients and for severe hepatotoxicity when HAART is initiated [4, 5, 7], our study found a significant association of the HCV coinfection with liver abnormality in Thai patients with HIV mostly receiving relatively longer suppressive ART in the ART clinic of a secondary care hospital. The transaminitis observed in the patients may suggest their potential to develop chronic liver diseases, possibly long-term ARV-associated hepatotoxicity and hepatocarcinoma [6, 8, 34, 35]. Our observational study suggests that screening of HBV and HCV coinfection before starting ART and the long term-monitoring of the progression to chronic liver diseases is essential in the HIV patients in a resource-limited setting such as Thailand.

Acknowledgments

Special thanks are due to the patients who voluntarily participated in this study and Pattarakan Thongkhonburi, M.D., Nakhon Nayok hospital, for her advice. The authors also thank Professor Pramuan Tepchaisri, Thammasat University, for reviewing the manuscript. This study was financially supported by the 2013-2014 fiscal year budget of Thammasat University, Thailand.

Conflict of interest statement: The authors have no conflicts of interest to declare.

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    Phanuphak P. Antiretroviral treatment in resource-poor settings: what can we learn from the existing programmes in Thailand?. AIDS. 2004; 18 Suppl 3: S33-8.

  • 15

    Chasombat S McConnell MS Siangphoe U Yuktanont P Jirawattanapisal T Fox K et al. National expansion of antiretroviral treatment in Thailand 2000-2007: program scale-up and patient outcomes. J Acquir Immune Defic Syndr. 2009; 50:506-12.

    • Crossref
    • Export Citation
  • 16

    Sungkanuparph S Anekthananon T Hiransuthikul N Bowonwatanuwong C Supparatpinyo K Mootsikapun P et al. Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents: the recommendations of the Thai AIDS Society (TAS) 2008. J Med Assoc Thai. 2008; 91:1925-35.

  • 17

    World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach: 2010 Revision. Geneva: World Health Organization; 2010. 165 p.

  • 18

    Sungkanuparpha S Techasathitb W Utaipiboonc C Chasombatd S Bhakeecheepe S Leechawengwongsf M Ruxrangthamg K Phanuphakg P. Thai national guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2010. Asian Biomed. 2010; 4: 515-28.

    • Crossref
    • Export Citation
  • 19

    Tsuchiya N Pathipvanich P Rojanawiwat A Wichukchinda N Koga I Koga M et al. Chronic hepatitis B and C co-infection increased all-cause mortality in HAART-naive HIV patients in Northern Thailand. Epidemiol Infect. 2013; 141:1840-8.

    • Crossref
    • Export Citation
  • 20

    Price JC Thio CL. Liver disease in the HIV-infected individual. Clin Gastroenterol Hepatol. 2010; 8: 1002-12.

    • Crossref
    • Export Citation
  • 21

    Lomtadze N Kupreishvili L Salakaia A Vashakidze S Sharvadze L Kempker RR et al. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis. PLoS One. 2013; 8:e83892.

    • Crossref
    • Export Citation
  • 22

    Lo Re V 3rd Wertheimer B Localio AR Kostman JR Dockter J Linnen JM et al. Incidence of transaminitis among HIV-infected patients with occult hepatitis B. J Clin Virol. 2008; 43:32-6.

    • Crossref
    • Export Citation
  • 23

    Wondimeneh Y Alem M Asfaw F Belyhun Y. HBV and HCV seroprevalence and their correlation with CD4 cells and liver enzymes among HIV positive individuals at University of Gondar Teaching Hospital Northwest Ethiopia. Virol J. 2013; 10:171.

    • Crossref
    • Export Citation
  • 24

    Servin-Abad L Molina E Baracco G Arosemena L Regev A Jeffers L et al. Liver enzymes elevation after HAART in HIV-HCV co-infection. J Viral Hepat. 2005; 12:429-34.

    • Crossref
    • Export Citation
  • 25

    Mbougua JB Laurent C Kouanfack C Bourgeois A Ciaffi L Calmy A et al. Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon. BMC Pub Health. 2010; 10:105.

