Impaired response to alpha interferon in patients with an inapparent hepatitis B and hepatitis C virus coinfection

Abstract

The possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an "inapparent" coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an "inapparent" coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6-12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5'NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all "responders" (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.

Occult Hepatitis B Virus Infection and Clinical Outcomes of Patients with Chronic Hepatitis C

“…However, a unique persistent infection known as occult HBV infection, which is characterized by positivity for HBV DNA in serum by using nested PCR assays, has been identified in HBsAg-negative patients with or without serological markers of previous HBV infection (anti-HBs or antiHBc) (1,2,12,21). Several recent studies have indicated that this occult HBV infection can be found in patients with chronic HCV infection at various frequencies (50 to 87%) (2,3,5,10,19,20,22). The high prevalence of the occult HBV infection in such patients has been suggested to have clinical implications in the pathogenesis of HCV-induced chronic liver disease.…”

“…However, we did not observe such an association in our study (Table 3). Occult HBV infection has been suggested to jeopardize the response to interferon therapy in patients with chronic hepatitis C (3,5,22); however, its impact on the response to combination therapy remains unknown. Our results showed that the sustained rates of response to combined alfa interferon and ribavirin therapy were similar between chronic hepatitis C patients with occult HBV infection and those without occult HBV infection (Table 3), and thus, low-level HBV infection does not interfere with the response to combination therapy against HCV.…”

“…More recently, this so-called occult HBV infection has frequently been identified in patients with chronic HCV infection (5,10,19), and in such patients this occult infection may be associated with more severe liver damage and even the development of hepatocellular carcinoma (HCC) (3,18,20). In addition, several studies have suggested that occult HBV infection may correlate with a lack of response to interferon treatment in patients with chronic hepatitis C (3,5,22). Taken together, a low-level HBV infection not only may contribute to the severity of HCV-related liver disease but also may be of prognostic importance.…”

Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: Clinically significant or purely “occult”?

“…This issue has so far not been addressed with the notable exception of some Italian studies that suggested that anti-HBc positivity might be associated with a lower response of HCV to standard interferon therapy. 92,93 HBV-HCV may also increase the risk of developing HCC. Several studies, based on HBV and HCV serologic markers, have clearly suggested that an association of serum HBsAg and anti-HCV positivity increased the relative risk of HCC in case-control studies (see meta-analyses and reviews in Tagger et al 94 ).…”

Molecular Modeling and Biochemical Characterization Reveal the Mechanism of Hepatitis B Virus Polymerase Resistance to Lamivudine (3TC) and Emtricitabine (FTC)

“…Chronic HBV infection can lead to cirrhosis, hepatocellular carcinoma, and liver failure. Treatment of chronically HBVinfected patients with alpha interferon (28) is limited by side effects, incomplete efficacy, restriction to patients with compensated disease, and the requirement for parenteral administration (8,37). HBV, a hepadnavirus, replicates through an intermediate reverse transcription step carried out by the viral polymerase (19,33), which is functionally and structurally related to human immunodeficiency virus (HIV) reverse transcriptase (RT).…”