Resolved and Unresolved Issues
J Gastroenterol Hepatol. 2014;29(1):26-30.
Abstract and Introduction
Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is not uncommon in HCV or HBV endemic areas and among subjects at risk of parenteral transmission. In patients dually infected with hepatitis C and B, the disease manifestations are usually more severe than those with either virus infection. In the past decade, the following issues have been resolved. In dually infected patients with active hepatitis C, combined pegylated interferon alfa plus ribavirin was effective, the treatment outcomes being similar to patients with HCV monoinfection. During long-term follow-up, the HCV response was sustained in around 97% of patients; and the long-term outcomes including the development of hepatocellular carcinoma and liver-related mortality were improved. However, several clinical issues remain to be resolved. First, host and viral factors influencing the long-term outcomes and treatment options in patients with dual HCV/HBV infection await further studies. Second, about 60% of dually infected patients with baseline undetectable serum HBV DNA levels develop HBV reactivation after the start of treatment. How to prevent and treat HBV reactivation should be clarified. Third, about 30% of dually infected patients lose hepatitis B surface antigen at 5 years after the end of combination therapy; the mechanisms need further investigations. Fourth, the optimal treatment strategies for dually infected patients with active hepatitis B or established cirrhosis should be explored in future clinical trials. Finally, the role of new direct-acting antiviral-based therapy for the treatment of patients with dual HCV/HBV infection also remains to be evaluated.
Worldwide, the majority of hepatitis C patients have chronic hepatitis C virus (HCV) monoinfection. In areas or countries where hepatitis B virus (HBV) infection is endemic, such as Taiwan, it is not uncommon to encounter patients infected with both hepatitis viruses. [1–3] In the past decade, the following issues regarding dual HCV/HBV infection were resolved. First, epidemiologic studies demonstrated that in patients with dual chronic hepatitis C and B, the disease manifestations are usually more severe than those with either virus infection. [4–6] In support of these data, a large follow-up study on Taiwanese patients demonstrated the combined effect of HCV and HBV infection on the progression of chronic liver disease.  Therefore, patients dually infected with hepatitis C and B should be followed more closely and require effective treatment. Second, recent studies supported that selection of priority virus to be treated in patients with dual chronic hepatitis C/B can be determined by the viral activity of either one. In dually infected patients with active hepatitis C, pegylated interferon (Peg-IFN) alfa plus ribavirin (RBV) was effective to achieve HCV RNA clearance, that is, sustained virological response (SVR).  Post-treatment 5-year follow-up demonstrated that the durability of HCV SVR was maintained in 97%.  Besides, using Peg-IFN-based therapy, hepatitis B surface antigen (HBsAg) seroclearance was also documented in 5.4% of dually infected patients per year. Third, in addition to the control of viral infection, a large retrospective population-based study well demonstrated that the use of Peg-IFN plus RBV combination therapy significantly reduced the risk of hepatocellular carcinoma (HCC) (hazard ratio [HR] 0.75), liver-related mortality (HR 0.45), and all-cause mortality (HR 0.39).  All these data were presented and certain unresolved issues will be discussed in this mini-review.
Clinical Significance of Dual Chronic Hepatitis C and B
Several cross-sectional or retrospective, hospital- or community-based, studies demonstrated that in patients with dual chronic hepatitis C and B, the disease manifestations are usually more severe than or at least as severe as those with either chronic HCV or HBV infection. [1–6] A prospective large cohort from Taiwan confirmed that the risk of developing HCC was higher in patients with dual chronic HCV/HBV infection than that with either virus infection.  The cumulative lifetime (age 30 to 75 years) incidences of HCC for men and women positive for both HBsAg and anti-HCV were 38.35% and 27.40%; for those positive for HBsAg only, 27.38% and 7.99%; for those positive for anti-HCV only, 23.73% and 16.71%; and for those positive for neither, 1.55% and 1.03%, respectively.
Patients with dual HCV/HBV infection may exhibit a wide spectrum of virological profiles during the long-term follow-up. Because most available data were based on cross-sectional observations, the possibility that HCV and HBV can alternate their dominance during co-infection cannot be excluded. In Italy, a longitudinal follow-up study revealed the patterns and dynamics of virological dominance in these cases. Of 103 untreated HBV/HCV dually infected patients, active infection with both HBV and HCV was revealed in 24 (23%) cases, inactive infection by both viruses was seen in 15 (15%) cases, active HBV/inactive HCV was seen in 15 (15%) cases, and active HCV/inactive HBV was found in 49 (48%) cases. During 12-month follow-up, dynamic virological profiles characterized by fluctuation of HBV and/or HCV viremia levels were documented in 32 subjects (31%). Nguyen et al. characterized HBV/HCV dual infection in a large multiethnic study in the United States.  They found that dual infected patients exhibited very little HBV/HCV codominance at baseline and throughout follow-up; patients had either HBV viremia with low or absent HCV RNA or detectable HCV RNA with low or absent HBV DNA. Asian ethnicity was predictive of HBV dominance after adjusting for sex, age, and baseline alanine aminotransferase elevation; and HCV dominance with undetectable HBV DNA is more common in non-Asian individuals.
