Prevalence of Hepatitis B and Hepatitis C Infection and Their Associated Factors Among HIV-Infected Individuals in Same-Day Antiretroviral Therapy Initiation Program in Bangkok, Thailand

Viral hepatitis is highly prevalent among people living with HIV (PLHIV) and can lead to chronic liver complications. Thailand started universal hepatitis B vaccination at birth in 1992. We explored prevalence rates of hepatitis B and C and associated factors among PLHIV from same-day antiretroviral therapy (SDART) service at the Thai Red Cross Anonymous Clinic, Bangkok, Thailand. We collected baseline characteristics from PLHIV enrolled in the SDART service between July 2017 and November 2019. Multivariate logistic regression was carried out to determine factors associated with positive hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV).

Background Viral hepatitis is highly prevalent among people living with HIV (PLHIV) and can lead to chronic liver complications. Thailand started universal hepatitis B vaccination at birth in 1992. We explored prevalence rates of hepatitis B and C and associated factors among PLHIV from same-day antiretroviral therapy (SDART) service at the Thai Red Cross Anonymous Clinic, Bangkok, Thailand.

Methods
We collected baseline characteristics from PLHIV enrolled in the SDART service between July 2017 and November 2019. Multivariate logistic regression was carried out to determine factors associated with positive hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV).

Results
We included a total of 4,011 newly diagnosed PLHIV who had HBsAg or anti-HCV results at baseline.

Conclusions
Around 5-10% of newly diagnosed PLHIV in Bangkok had hepatitis B infection after 25 years of universal vaccination. Anti-HCV positivity was found in 4-5% of PLHIV who were MSM and TGW. Every PLHIV should be routinely tested for hepatitis B and C and immediately linked to appropriate prevention and treatment interventions.

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are prevalent worldwide. In 2015, chronic HBV infection was estimated to be in 3.5% of the world population [1]. People living with HIV (PLHIV) had a higher estimated prevalence rate of 7.4% [1]. In Thailand, a study estimated that 5.1% of the general population was infected with HBV in 2015 [2]. The rates of infection were higher at 8.1% among men who have sex with men (MSM) and 8.1% among PLHIV [2]. A study conducted from 2006 to 2008 reported an infection rate of 13.8% among MSM living with HIV [3]. Worldwide hepatitis C prevalence in 2015 was 1.0%, and among PLHIV was 6.2%, though subgroup prevalence ranged from 82.4% in PLHIV who inject drugs and 6.4% in MSM living with HIV to 2.4% in PLHIV without those risk factors [1]. In Thailand, a national survey of the general population in 2014 showed hepatitis C antibody (anti-HCV) seroprevalence of 0.9% [4]. In contrast, a study focused on PLHIV found that anti-HCV seroprevalence in this population was 7.7% [5].
More than 70% of people infected with HCV and less than 6% of people who acquired HBV as an adult could turn into chronic carriers [1,6]. Twenty per cent of chronic carriers could develop cirrhosis and hepatocellular carcinoma which are life threatening [1]. Having cofactors such as HIV infection and alcohol use can also accelerate the development of end-stage liver diseases [1,6]. HBV and HCV are not only transmitted from mother to child but also sexually transmitted and share routes of transmission: percutaneous and mucosal exposures [6,7]. Having unprotected sex, multiple partners, injection drug use, and a history of other sexually transmitted diseases are important factors associated with HBV acquisition [6]. HCV is transmitted mainly through unsafe healthcare settings and injection drug use [1].
Unlike HCV infection, HBV infection is a vaccine-preventable disease. Universal hepatitis B vaccination at birth was integrated into Thailand's Expanded Program on Immunization (EPI) in 1992 [17]. In 2014, a difference in HBV infection rate was seen among population born before 1992 (4.5%) and population born after 1992 (0.6%) [17]. The program reached over 95% coverage in 1999. Nonetheless, in 2014, 55.2% of population born after 1992 still had negative hepatitis B surface antibody, and thus were susceptible to HBV infection [17]. National HIV treatment guidelines recommended baseline screening of newly diagnosed PLHIV with hepatitis B surface antigen (HBsAg) and anti-HCV, as HBV and HCV coinfections are commonly found and play a role in selecting antiretroviral therapy regimens [18].
The Thai Red Cross Anonymous Clinic (TRCAC) is the largest testing center for HIV and sexually transmitted infections in Bangkok, Thailand. Eligible clients who test positive for HIV are included in the same-day antiretroviral therapy (SDART) service [19]. Because this service includes a mixed population consisting of general population, MSM, TGW, and TGM, this study aimed to explore prevalence rates and associated risk factors of HBV and HCV seropositivity among PLHIV in the SDART service and prompt providers to consider management plans according to the risk factors.

