Persons with hepatitis C virus (HCV) and hepatitis B virus (HBV) co-infection are at an increased risk of developing liver cirrhosis and hepatocellular carcinoma compared to those having mono-infection of either virus. Hepatitis B surface antigen loss and hepatocellular carcinoma development in patients with dual hepatitis B and hepatitis C infection [1–5]. HBV and HCV share similar modes of transmission, and co-infection is not uncommon, but there are limited global or regional estimates of co-infection. Studies from Western Europe and East and Central Asian countries show that 2%–10% of HCV antibody reactive participants have chronic hepatitis B [4].

Currently, there are very effective medications for treating HCV infection, with 8- to 12-week pan-genotypic oral treatment regimens achieving sustained virologic response (SVR) in up to 94% of patients [6]. While there is no antiviral medication that leads to clearance of cccDNA in HBV infection, functional cure defined by the loss of HBsAg is possible. Furthermore, more than 90% of patients with chronic HBV infection who stay on treatment achieve viral suppression and observe a reduction in risk for the development of cirrhosis and liver cancer [7, 8]. According to current treatment guidelines, the majority of patients with chronic hepatitis B who start antiviral treatment will likely need to take medication for the rest of their lives [9]. Vaccination against HBV is highly effective and safe and provides long-term protection after three doses of the hepatitis B vaccine [9, 10].

Current evidence suggests that direct-acting antiviral (DAA) regimens are highly effective in treating HCV infection in patients co-infected with HBV, and treatment response is not different from that in those with HCV mono-infection [3, 11]. However, a major challenge in treating persons with HCV-HBV co-infection with DAAs is the possibility of reactivation of HBV infection and flares characterised by elevated HBV DNA and alanine transaminase (ALT) levels [12, 13]. A recent meta-analysis showed that the pooled HBV reactivation rate after HCV treatment was 14.1%, with the risk of reactivation highest during the treatment period, and 12% of patients with HBV reactivation experienced clinical signs of viral hepatitis and required HBV treatment [14].

There are different recommendations on how to approach treatment and prevention of HBV reactivation among persons co-infected with HCV [15]. According to the European Association for the Study of the Liver (EASL) guidelines, HCV-HBV co-infected patients who are HBV surface antigen (HBsAg) positive should be considered for prophylaxis with nucleoside or nucleotide analogues (NA) at the start of DAA therapy and for at least 12 weeks after the end of DAA therapy [13]. WHO guidelines recommend HBV treatment initiation for all adults and adolescents (aged ≥ 12 years) co-infected with HCV, irrespective of HBV DNA or ALT levels or of the aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) score, with annual monitoring of treatment response [9]. On the other hand, the American Association for the Study of Liver Disease (AASLD) hepatitis B guidelines take into consideration HBV DNA, fibrosis staging and ALT levels to determine hepatitis B treatment eligibility. All persons with detectable HBsAg who do not meet the AASLD hepatitis B treatment eligibility guidelines can receive prophylactic HBV treatment for the duration of DAA treatment until assessment for SVR 12 weeks after the end of treatment. HCV-HBV co-infected patients, irrespective of hepatitis B treatment eligibility, should be monitored for HBV DNA and ALT every 4–8 weeks during DAA treatment and for 3 months after the end of DAA treatment [13]. Georgia does not have unified national guidelines for treating HCV-HBV co-infected patients.

Georgia launched its national Hepatitis C Elimination Program in 2015 [16], which offers free diagnostics and treatment with DAAs to all persons aged ≥ 12 years with HCV infection. Since 2015, treatment regimens have evolved considerably from only using sofosbuvir in combination with ribavirin with or without interferon, based on HCV genotype and fibrosis level, to changes in 2016, when ledipasvir/sofosbuvir became available and was recommended for all patients, but was prescribed with or without ribavirin depending on genotype and fibrosis level [17]. Finally, in late 2018, the pangenotypic velpatasvir/sofosbuvir was introduced and by 2020 represented nearly all treatments prescribed [18]. The program also includes free screening for HBsAg and hepatitis B vaccination (for susceptible individuals) for all persons eligible for hepatitis C treatment. However, further hepatitis B management including HBV DNA testing and treatment is not covered by the program nor standard health insurance. The hepatitis B vaccine was introduced in Georgia’s national immunisation program in 2001, with birth dose (HepB-BD) for all newborns introduced in 2003 [19]. Hepatitis B vaccination is not universally offered to adults in Georgia, but it is free for some high-risk groups, including patients with HCV infection and persons who inject drugs (PWID).

