Therapeutic Effects of Pegylated Interferon Plus Ribavirin in Chronic Hepatitis C Patients with Occult Hepatitis B Virus Dual Infection

[Guest guest]

Therapeutic Effects of Pegylated Interferon Plus Ribavirin in Chronic Hepatitis C Patients with Occult Hepatitis B Virus Dual Infection

Abstract

Background and aim: Occult hepatitis B virus (HBV) infection is defined by the detectable serum HBV–DNA in HBV surface antigen-negative patients. This retrospective study aims to evaluate the therapeutic effects of combined pegylated interferon (PEG–IFN) plus ribavirin (RBV) in patients with concurrent occult HBV/hepatitis C virus (HCV) dual infection.Methods: In total, 126 consecutive chronic hepatitis C (CHC) patients who received combined PEG–IFN and RBV therapy were included. Patients were divided into the occult HBV/HCV dual infection group or the HCV-monoinfected group according to whether or not they had the detectable serum HBV–DNA. The biochemical and virological responses to combined therapy were compared between these two groups. Serum HCV-RNA and HBV–DNA were checked before treatment, at the end of treatment as well as at 6- and 12-months' follow up in the occult HBV/HCV group.Result: Six patients

were seropositive for HBV–DNA and were included in the occult HBV/HCV dual infection group. There were no statistical differences in the biochemical and virological responses to combined therapy between these two groups. Undetectable serum HBV–DNA was noted at the end of the treatment and the 6- and 12-months' follow up in patients with occult HBV/HCV dual infection.Conclusion: Occult HBV infection in CHC patients is rare. The biochemical and virological responses to combined PEG–IFN and RBV therapy might be similar in CHC patients with or without occult HBV infection. The serum HBV–DNA level was low in patients with occult HBV/HCV dual infection who responded to combined therapy.

Introduction

Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is common since both viruses have similar routes of transmission.[1,2] Occult HBV infection is defined by the presence of HBV–DNA in the patient's serum without detectable HBV surface antigen (HBsAg).[3,4] Previous studies have shown that HBV–DNA is detected in 11.8%–17.2% of HCV monoinfected patients who are seropositive for antibodies against HBV core and surface antigens (anti-HBc and anti-HBs).[5–7]

Several epidemiological studies have demonstrated that dual HBV and HCV infection can increase the risk of severe liver disease and hepatocellular carcinoma development.[8–10] However, some studies have shown that occult HBV infection does not influence the clinical outcome and the effects of conventional interferon therapy in chronic hepatitis C (CHC) patients.[5,6,11] Currently, the administration of pegylated interferon (PEG–IFN) plus ribavirin (RBV) is considered the gold standard for the treatment of CHC worldwide.[12–14] It should be clarified whether occult HBV infection influences the therapeutic effects of PEG–IFN plus RBV in dual HBV/HCV-infected patients. Thus, the present retrospective study aims to elucidate

the role of occult HBV infection in this regard.

Methods

From October 2005 to April 2007, 139 consecutive CHC patients with at least two instances of serum alanine aminotransferase (ALT) level elevation more than two times the upper limit of normal (ULN) 1 month apart were enrolled for PEG–IFN and RBV therapy. All the patients were seropositive for anti-HCV and HCV-RNA for 6 months, but seronegative for HBsAg, hepatitis D virus (HDV) and HIV infection. They were treated with 180 µg PEG–IFN α-2a or 1.5 µg/kg PEG–IFN α-2b once a week in combination with 1000 mg (when body weight < 65 kg) or 1200 mg (when body weight ≥ 65 kg) RBV for a period of 24 weeks and were followed up for an additional 24 weeks. Thirteen patients who could not complete the therapeutic course because of intolerance to drug side-effects or missed follow-up appointments were excluded from this study. The remaining 126 patients were included and were followed up monthly or bimonthly during treatment and after the end of the

therapy.

Additional weekly or biweekly visits were arranged if a patient's serum ALT was found to be increasing or was more than five times the ULN range.

Routine follow-up studies comprising both clinical assessment and conventional liver biochemical tests were conducted using routine automated techniques at the clinical pathology laboratories of Chang Gung Memorial Hospital. HBsAg, anti-HBc, anti-HBs and antibodies to HDV were measured using a commercially-available radioimmunoassay kit (Austria II and Anti-Delta; Abbott Laboratories, North Chicago, IL, USA). The serum anti-HCV was assayed using a third-generation enzyme immunoassay kit (Axsyn HCV, version 3.0; Abbott Laboratories, USA). Stored serum specimens from these 126 patients were assayed for HBV–DNA retrospectively. The serum HBV–DNA was quantified using a branched DNA (bDNA) assay (Bayer Versant 3.0 kit, Tarrytown, NY, USA), which has a detection limit of 2000 copies/mL (357 IU/mL). The HCV-RNA was extracted and genotyped using a bDNA assay (Bayer Versant 3.0 kit, USA) that has a detection range of 3.2 × 103 to 4 ×

107 copies/mL. Both serum HCV-RNA and HBV–DNA were assessed before treatment, at the end of treatment and at 6- and 12-months' follow up in the case of patients with concurrent occult HBV and HCV infection. The lower limit of viral load to analyze HBV genotype is 104 copies/mL in our laboratory. A HBV genotype analysis was not performed in this study.

