Infection with either hepatitis B (HBV) or hepatitis C (HCV) virus is one of the major causes of chronic liver disease globally (Konstantinou 2015). Due to shared routes of transmission, coinfection with HBV and HCV is not uncommon among individuals in areas of high HBV prevalence and among individuals at high risk of parenterally transmitted infections, such as people who inject drug (PWID) (Pallas 1999), those with an increased number of lifetime sexual partners (Bini 2010), patients on haemodialysis (Reddy 2005), patients undergoing organ transplantation (Aroldi 2005) and HIV positive individuals (Zhou 2007, Jansen 2015). Due to a lack of large-scale population-based studies the exact number of people coinfected with HBV/HCV is unknown. Dual infection ranges from 9% to 30%, depending on the geographic region (Zarski 1998, Liaw 1995, Tyson 2013). These numbers may underestimate the true number of people with HBV/HCV coinfection, as there is a well-known entity of occult HBV infection (patients with negative hepatitis B surface antigen [HBsAg] but detectable serum HBV DNA) in patients with chronic HCV (Cacciola 1999, Torbenson 2002, Raimondo 2005, Wiegand 2015).
People with a first episode of acute hepatitis should be screened for all viral causes including HBV and HCV (see chapter 8 on diagnostic tests in acute and chronic hepatitis B and chapter 11 for hepatitis C). Some patients may be inoculated with both viruses simultaneously and will present with acute hepatitis due to both viruses. In addition, HBV superinfection in patients with chronic HCV, and HCV superinfection in patients with chronic HBV have both been reported (Liaw 2000, Liaw 2002, Liaw 2004). Therefore, episodes of acute hepatitis in patients with known chronic HBV or HCV infection, especially those with ongoing risk behavior for hepatitis infections such as injecting drug use or multiple sex partners, should undergo screening for superinfection. In addition, in patients with chronic HCV, ruling out occult HBV infection beyond HBsAg testing, e.g., by polymerase chain reaction (PCR), should be done when clinically indicated (Squadrito 2013).
Patients with both HBV and HCV may show a large spectrum of virologic profiles and different viral dominance patterns have been documented. In most cases, HCV is dominant and suppresses HBV replication (Liaw 2001), resulting in lower HBV DNA levels and decreased activity of HBV DNA polymerase (Chu 1998). Moreover, HCV was demonstrated to inhibit HBsAg production by mechanisms mediated by host immune responses. HBsAg levels were found even lower compared with HBV-monoinfected patients undergoing treatment with nucleos(t)ide analogues but comparable to low replicative HBsAg carriers (Wiegand 2015). Superinfection with HCV in patients with chronic HBV might even induce seroconversion of HBsAg (Liaw 1994, Liaw 1991). Most recent clinical findings postulate that HCV coinfection itself is not associated with seroconversion but a higher ALT level >80 U/L is the major determinant of HBsAg loss in patients with HBV/HCV coinfection (Yang 2016).
Several authors have reported that HBV can reciprocally inhibit HCV replication (Sato 1994). HBV DNA replication has been shown to correlate with decreased HCV RNA levels in coinfected patients (Zarski 1998). Coinfection with HBV was sometimes associated with a higher spontaneous HCV clearance (Islam 2016).
Furthermore, patients with coinfection have lower levels of both HBV DNA and HCV RNA than corresponding monoinfected controls, indicating that simultaneous suppression of one virus by the other might occur (Jardi 2001). Thus, either HBV or HCV can play the dominant role, HBV and HCV can inhibit each other simultaneously and they can alternate their dominance (Liaw 1995). Both viruses have the ability to induce seroconversion of the other. The chronology of infection may have a role in determining the dominant virus.
Interestingly, recent in vitro studies revealed that there is most probably no direct interference between HBV and HCV replication, making interindividual differences in innate and/or adaptive host immune responses responsible for viral interference observed in coinfected patients (Bellecave 2009, Eyre 2009). A modulation of human dendritic cells induced by the combined effects of HBV and HCV core proteins, leads to an inefficient antigen presentation to CD4+ T cells and thus suppresses the induction of cellular immune response (Agrawal 2014, Yoshio 2016). These findings show a possible mechanism by which HBV and HCV synergistically induce immune tolerance that may be fundamental in establishing chronic, persistent infection.