A better understanding of the burden of HCV and HBV co-infection in Georgia is necessary to inform hepatitis B management and elimination efforts. The aim of this evaluation was to assess the prevalence of HCV-HBV co-infection among all patients treated for HCV infection in Georgia during 2017–2023. In addition, we explore socio-demographic characteristics, behaviours and clinical and laboratory parameters associated with HCV-HBV co-infection.

Among 54,994 adults treated for HCV infection within the Hepatitis C Elimination Program in Georgia from 2017 to the end of 2023, who received testing for HBV infection, 2.6% had HCV-HBV co-infection. Compared to patients with HCV-mono-infection, patients who were aged 18–45 years (compared to aged 46–60 years), male, reported a history of injecting drugs, were infected with HCV genotype 3 versus genotype 1, had elevated ALT at week 8 of the treatment, and at the end of treatment and did not achieve SVR, were more likely to have HCV-HBV co-infection.

At the start of DAA treatment, we observe that more than two-thirds of all patients have elevated ALT levels (> 40 IU/L); however, we do not find that patients with elevated ALT levels are more likely to be co-infected. After 8 weeks of treatment and at the end of the treatment, approximately 1 in 10 patients still have elevated ALT levels, but at this point, those with elevated ALT are more likely to be co-infected. These findings suggest that some patients who were treated for HCV infection for more than 8 weeks still had signs of worsening liver disease. One potential explanation for this finding is worsening of liver disease due to HBV reactivation after receiving DAA treatment. Other studies have shown that compared to untreated HBV mono-infected controls, HCV-HBV co-infected patients receiving DAAs had a significantly higher risk of HBV reactivation, especially once HCV infection had been successfully cured [11]. HBV reactivation can have serious clinical consequences, and this has prompted the US Food and Drug Administration to include a boxed warning on all DAAs regarding the risk of HBV reactivation in individuals with HCV-HBV co-infection [11, 12, 21]. In this study, we did not have access to HBV DNA results, which are necessary to determine whether the worsening of liver status is due to HBV reactivation or another reason. To reduce the complications of HBV reactivation among co-infected patients, all patients undergoing HCV treatment should be tested for HBsAg and HBV DNA, monitored throughout the treatment process, evaluated for eligibility for HBV treatment, and offered treatment if eligible.

After conducting inverse probability weighting to assess the effect of missing values for ALT and other variables, we observed that patients with higher ALT levels at week 4 of treatment were more likely to have been co-infected. In contrast, the unweighted analysis did not reveal a statistically significant association at week 4 of treatment. This finding suggests that for some patients, HBV reactivation could start much earlier in the DAA treatment, and co-infected patients should be closely monitored from the start of the DAA treatment [14].

Several reviews showed that, especially in low and middle-income countries, testing for HBV is inaccessible mainly due to high costs or a lack of trained personnel, resulting in poor linkage to care and treatment and an increase in HBV transmission [22, 23]. The Hepatitis C Elimination Program in Georgia includes one free screening for HBsAg, but HBV DNA testing and further management and treatment for hepatitis B must be paid out of pocket by patients. These additional costs could be a substantial barrier for many patients to get evaluated for HBV treatment in Georgia, and this is one of the reasons we did not have access to HBV DNA results that would help us better understand the reasons for elevated ALT levels among some patients after starting DAA treatment. Ensuring that hepatitis B testing, management and treatment are accessible to all patients would improve the clinical management of those co-infected with HCV and HBV, as well as all patients with HBV infection.

While almost one in four persons in our patient cohort had advanced liver fibrosis, they were not more likely to be co-infected. Several studies have shown that patients with advanced liver fibrosis and HCV-HBV co-infection had a higher risk of developing cirrhosis and liver cancer [1–3]. These studies indicated that co-infected patients with elevated pre-treatment FIB-4 or liver elastography score were more susceptible to liver disease progression and should be regularly monitored after HCV cure. Recent analysis from Georgia demonstrated a substantial reduction in overall and liver-related mortality for patients treated for HCV infection [24]. We did not find a significant difference in the adjusted odds of all-cause mortality among patients with HCV-HBV co-infection compared to those with HCV infection and exposure to HBV and HCV mono-infected patients. However, a more in-depth analysis of mortality among these two groups is recommended due to the smaller numbers of deaths in both groups and wide confidence intervals in our analysis. Given the increased risk for liver disease progression among HCV-HBV co-infected patients with advanced liver fibrosis, regular follow-up visits and HBV treatment should be considered in Georgia [11].

