Hepatitis B virus/hepatitis C virus coinfection: Epidemiology, clinical features, viral interactions and treatment

Authors

  • Chi-Jen Chu,

    1. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, and National Yang-Ming University, School of Medicine, Taipei, Taiwan
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  • Shou-Dong Lee

    1. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, and National Yang-Ming University, School of Medicine, Taipei, Taiwan
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Shou-Dong Lee, Department of Medicine, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec. 2, Taipei, Taiwan 112. Email: sdlee@vghtpe.gov.tw

Abstract

Because of the shared modes of transmission, hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection is not uncommon in highly endemic areas and among subjects with a high risk of parenteral infections. The worldwide prevalence of HBV/HCV coinfection is unknown and might be underestimated with the phenomenon of silent (occult) HBV infection. HCV superinfection in patients with chronic HBV infection was the most common clinical features of coinfection in Asia–Pacific countries. Further, most, but not all, clinical observations suggested that interference between the two viruses was more frequently characterized by an inhibition of HBV replication exerted by HCV. However, longitudinal follow-up studies have demonstrated that the virological patterns in coinfection cases are widely divergent and have dynamic profiles over time. As compared with monoinfected patients, HBV/HCV coinfected persons tend to have more severe liver injury, a higher probability of liver cirrhosis and hepatic decompensation, and a higher incidence of hepatocellular carcinoma. Detailed serological and virological evaluations are required for coinfected patients before initiation of antiviral therapy. Previous studies demonstrated that HBV/HCV coinfected patients responded poorly to interferon (IFN) monotherapy. Currently, for patients with dominant HCV infection and low level HBV viremia (<104 IU/mL), IFN or pegylated IFN plus ribavirin can achieve comparable sustained virus response as expected with HCV monoinfection. However, phenomenon of reciprocal viral interference can happen, and resultant “flare” of hepatitis activity may cause liver function deterioration. For coinfected patients with dually-active HBV/HCV, the optimal regimen for therapy remains unclear although adding oral nucleos(t)ide analogs to pegylated IFN and ribavirin seems a reasonable empiric option.

Introduction

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are important global public health problems. Regarding the disease burden, the World Health Organization estimated that more than 350 million and 170 million people are chronic carriers of HBV and HCV, respectively. Because of their shared modes of transmission, coinfection with HBV and HCV is a fairly frequent occurrence, particularly in areas where the two viruses are endemic, and among subjects with a high risk of parenteral infections.1–5 The clinical relevance of HBV/HCV coinfection for disease severity and adverse outcomes, as well as for selection of treatment options is important, although information concerning many aspects of dual infection remains largely incomplete. Accumulating evidence suggest that coinfection by HBV and HCV is heterogeneous with respect to varying states of replication for each virus and profiles of immunity. The aims for this review article were to summarize the risk factors and epidemiology of HBV/HCV coinfection, its clinical features and impact on liver disease, and how to treat coinfected patients.

Epidemiology of HBV/HCV coinfection and risk factors

The worldwide prevalence of coinfection with HBV and HCV is unknown due to lack of large-scale population-based studies. Moreover, occult or clinically silent HBV infection (undetectable hepatitis B virus surface antigen [HBsAg] with detectable HBV DNA in serum) has been described in patients with chronic hepatitis C (CHC) infection by highly sensitive molecular techniques.6–8 Therefore, testing for HBsAg alone may substantially underestimate the true prevalence of HBV/HCV coinfection.

In general, approximately 2–10% of anti-HCV-positive patients are found to be HBsAg positive. In published studies,2,9–20 the prevalence of anti-HCV has been approximately 5–20% of patients with chronic hepatitis B (CHB) infection; a summary of selected studies is shown in Table 1. In addition to those with chronic liver disease, HBV/HCV coinfection is frequently found in several high-risk populations, such as injection drug users (IDU),21 patients on hemodialysis,22 patients undergoing organ transplantation,23 HIV-positive individuals24,25 and β-thalassemia patients.26

Table 1.  Prevalence of anti-hepatitis C virus (HCV) among patients with chronic hepatitis B virus (HBV) infection in selected studies
Geographic areaYearAuthorsNumber of subjectsPrevalence (%)
Italy1991Fattovich et al.918415
1999Di Marco et al.1030214
2003Gaeta et al.118377.0
Spain1994Crespo et al.213213
Taiwan1991Chan et al.123233.4
1994Liaw et al.13149812
2001Dai et al.1410018
Japan1994Sato et al.158222
1994Ohkawa et al.1615613
China1994Li et al.1719311
1999Chen et al.1810315
India2001Xess et al.194933.0
Thailand1999Pramoolsinsap et al.202962.7

