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Epidemiological trends of HBV and HDV coinfection among Viennese HIV+ patients

Abstract Background and Aims Despite vaccination recommendations, hepatitis B (HBV) and D (HDV) coinfections are common in HIV+individuals. Methods HBV immunization status (anti‐HBs) as well as HBV (HBsAg/HBV‐DNA) and HDV (anti‐HDV) coinfection rates were assessed in 1870 HIV+individuals at HIV diagnosis (baseline, BL) and last follow‐up (FU). Results Sixty‐eight (3.6%) HIV patients were never tested for HBV. At BL, 89/1802 (4.9%) HIV patients were HBV coinfected. Four hundred and fifteen (23.0%) showed virological HBV clearance [HBsAg(‐)/anti‐HBc(+)/anti‐HBs(+)] and 210 (11.7%) presented with anti‐HBc(+) only. Seven hundred and ten (39.4%) were HBV naïve [HBsAg(‐)/anti‐HBs(‐)/anti‐HBc(‐)/HBV‐DNA(‐)], but only 378 (21.0%) received vaccinations with detectable anti‐HBs(+) titres. Among the 89 HBV/HIV‐coinfected patients, only 52 (58.4%) were tested for HDV: 11/49 (22.4%) had anti‐HDV(+) and 3/12 (25.0%) showed HDV‐RNA viraemia. During a median FU of 6.5 (IQR 7.2) years, 44 (4.6%) of the 953 retested BL HBV‐negative patients acquired new HBV infection (including 15/304, 4.9% of vaccinated patients). Of the 89 patients, 22 (24.7%) patients cleared their HBsAg, resulting in 60/1625 (3.7%) HIV/HBV individuals at FU: 34 (56.7%) showed HBV‐DNA suppression and 15 (25.0%) were HBV viraemic, while 12/89 (13.5%) remained without a FU test. Vaccinations induced anti‐HBs(+) in 137 of the retested 649 (21.1%) BL HBV‐naïve patients. Conclusion HBV testing is well established among Viennese HIV+patients with HBV coinfection rates around 4%‐5%. HBV vaccinations are insufficiently implemented since anti‐HBs titres were detected in only 21.1% of HBV‐naive HIV(+) patients and new HBV infections occurred in previously vaccinated patients. HDV testing is not systematically performed despite up to 25% of HIV/HBV patients may show HDV coinfection.


| INTRODUC TI ON
However, the percentages of HIV/HBV coinfection exhibit vast geographical differences, and regional risk groups vary. 1 Austria represents a low-prevalence country for HBV monoinfection as well as for HIV/HBV and HBV/HDV coinfection, 3,4 but recent immigration trends and emerging local risk groups may have changed the national epidemiology of HBV infection. While people who inject drugs (PWIDs) used to represent the majority of the Austrian people living with HIV, recent epidemiological analyses identified new risk groups for HIV and viral hepatitis infection, such as men who have sex with men (MSM). 3,5 Due to the high global burden of HBV-associated liver disease, the WHO has set the goal of HBV elimination by 2030. 6 In order to achieve this public health objective, specific consideration and targeting of risk groups are essential. 7 Especially in HIV-coinfected patients, who require lifelong antiretroviral therapy (ART) in order to preserve immune function and avoid HIV-associated disease progression, treatment with HBV-active ART (ie tenofovir or lamivudine containing regimens) is an effective way of reducing plasma HBV-DNA levels and the risk for progression of liver fibrosis. 1 Moreover, it may also induce liver fibrosis regression and prevent the development of hepatic decompensation, that is the transition from compensated to decompensated cirrhosis. 8 Finally, the use of HBV-active ART may also have a protective effect regarding de novo HBV infection. 9 However, due to the persistence of cccDNA and HBsAg, HBV viraemia frequently rebounds after treatment cessation. 1 A cure for chronic HBV infection is not available at the moment. In case of HDV co-or superinfection, treatment options are even more limited: While interferon-based therapy has shown some effect on plasma HDV RNA levels and liver disease progression, its application is limited by considerable rates of contraindications and adverse events and the rebound-rate after cessation of therapy approximates 75%-80%. [10][11][12] Considering these preconditions, systematic screening and prophylactic vaccination against HBV infection represent the most crucial strategies in the reduction of HBV-associated liver disease. 7 In Austria, a governmental programme to prevent vertical HBV transmission has been in place since 1992 for all pregnant women regardless of citizenship. 13 In addition to the implementation of HBV vaccination in the national children's vaccination programme in 1998 (free of charge for all children up to the age of 15 years living in Austria, irrespective of citizenship), vaccination for HBV has been promoted by national campaigns for all adult people living in