Definitions

Dual infection with occult HBV and HCV was defined as the presence of both HBV–DNA and HCV-RNA in HBsAg-negative CHC patients. Sustained virological response (SVR) is defined as the absence of serum HCV-RNA at the end of treatment and 6-months' follow up.

Statistical Analysis

The results are represented as the mean ± standard deviation for numeral data. A two-sample t-test was applied to compare the mean values. Differences in clinical conditions (independent variables) among the two groups were analyzed by the χ2-square test. All the statistical tests were two tailed at the 5% level of significance. A value of P < 0.05 was considered statistically significant. Statistical analyses were performed using the Statistical Package for the Social Science version 13.0 for Windows (SPSS, Chicago, IL, USA).

Results

The demographic data of patients with concurrent occult HBV and HCV infection and HCV monoinfection are shown in Table 1 . There were no statistical difference in age, sex, body mass index (BMI), total bilirubin level or fatty change between these two groups (all P > 0.05). However, patients with occult HBV/HCV dual infection showed a marginally-significant lower serum ALT level (64.5 ± 25.2 vs 126.9 ± 98.0; P = 0.06), liver histological hepatitis activity index (HAI) scores (6.3 ± 2.9 vs 8.0 ± 2.9; P = 0.08) and fibrosis scores (2.0 ± 0.9 vs 2.5 ± 0.9; P = 0.09) than those with HCV monoinfection. Anti-HBc was detected in 65.8% of CHC patients and anti-HBs was detected in 56.3% of CHC patients. In 55 CHC patients who were seropositive for both anti-HBc and anti-HBs, only five (5/55, 9%) were

concurrently infected with occult HBV.

Figure 1 shows the changes noted in the serum HCV-RNA and HBV–DNA levels of patients with occult HBV/HCV dual infection. Among the six occult HBV/HCV dually-infected patients, the serum HBV–DNA was undetectable at the end of treatment and 6- and 12-months' follow up. The virological and biochemical response (ALT normalization) rate to PEG–IFN and RBV therapy at the end of the treatment and 6-months' follow up is shown in Table 2 and Table 3 . There was no statistical difference of virological and biochemical responses between dually-infected patients and HCV-monoinfected patients according to the classification of the HCV genotype (all P > 0.7). Thus, the virological and biochemical response rates between patients with occult HBV/HCV dual infection and those with HCV

monoinfection were similar.

(Enlarge Image)

Figure 1.

(a) Hepatitis C virus-RNA (HCV-RNA; 1 million copies [MCps]/mL) and ( hepatitis B virus–DNA (HBV–DNA; 100 copies [Cps]/mL) levels in the sera of six patients with occult HBV/HCV dual infection before treatment and at 1, 6 or 12 months after combined pegylated interferon and ribavirin therapy.

[ CLOSE WINDOW ]

Figure 1.

(a) Hepatitis C virus-RNA (HCV-RNA; 1 million copies [MCps]/mL) and ( hepatitis B virus–DNA (HBV–DNA; 100 copies [Cps]/mL) levels in the sera of six patients with occult HBV/HCV dual infection before treatment and at 1, 6 or 12 months after combined pegylated interferon and ribavirin therapy.

Among the 80 patients with undetectable HCV-RNA in their serum at 6-months' follow up after treatment (SVR patients), there were 10 patients without ALT normalization. Notably, the value of BMI in the patients with ALT normalization was less than the patients who failed to normalize ALT (BMI 23.3 vs 25.1 kg/m2, P = 0.07). In the occult HBV and HCV dually-infected patients, there was no ALT flare up in the three SVR patients.

According to the chart records, only severe adverse effects or those affected by PEG–IFN/RBV dose adjustments were recorded. Notably, the incidence of adverse effects was lower than other prospective studies. The most common adverse effects were anemia (15/126, 11.9%), flu-like symptoms (fever, malaise or general soreness; 7/126, 5.6%), skin rash (5/126, 4%), leukopenia and thrombocytopenia (5/126, 4%), hair loss (2/126, 1.6%) and depression (1/126, 1%). The adverse effect rate was similar between the dually-infected patients (1/6, 16.7%) and HCV monoinfected patients (19/120, 15.8%).

