By Liz Highleyman

Due to overlapping transmission routes, many people have been exposed to both hepatitis B virus (HBV) and hepatitis C virus (HCV), and a smaller proportion are chronically infected with both viruses. HBV-HCV coinfection appears to lead to more rapid liver disease progression, but the natural history and treatment of HBV-HCV coinfection have not been extensively studied.

Considerable research indicates that HBV and HCV interact with each other and inhibit one another's replication, but this remains subject to debate, and recent studies have produced mixed findings.

Lab Model Shows No Direct Interference

As reported in the March 16, 2009 advance online edition of Hepatology, Pantxika Bellecave of the University of Lausanne in Switzerland and colleagues established a novel model system to investigate interactions between HBV and HCV in the laboratory. Stable Huh-7 cell lines containing replicating HBV were transfected with HCV replicons (models of replicating virus) or infected with HCV derived from cell cultures.

In this system, the researchers found, both HBV and HCV replicated in the same cells without obvious interference. Inhibition of one virus did not affect the replication and gene expression of the other. Furthermore, cells harboring replicating HBV could be infected with cell culture-derived HCV -- contradicting the hypothesis that superinfection is not possible -- and cells harboring replicating HBV supported efficient production of infectious HCV virions.

Based on these findings, the researchers concluded, "HBV and HCV can replicate in the same cell without evidence for direct interference in vitro."

Therefore, they continued, "the viral interference observed in coinfected patients is probably due to indirect mechanisms mediated by innate and/or adaptive host immune responses."

Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland; Department of Medicine II, University of Freiburg, Freiburg, Germany; Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.

Clinical Studies Demonstrate Interaction

Two recent studies add to the evidence that HBV and HCV do interfere with one another in coinfected patients, despite the foregoing laboratory findings.

In the April 2009 issue of Hepatology, Evangelista Sagnelli and colleagues from Italy described a study evaluating the impact of HBV superinfection in chronic hepatitis C patients in a long-term follow-up study.

The analysis included 29 patients with chronic hepatitis C (persistent anti-HCV antibody status) and acute HBV infection, and 29 HCV negative control subjects with acute hepatitis B. Participants in the 2 groups were matched for sex, age (within 5 years), and HBV acquisition risk factors.

Newly coinfected patients and those with acute hepatitis B alone had similar initial HBV viral loads and a similar trend of becoming HBV DNA negative. The course of acute hepatitis B was more often severe in HCV positive compared with HCV negative participants (35% vs 7%; P < 0.05).

One patient in the coinfected group died of liver failure. Of the remaining 28 coinfected individuals still alive at the end of the acute phase of hepatitis B, 24 were followed for a median of 5 years (range 2-6). Within this group, 22 patients became hepatitis B surface antigen (HBsAg) negative, while 2 progressed to HBsAg positive chronic hepatitis B.

During the acute phase of hepatitis B, all the coinfected patients had undetectable HCV viral load. Among the 24 participants who underwent long-term follow-up, HCV RNA became detectable in 7 patients (29%) after 1 year, in 14 (58%) after 2 years, and in 18 (75%) after 3-6 years.

The 6 patients who achieved sustained HCV clearance had higher ALT and AST levels compared with the 18 individuals who experienced reactivation of HCV replication. The individuals who cleared HCV also were significantly more likely to have had severe acute hepatitis B illness (83% versus 22%; P < 0.05).

Although it can be life-threatening, the study authors concluded, "HBV superinfection in HCV chronic carriers may lead to clearance of chronic HCV infection, especially in patients with severe [acute hepatitis B]."

Department of Public Medicine, Section of Infectious Diseases, 2nd University of Naples, Naples, Italy; Division of Infectious Diseases, Azienda Ospedaliera Sant'Anna e San Sebastiano di Caserta, Caserta, Italy.

Impact of Hepatitis C Treatment

As previously reported, in the February 2009 issue of Gastroenterology investigators from described a study showing that hepatitis C treatment using pegylated interferon plus ribavirin was equally effective in HCV monoinfected individuals and those with dual chronic HBV-HCV infection. However, 36% of patients who had undetectable HBV DNA before interferon-based therapy eventually developed detectable HBV viremia.

Taken together, these findings underline the need for more research on HBV-HCV coinfection, and suggest that caution is warranted in the meantime, since treatment that suppresses one virus may enable reactivation of the other.

4/17/09

References

P Bellecave, J Gouttenoire, M Gajer, and others. Hepatitis B and C virus coinfection: A novel model system reveals the absence of direct viral interference. Hepatology. March 16, 2009 [Epub ahead of print]. (Abstract).

E Sagnelli, N Coppola, M Pisaturo, and others. HBV superinfection in HCV chronic carriers: A disease that is frequently severe but associated with the eradication of HCV. Hepatology 49(4): 1090-1097. April 2009. (Abstract).