Based on these observational data, careful longitudinal follow-up of serum HBV DNA and HCV RNA levels is essential before the diagnosis of the viral dominance. These viral interactions will very likely influence the therapeutic strategies in dually infected patients.
Treatment of HCV and HBV Dual Infection: Determine the Virus(es) to Be Treated
Active hepatitis C is found in more than 50% of dually infected patients.  Besides, HCV can be successfully eradicated in at least 70% of patients with chronic HCV mono-infection using combination therapy of Peg-IFN and RBV in Asian-Pacific region.  Accordingly, HCV seems to be the priority target to be managed in dually infected patients with active hepatitis C (Fig. 1).
Figure 1. Priority and potential strategy for the treatment of hepatitis C virus (HCV) and hepatitis B virus (HBV) dual infection. Active HCV, serum HCV RNA positive; inactive HCV, serum HCV RNA negative; active HBV, serum HBV DNA level ≥ 2000 IU/mL; inactive HBV, serum HBV DNA < 2000 IU/mL; P, peginterferon; R, ribavirin; NUC, nucleos(t)ide analogue. New direct-acting antiviral (DAA)-based triple therapy could also be considered for the treatment of active HCV infection in dually infected patients. HBsAg, hepatitis B surface antigen.
Treatment of Hepatitis C in Dual Hepatitis C/B Patients With Active Hepatitis C
IFN Plus RBV
Early small care series found that interferon (IFN) alone was not effective in the clearance of HCV RNA in dually infected patients.  Later on, we demonstrated that combination therapy of conventional IFN plus RBV had better, albeit not satisfactory, HCV SVR rates. [14–16]
Peg-IFN Plus RBV
In the treatment of patients with HCV mono-infection, Peg-IFN in combination with RBV becomes the standard of care in the past decade. Our recent data supported that the efficacy of treatment of dually infected patients may also be enhanced through Peg-IFN plus RBV.  For genotype 1 infection, HCV SVR at 6 months after end of treatment was 72.2% in dually infected patients and was 77.3% in mono-infected patients. For genotype 2/3 infections, SVR was 82.8% in dually infected patients and 84.0% in mono-infected patients. The results confirmed that replacing conventional IFN with Peg-IFN in the combination therapy significantly improved the SVR rate of HCV genotype 1 in the dually infected patients. In addition to our multicenter trial, a satisfactory HCV SVR rate was also documented is another two small series of patients with dual HBV/HCV infection using Peg-IFN alfa plus RBV combination therapy. [17, 18] The results are summarized in Figure 2.
Figure 2. Summary of treatment outcomes in hepatitis C virus (HCV)/hepatitis B virus (HBV) dually infected patients receiving peginterferon plus ribavirin combination therapy for chronic hepatitis C. Treatment regimen: (1) 48 weeks for genotype 1 infection and 24 weeks for genotype non-1 infection; (2) weight-adjusted peginterferon alfa-2b and ribavirin for 48 weeks; (3) 24 weeks for genotype 2/3 infection and 48 weeks for genotype non-2/3 infection.
Durability of HCV Responses Post-treatment
Previous studies suggested that hepatitis C may relapse in 0.9~ 10% of simple chronic hepatitis C patients who initially obtained virological response (VR) after end of the treatment. To address this issue, the durability of hepatitis C clearance in these dually infected patients was investigated by a 5-year follow-up study.  Our results revealed that after a median follow-up of 4.6 ± 1.0 years, only 6 (2.6%) of the 232 patients achieving SVR developed HCV RNA reappearance, including five HCV genotype 1/HBV coinfected patients and one HCV genotype 2/3 mono-infected patient. These data suggested that Peg-IFN alfa and RBV therapy provided a good durability of HCV SVR.
