The extinction of chronic viral hepatitis?

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Abbreviations

cccDNA

covalently closed circular DNA

DAA

direct‐acting antiviral

HBV

hepatitis B virus

HCV

hepatitis C virus

HDV

hepatitis D virus

Chronic viral hepatitis from hepatitis B virus (HBV) and hepatitis C virus (HCV) is a significant global health problem, with the World Health Organization (WHO) estimating 240 million people worldwide to be chronically infected with HBV and 170 million people infected with HCV.1, 2 Patients with chronic infection are at risk for significant morbidity and mortality due to long‐term complications of the disease, including cirrhosis and hepatocellular carcinoma. Many years of research have resulted in remarkable advances in the elucidation of the biology of these viruses, resulting in the development of highly effective therapies for these conditions that are reducing the terrible human toll taken by these diseases. The high worldwide prevalence of these infections, vast numbers of as yet undiagnosed patients, continued transmission of the causative viruses, and disparities in access to health care dispel any notion that these diseases will be eliminated in the near future. However, the tools are now available to enable us to envision a future in which these infections will affect far fewer people and eventually be eradicated (Table 1).

Table 1.

Routes to Elimination of Hepatitis B and C (2015)

	Immunization	Therapy
Hepatitis B	Yes	Yesa
Hepatitis C	No	Yes

^aLong‐term suppression

Despite its higher worldwide prevalence, the actual eradication of HBV is probably a more realistic goal than that of HCV because of the availability of effective immunization. The development of an effective vaccine for hepatitis B, first a plasma‐derived product more than three decades ago followed by a recombinant vaccine more than three decades ago, can justly be regarded as one of the great medical advances of the 20th Century. Infant immunization is highly effective in conferring long‐lasting protection against infection, and is more than 95% effective in preventing acquisition of infection even from highly viremic mothers, with concomitant third trimester antiviral therapy in mothers boosting protection against transmission to nearly 100%. Immunization programs have resulted in a reduction in the global prevalence of infection, and in countries with effective immunization programs a reduction in hepatocellular carcinoma incidence at young ages has been demonstrated.3 If socioeconomic conditions and health care systems permitted universal immunization in infants, as currently recommended, the near or complete eradication of HBV infection should theoretically be attainable in the next two generations. Failure to attain this goal, which is likely, will entail needless tragedies.

Effective treatment of existing HBV infection reduces inflammation and fibrosis and is critical to the reduction of morbidity and mortality from cirrhosis and liver cancer in affected individuals,4, 5, 6 and reduces or eliminates the risk of transmission (Table 2). The hepatitis B virus is unlike HCV in that infection results in an intranuclear, minichromosomal form of the viral genome. The fundamental limitation of current HBV therapy is that it confers profound suppression of viral replication but seldom eliminates the carrier state. The episomal, intranuclear covalently closed circular DNA (cccDNA) of the virus serves as a template for viral transcription and is impervious to the action of the currently used nucleotides and nucleosides, which exert their effect on HBV DNA replication in the cytoplasm, including its reverse transcription via an RNA intermediate. Interferon‐α can result in viral clearance, but similarly is not known to directly target cccDNA and has limited efficacy and systemic side effects, making it a suboptimal treatment option. Research efforts currently focus on the development of novel approaches with the capacity to suppress the production of multiple viral proteins, including hepatitis B surface antigen, with such agents as small interfering RNA (siRNA) agents, or to target cccDNA itself. Immunomodulatory approaches are also being investigated.7, 8, 9 The long‐term outlook for such novel approaches is favorable, but current investigational programs are early in their development.

Table 2.

Benefits of Antiviral Therapy (Hepatitis B and C)

Normalization of liver enzymes

Reduced liver necroinflammation

Arrested progression of fibrosis

Regression of fibrosis

Reduced risk of hepatic decompensation

Reduced risk of hepatocellular carcinoma

Reduction/elimination of risk of transmission

For HCV, an RNA virus in the flavivirus family, the development of a vaccine has been highly challenging, and a vaccine is neither available nor expected to be in the near future. The distinguishing feature of HCV treatment is the capacity to effect virological cure, a concept widely accepted because of the absence of an archived form of the viral genome and the nearly invariable long‐term durability of response once treatment has been stopped. Pegylated interferon (PEG IFN) and ribavirin (RBV) were the foundation of treatment of HCV for more than a decade, but suboptimal rates of sustained virologic response and significant side effects spurred the development of novel drugs, including several classes of direct‐acting antiviral agents (DAAs) that target the NS3/4A protease, NS5B RNA‐dependent RNA polymerase, and the NS5A serine protease.10 Combinations of these new drugs have demonstrated potent antiviral activity and high barriers to resistance, resulting in high rates of cure surpassing 90% or even 95% in many patient populations. Combined with minimal side effects and a shorter duration of treatment, these all‐oral courses of therapy now offer curative treatment options to most patients, even in the traditionally “difficult‐to‐treat” patient populations.

With the recent availability of DAA treatment regimens comes the potential for universal eradication of HCV. The realization of this health care goal, however, requires overcoming specific barriers that currently exist, beginning with identification of those with disease. Of the estimated 3.2 million people in the United States with chronic HCV infection, approximately 50% are unaware of their infection status. In an attempt to identify the undiagnosed population, the Centers for Disease Control and Prevention and the US Preventive Services Task Force have recommended birth cohort screening for those born between 1945 and 1965, who account for at least two‐thirds of infected Americans, in addition to those at high risk for infection. A recent retrospective study showed that birth cohort screening supersedes identification of those with disease compared to risk‐based screening, supporting the change in guidelines.11 An effective screening method must then be followed by linkage to care and access to treatment through programs utilizing resources such as telemedicine and knowledge networks with the goal of educating a wider spectrum of providers. In addition, cost of diagnosis and treatment must be minimized to provide mass treatment programs.12 Ultimately, although treatment of those currently infected will diminish transmission rates, it is also important to implement prevention strategies through behavioral intervention.

The quest for making hepatitis C a disease of the past will not inevitably succeed even with the revolutionary treatment options available to patients, because effort for HCV eradication faces formidable barriers. Much attention has been focused on the high cost of the currently approved DAA regimens in the United States, which have led to denial of coverage by some carriers for patients with mild hepatic fibrosis. It is hoped that this state of affairs will not persist indefinitely. Ultimately, with appropriate global health initiatives and dedication from physicians, pharmaceutical companies, and insurance companies, the potential does exist to reduce hepatitis C to the status of a far less harmful international public health problem. Agreements between manufacturers and various governments have resulted in marked discounting of DAA therapies in some countries. Still, given the large numbers of unidentified patients and the barriers to care that are unlikely to be lifted soon in many parts of the world, we can be optimistic about a marked reduction in the burden of disease from HCV in the next generation as well as a major reduction in the global prevalence of the disease, but eradication by 2050 is difficult to envision.

Hepatitis D virus, or delta agent, is a pathogen related to viroids in plants. Most common in the Mediterranean region, it has an RNA genome which does not code for the surface protein of the virus, which consists of hepatitis B surface antigen. Hence, the agent is entirely dependent on concomitant HBV infection, whether with or without active replication, for its own life cycle. It is highly pathogenic, being associated in general with progressive liver disease and a substantial risk of cirrhosis even in the absence of HBV replication. Prolonged interferon treatment is occasionally effective, whereas anti‐HBV agents are ineffective and HDV‐specific oral agents are still in development. In the long term, the eradication of HDV can be expected to follow the path toward eradication of HBV.