    • Crossref
    • Export Citation
  • 26

    Yang R Gui X Xiong Y Gao S Zhang Y Deng L et al. Risk of liver-associated morbidity and mortality in a cohort of HIV and HBV coinfected Han Chinese. Infection. 2011; 39:427-31.

    • Crossref
    • Export Citation
  • 27

    Sterling RK Contos MJ Smith PG Stravitz RT Luketic VA Fuchs M et al. Steatohepatitis: risk factors and impact on disease severity in human immunodeficiency virus/hepatitis C virus coinfection. Hepatology. 2008; 47:1118-27.

    • Crossref
    • Export Citation
  • 28

    Machado MV Oliveira AG Cortez-Pinto H. Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: a meta-analysis of the risk factors. Hepatology. 2010; 52:71-8.

    • Crossref
    • Export Citation
  • 29

    Thein HH Yi Q Dore GJ Krahn MD. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS. 2008; 22: 1979-91.

    • Crossref
    • Export Citation
  • 30

    Chauvel O Lacombe K Bonnard ? Lascoux-Combe C Molina JM Miailhes P et al. Risk factors for acute liver enzyme abnormalities in HIV-hepatitis B virus-coinfected patients on antiretroviral therapy. Antivir Ther. 2007; 12:1115-26.

  • 31

    Mulu W Gidey B Chernet A Alem G Abera B. Hepatotoxicity and associated risk factors in HIV-infected patients receiving antiretroviral therapy at Felege Hiwot Referral Hospital Bahirdar Ethiopia. Ethiop J Health Sci. 2013; 23:217-26.

  • 32

    Anigilaje EA Olutola A. Prevalence and clinical and immunoviralogical profile of human immunodeficiency virus-hepatitis B coinfection among children in an antiretroviral therapy programme in Benue State Nigeria. ISRN Pediatr. 2013; 2013:932697.

  • 33

    Idoko J Meloni S Muazu M Nimzing L Badung B Hawkins C et al. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria. Clin Infect Dis. 2009; 49:1268-73.

    • Crossref
    • Export Citation
  • 34

    Wen CP Lin J Yang YC Tsai MK Tsao CK Etzel C et al. Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases. J Natl Cancer Inst. 2012; 104:1599-611.

    • Crossref
    • Export Citation
  • 35

    Chalermchai T Hiransuthikul N Tangkijvanich P Pinyakorn S Avihingsanon A Ananworanich J. Risk factors of chronic hepatitis in antiretroviral-treated HIV infection without hepatitis B or C viral infection. AIDS Res Ther. 2013; 10:21.

    • Crossref
    • Export Citation

Footnotes

*P < 0.05. ARV = antiretroviral, BMI = body mass index, AST = aspartate aminotransferase, ALT = alanine aminotransferase. ULN = upper limit of normal, HBsAg = hepatitis B vims (HBV) surface antigen, HBeAg = extracellular form of HBV core antigen; HCV = hepatitis C virus
*P < 0.05. ARV = antiretroviral, BMI = body mass index, AST = aspartate aminotransferase, ALT = alanine aminotransferase. ULN = upper limit of normal, HBsAg = hepatitis B vims (HBV) surface antigen, HBeAg = extracellular form of HBV core antigen; HCV = hepatitis C virus
aP < 0.05
bP < 0.001
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus
*P < 0.05, OR = Odds ratio, CI = Confidence interval, HBsAg = HBV surface antigen, HCV = hepatitis C virus

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  • 1

    Joshi D O’Grady J Dieterich D Gazzard B Agarwal K. Increasing burden of liver disease in patients with HIV infection. Lancet. 2011; 377:1198-209.

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  • 2

    Operskalski EA Kovacs A. HIV/HCV co-infection: pathogenesis clinical complications treatment and new therapeutic technologies. Curr HIV/AIDS Rep. 2011;8:12-22.

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  • 3

    Mallet V Vallet-Pichard A Pol S. The impact of human immunodeficiency virus on viral hepatitis. Liver Int. 2011;1:135-9.