Results
The total number of PLHIV who had HBsAg or anti-HCV results at baseline was 4,011 out of 6,037.
Of the included clients, 46.0% were born after EPI, 25.9% had a CD4 count of less than 200 cells/mm 3 , and 19.3% had syphilis diagnosed at baseline. This study is a cross-sectional descriptive study collecting demographic and laboratory data of clients in the SDART service from 13 July 2017 to 30 November 2019. Included in this study were PLHIV newly diagnosed at TRCAC who tested for either HBsAg or anti-HCV at baseline. Demographic data included gender, age, birth year, educational level, residential location, and level of income. Persons born in or after 1992 were classi ed as "born after EPI," and persons born before 1992 were "born before EPI." This translates to the age of 25 years for individuals who tested in 2017, 26 in 2018, and 27 in 2019. Baseline laboratory tests included HBsAg, anti-HCV, CD4 count, alanine aminotransferase (ALT), creatinine clearance (CrCl), treponemal test, and nontreponemal test. A severe decrease in CD4 count was de ned as a CD4 count of less than 200 cells/mm 3 [20]. Regarding ALT, a cutoff of 62.5 U/L calculated from 1.25 times the upper normal limit of the local laboratory was used to indicate a mild increase [20]. Creatinine clearance was calculated with the Cockcroft-Gault equation and categorized as severely decreased if less than 60 ml/min [20]. Syphilis was diagnosed when the treponemal test (enzyme immunoassay, chemiluminescent microparticle immunoassay, rapid immunochromatographic assay, or treponema pallidum hemagglutination assay) and nontreponemal test (either rapid plasma reagin or venereal disease research laboratory) were both positive. Clients who did not initiate antiretroviral therapy at TRCAC might not have all baseline laboratory test results.

Data analysis
Data were analyzed using Stata Version 15.0. Continuous parameters were presented as median with interquartile range (IQR). Categorical parameters were expressed in frequency and percentages. The prevalence rates of positive HBsAg and anti-HCV were calculated. Univariate and multivariate analyses were carried out to determine factors associated with positive HBsAg and anti-HCV. Univariate analysis comparing HBsAg-positive PLHIV with HBsAg-negative using the simple logistic regression model was tested. Factors with p value of less than 0.2 were carried over to the multivariate analysis. Multivariate analysis with a stepwise multiple logistic regression model including associated factors related to positive HBsAg or anti-HCV was tested and reported with an adjusted odds ratio (aOR) and a 95% con dence interval (CI). A p value of less than 0.05 was considered signi cant. The overall prevalence of positive HBsAg was 6.0%. TGW had a prevalence of 9.3%, followed by MSM, 6.2%. People born after the EPI (in or after 1992) had a prevalence of 3.6% as compared to 8.1% in people born before the EPI.
Regarding HCV infection, the overall anti-HCV seroprevalence was 4.1%. MSM carried the highest prevalence among all study population (4.7%). People aged over 30 years had a prevalence of 5.2%, while it was 3.5% among people younger than 30 years. Of 3,990 who tested for both HBsAg and anti-HCV, 12 (0.3%) were positive for both. They were counted toward the HBsAg-positive and anti-HCV-positive groups according to their viral hepatitis pro le. Overall and age-strati ed prevalence of HBsAg and anti-HCV are shown in Table 2. HBsAg, hepatitis B surface antigen; anti-HCV, hepatitis C antibody Factors found signi cant at the 95% con dence level from the univariate analysis were carried over to the multivariate analysis as presented in Table 3 and   Anti-HCV, hepatitis C antibody; CI, con dence interval; ALT, alanine aminotransferase; CrCl, creatinine clearance. † n = 3901