In general, the risk factors of HBV/HCV coinfection were found to be similar to those of HBV or HCV monoinfection. A multicenter prospective study in Italy11 showed that an age more than 42 years, a history of IDU and/or blood transfusion, and residence in the south of the country were independent factors associated with HBV/HCV coinfection. Another study revealed risk factors for HCV superinfection in patients with CHB infection in Taiwan as blood transfusion, IDU, instrumentation, and household or community contact.27

Screening of HBV/HCV coinfection

Laboratory evaluation for all possible viral causes including HBV and HCV should be arranged in patients presenting with acute hepatitis. Acute hepatitis can result from simultaneous infection by the two viruses. In addition, for cases of CHB or CHC infection that present with acute exacerbation, the possibility of superinfection by other viruses should be considered, particularly if the above-mentioned risk factors are noted.27,28 In addition, silent or occult HBV infection can be found in some patients with CHC infection.29,30 This state of coinfection will not be appreciated if only HBsAg has been checked; confirmatory tests, such as HBV DNA testing by polymerase chain reaction (PCR), should also be arranged when clinically indicated.

Clinical features of HBV/HCV coinfection

Acute hepatitis by simultaneous infection of HBV and HCV

Simultaneous acute hepatitis with HBV and HCV has always been rare, but the situation could occur after accidental needle-stick injury,31 and blood transfusion in the past.32 Mimms et al. followed five patients with concurrent acute infection with HBV and HCV;33 the patients tended to have delayed appearance of HBsAg and a shorter duration of hepatitis B surface antigenemia as compared with those with acute HBV infection alone. Another study from Italy enrolled 30 patients presenting with acute hepatitis in whom markers of active HBV and HCV infection coexisted.3 The clinical features and chronicity rates were comparable to patients with acute HBV or HCV infection, but the phenomenon of biphasic alanine aminotransferase (ALT) elevation was evident in some patients.

Hepatitis C superinfection

In areas of high prevalence of HBV infection, such as Asia–Pacific countries, HCV superinfection in individuals with CHB infection is the most common scenario of HBV/HCV coinfection.27,34 Two studies from Taiwan showed that a significant proportion of instances of fulminant/subfulminant hepatitis in those with CHB infection (HBsAg carriers) could be attributed to HCV superinfection.35,36 A recent study by Liaw et al. found that acute HCV infection in patients with CHB infection could be associated with more severe symptoms during the acute phase.27 More importantly, long-term follow-up analyses showed that those with HCV superinfection had higher cumulative rates of liver cirrhosis (48% at 10 years) and hepatocellular carcinoma (HCC) (32% at 20 years) than acute HBV superinfection or CHB. Underlying HBV infection is also an important factor determining the clinical course of acute HCV infection. Another prospective study from Taiwan showed that in patients admitted with acute HCV, the occurrence of fulminant hepatic failure was significantly higher among those with underlying HBV infection than those without (23% vs 3%, P < 0.01).37

Hepatitis B superinfection

Superinfection with HBV in patients with CHC is less common. Previous case reports28,38 indicated that HBV superinfection was associated with acute deterioration of liver function among patients with underlying HCV infection, and one study28 found that anti-HCV can disappear during HBV superinfection. Another small study showed the incidence of hepatic encephalopathy or ascite formation was higher in HCV patients with HBV superinfection as compared to acute HBV infection alone (29% vs 0%, P < 0.05).39 The clinical significance of HBV superinfection remains to be clarified due to lack of sufficient data, but physicians should be aware that HBV superinfection is one possible cause for fulminant hepatitis in patients with CHC infection.

Occult HBV infection in patients with HCV infection

Occult HBV infection has frequently been identified in patients with CHC infection. The prevalence of “occult” HBV infection among HCV-infected persons is unknown, but has been detected in as many as 50% of patients in some series.7,30,40 To date, growing evidence has suggested that occult HBV infection might aggravate the clinical outcome of CHC and contribute to the development of liver cirrhosis and HCC.41–44 However, the detailed pathogenesis remains to be studied. Occult HBV infection might also affect the antiviral response in CHC patients, and this will be discussed in the treatment section.