Key points
• HBV testing was regularly performed in our Viennese HIV+cohort.
• HDV testing was not systematically performed in our cohort.
Austria, especially emphasizing at-risk key populations like immunocompromised patients. 14,15 HIV-infected individuals are therefore entitled to HBV vaccination, and screening for protective anti-HBs antibodies or HBV coinfection should be performed in all patients diagnosed with HIV infection. 7 While HBV vaccination for healthcare   workers has been provided free of charge since 1991 in Austria, all   other adult individuals-including key population groups like HIV(+) patients-have to cover the costs for HBV vaccination themselves despite the recommendations in place. 15 However, the universal healthcare system in Austria entitles all citizens with or without employment to equal medical care, including screening, treatment and follow-up programmes regarding infectious diseases. While the improvement of the cross-management concerning disadvantaged groups like PWIDs and prisoners still remains an issue, these populations should be included in disease-prevention programs and need specific targeting, for example through the involvement of lowthreshold facilities or the national opioid substitution programme in the case of PWIDs. 16 We aimed to investigate epidemiological HBV trends with and without HDV co-or superinfection within the Viennese HIV(+) population in order to provide a basis for elimination programmes for viral hepatitis in this special population.

| Study design and patient cohort
This study was performed at the Vienna General Hospital, a large tertiary care including 1874 adult patients with an established diagnosis of HIV attending our HIV and/or liver clinics between 1 January 2014 and 31 December 2016. There were no exclusion criteria. Data acquisition was carried out using the available electronic health records. HBV and HDV serology, as well as HBV-DNA and HDV-RNA PCR results, were assessed at first examination after HIV diagnosis (defined as the baseline [BL] date) and at last contact at our institution (defined as follow-up [FU] date) (see Data S1).

| Ethics statement
The study was approved by the ethics committee of the Medical University of Vienna on 7 July 2017 (EC Number: 1527/2017).

| HBV testing
Of the 1870 patients, 1802 (96.4%) received at least 1 HBV test, that is by HBV serology and/or by HBV-DNA PCR. At BL, all 1802 patients were tested by HBV serology, and 111 (6.2%) received an additional HBV-DNA PCR. In 36 (32.4%) of the 111 patients who received a PCR test at BL, HBsAg(+) had been detected through HBV serology ( Figure 1, Figure 2A).

| FU of BL HBV-exposed and HBVvaccinated patients
Among 793 patients who showed protective anti-HBs(+) at BL, no

| FU of BL HBV-infected patients
Of

| D ISCUSS I ON
In line with the WHO goal of eliminating viral hepatitis until 2030, 6,7 we aimed to analyse epidemiological trends of HBV and HDV coin-  While the prevalence and incidence of HBV/HDV coinfection among HIV(+) remain mostly unclear, the HDV prevalence among HBV patients has been estimated from 13  The HBV coinfection rate among Viennese HIV+patients slightly decreased from 4.9% to 3.7% during the study observation period.
HDV testing is not systematically performed despite the fact that as many as one-third of HIV/HBV patients may show HDV coinfection.
Strengthening the HBV vaccination programme currently represents the most efficient route to reach the WHO goal of viral hepatitis elimination, and it will be meaningful to mandate vaccination not only for early childhood but also for adults in the high-risk groups.
Our data demonstrate the importance of HBV/HDV surveillance and prophylaxis in the special risk group of HIV+patients, and will support future prospective studies aimed at viral hepatitis elimination.

ACK N OWLED G EM ENTS
Nothing to disclose.