Editorial Board: Emmet B. Keeffe, MD (Chair);

Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD

HBV Watch^™

Timely Information for Practicing Physicians

JUNE 2003

Review on Occult HBV INFECTION

It is widely believed that recovery from acute hepatitis B is associated with HBsAg seroconversion to anti-HBs, clearance of viremia, loss of infectivity, and resolution of liver injury. The advent of highly sensitive PCR assays has challenged this dogma, and identified a population of patients who are negative for HBsAg but harbor low levels of HBV DNA in serum or liver tissue. This has been termed “occult HBV infection.” Occult hepatitis B can be further classified as “seropositive,” indicating patients who are positive for anti-HBc (with or without concomitant anti-HBs), or “seronegative,” to denote those who are negative for both anti-HBc and anti-HBs. Previous studies have demonstrated a wide range in the prevalence of occult HBV infection, depending on the population studied and the sensitivity of the PCR assay used. In general, the prevalence of occult HBV infection is highest in those who are anti–HBc-positive but anti–HBs-negative, intermediate in patients positive for both anti-HBc and anti-HBs, and quite rare in the seronegative group. Low serum HBV DNA titers, in the range of 10² to 10³ copies/mL, are typical in occult HBV infection.

The clinical significance of occult HBV infection remains the source of continued controversy. There is no clear evidence that persistence of low titer HBV DNA is a cause of progressive liver injury. However, occult HBV infection represents a heterogeneous entity, with clinical relevance in certain circumstances. Transmission of HBV via blood transfusion or organ transplantation from anti–HBc-positive donors has been well documented, and may be due to occult HBV infection. Reactivation of occult hepatitis B following immunosuppression has also been described. Occult HBV infection has been associated with cryptogenic chronic hepatitis and hepatocellular carcinoma, although a causal role has not been conclusively established. Some, but not all, studies have demonstrated a higher prevalence of concomitant occult HBV infection in chronic hepatitis C patients with advanced fibrosis/cirrhosis compared with those with early stage disease. Some studies have also suggested that occult hepatitis B may decrease responsiveness of chronic hepatitis C to interferon therapy. In current clinical practice, the precise role of occult HBV infection remains unclear. Testing for HBV DNA by PCR may be reasonable in HBsAg-negative, anti–HBc-positive patients with cryptogenic liver disease, and in anti–HBc-positive patients in whom immunosuppression is anticipated. The role of antiviral therapy in occult HBV infection is unknown, although the response would be anticipated to be relatively poor. We will continue to report the findings of emerging studies that shed new light on the clinical implications of occult hepatitis B.

Interferon Therapy

Long-term suppression. Pietro Lampertico and others from the University of Milan treated 101 consecutive patients with chronic hepatitis B who were HBeAg-negative with 6 MU of interferon alfa-2b 3 times weekly for 24 months. A sustained response (normal serum aminotransferase levels and undetectable serum HBV DNA by PCR) was achieved in 30 (30%) patients. Multivariate analysis identified young age (p = 0.041) and high pretreatment serum levels of IgM anti-hepatitis B core antigen (IgM hepatitis B core antibody) (p = 0.004) to predict for sustained response. Liver disease progressed in 16 (22%) treatment-failure patients, while none (0%) of the sustained responders experienced liver disease progression (p = 0.002). In addition, the 8-year complication-free survival rate was 90% for sustained responders compared to 60% for patients with treatment failure (p <0.001). The 8-year overall survival rates and the incidences of hepatocellular carcinoma, however, were similar in the 2 patient groups. These findings show that 24 months of interferon alfa-2b therapy can result in sustained disease suppression in patients with HBeAg-negative chronic hepatitis B. (Lampertico P, et al. Hepatology 2003;37:756-763)

Lamivudine Therapy

Durability of response. Jules Dienstag and colleagues conducted a multicenter study in which 40 chronic HBV patients with HBeAg seroconversion after lamivudine therapy were followed for durability of the serologic responses. After a median follow-up of 36.6 months (range, 4.8-45.6 months), HBeAg seroconversion continued to be demonstrated in 30 (77%) of 39 evaluable patients. When the authors included all 65 patients who had HBeAg seroconversion in previous trials, some of whom had relapsed or were lost to follow-up, and therefore not included in the prospective long-term follow-up, the 3-year durability rate of HBeAg seroconversion following lamivudine therapy was estimated to be 64%. Seven of 8 patients who received lamivudine retreatment for reappearance of HBV markers had biochemical and/or virological improvement. No safety issues were identified. These results demonstrate that HBeAg seroconversion achieved during lamivudine treatments is durable in most patients. (Dienstag JL, et al. Hepatology 2003;37:748-755)

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