HBV Responses and Clearance of HBsAg
VR of HBV to Peg-IFN and the potential risk for reactivation of HBV DNA during treatment of coexisting chronic hepatitis C are two major clinical concerns that needed to be addressed in dually infected patients receiving effective anti-HCV therapy.  HBsAg clearance at 6 months after end of therapy was found in 18 (11.2%) of the 161 dually infected patients. During 5-year post-treatment follow-up, the rate of HBsAg seroclearance was 5.4% per year, reaching 30% at the end of follow-up. [9, 19]
Improvement of Long-term Outcomes Post-treatment
Reduction of Development of HCC and Improvement of Overall Survival: A Population-based Study in Taiwan
Whether Peg-IFN and RBV combination therapy could reduce the risk of HCC or improve survival in HCV/HBV dually infected patients was evaluated in a large population-based cohort from Taiwan.  We examined the risk of HCC, mortality, and adverse events in 1096 treated and 17 562 untreated HCV/HBV dually infected patients. After adjustment, combination therapy significantly reduced the risk of HCC ([HR] 0.75, 95% confidence interval [95%CI] 0.58–0.96), liver-related mortality (HR 0.45, 95% CI 0.35–0.57), and all-cause mortality (HR 0.39, 95%CI 0.32–0.48) ( Table 1). Nevertheless, the underlying HBV infection was still a risk factor for HCC and mortality after treatment. Our data demonstrated that combination therapy decreased the risk of developing HCC and improved survival in HCV/HBV dually infected patients. [10, 20]
|All-cause mortality||Liver-related mortality||Incidence of HCC|
|HR||95% CI||P-value||HR||95% CI||P-value||HR||95% CI||P-value|
|Peg-IFN α + RBV||0.42||(0.34–0.52)||< 0.001||0.47||(0.37–0.60)||< 0.001||0.76||(0.59–0.97)||0.030|
A population-based, retrospective cohort study examining the risk of HCC and mortality in 1096 treated and 1096 matched untreated HCV/HBV dually infected patients.
CI, confidence interval; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazards ratio; Peg-IFN α, peginterferon alfa; RBV, ribavirin
Prevention and Management of HBV Reactivation
In our treatment cohort, of 76 patients with pretreatment serum HBV DNA < 200 IU/mL, reappearance of HBV DNA was found in 47 (61.8%) patients.  These patients should be monitored regularly and prompt anti-HBV therapy should be implemented if clinically indicated.
Host and Viral Factors Affecting Natural and Treatment Outcomes of Patients With Dual Chronic HCV/HBV
The outcomes of chronic viral hepatitis B or C are likely to be influenced by certain host and viral genomic factors. The impacts of the viral factors and host factors await further investigations. Furthermore, the treatment outcomes using similar Peg-IFN/RBV combination regimen in other ethnicity and populations with different chronological sequence of HCV and HBV infection should also be evaluated. 
Factors Associated With Seroclearance of HBsAg
In our treatment cohort, only baseline low pretreatment serum HBsAg level correlated significantly with sustained HBsAg seroclearance ( P < 0.05). [8, 9, 21] In another study, we identified the host genetic factors associated with spontaneous HBsAg seroclearance; rs9277535 polymorphism for HLA-DPB1 region was associated with HBsAg seroclearance in chronic hepatitis B (CHB) patients.  Host and viral factors potentially affecting treatment-induced seroclearance of HBsAg in dually infected patients are under active investigations.
Role of New Direct-Acting Antiviral (DAA)-based Therapy
Currently, DAA-based triple therapy is the standard of care for patients with HCV genotype 1 infection in the United States and the European Union. Boceprevior- or telaprevir-based therapy significantly improved the SVR rate in naïve and experienced patients.  Around 25~ 30% of HCV genotype 1 dually infected patients did not respond to Peg-IFN/RBV therapy.  The value of new DAA-based triple therapy in this difficult-to-treat subgroup should be investigated soon. Whether IFN-free DAA-based therapy is effective in the control of HCV infection in dually infected patients is another interesting issue to be resoled. To be noted, in the latter scenario, IFN-free regimen would not be able to clear HBsAg.
Summary and Future Directions
HCV/HBV dual infection is not uncommon in areas endemic for HCV or HBV infection and among subjects at risk of parenteral transmission. Before the implementation of antiviral therapy, thorough serological and virological examinations are required to determine the viral dominance as well as to determine the optimal antiviral regimen. For dually infected patients with active hepatitis C, the same genotype-dependent treatment recommendations for single chronic hepatitis C still hold true.[23–26] However, for dually infected patients with active hepatitis B or with established cirrhosis, [27, 28] more studies are needed to determine the optimal regimen to treat both viruses at the same time. The value of DAA-based triple therapy in this population also remains to be clarified.\
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