Discussion
Among PLHIV who were newly diagnosed at the largest HIV testing center in Bangkok, we found 6% prevalence of HBV and 4% prevalence of anti-HCV positivity. Being MSM, TGW, and born before the inclusion of universal hepatitis B vaccination in Thailand's EPI were associated with HBV infection.
Moreover, being MSM and having syphilis increased the chance of being anti-HCV positive.
More than 70% of our population were MSM, and 5% were TGW, re ecting proportions of new HIV infections in Thailand as projected by the AIDS Epidemic Model [21]. We found the HBV prevalence to be highest among TGW (9%), followed by MSM (6%). The anti-HCV seroprevalence was highest among MSM (5%), followed by TGW (4%). These data con rmed ndings from previous studies which demonstrated higher prevalence rates of HBV and HCV among PLHIV who were MSM and TGW than those who were general population [1,15,[22][23][24][25]. The HBV prevalence shown in our population is quite concerning as almost half of them were born after EPI, indicating that the HBV epidemic is still ongoing. Nevertheless, the prevalence of HBV and HCV found in our study were slightly lower than that of the global and Thai reports among PLHIV [1,2,5], likely due to the younger age of our population. Apart from viral hepatitis, almost 20% of our clients had syphilis at baseline, showing higher burden than what was reported in general MSM population by World Health Organization (WHO; 6%) in 2018 [26].
MSM and TGW had 1.6 and 2.9 times higher odds of HBV infection than the general population, respectively, which could be explained by sexual practices and routes which are more prone to mechanical trauma [27]. Consistent with the national survey [17], we saw a contrast of HBV prevalence between people who were born before and after EPI (8% vs. 4%). PLHIV who were born before EPI had 2.3 times higher odds of having HBV infection. Another explanation of the association to birth year would be that younger people had less time exposed to the infection than older people. Nonetheless, this study exhibited that HBV infection was not completely eliminated by the EPI. Some newborns might be born to an HBV-infected mother, not complete the full course of the immunization, not respond to HBV vaccination, or be unvaccinated. Regarding PLHIV who do not have immunity to HBV, it is advised to immunize all PLHIV regardless of CD4 level [18], even though the lower CD4 count is one of the factors affecting the effectiveness of the HBV immunization [28][29][30].
Studies on people who did not use injection drugs found that HCV infection was still associated with recreational drug use and syphilis [34,36,45], suggesting transmission of HCV associated with sexual encounter. Unfortunately, we did not collect data on substance use and chemsex systematically in our study and could not look at these potential associations. However, as MSM and syphilis were key factors associated with HCV infection among our clients, we hypothesized that HCV acquisition in our HIVpositive MSM population was likely linked to sexual transmission and possibly in the chemsex context.
There were a few limitations in this study. This study was conducted at one site and two-thirds of our PLHIV clients lived in Bangkok. Thus, our study population might not represent the overall population of PLHIV in Thailand. We could not retrieve hepatitis B vaccination history from original medical records, and therefore needed to use PLHIV clients' birth year as a surrogate. We did not record substance use and chemsex data and could not explore their associations with HBV and HCV infections in our study. Lastly, we did not perform HCV RNA in anti-HCV-positive clients; therefore, the observed anti-HCV seroprevalence may be higher than the actual infection rate.
WHO aimed to eliminate hepatitis B and C infections by 2030 [46]. To achieve this, a country must target the areas determined to have bene cial impacts as described in  Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests. Funding