Viral interactions between HBV and HCV

Clinical and laboratory studies have shown that the HBV and HCV interact with each other and affect immune responses. HCV infection can suppress HBV replication, as demonstrated by acute HCV superinfection in chimpanzees with CHB infection that result in a significant reduction of serum HBsAg titer.45,46 Clinical observations show that most coinfected cases have detectable levels of HCV viremia and very low values of serum HBV DNA,9,15,47–49 suggesting that the interference between the two viruses is more frequently characterized by an inhibition of HBV exerted by HCV. In cases of HCV superinfection, hepatitis B e antigen (HBeAg) seroconversion and HBsAg clearance have been reported.34,50 These observations may explain the phenomenon whereby occult HBV infection is frequently found in patients with CHB infection. “In vitro” studies have also revealed that HCV is capable of suppressing HBV replication, and this inhibitory effect is mediated by HCV core protein.51–54 One study found the inhibitory effect of HCV was genotype-dependent,53 being more pronounced in genotype 1 HCV infections. However, more research is needed before reaching a firm conclusion on this aspect.

It should be mentioned that clinical studies do not uniformly report a dominant role of the HCV in cases of combined infection. Some findings suggest a reciprocal interference, or even a dominant effect of HBV.5,15,16,55 Zarski et al. found that HCV RNA levels were significantly decreased in HBV/HCV coinfected patients with positive serum HBV DNA as compared to HBV DNA negative cases.5 Another Italian study showed coinfected patients had a significantly higher rate of HCV RNA clearance as compared to ones with HCV monoinfection (71% vs 14%).56

In summary, patients with combined HBV and HCV infection may show a large spectrum of virological profiles. Although most HBV/HCV coinfected patients appear to have active HCV and inactive HBV replication, some patients have high HBV viremia levels and undetectable HCV RNA. Because most available data are based on cross-sectional observations, the possibility cannot be ruled out that HBV and HCV can alternate their dominance during different periods of infection. A multicenter longitudinal follow-up study in Italy showed that patterns of virological response in these cases are widely divergent and change over time.57 Based on the above findings, it is reasonable to postulate that, at least in some HBV/HCV coinfected patients, each virus might exert its own pathogenetic role, causing a cumulative effect in terms of liver injury that may explain the high grade of disease severity frequently observed in case of coinfection.

Fibrosis progression in HBV/HCV coinfection

Several studies have compared the histological findings between HBV/HCV coinfection with single viral infection. Zarski et al.5 found that liver injury was more severe in dual infection than in HCV single infection; criteria included Knodell score, piecemeal necrosis and fibrosis, and incidence of liver cirrhosis. Similar results have been shown by studies from Asian and Western countries.58–60 In addition, several cross-sectional studies2,4,5,9,61 found that HBV/HCV coinfection is associated with a higher prevalence of liver cirrhosis and hepatic decompensation as compared with monoinfection alone.

Although many studies suggested that coinfected patients had more severe liver disease than those with HBV or HCV monoinfection, this finding has not always been supported by other studies.62,63 Possible reasons to explain the discrepancies may include relatively small sample size, retrospective study design, sensitivity of anti-HCV assays, and confounding by the phenomenon of occult HBV infection. Further, large-scaled comprehensive studies are highly warranted to determine whether HBV/HCV coinfection is associated with more severe liver disease than either CHB or CHC. In addition, longitudinal studies with sequential liver biopsies are needed to evaluate the rate of fibrosis progression in coinfected subjects.

Impact of HBV/HCV coinfection on development of HCC

Coinfection with HBV and HCV has been shown in many case-control studies to correlate with an increased risk of developing HCC.4,64–66 Benvegnu et al.67 conducted a prospective study of 290 cirrhotic patients and found that coinfection (detectable anti-HCV and HBsAg) was an independent predictor for development of HCC by both univariate and multivariate analyses. A subsequent longitudinal study confirmed these results.68 The incidence of HCC (per 100 person years) was 6.4 in dually-infected patients, compared to 2.0 in HBV and 3.7 in HCV monoinfected patients, while the cumulative risk of developing HCC at 10 years was 45% in coinfected patients, compared with 16% and 28% in HBV and HCV monoinfected disease controls. However, a study from Japan suggested that dual infection was rare (2%) in Japanese patients with liver cirrhosis and did not play an important role in the occurrence of HCC.69