Different scenarios of infection have been described with HBV/HCV coinfection including acute hepatitis with HBV and HCV (Alberti 1995), occult HBV coinfection of chronic HCV (Sagnelli 2001), and superinfection by either virus in patients with pre-existing chronic hepatitis due to the other virus (Figure 1). Frequently the sequence of infection cannot be defined.
Simultaneous coinfection with HBV and HCV is rarely seen, but the interaction of HBV and HCV appears to be similar to chronic infection. In acute infection with HBV and HCV, patients showed delayed HBsAg appearance and a shorter hepatitis B surface antigenaemia compared to those with acute HBV alone (Mimms 1993). Biphasic alanine aminotransferase (ALT) elevation was found in some patients, although rates of viral clearance were similar to those in patients with HBV or HCV monoinfection (Alberti 1995). Simultaneous infection often has a self-limiting, benign course with complete recovery from one or both infections (Chen 2007, Chu 1995).
HCV superinfection is frequent in endemic areas of HBV infection, such as Asia, South America and sub-Saharan Africa (Liaw 2002, Liaw 2004), which can result in the suppression of HBV replication and termination of HBsAg carriage. However, long-term follow-up analyses have described a higher rate of liver cirrhosis and hepatocellular carcinoma (Liaw 2004, Yang 2016). Fulminant hepatic failure was significantly higher among patients with underlying HBV infection than those without (23% vs. 3%) (Chu 1999, Wu 1994, Chu 1994).
HBV superinfection is less common in people living with HCV and limited data is available. In a case control study, HCV RNA was undetectable in all observed patients during acute HBV infection, indicating that superinfection of HBV leads to long lasting suppression of HCV (at one year 71% remained negative, at two years 42%) and in up to 25% of cases even can lead to permanent clearance of chronic HCV infection, especially in patients with severe acute HBV infection (Sagnelli 2009, Liaw 2000, Wietzke 1999). Patients with superinfection and those with HBV monoinfection showed similar initial HBV viral load and a similar trend of becoming negative for HBV DNA. HBV superinfection is associated with acute deterioration of liver function and showed a severe course during acute illness more frequently (34.5% in superinfection versus 6.9% in HBV monoinfection). The risk of fulminant hepatitis is increased (Sagnelli 2009, Sagnelli 2002).
Occult HBV infection, defined as detectable HBV DNA in liver or serum and undetectable HBsAg (Ozaslan 2009, Torbenson 2002), has been identified in up to 50% of patients with chronic HCV (Matsuoka 2008). Importantly, a relation to HCV treatment outcomes has been described (Zignego 1997, Fukuda 2001, Sagnelli 2001). HCV infection with occult HBV infection has been associated with higher ALT levels, greater histological activity index and liver disease more often progressing to liver cirrhosis (Fukuda 1999, Cacciola 1999, Sagnelli 2001). Occult HBV infection seems to significantly shorten life expectancy compared to HCV monoinfection (Squadrito 2014, Coppola 2016).
Patients with detectable serum HBV DNA and HCV RNA are at highest risk of severe liver disease and therefore should be considered for treatment. Large follow-up studies show that patients with HBV viraemia are at higher risk for cirrhosis, HCC and overall death than people with HCV monoinfection (36.8, 6.9, and 41.7 versus 17.4, 3.6, and 31.4 per 1000 person years, respectively) (Kruse 2014, Bini 2014). Active HCV infection (HCV RNA+) in the setting of inactive HBsAg (HBsAg+/HBV DNA-) is associated with a clinical course similar to that of HCV monoinfection. Another possibility is active HBV infection in patients with inactive or prior HCV infection (HBV DNA+/HCV RNA-/anti-HCV+). This immune profile is less common, and may indicate HBV suppression of HCV. A longitudinal study of virologic monitoring of 103 HBV/HCV-coinfected patients revealed a fluctuation in the virologic pattern (Raimondo 2006). Asian ethnicity is a major independent predictor of HBV dominance, while HCV-dominant disease is more common in non-Asian individuals (Nguyen 2011). Thus, careful longitudinal follow-up of levels of serum HBV DNA and HCV RNA is needed for a correct diagnosis and decision on the most successful treatment strategy. Table 1 shows the immune profiles found in patients with chronic HBV/HCV infection.
