Antiviral therapy and resistance with hepatitis B virus infection

Abstract

Hepatitis B virus (HBV) infection is still the most common cause of hepatocellular carcinoma and liver cirrhosis world wide. Recently, however, there has been quite dramatic improvement in the understanding of HBV associated liver disease and its treatment. It has become clear that high viral replication is a major risk factor for the development of both cirrhosis and hepatocellular carcinoma. Early studies have shown lamivudine lowers the risk of HBV associated complications. There are currently three nucleos(t)ides licensed, in addition to interferon, and there are more drugs coming to the market soon. Interferon or its pegylated counterpart are still the only options for treatment with defined end points, while nucleos(t)ides therapy is used mostly for long term treatment. Combination therapies have not been shown to be superior to monotherapy in naive patients, however, the outcome depends on how the end point is defined. Interferon plus lamivudine achieves a higher viral suppression than either treatment alone, even though Hbe-seroconversion was not different after a one year treatment. HBV-genotypes emerge as relevant factors, with genotypes "A" and "B" responding relatively well to interferon, achieving up to 20% HBsAg clearance in the case of genotype "A". In addition to having a defined treatment duration, interferon has the advantage of lacking resistance selection, which is a major drawback for lamivudine and the other nucleos(t)ides. The emergence of resistance against adefovir and entecavir is somewhat slower in naive compared to lamivudine resistant patients. Adefovir has a low resistance profile with 3%, 9%, 18%, and 28% after 2, 3, 4, and 5 years, respectively, while entecavir has rarely produced resistance in naive patients for up to 3 years.

Figure 1

HBsAg seroconversion occurs more frequently on HBV gentoype “A” compared to the other Genotypes. Date given in percent (%). Adapted from Lau GK, et al. N Engl J Med 2005.

Figure 2

Pre-emptive lamivudine is associated with lower frequency and lower severity of hepatitis during chemotherapy. Date given in percent (%). Adapted from Li YH, et al. Cancer 2006.

Figure 3

Viral load reduction at the end of treatment and at 24 wk follow-up in the different treatment arms. Adapted from Lau GK, et al. N Engl J Med 2005.

Figure 4

Different response pattern on famciclovir. Adapted from Tillmann HL et al. Hepatology 1998.

Figure 5

Improvement on famciclovir in a patient with continuous deterioration prior to initiation of famciclovir therapy. Arrow indicates start of famciclovir, where after Bilirubin slowly normalised, and both Quick test (Marker for impaired clotting function) and cholinesterase (CHE) stabilised indicating stabilisation of liver function. (unpulished).

Figure 6

Reduction in HBV-DNA, as well as histological improvement in inflammation and fibrosis according to the Knodell score after 48 wk therapy with 10, 30 mg ADV. Adapted from Marcellin P, et al. N Engl J Med 2003.

Figure 7

Prevalence of resistance on different antivirals, up to 2 (A) and up to 5 (B) year data.