A meta-analysis conducted by Donato et al. enrolled 32 case-control studies to investigate the impact of HBV/HCV coinfection on the development of HCC.70 This study showed the relative risk of HCC in coinfected patients (odds ratio [OR] = 165) was significantly higher than HBV (OR = 22.5) and HCV (OR = 17.3) infection alone. The bulk of published evidence therefore is consistent with the existence of synergism between these HBV and HCV viruses in hepatocarcinogenesis. It is generally recommended that patients with HBV/HCV coinfection and known or suspected cirrhosis should be followed regularly, every 3–6 months, or more frequently with α-fetoprotein and hepatic imaging studies.

Treatment of HBV/HCV coinfection

Because very limited data regarding therapy of HBV/HCV coinfected patients are available, there are currently no established treatment guidelines for these patients. It is very important to determine the “dominant” virus by serological and virological testing before initiation of therapy. Treatment guides in existence for patients with CHB and CHC monoinfection can be applied to coinfected patients.71–74 Patients with CHC and detectable serum HCV RNA are candidates for 24–48 weeks of antiviral therapy based on HCV genotype. Currently, standard treatment for hepatitis C is interferon (IFN) or pegylated IFN plus ribavirin. Currently licensed drugs (details vary between countries) for CHB include IFN-α-2b, pegylated IFN-α-2a, lamivudine, adefovir, entecavir and telbivudine. IFN therapy is not recommended in patients with decompensated liver cirrhosis or in the setting of fulminant hepatitis, and these patients should be considered for liver transplantation.

Interferon monotherapy for HBV/HCV coinfection

Through antiviral and immunomodulatory actions, IFN is one of the approved therapies for HBV and HCV. According to the previous published reports, the sustained virological response (SVR) in CHC patients treated with IFN monotherapy and IFN plus ribavirin was approximately 10% and 43%, respectively.71 The SVR rate for CHB patients with positive HBeAg treated with IFN was approximately 35%.75 To date, IFN has been the most studied agent in treatment of HBV/HCV coinfected patients because of its proven activity against both viruses. Case reports in the early 1990s suggested treatment of HBV/HCV coinfected patients with IFN could achieve HBeAg loss and HCV RNA clearance.76 The initial studies77,78 using 3 million units (MU) IFN thrice weekly (TIW) for 6 months to treat HBV/HCV coinfected patients achieved sustained biochemical response (SBR) in approximately 12.5% to 19% of cases. HBsAg clearance was observed in a small proportion of patients, but these studies did not report the virological response of HBV or HCV.

Table 2 summarizes the efficacy of using IFN monotherapy for patients with HBV/HCV coinfection. In 1997, Liaw et al. retrospectively analyzed the treatment response of IFN for HBeAg-positive CHB patients with or without HCV markers who had been previously enrolled into clinical trials.79 These patients received therapy with lymphoblastoid 4–6 MU/m2 IFN TIW for 12 weeks or 9 MU IFN-α-2a TIW for 14 weeks. Of the 15 patients seropositive for HCV, only one (6.7%) responded with seroclearance of HBV DNA and HBeAg, as compared with 46 (28%) of 164 HCV-negative patients (P = 0.058). In addition, none of these 15 coinfected patients cleared serum HCV RNA through the course of therapy and follow up. Later, Guptan et al.80 reported the experience of treating seven HBV/HCV coinfected patients with 6 MU IFN-α-2b for 6 months. After 6 months follow up, the authors reported 100% of patients lost HBV DNA by a non-PCR-based assay, and 100% of HBeAg-positive patients lost HBeAg (3/3). The SVR for HCV infection was 29%.

Table 2.  Interferon monotherapy for HBV/HCV coinfection: a summary of published studies
YearAuthorsHCV characteristicsHBV characteristicsNo. of patientsRegimenHBeAg loss (%)SVR for HBV (%)SVR for HCV (%)SBR (%)
  • HBV DNA measured by non-polymerase chain reaction (PCR) assay,

  • HBV DNA measured by PCR assay.

  • HBeAg, hepatitis B e antigen; HBsAg, hepatitis B virus surface antigen; IFN, interferon; MU, million units; N/A, not applicable; SBR, sustained biochemical response; SVR, sustained virological response; TIW, thrice weekly.