  • 4

    Law WP Dore GJ Duncombe CJ Mahanontharit A Boyd MA Ruxrungtham K et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort Thailand 1996-2001. AIDS. 2003; 17:2191-9.

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  • 5

    den Brinker M Wit FW Wertheim-van Dillen PM Jurriaans S Weel J van Leeuwen R et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000; 14:2895-902.

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  • 6

    Moodie EE Pant Pai N Klein MB. Is antiretroviral therapy causing long-term liver damage? A comparative analysis of HIV-mono-infected and HIV/ hepatitis C co-infected cohorts. PLoS One. 2009; 4: e4517.

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  • 7

    Puoti M Nasta P Gatti F Matti A Prestini K Biasi L et al. HIV-related liver disease: ARV drags coinfection and other risk factors. J Int Assoc Physicians AIDS Care (Chic). 2009; 8:30-42.

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  • 8

    Merchante N Merino E Lopez-Aldeguer J Jover F Delgado-Fernandez M Galindo MJ et al. Increasing incidence of hepatocellular carcinoma in HIV-infected patients in Spain. Clin Infect Dis. 2013; 56:143-50.

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  • 9

    Nunnari G Berretta M Pinzone MR Di Rosa M Berretta S Cunsolo G et al. Hepatocellular carcinoma in HIV positive patients. Eur Rev Med Pharmacol Sci. 2012; 16:1257-70.

  • 10

    MacDonald DC Nelson M Bower M Powles T. Hepatocellular carcinoma human immunodeficiency virus and viral hepatitis in the HAART era. World J Gastroenterol. 2008; 14:1657-63.

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  • 11

    Zhou J Dore GJ Zhang F Lim PL Chen YM Database TAHO. Hepatitis B and C virus coinfection in The TREAT Asia HIV Observational Database. J Gastroenterol Hepatol. 2007; 22:1510-8.

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  • 12

    Sungkanuparph S Vibhagool A Manosuthi W Kiertiburanakul S Atamasirikul K Aumkhyan A et al. Prevalence of hepatitis B virus and hepatitis C virus co-infection with human immunodeficiency virus in Thai patients: a tertiary-care-based study. J Med Assoc Thai. 2004; 87:1349-54.

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    Sungkanuparph S Wongprasit P Manosuthi W Atamasirikul K. Compliance with hepatitis B and hepatitis C virus infection screening among HIV-1 infected patients in a resource-limited setting. Southeast Asian J Trop Med Public Health. 2008; 39: 863-6.

  • 14

    Phanuphak P. Antiretroviral treatment in resource-poor settings: what can we learn from the existing programmes in Thailand?. AIDS. 2004; 18 Suppl 3: S33-8.

  • 15

    Chasombat S McConnell MS Siangphoe U Yuktanont P Jirawattanapisal T Fox K et al. National expansion of antiretroviral treatment in Thailand 2000-2007: program scale-up and patient outcomes. J Acquir Immune Defic Syndr. 2009; 50:506-12.

    • Crossref
    • Export Citation
  • 16

    Sungkanuparph S Anekthananon T Hiransuthikul N Bowonwatanuwong C Supparatpinyo K Mootsikapun P et al. Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents: the recommendations of the Thai AIDS Society (TAS) 2008. J Med Assoc Thai. 2008; 91:1925-35.

  • 17

    World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach: 2010 Revision. Geneva: World Health Organization; 2010. 165 p.

  • 18

    Sungkanuparpha S Techasathitb W Utaipiboonc C Chasombatd S Bhakeecheepe S Leechawengwongsf M Ruxrangthamg K Phanuphakg P. Thai national guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2010. Asian Biomed. 2010; 4: 515-28.

    • Crossref
    • Export Citation
  • 19

    Tsuchiya N Pathipvanich P Rojanawiwat A Wichukchinda N Koga I Koga M et al. Chronic hepatitis B and C co-infection increased all-cause mortality in HAART-naive HIV patients in Northern Thailand. Epidemiol Infect. 2013; 141:1840-8.

    • Crossref
    • Export Citation
  • 20

    Price JC Thio CL. Liver disease in the HIV-infected individual. Clin Gastroenterol Hepatol. 2010; 8: 1002-12.

