Seroprevalence of hepatitis E virus in HIV-infected patients in China

Abstract

 

The seroprevalence of hepatitis E virus (HEV) in HIV-infected patients in China has never been reported. Thus, anti-HEV in HIV-infected patients recruited in five provinces in China was tested. The seroprevalence of HEV was 39.7%, which was higher than that in the general population (23.5%). HEV infection might be a frequent cause of hepatitis in HIV-infected patients.

Hepatitis E virus (HEV), a major cause of acute viral hepatitis worldwide, is a single-stranded, nonenveloped, RNA virus, which is transmitted mainly through the enteric route ^[1]. Hepatitis E was originally thought to be self-limited and usually required no special treatment. However in recent years, chronic hepatitis E cases have been increasingly reported in immunocompromised individuals, such as solid organ transplant recipients and HIV-infected patients ^[1].

Earlier studies have reported that HIV-infected patients show increased seroprevalence of HEV infection when compared with HIV-negatives ^[2]. In addition, some case reports have found that HEV infection can persist for 2–4 years in HIV-infected patients and severe outcomes can occur, including liver fibrosis and cirrhosis ^[3,4]. However, there are also reports of minimal to zero HIV/HEV superinfection rates for some geographical regions, particularly in the developed countries with low HEV endemicity ^[2]. Consequently, there remains a need for additional epidemiological studies to provide a backcloth for addressing a range of unanswered questions in relation to HEV chronicity and its association with the immune impairment caused by HIV infection, such as the route of infection, factors that affect prevalence and the frequency that such infections become chronic.

HEV infection is endemic in China, with the predominant genotype isolated being HEV genotype 4 ^[5]. In addition, by the end of 2011, China had an estimated 780 000 people infected with HIV ^[6]. However, to-date there is no published data addressing the epidemiology and clinical importance of HEV/HIV superinfection in China. Therefore, the current study aimed at presenting the prevalence and possible risk factors of HEV/HIV superinfected individuals in China.

This study was reviewed and monitored by the Institutional Review Boards at the National Center for AIDS/STD Control and Prevention of the Chinese Center for Disease Control and Prevention (CDC). All patients provided an Informed Consent Form in writing, giving us permission to store and process their serum samples. The study population included 639 HIV-infected patients enrolled by Chinese CDC from five provinces (Anhui, Henan, Xinjiang, Yunnan and Zhejiang) during January 2009 to December 2010. Among these patients, 253 of them had follow-up samples in 2010. Selected characteristics of the study cohort for 639 HIV-infected patients are shown in the Supplementary data, https://links.lww.com/QAD/B128. All samples were tested for anti-HEV IgM and IgG (Wantai, Beijing, China) under the manufacturer's instructions. Nested reverse transcription PCR was performed to detect the HEV RNA in anti-HEV IgM-positive sample as previously published ^[5]. The CD4⁺ cell count was measured using flow cytometry (FACSC Calibur; BD Company, Franklin Lakes, New Jersey, USA). Plasma HIV RNA was extracted by using the QIAamp mini-viral RNA kit (QIAGEN, Hilden, Germany) and quantified with real-time NASBA (NucliSense Easy Q; BioMérieux, Marcy-l’Étoile, France) according to the manufacturers’ recommendations. The HIV genotype was determined as previously described ^[7].

Statistical analysis included descriptive statistics expressed as the number of cases (percentages) for categorical variables and medians (interquartile ranges) for continuous variables. We compared the characteristics among those with and without anti-HEV positivity using a chi-square test or Fisher's exact test. Associations between the presence of anti-HEV and age, sex, ethnicity, education level, geographical distribution and CD4⁺ cell count were examined by univariate analysis. Analyses were carried out using the SPSS statistical software package version 18.0 (IBM Corporation, Somers, New York, USA). All P values were two-sided and P < 0.05 was considered statistically significant.

Anti-HEV IgM and IgG antibodies were demonstrated in 0.3% (2/639) and 39.4% (252/639) HIV-infected patients, respectively. In Chinese blood donors ^[8,9], the seroprevalence rate of anti-HEV IgM was nearly 1.0% indicating a relatively low incidence of HEV infection as observed in our cohort. The prevalence of anti-HEV IgG for Yunnan, Henan, Zhejiang, Anhui province and Xinjiang Uygur Autonomous region was 56.8%, 44.2%, 41.1%, 31.3% and 25.5%, respectively. The overall seroprevalence of HEV in the HIV-infected patients was 39.7% (254/639) which is higher than that of the Chinese general population (23.5%) ^[10]. Particularly, in Yunnan (58.0% vs. 30–45%), Henan (44.2% vs. 15–30%), Zhejiang (41.1% vs. 15–30%) and Anhui (31.3% vs. 15–30%), an increased seroprevalence of HEV in those infected with HIV was observed when comparing with the general population in the same province ^[10]. Regarding the two anti-HEV IgM-positive samples, the anti-HEV IgG was negative, and we have performed HEV RNA detection using a nested reversed transcription PCR ^[5]. No HEV RNA was detected.

In the univariate analysis, sex, age, ethnicity and region were found to be associated with the positivity of anti-HEV, indicating a higher risk of HEV infection (Table 1). HEV-seropositive individuals were more often over 50 years (P = 0.0362), living in Anhui (P = 0.0168) and Yunnan (P = 0.0004).

Table 1: Characteristics and role of hepatitis E virus infection in 639 HIV-infected patients in China, 2009–2010.

Of the 639 HIV-infected patients recruited, 253 HIV-infected patients were visited again in 2010. There were 39 individuals who had experienced a positive or negative seroconversion to HEV IgG during the study period. Ten (25.6%, 10/39) of these patients had a positive seroconversion to anti-HEV IgG, and 29 (74.4%, 29/39) became seronegative for anti-HEV IgG at the follow-up time point. Patients with negative seroconversion may be in risk of reinfection of HEV.

The prevalence of anti-HEV in the HIV-infected patients in the study cohort is 39.7% (254/639), which is higher than 23.5% reported in a national survey of general population in China (10), suggesting a higher risk of HEV infection in HIV-infected patients. The results of an increased seroprevalence of HEV are consistent when the study cohort is divided by province, except for Xinjiang. Sex, age, ethnicity and region are possible risk factors that are associated with an increased seroprevalence of HEV (Table 1).

The current study has two major potential limitations. First, the sampling size and timing is limited. Second, the detection of HEV RNA was not performed in all available samples as seroconversion to anti-HEV may be delayed in HIV-infected individuals.

In summary, the results show remarkable evidence of past HEV infection in our cohort, indicating that this population was at higher risk than the general population. In the future, studies involving larger samples size are warranted.

Acknowledgements

We thank Prof Malcolm A. McCrae from University of Warwick, UK, for proofreading this article.

The study was supported by the Beijing Natural Science Foundation (Grant no. 7162103), the National Natural Science Foundation of China (81471962 and 81261120393) and the Ministry of Science and Technology of China (2012ZX10001-002).

Conflicts of interest

There are no conflicts of interest.