Discussion

Despite using sensitive and quantitative bDNA assays (lower limit to detect 357 IU/mL), only six (5%) of the 126 CHC patients were found to have occult HBV infection. This result is similar to previous reports that the prevalence of occult HBV infection in HCV-infected patients is generally less than 10%.[3–6,10,15] In this study, the serum HBV–DNA level in patients with concurrent occult HBV/HCV infection was low (923 IU/mL, range 375–1589 IU/mL). With a low HBV viral load in patients with HCV and occult HBV dual infection, more sensitive methods, such as real-time polymerase chain reaction, should be applied to increase the serum HBV–DNA and the detection rate of occult HBV-infected patients.

The incidence of occult HBV infection was found to be high in the patients who were seropositive for anti-HBs or anti-HBc (46–80%); however, neither of these markers were predictors of occult HBV infection in HCV-infected patients.[2,5] In a previous study, HBV–DNA was detected in the serum of four (7.5%) of 53 HCV-infected patients, irrespective of the status of anti-HBc titer.[10] In the current study, occult HBV infection was found in only five (9%) CHC patients who were seropositive for both anti-HBc and anti-HBs. Thus, occult HBV infection could not be predicted by anti-HBc and anti-HBs serum markers in CHC patients.

Although patients who are seronegative for HBsAg but seropositive for anti-HBs are considered to have developed immunity against HBV infection, HBV–DNA can still be detected in their sera. One possible reason for the inability to detect HBsAg in HCV-infected patients is that the HCV core protein could suppress HBV transcription, encapsidation and replication.[16]

Previous studies have shown that occult HBV infection does not affect the progression of liver fibrosis.[17,18] The present study demonstrated that patients with occult HBV/HCV dual infection showed lower ALT levels and liver tissue HAI and fibrosis scores than those with HCV monoinfection, although the statistical analysis is marginal (P = 0.06, 0.08 and 0.09, respectively).

Fukuda et al. and Liu et al. reported that the serum titer of HCV-RNA was visibly higher in patients with concurrent HBV and HCV infection than those with HCV monoinfection.[15,19] However, this phenomenon was found mainly in genotype I patients by the Fukuda et al. study and genotype II patients by the Liu et al. study. In this study, we found that the mean serum HCV-RNA was similar in both groups. It was compatible with previous reports, although no difference was observed in the HCV titers between patients with and without occult HBV infection.[3,5,17] The serum HBV–DNA was not detected in all patients with occult HBV and HCV dual viral infection, both at the end of treatment and at 6- and 12-months' follow up after combined PEG–IFN and RBV therapy. This

finding was compatible with Liu et al.'s study.[15] The CHC patients with occult HBV infection responded to PEG–IFN plus RBV therapy.

Fukuda et al. further demonstrated that the response rate to IFN therapy is lower in concurrent occult HBV/HCV-infected patients than in HCV-monoinfected patients.[19] However, Kao et al. and Liu et al. have shown that the presence of occult HBV infection has no effect on the response to conventional or PEG–INF therapy in CHC patients residing in HBV-endemic areas.[5,15] The present study also confirmed that the virological response rate after PEG–INF plus RBV therapy in patient with occult HBV/HCV dual infection was similar to those with HCV monoinfection (5/6, 83.3% vs 83/101, 82.2% at end of the treatment, 3/6, 50% vs 67/101, 66.3% at 6-months' follow up; P > 0.7).

According to the Liu et al. study, the reciprocal viral interference between HBV and HCV was observed in dually-infected patients.[15] They found 24% of the dually-infected patients with HCV SVR still had abnormal serum ALT activity, which suggests HBV reactivation or residual chronic hepatitis B after HCV eradication. In this study, there was no abnormal ALT finding in the three SVR dually-infected patients. Thus, the reciprocal viral interference and the possibility regarding reactivation of HBV after HCV eradication could not be observed in this study.

The most limiting factor of this study is the small sample size in the dual occult HBV and HCV infection group. The unequal numbers between the dually-infection and monoinfected groups can induce less significance when performing statistical analyses. More patients and more sensitive HBV–DNA detection methods should be applied in further studies.

In conclusion, occult HBV infection was rare in CHC patients in this study. The clinicopathological features and the virological response rate after combined PEG–IFN plus RBV therapy might be similar between patients with HCV monoinfection and those with dual occult HBV/HCV infection. The serum HBV–DNA levels in occult HBV and HCV dual infection were low and the patients responded to combined PEG–IFN and RBV therapy.

http://www.medscape.com/viewarticle/716635?src=rss