1997Liaw et al.79Anti-HCV+
HCV RNA+
HBsAg+
HBeAg+
HBV DNA+
15Lymphoblastoid IFN
4–6 MU/m2 IFN TIW × 12 weeks or
9 MU IFN-α-2a TIW × 14 weeks
6.7%6.7%0%6.7%
1999Guptan et al.80Anti-HCV+
HCV RNA+
HBsAg+
3 HBeAg+
HBV DNA+
7IFN-α-2b 6 MU TIW × 6 months100% (3/3)100%29%N/A
1999Utili et al.81Anti-HCV+
HCV RNA±
HBsAg+
13 HBeAg+
165 MU IFN TIW for 12 months15% (2/13)N/A44%50%
2000Villa et al.82Anti-HCV+ HCV RNA+HBsAg+ 30 anti-HBe+
HBV DNA±
306 MU IFN-α TIW × 6 months (n = 14)
or 9 MU IFN-α TIW × 6 months
(n = 16)
 0% (0/2)
100% (4/4)
17%
31%
20%
38%

In 1999, Utili et al.81 treated 16 HBV/HCV coinfected patients with 5 MU IFN TIW for 12 months, 13 of them were HBeAg positive. The results showed that overall SVR for HCV infection was 44% and the response rate was higher (67%) in HBeAg-negative patients. HBeAg loss was seen in 15% (2/13) HBeAg-positive patients, but no significant change in mean serum HBV DNA levels was found. In 2001, a prospective randomization study from Italy enrolled 30 HBV/HCV coinfected patients to receive either 6 (n = 14) or 9 (n = 16) MU IFN-α TIW for 6 months.82 Five patients treated with 9 MU IFN consistently cleared HCV RNA and HBV DNA, whereas none of those treated with 6 MU reacted in a similar fashion (P < 0.05). Responders showed significant improvement of histological activity index in comparison with non-responders. Longitudinal follow up showed that none of the patients treated with high-dose IFN developed cirrhosis, whereas four of 14 patients treated with low doses did. This was the first study to suggest that higher doses of IFN may be indicated in coinfected patients.

Regarding therapy of CHC patients with occult HBV infection, Zignego et al. reported 14 CHC with silent HBV coinfection (anti-HCV-positive, HBsAg-negative, HBV DNA-positive by PCR) patients treated with 3 MU IFN-α-2a TIW for 12 months.83 At the end of therapy, biochemical response was 28% and undetectable HBV DNA and HCV RNA by PCR was found in 29% and 36% of patients, respectively. However, all patients with biochemical response relapsed after cessation of therapy. As compared with 111 patients with CHC infection alone (biochemical relapse, 47%), the treatment response of those with HCV and occult HBV infection was significantly worse. A later study by Fukuda et al.29 showed silent HBV infection was associated with higher ALT levels, greater histological activity scores and poor efficacy of IFN treatment. One study suggested that this phenomenon might be attributed to the downregulation of type 1 IFN receptor gene expression within the liver by HBV.30

Interferon plus ribavirin for HBV/HCV coinfection

Therapy for coinfected patients with IFN plus ribavirin had been reported from several Taiwanese studies, as summarized in Table 3. Liu et al. treated 21 coinfected patients with HCV viremia with a 24-week course of IFN-α-2a (6 MU TIW for 12 weeks followed by 3 MU TIW for 12 weeks) plus 1200 mg ribavirin daily.84 Only one case was HBeAg positive, but virological testing showed 17 of 21 patients were positive for HBV DNA by PCR assay. After therapy, the SVR rate for HCV was comparable between coinfected patients (43%) and HCV monoinfected controls (60%). Six of 17 patients (35%) with detectable HBV DNA at baseline also had disappearance of HBV DNA at the end of treatment, and three of the six patients had sustained undetectable serum HBV DNA at 24 weeks after completion of treatment. The SBR rate of combination therapy was 43%. However, using the same regimen to treat another three HBV/HCV coinfected but HBV dominant (defined by HBV DNA-positive, HCV RNA-negative by PCR) patients showed poor (none of three) virological or biochemical response. In summary, the results demonstrated in HBV/HCV coinfected patients with HCV viremia, combination of IFN (or pegylated IFN) with ribavirin could achieve a SVR comparable to that with HCV alone. However, IFN plus ribavirin might be inadequate for early coinfections with dominant HBV viremia.