While the vast majority of patients who were tested for SVR achieved HCV cure (98.6%), patients who did not achieve SVR were almost twice as likely to have HCV-HBV co-infection compared to patients who were HCV mono-infected. Our findings differ from recent meta-analysis and the large longitudinal study of HCV-HBV co-infected patients, which did not find a significant reduction in SVR rates among co-infected patients who were treated with DAAs and were not treated for HBV infection [3, 14]. Although a higher percentage of co-infected patients were found to have HCV genotype 3 –likely through exposure by injecting drug use [25], which can be more challenging to treat – this finding remained significant after adjusting for genotype in the multivariable model. Further, previous analyses have shown similarly high rates of SVR for all genotypes in Georgia [17], even before the program began transitioning to pangenotypic regimens in December of 2018 [26].

Another interesting finding in our study is the higher probability of achieving SVR among patients with HCV infection and previous exposure to HBV compared to HCV mono-infected patients, which is different from other studies [3]. While not reaching SVR among patients treated with DAAs is rare in Georgia, when it happens, HCV-HBV co-infection could be an important reason for the treatment failure. This could happen because patients with co-infection had more frequent side effects or experienced acute flares of hepatitis related to HBV reactivation, which could impact adherence to DAAs and their effectiveness. However, reasons for not achieving SVR among HCV-HBV co-infected patients in Georgia were unavailable; future clinical studies should explore this area. In the meantime, all patients who do not achieve SVR in Georgia should be re-tested for HBsAg and HBV DNA and evaluated for hepatitis B treatment.

Our analysis showed that patients with a history of injection drug use were more likely to be co-infected with HBV or to have been previously exposed to HBV, which is similar to the results of several recent reviews [27, 28]. Significant strides have been made in Georgia to reduce the HCV prevalence among PWID. In a 2021 serosurvey, 18% of persons who ever injected drugs had HCV infection, which was a substantial drop from 51% in 2015 [29]. However, results from a 2022 integrated bio-behavioural survey among PWID in six Georgian cities reported that 13% of PWID who were cured of HCV had HCV re-infection, 2.5% were positive for HBsAg, only 7% reported being vaccinated against HBV, and only 28% of non-vaccinated individuals were willing to be vaccinated against HBV [30]. Given the high burden of HCV and HBV infections among PWID in Georgia, testing for HBsAg and evaluation for HBV treatment for those found to have chronic HBV should be added to the current set of harm reduction services available for PWID in Georgia (e.g., syringe service programs and opioid substitution treatment) [31, 32].

We reported the strength of the associations between multiple socio-demographic characteristics, behaviours and clinical parameters and HCV-HBV co-infection. However, given that this is a cross-sectional study, we can only report associations between variables and cannot claim causality. We hypothesise that increased ALT during and at the end of DAA treatment among some of the patients treated for HCV could be due to HBV reactivation. However, HBV DNA levels at the start or end of DAA treatment were not available, and we did not have clinical measures that could confirm HBV reactivation or eligibility for HBV treatment. Our dataset also lacked information about HBV treatment for patients with HBV-HCV co-infection. Patients who did not achieve SVR were more likely to have HCV-HBV co-infection, but future clinical outcomes for these patients and if they received HBV treatment after the treatment with DAAs are unknown. Several variables used in our analysis had high percentages of missing values. To address this issue, we used inverse probability weighting to estimate the impact of missing data on regression analysis. Some self-reported variables, like history of injecting drugs, may be underreported due to social desirability bias. Despite these limitations, we believe our evaluation includes a well-defined, robust cohort of patients with HCV-HBV co-infection treated for HCV infection using DAAs, and containing clinical parameters and treatment outcomes.

In conclusion, our analysis found that patients with HCV-HBV co-infection were more likely to have elevated ALT at the end of DAA treatment and less likely to achieve SVR for hepatitis C. Ensuring that hepatitis B testing, management and treatment are accessible for patients co-infected with HCV and HBV, as well as all patients with HBV infection, may prevent disease progression and HBV reactivation. Studies are needed to better understand the reasons for lower SVR after DAA treatment among patients with HCV-HBV co-infection in Georgia.

Additional supporting information can be found online in the Supporting Information section. Data S1: jvh70067-sup-0001-Supinfo.docx.