|HBV and HCV active||Occult HBV in chronic active HCV||HCV active in HBsAg carrier|
Higher rates of cirrhosis have been shown in people with HBV/HCV coinfection. In comparison to patients with HBV monoinfection, higher rates of cirrhosis (44% vs. 21%) and decompensated liver disease (24% vs. 6%) were demonstrated in people with coinfection (Fong 1991). Compared to HCV monoinfection, a higher rate of cirrhosis (95% vs. 49%) and more decompensated liver disease (Child-Pugh class C 37% vs. 0%) were found in people with HBV/HCV coinfection (Mohamed Ael 1997).
In many studies, coinfection with HBV and HCV is associated with an increased risk of HCC development, confirmed by three large meta-analyses (Cho 2011, Shi 2005, Donato 1998).
In one longitudinal study, incidence of HCC was 6.4 per 100 person years in people with HCV/HBV coinfection compared to 2.0 and 3.7 in HBV and HCV monoinfection, respectively. The cumulative risk of developing HCC after 10 years was 45% in HBV/HCV coinfection compared to 16% in HBV and 28% in HCV monoinfection (Chiaramonte 1999). Possible associated risk factors for HCC development in coinfection are longer duration of infection, higher HCV RNA levels, and higher levels of fibrosis (Zampino 2015). Patients with HBV/HCV coinfection should undergo a screening routine for HCC with liver ultrasound and α fetoprotein levels in serum at least every six months.
In this context, however, it has to be mentioned that dually infected patients are an extremely heterogeneous population and most of the data available does not take into account the differences in the viruses (genotypes, main HBV genomic mutations, activity status of one or both viruses, etc.) or those regarding patients’ characteristics and comorbidities (presence of diabetes, alcohol intake, etc.) (Huang 2011).
Despite the individual clinical importance, solid evidence and well-established treatment guidelines for HBV/HCV coinfection are currently lacking. Generally, treatment guidelines for monoinfection should be applied to coinfection after carefully characterising the replicative status of HBV, HCV and hepatitis delta virus infection. Due to the variety of virologic profiles in HBV/HCV coinfection it is important to assess the dominant virus prior to initiating therapy. In people with coinfection, treatment should be initiated when inclusion criteria for standard treatment guidelines of HBV and HCV monoinfection are met (see chapter 9 on HBV treatment and chapter 12 on HCV treatment). Treating HBV/HCV coinfection leads to a risk reduction of HCC and improved survival (Liu 2014, Konstantinou 2015). As with monoinfection, treatment of people with coinfection should be started before liver decompensation occurs.
Due to loss of viral suppression from the successfully treated dominant virus, acceleration of liver disease has been reported (Yalcin 2003) and caution must be exercised upon initiation of therapy.
In coinfection with dominance of HCV infection, PEG-IFN plus ribavirin is still used because of its proven activity against both viruses (Table 2). Data from a meta-analysis show that the SVR achieved in HBV/HCV coinfection are comparable to those in HCV monoinfection (OR = 1.03, 95% CI: 0.37–2.82 and OR = 0.87, 95% CI: 0.62–1.21, respectively) (Liu 2012, Kim 2011, Liu 2009). HCV SVR is maintained in 97% in a five-year follow-up (Yu 2013). Furthermore, HBsAg loss occurs in about 30% within five years after treatment start and there is evidence of an increased possibility of HBeAg seroconversion during or post-treatment with PEG-INF and ribavirin (Liu 2016, Yu 2013, Liu 2009, Viganò 2009, Yu 2009).
|Patients (n)||HCV SVR (%)||HBV DNA negative (%)||HBsAg loss (%)||HBV reactivation # (%)||Reference|
|19||70*, 78**||33||0||31||Potthoff 2008|
|161||72*, 83**||56||11||35||Liu 2009|
|50||40*, 75**||100||0||24||Yu 2009|
|18||60*, 88**||12||na||na||Kim 2011|
HBV replication may become detectable in up to 60% of patients with undetectable pre-treatment HBV DNA levels, either during the course of treatment (38%) or during the treatment follow-up (60%). Reactivation was only transient in 45% (Liu 2014, Yu 2013, Potthoff 2009, Liu 2009). HBV DNA reactivation was found to be independently associated with younger age, HCV SVR and baseline HBV DNA ≥2000 IU/mL (Hung 2012). Thus, close monitoring of both viruses is recommended during and after combination therapy. In case of HBV reactivation or if HBV replication is detectable at a significant level, concurrent HBV nucleos(t)ide analogue (NA) therapy is indicated.
