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

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.

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.