    • Crossref
    • Export Citation
  • 21

    Lomtadze N Kupreishvili L Salakaia A Vashakidze S Sharvadze L Kempker RR et al. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis. PLoS One. 2013; 8:e83892.

    • Crossref
    • Export Citation
  • 22

    Lo Re V 3rd Wertheimer B Localio AR Kostman JR Dockter J Linnen JM et al. Incidence of transaminitis among HIV-infected patients with occult hepatitis B. J Clin Virol. 2008; 43:32-6.

    • Crossref
    • Export Citation
  • 23

    Wondimeneh Y Alem M Asfaw F Belyhun Y. HBV and HCV seroprevalence and their correlation with CD4 cells and liver enzymes among HIV positive individuals at University of Gondar Teaching Hospital Northwest Ethiopia. Virol J. 2013; 10:171.

    • Crossref
    • Export Citation
  • 24

    Servin-Abad L Molina E Baracco G Arosemena L Regev A Jeffers L et al. Liver enzymes elevation after HAART in HIV-HCV co-infection. J Viral Hepat. 2005; 12:429-34.

    • Crossref
    • Export Citation
  • 25

    Mbougua JB Laurent C Kouanfack C Bourgeois A Ciaffi L Calmy A et al. Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon. BMC Pub Health. 2010; 10:105.

    • Crossref
    • Export Citation
  • 26

    Yang R Gui X Xiong Y Gao S Zhang Y Deng L et al. Risk of liver-associated morbidity and mortality in a cohort of HIV and HBV coinfected Han Chinese. Infection. 2011; 39:427-31.

    • Crossref
    • Export Citation
  • 27

    Sterling RK Contos MJ Smith PG Stravitz RT Luketic VA Fuchs M et al. Steatohepatitis: risk factors and impact on disease severity in human immunodeficiency virus/hepatitis C virus coinfection. Hepatology. 2008; 47:1118-27.

    • Crossref
    • Export Citation
  • 28

    Machado MV Oliveira AG Cortez-Pinto H. Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: a meta-analysis of the risk factors. Hepatology. 2010; 52:71-8.

    • Crossref
    • Export Citation
  • 29

    Thein HH Yi Q Dore GJ Krahn MD. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS. 2008; 22: 1979-91.

    • Crossref
    • Export Citation
  • 30

    Chauvel O Lacombe K Bonnard ? Lascoux-Combe C Molina JM Miailhes P et al. Risk factors for acute liver enzyme abnormalities in HIV-hepatitis B virus-coinfected patients on antiretroviral therapy. Antivir Ther. 2007; 12:1115-26.

  • 31

    Mulu W Gidey B Chernet A Alem G Abera B. Hepatotoxicity and associated risk factors in HIV-infected patients receiving antiretroviral therapy at Felege Hiwot Referral Hospital Bahirdar Ethiopia. Ethiop J Health Sci. 2013; 23:217-26.

  • 32

    Anigilaje EA Olutola A. Prevalence and clinical and immunoviralogical profile of human immunodeficiency virus-hepatitis B coinfection among children in an antiretroviral therapy programme in Benue State Nigeria. ISRN Pediatr. 2013; 2013:932697.

  • 33

    Idoko J Meloni S Muazu M Nimzing L Badung B Hawkins C et al. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria. Clin Infect Dis. 2009; 49:1268-73.

    • Crossref
    • Export Citation
  • 34

    Wen CP Lin J Yang YC Tsai MK Tsao CK Etzel C et al. Hepatocellular carcinoma risk prediction model for the general population: the predictive power of transaminases. J Natl Cancer Inst. 2012; 104:1599-611.

    • Crossref
    • Export Citation
  • 35

    Chalermchai T Hiransuthikul N Tangkijvanich P Pinyakorn S Avihingsanon A Ananworanich J. Risk factors of chronic hepatitis in antiretroviral-treated HIV infection without hepatitis B or C viral infection. AIDS Res Ther. 2013; 10:21.

    • Crossref
    • Export Citation
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