Background on Hepatitis C
Hepatitis C virus (HCV) is a single strand RNA virus that replicates in the liver of its host. After entry, the virus particle is uncoated and translation takes place to produce a single polyprotein precursor that is cleaved to yield 3 structural and 6 nonstructural (NS) proteins, Figure 1. The viral NS proteins are mainly enzymes and are essential for viral replication. The newly produced viral RNA is assembled, with structural proteins, packaged and exported out of the hepatocyte. There are 6 main genotypes of the HCV virus, varying by approximately 30% in their genetic composition across the six strains. The responsiveness to interferon-based therapy in chronic HCV varies significantly among genotypes1. The high prevalence of genotype 1 in the US and Western Europe, coupled with its poor response to therapy, has driven the search for more effective and better tolerated treatments for chronic HCV.
HCV is a non-cytopathic virus (does not kill its host cell) that establishes chronic infection with a high degree of frequency in hosts. HCV has a high replication frequency, producing approximately 1012 particles per day2. Viral replication is highly error prone and many mutations occur daily. This serves as an effective survival strategy for the virus and is proving to be an obstacle for the development of effective new pharmacological therapies. For example, potent inhibitors of the viral protease NS3/4 are effective anti-virals; however, resistant mutants quickly emerge and efficacy is consequently lost3. Similar loss in efficacy is observed with inhibitors of the RNA polymerase NS5B3. It is now clear that these newer HCV targeted therapies will not be effective as stand alone monotherapies. As a result, these agents are being studied in combination with the current standard of care, pegylated interferon-alpha (peg-IFN-α) + ribavirin, in efforts to increase efficacy4. New strategies employing oral drug cocktails, reminiscent of effective HIV therapies, may be the future for treatment of chronic HCV.
Figure 1. Components of HCV life cycle
Hepatitis C Infection: Treatment and Response
HCV infection can be acute or chronic. Acute infection can result from a needle-stick injury and about 20% of patients spontaneously clear this asymptomatic infection. Those who do not are deemed to have chronic HCV infection after 6 months. Viral loads are typically 104-107.5 particles per mL5.
Currently approved treatment options for chronic HCV patients are limited and involve combination therapy consisting of injected peg-IFN-α and oral ribavirin. Sustained viral response (SVR), defined as undetectable serum levels of HCV RNA 24 weeks after the cessation of therapy, is considered a successful clinical outcome. Achieving SVR is a strong indication that the patient is no longer infected with virus and is, in fact, cured. The various patterns of response to therapies are depicted in Figure 26. Failure to achieve a 2 log reduction in viral RNA after 12 weeks of therapy is defined as a "null" response. Since it is unlikely that these patients will realize any benefit from further treatment, therapy is often stopped at this point.
Figure 2. Patterns of response to treatment in chronic hepatitis C (adapted from Mauss et al6)
A partial response is defined as achieving greater than a 2 log reduction in viral RNA but not reducing RNA below the limit of detection by week 24 of treatment. As in the null responders, patient treatment is generally terminated. Patients achieving a good response, where viral load is reduced below the limit of detection, but who rebound while on treatment, are considered breakthrough patients. Lastly, patients with undetectable virus at the end of treatment but who rebound prior to 24 weeks post-treatment are considered relapsing patients.
All patients who do not achieve SVR as well as those who begin treatment but cannot tolerate therapy due to side effects are generally classified as treatment failures. A substantial percentage of chronic HCV patients fall into this broad category. In addition, there are also patients with preexisting conditions for whom IFN-based therapy is not recommended due to other existing medical conditions. In total, these patient populations represent a significant percentage of the total HCV population7. The long term prognosis for these patients is generally poor, as persistent HCV infection is a major cause of end-stage liver disease and hepatocellular carcinoma.
Kinetics of Viral Clearance
Interferon–α has been shown to cause a two-phase decline in HCV viral load8 (Figure 3). The first phase is a rapid reduction (within 24 hours), and is probably due to inhibition of virus production as well as to intrinsic clearance of the virus. Direct antiviral agents (STAT-C: Specifically Targeted Antiviral Therapy for HCV) show a similar first phase response due to their inhibition of viral protein activity and viral replication. Antiviral effectiveness is usually measured in a logarithmic (log) scale, and therefore a 1 log reduction in viral load corresponds to 90% effectiveness, and a 2 log reduction corresponds to 99% effectiveness in preventing infection or eliminating infected cells.
Figure 3. Viral decline in response to interferon treatment
The second phase involves a continued viral load reduction (days to several weeks) followed by a renewed phase of viral decline, which can continue for several months. During this time, the ratio of infected to uninfected cells gradually decreases (Figure 4). Interferon and other immunomodulators up-regulate the immune system, leading to more efficient clearance of virus-infected cells. Ribavirin can also have an impact in this second phase by increasing the mutation rate of the virus, thereby making viral infection less efficient9. Ribavirin may also non-specifically up-regulate the immune system, which can increase the clearance of virus-infected cells.
Figure 4. Schematic of anti-viral interventions during the first and second phases of viral elimination
Challenges to Anti-viral Therapy
There are many challenges to achieving viral clearance in chronically infected HCV patients. The virus mutates frequently and rapidly, and drug resistant mutants are especially a problem with STAT-C therapies because they prevent cures. In order to have an impact on second phase anti-viral kinetics, treatments must be in place for several months. Patients can only be cured when all the HCV infected cells are cleared. Clinical experience in the last decade has shown that combination therapy is the key to curing HCV.
Conatus is developing a drug, CTS-1027, that may have an effect on the second phase of viral clearance kinetics by blocking infectivity and by enhancing the effect of interferon. This is described in more detail in CTS-1027 in Liver Disease.
References:
- Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M. The Way Forward in HCV Treatment – Finding the Right Path. Nat. Rev. Drug Discovery. 2007, 6(12): 991-1000.
- Rehermann B, Nascimbeni M. Immunology of Hepatitis B Virus and Hepatitis C Virus Infection. Nat Rev. Immunology. 2005, 5 (3):215-229.
- McGovern BH, Abu Dayyeh BK, Chung RT. Avoiding Therapeutic Pitfalls: The Rational Use of Specifically Targeted Agents Against Hepatitis C Infection. Hepatology. 2008, 48(5): 1700-1712.
- Francsicus A. HCV: Genotype and Quasispecies. Hepatitis C Support Project 2006, February Fact Sheet
- Hoofnagle JH, Seeff LB. Peginterferon and Ribavirin for Chronic Hepatitis C. N. Eng. J. Med. 2006, 355(23): 2444-2451.
- Mauss S, Berg T, Rockstroh J, Sarrazin C, Wedemyer H. Eds. Hepatology – A Clinical Textbook 2009, Flying Publisher p. 199. (ISBN 978 3 92477639)
- Stader DB, Wright, T, Thomas DL, Seef LB. American Association for the Study of Liver Diseases. Diagnosis, Management and Ttreatment of Hepatitis C. Hepatology 2004, 39: 1147-1171.
- Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS. Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon-a Therapy. Science. 1999, 282: 103-107.
- Hofmann WP, Herrmann E, Sarrazin C, Zeuzem S. Ribavirin Mode of Action in Chronic Hepatitis C: From Clinical Use Back to Molecular Mechanisms. Liver International. 2008, 1478-3223.