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Treatment of Hepatitis C - An Evolving Era

The epidemiology of Hepatitis C infection in Hong Kong

Whilst viral hepatitis A and B remain endemic diseases in Hong Kong, the data for Hepatitis C is incomplete. Transmission is mainly via blood, such as the sharing of needles in intravenous drug users, vertical transmission during labour and post transfusion of contaminated blood products. The rate of transmission via the latter route has greatly diminished since screening of blood products was introduced in 1991. It is estimated that less than 0.5% of the Hong Kong population are carriers of HCV, with the majority being blood product recipients and intravenous drug users. Genotype 1b and 6a remain the commonest among the local population.

The Hepatitis C virus

The hepatitis C virus particle consists of a core of single stranded genetic material (RNA), surrounded by a protective shell of protein, and further encased in a fatty envelope of cellular origin. The replication of HCV involves several steps, and takes place mainly in the cells of the liver, with an estimated one trillion virus particles being replicated each day. The RNA is first translated into a single long protein, which is then divided by proteases into several structural and non-structural (NS) proteins. The NS proteins then recruit the viral genome to produce an RNA replication complex. RNA replication then takes places via the viral RNA-dependent RNA polymerase NS5B. The new RNA can then be further translated, replicated or packaged to be released at the cell surface.

Treatment of Hepatitis C

The goal of antiviral therapy in patients with chronic Hepatitis C is the sustained eradication of HCV RNA.

For many years, the standard treatment for Hepatitis C has been a combination of oral ribavirin given daily, and pegylated interferon given subcutaneously once a week. This regimen lasts anywhere between 12 to 48 weeks, depending on the genotype as well as HCV RNA response which is monitored regularly throughout the duration of the treatment. Classically, genotypes 2 and 3, which are more responsive, require 12 to 24 weeks of therapy; genotypes 1,4,5 and 6 are less responsive, and require up to 48 weeks of therapy. Other factors that come into play include the presence of cirrhosis, co-infections such as Hepatitis B or HIV, previous failed attempts at treatment, side effects and patient characteristics.

Interferon works by in interfering with the signaling of the immune system, which is involved in viral reproduction. The greatest limiting factor of the traditional ribavirin / interferon combination treatment is its side effects, which are sometimes severe enough to warrant cessation of treatment. Side effects of interferon include pancytopaenia, fatigue, autoimmune diseases, and psycho neurological disturbances. Ribavirin is a nucleoside analog which interferes with viral replication. Its major side effect is anaemia; it can also cause foetal malformation and patients are advised to use two forms of contraceptives whilst they are on treatment and for 6 months afterwards.

The treatment of Hepatitis C has developed in leaps and bounds in the last 2 years, so much so that its treatment guidelines are almost having to be updated daily to keep up with the evolving changes. Many investigational agents are undergoing phase II and phase III trials. A few drugs and regimens approved by the U.S or European FDA in the last 18 months will be mentioned. Of these, sofosbuvir and daclatasvir are available in Hong Kong on a patient named basis, and are still awaiting licensing by the Department of Health.

  • Sofosbuvir (trade name Sovaldi), an oral anti-viral, works by inhibiting the aforementioned NS5B, a viral RNA-dependent RNA polymerase critical for viral replication (USD$1000 per pill); major side effects are fatigue, nausea and headache
  • Simeprevir (trade name Olysio) is an oral NS3/5A protease inhibitor, and works by inhibiting protein synthesis (UDS$790 per pill); side effects similar to sofosbuvir
  • Ledipasvir inhibits NS5A, which is involved in viral replication, assembly, and secretion
  • The ledipasvir/sofosbuvir combination (trade name Harvoni) is the first interferon and ribavirin free, oral once a day treatment available (USD$1125 per pill)
  • The combination of simeprevir and sofosbuvir has also been approved for the treatment of Hepatitis C genotype 1
  • Daclatasvir (trade name Daklinza) inhibits NS5A; its use in combination with sofosbuvir has been approved for the treatment of Hepatitis C; side effects similar to sofosbuvir
  • Previously, telaprevir and boceprevir, both direct anti-viral agents have also been approved. Its use, however, is limited to being combined with interferon and ribavirin, and has also been associated with higher rates of serious adverse events; thus they are no longer recommended in the treatment algorithm of Hepatitis C

Summary

New research on the treatment of Hepatitis C is being presented almost on a daily basis. Hepatitis C, in particular the non-2/3 genotypes, have traditionally been difficult to treat; its treatment has been associated with many side effects. We are in an exciting era of having an arsenal of agents which have an efficacy of 85% to 100% in the treatment of Hepatitis C, even in the less responsive genotypes. The major limiting factor would be its cost. The good news is that Hepatitis C typically progresses slowly. By 2025, when generic manufacturers can produce these new direct anti-viral agents, study analyses claim that a 12 week course of treatment for Hepatitis C may cost as little as UDS$100 to $250.