Table 3.  Treatment of HBV/HCV coinfected patients with IFN/ribavirin
YearAuthorsHCV characteristicsHBV characteristicsNo. of patientsregimenHBeAg loss (%)SVR for HBV (%)SVR for HCV (%)SBR (%)
  • HBsAg seroconversion developed in 12% of patients.

  • All studies measured HBV DNA by PCR-based assays.

2003Liu et al.84Anti-HCV+
HCV RNA+
HBsAg+
1 HBeAg+
HBV DNA±
216 MU IFN α-2a TIW ×  12 weeks then 3 MU IFN TIW × 12 weeks, plus 1200 mg/day ribavirin100% (1/1)35.3%
(6/17)
43%43%
Anti-HCV+
HCV RNA-
HBsAg+
2 HBeAg+
HBV DNA+
36 MU IFN α-2a TIW ×  12 weeks then 3 MU IFN TIW × 12 weeks, plus 1200 mg/day ribavirin100% (2/2)0% 0%
2005Hung et al.85Anti-HCV+
HCV RNA+
HBsAg+
1 HBeAg+
HBV DNA±
363–5 MU IFN α-2b TIW plus 800–1200 mg/day ribavirin  × 6 months0%11%
(2/18)
69%56%
2005Chuang et al.86Anti-HCV+
HCV RNA+
HBsAg+
HBV DNA±
426 MU IFN-α TIW plus 1000–
1200 mg/day ribavirin × 24 weeks
50%31%69%55%

In 2005, Hung et al. treated 33 coinfected patients with IFN-α-2b (3 or 5 MU TIW) plus ribavirin (800–1200 mg/day) for 24 weeks. Another 72 patients with HCV infection alone served as controls.85 Based on an intent-to-treat analysis, the biochemical response and serum HCV clearance rate at the end of 48 weeks follow up were similar in patients with dual infection and HCV infection alone (56% vs 72%; and 69% vs 71%, respectively). There was no significant difference in sustained HCV clearance rate between the 3-MU group (n = 13) and the 5-MU group (n = 23; 85% vs 61%). At the end of 48 weeks follow up, two (11%) of 18 pretreatment viremic patients had negative serum HBV DNA (<200 copies/mL), while eight (53%) of those without pretreatment viremia had reoccurrence of HBV DNA. Another study by Chuang et al.86 confirmed that combination therapy with 24 weeks IFN-α-2b (6 MU TIW) and ribavirin (1000–1200 mg/day) can achieve similar SVR in HBV/HCV coinfected (69%) and HCV monoinfected (67%) patients. Interestingly, reciprocal viral interference was quite common. Compared with HCV non-responders, HCV responders were less likely to achieve HBV DNA clearance (8.3% vs 100%) and more likely to have reactivation of HBV (59% vs 12.5%) or HBV flares (45% vs 8.3%).

Interferon plus lamivudine for HBV/HCV coinfection

Only one study has reported the efficacy of using IFN plus lamivudine for HBV/HCV coinfection.87 Eight patients with dually-active HBV and HCV (HBeAg-positive, HBV DNA-positive or HCV RNA-positive) were treated with 5 MU IFN and 100 mg/day lamivudine for 12 months, followed by lamivudine alone for 6 months. After therapy, the SVR for HCV was 50%. HBeAg clearance was observed in three patients, two of them seroconverted to anti-HBe. Three patients had clearance of HBV DNA by PCR assay at the end of therapy, however, HBV DNA became detectable again in two patients at the end of follow up. Based on these, combination therapy with IFN and oral nucleos(t)ide analogs might be an option for dually-active HBV and HCV coinfection. However, the best treatment regimen for these patients remained to be determined.

Pegylated IFN plus ribavirin for HBV/HCV coinfection

Pegylated IFN plus ribavirin is the current standard of care therapy for patients with CHC infection.71,73 As compared with short-acting IFN, the SVR by pegylated IFN can be elevated approximately 10–15% more, especially in patients with genotype 1 HCV infection.88–91 Two case reports suggested that pegylated IFN plus ribavirin was effective for HBV/HCV coinfection.92,93 Recently, a large-scale prospective trial designed to evaluate the efficacy of pegylated IFN-α-2a plus ribavirin combination in HBV/HCV coinfected patients has been conducted.94 Patients were treated with pegylated 180 μg/week IFN-α-2a plus 1000–1200 mg/day ribavirin, for 48 weeks with genotype 1 HCV, or 24 weeks for genotypes 2 or 3. The results showed that high rates of SVR for HCV can be achieved in both genotype 1 (73%) and 2/3 (86%) patients, and there was no significant differences in SVR between monoinfected HCV and coinfected patients (Table 4). A total of 68 HBV/HCV coinfected patients had detectable HBV DNA by PCR assay at baseline, 69% of these achieved HBV DNA negativity at the end of treatment, and HBV DNA remained undetectable at the end of 24 weeks follow up in 56% of cases. In addition, HBsAg clearance occurred in 10% of coinfected patients. However, for patients who had undetectable HBV DNA at baseline, 36% demonstrated HBV DNA rebound during the treatment period or follow up.