Direct acting antivirals (DAA) still need to be further evaluated in people with HBV/HCV coinfection. IFN-free DAA-based regimes will not be able to clear HBsAg and simultaneous or on-demand nucleos(t)ide analogues will be needed if clinically indicated. In the setting of the IFN-free DAA-based therapies, the possibility of HBV reactivation during HCV treatment is raised due to viral interferences. Post-marketing cases of HBV reactivation under different combinations of DAAs have been reported (De Monte 2016, Hayashi 2016, Takayama 2016, Collins 2015). On the other hand, a recent analysis of 103 previously HBV infected patients showed no evidence of HBV reactivation under DAA treatment (Sulkowski 2016). Nevertheless, positive HBsAg status before DAA treatment is a strong risk factor for developing hepatitis due to HBV activation during treatment (HR 15.0) (Wang 2017). Due to this potential risk of early HBV reactivation during IFN-free HCV therapies, it is necessary to closely monitor and preemptively treat HBV coinfection, regardless its stage (chronic, occult, resolved), whatever HCV genotype or class of DAA used. Furthermore, in patients receiving tenofovir as concomitant anti-HBV treatment, the eGFR and tubular function should be monitored during treatment with simeprevir or sofosbuvir/ledipasvir as tenofovir exposure is significantly increased.
In patients with dominant HBV, IFN +/- HBV polymerase inhibitors are an upcoming option. Data exists from a small cohort of people with HBV/HCV coinfection treated with lamivudine in combination with standard interferon for 12 months followed by lamivudine for an additional 6 months (Marrone 2004). In this study, clearance of HBeAg was found in 3/8, two patients showed HBeAg seroconversion, and HBV DNA clearance was observed in 3/8 at the end of therapy. HBV DNA became detectable again in two patients at the end of follow-up. HCV clearance was achieved in 50%. In another study, tolerability and efficacy of anti-HBV nucleos(t)ide analogues (lamivudine plus adefovir [n=10], entecavir [n=7], telbivudine [n=4], tenofovir disoproxil fumarate [n=3]) were investigated in a cohort of 24 cirrhotic patients with HBV/HCV coinfection (Coppola 2013). Clearance of HBV DNA was found in 96% of patients after 18 months, while HCV reactivation was low (12.5%). However, while the virologic response was favourable in all patients and treatment was well tolerated, progression of liver cirrhosis was seen in up to one-third. Patients who were HCV RNA positive at baseline deteriorated more frequently. Thus, a favourable clinical impact in HBV/HCV cirrhotic patients was seen only in patients who were HCV RNA negative at baseline.
Based on these observations, NA such as tenofovir, adefovir, entecavir and telbivudine showing a higher genetic barrier in combination with PEG-IFN are a possible treatment option. In cirrhotic patients with HBV/HCV coinfection with detectable HCV RNA, exclusive treatment with NA has a high risk of clinical deterioration. However, further studies are needed to estimate the treatment value of these newer drugs in different clinical scenarios.
Interestingly, fibrosis progression rate after orthotopic liver transplantation in patients with HBV/HCV coinfection is lower compared with HCV monoinfection (Taniguchi 2000, Féray 1999). The one- and five-year patient and graft survival rates were 80% and 70%, respectively. The five-year fibrosis progression rate was 0.17 +/- 0.08 units (Manzia 2010).
Coinfection with HBV and HCV is not uncommon, especially within areas of high hepatitis B prevalence. HBV/HCV coinfection is a challenge for clinicians due to the complex interactions of HBV and HCV, and the propensity for developing severe liver disease. No treatment standard has been established for patients with HBV/HCV coinfection. Treatment decisions must be made based upon identification of the dominant virus. Combination therapy of PEG-IFN plus ribavirin has been shown to be highly effective in inducing virologic response. Systematic treatment experience with DAAs in the setting of HBV/HCV coinfection is lacking and decisions currently have to be made on an individual basis.
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