Table of Contents
I. Introduction
• World Hepatitis Day and its significance
• Global concern for chronic hepatitis B virus infection
• Importance of HBV cure research
II. Novel Therapeutic Strategies for HBV Cure
• Combination of antiviral approaches
• Pre-clinical studies on mice and their promising results
• Antiviral therapy goal and combination of peginterferon and nucleotide analog
III. Insights into the Immune System Responses for HBV Cure
IV. Viral Biomarkers for Monitoring Chronic Hepatitis B Virus Infection
V. Conclusion
It is widely known that hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most common blood-borne pathogens worldwide. Both viruses can lead to chronic infection leading to complications associated with liver-related morbidity and mortality. Chronic HBV infection is the leading cause of hepatocellular carcinoma (HCC) worldwide, while chronic HCV is the number one cause in the United States (US). More than 350 million individuals suffer from chronic HBV infection with one million deaths annually worldwide and it is estimated that more than 150 million individuals are chronically infected with HCV worldwide.
Hepatitis B and updates
Hepatitis B consists of a partially double-stranded relaxed circular DNA (rcDNA) genome. Upon entry into human hepatocytes, rcDNA is subsequently converted to a tightly coiled plasmid-like covalently closed circular DNA (cccDNA) in the host nucleus. cccDNA is unusually stable and is able to avoid DNA-sensing cellular machinery. The production of tolerogenic proteins (HBsAg and hepatitis B e-antigen [HBeAg]) can lead to T-cell exhaustion. Patients recover from HBV infection still harbour cccDNA in hepatocyte nuclei for life acting as a reservoir for reactivation of viral genome replication when these patients undergo immunosuppressive therapies.
At present, there are seven treatments approved for chronic HBV infection: two formulations of interferon (interferon alfa-2b, peginterferon alfa-2a) and five nucleos(t)ide agents. Interferon mainly has immunomodulatory effects and whereas nucleos(t)ide analogues (NA) work by inhibiting the reverse transcriptase activity of HBV polymerase, thereby suppressing viral replication. The current nucleos(t)ide agents approved for use are lamivudine, telbivudine, entecavir (ETV), adefovir dipivoxil and tenofovir disoproxil fumarate (TDF). The preferred first-line treatment choices among the oral nucleosides/nucleotides are entecavir and tenofovir because of their superior efficacy.
“Our results suggest that for healthier patients, TDF and [Baraclude] are comparable [chronic HBV] treatment choices regarding renal safety,” Sam Trinh, BS, from Stanford University Medical Center in California, and colleagues wrote. “However, for those with moderate renal impairment or over 60 years old, renal outcomes with TDF may be worse while improvement can be expected for patients treated with [Baraclude].” Baraclude is entecavir, Bristol-Myers Squibb.
In routine practice, standard interferon alfa-2b has largely been replaced by peginterferon alfa-2a. While the implementation of HBV vaccine has led to a decline in the incidence of new HBV infection, the prevalence of chronic HBV infection still remains high as these therapies also do not affect cccDNA, and thus cannot lead to a true cure of chronic HBV infection.
“In the United States, about 1,800 death certificates annually list hepatitis B virus (HBV) as an underlying or contributing cause of death,” researchers wrote. “However, accurately quantifying mortality related to hepatitis is difficult because of the prolonged period between infection and death and because death is not always linked to underlying infection. … Underestimating the true prognosis of [chronic hepatitis B (CHB)] infection may have real consequences for patients.
Hepatitis C and updates
HCV has been classified into six major genotypes (1–6) and are found to be distributed in different geographical locations. Genotype 1 is predominantly found in North American and European populations. Genotype 3 is the second most common genotype and accounts for the majority of infections in Asia, while North African and Middle Eastern populations are typically infected with genotype 4 virus.
For more than 20 years Interferon therapy was the mainstream treatment. The combination of interferon with ribavirin improved Sustained virologic response (SVR) rates by up to 40%, with greater success in genotype 2 and 3 patients. SVR is considered achieved after the treatment course when the HCV RNA is below the lower limit of quantification. Development of pegylated interferon and its co-administration with ribavirin further increased SVR rates to 80% in genotype 3 patients, but remained under 50% for genotype 1 patients.
Inside the host cell HCV encodes a large polyprotein that is cleaved by both host and viral proteases to produce ten viral proteins. This includes structural proteins (core, E1 and E1 glycoproteins), integral membrane protein (p7) and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B). Non-structural proteins are essential for their replication, assembly and export. Inhibition of the non-structural (NS) proteins has become the major target in the development of direct-acting antiviral (DAA) agents. DAA’s is a shorter treatment course than interferon therapy and cure rates exceeding 90% in many populations. The most recent guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend DAAs as the primary treatment for all genotypes of HCV.
Hepatitis B and hepatitis C are among the most common causes of liver disease, according to the Centres for Disease Control and Prevention (CDC) — but having both viruses at the same time significantly increases risk of liver damage. Patients with co-infection have higher incidents of liver cancer, liver failure, and the need for liver transplantation. The viruses act together to cause more inflammation and scarring of the liver, compared to mono-infection.
Coinfection of HBV and HCV
In people with both HBV and HCV, the two viruses seem to interact and keep each other in check. HBV DNA viral load is often low or undetectable and HCV is typically the main driver of active liver disease. But when hepatitis C is cured with DAAs, HBV has an opportunity to reactivate, often indicated by a rapid increase in HBV DNA and ALT liver enzyme levels and sometimes jaundice. In severe cases it can lead to fulminant hepatitis, liver failure and death. This phenomenon may not have been apparent in the interferon era because interferon alfa is active against both viruses.
The American Association for the Study of the Liver (AASLD) and Infectious Diseases Society of America (IDSA) issued new recommendations for HBV/HCV co-infected patients in a September 16 update to its HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, available at www.hcvguidelines.org.
The revised recommendation states:
- All patients initiating HCV direct-acting antiviral therapy should be assessed for HBV coinfection with HBsAg, anti-HBs and anti-HBc.
- For HBsAg+ patients who are not already on HBV suppressive therapy, monitoring of HBV DNA levels during and immediately after DAA therapy for HCV is recommended and antiviral treatment for HBV should be given if treatment criteria for HBV are met.
Updated guidelines from the European Association for the Study of the Liver (EASL), released at a special meeting in Paris, likewise state that people coinfected with HBV and HCV can be treated for hepatitis C using the generally recommended regimens, but “If chronic hepatitis B or ‘occult’ HBV infection is detected, concurrent HBV nucleoside/nucleotide analogue therapy is indicated.”
Future map
In the last few years there has been a development of novel therapies which is due to a better understanding of the lifecycle of these viruses. In chronic HBV infection, a combination therapy has been recommended to achieve a functional or complete cure. In chronic HCV infection, effective therapy now exists for all populations regardless of severity of liver disease, HIV co-infection or other co-morbidities such as CKD. As research into HCV treatment continues, we can expect shorter treatment course and a complete cure rates for all the populations.