Table 4.  Treatment of HBV/HCV coinfected patients with pegylated IFN-α-2a (180 μg/week) plus ribavirin (1000–1200 mg/day)
 Genotype 1 (n = 207)Genotype 2 or 3§ (n = 114)
HCV monoinfected
(n = 110)
HBV/HCV coinfected
(n = 97)
HCV monoinfected
(n = 50)
HBV/HCV coinfected
(n = 64)
  • Data are from Liu et al.,94 used by permission.

  • Treatment for 48 weeks.

  • §

    Treatment for 24 weeks.

  • ALT, alanine aminotransferase.

Male (%)60654666
Mean age (year)48515151
Median baseline HCV RNA (copies/mL)6.54 × 1065.86 × 1063.98 × 1051.21 × 106
Median baseline HBV DNA (IU/mL) <103 <103
Median baseline ALT (IU/L)101848793
SVR for HCV (%)77738886
Sustained biochemical response (%)70627867

Recommendations of therapy

The above analysis of available published work leads us to formulate the recommendations for therapy, as summarized in Table 5. In general, the most important factor to determine the antiviral regimen of HBV/HCV coinfected patients appears to be the viral activity. Therefore, detailed serological and virological testing to establish the “dominant” virus infection is required before initiation of therapy. For coinfected patients with negative HBeAg and low level viremia (<104 IU/mL, which is approximately equivalent to 0.5 × 105 copies/mL), pegylated IFN plus ribavirin can berecommended. However, the phenomenon of reciprocal viral interference can develop during or after therapy, and this may cause exacerbation of liver disease. For patients with dually-active HBV/HCV coinfection (i.e. HCV RNA positive, HBeAg positive or HBV DNA > 104 IU/mL), very little information is available relevant to this situation, and some limited data indicate that IFN/pegylated IFN plus ribavirin might be inadequate. Adding one or more nucleos(t)ide analogs to suppress HBV replication might be feasible, but more studies are needed to elucidate this issue.

Table 5.  Recommendations for therapy of HBV/HCV coinfected patients
HCV statusHBV statusRecommendations
Anti-HCV+HBsAg±1. Pegylated IFN plus ribavirin can achieve comparable results as for HCV monoinfection
HCV RNA+HBeAg-
HBV DNA <104 IU/mL
2. Reciprocal viral interference can develop during or after therapy
Anti-HCV+
HCV RNA+
HBsAg+
HBeAg±
HBV DNA ≥104 IU/mL
1. Very few data are available; pegylated IFN plus ribavirin might be inadequate; addition of a nucleos(t)ide analog appears to be a feasible option (see text)
2. Best treatment regimen remains to be determined
Anti-HCV+
HCV RNA-
HBsAg+
HBeAg±
HBV DNA+
Treat as patients with chronic HBV infection

Summary and future directions

Because of the shared modes of transmission, HBV/HCV coinfection is not uncommon in highly endemic areas and among subjects with a high risk of parenterally transmissable infections. Coinfected patients represent a diverse group with various viral replication and immunity profiles. Most studies indicate that coinfected patients tend to have more severe hepatic necroinflammation, higher prevalence of liver cirrhosis and higher incidence of HCC. Before initiation of therapy, thorough serological and virological examinations are required to evaluate the individualized viral activity so as to determine the most appropriate antiviral regimen. For CHC patients with low-level HBV viremia, currently available data indicate that pegylated IFN plus ribavirin given in dose and duration regimens dictated by HCV viral genotype could achieve comparable SVR as for HCV monoinfected patients. However, for patients with dually-active HBV/HCV coinfections, more studies are needed to determine the optimal regimen, and particularly the additional role of oral nucleos(t)ide analogs.

Ancillary