Introduction to hepatitis viruses

Although liver inflammation or ‘hepatitis’ can be caused by many infectious and non-infectious conditions, there are at least five viruses for which hepatitis is the primary (or only) clinical manifestation and are thus named: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D (or delta) virus (HDV) and hepatitis E virus (HEV).

Viral hepatitis occurs worldwide. All five hepatitis viruses are found in nearly every region of the world. Nonetheless, there are major differences in the worldwide prevalences of these infections that correspond to the degree to which they are transmitted by percutaneous exposure, by sexual intercourse, from a mother to her infant, by oral intake or by other means (table 1). In countries with limited sanitary capabilities, HAV infection from ingestion of contaminated food or water is nearly universal in childhood, but occurs uncommonly in economically advanced settings. In many regions in Asia and sub-Saharan Africa, nearly 80% of the population has been exposed to HBV infection by adolescence, compared with <15% of people in some regions of Europe or the USA.1 2 In Egypt and other settings where percutaneous injections were common, HCV infection can be found in nearly 20–30% of the population compared with <1–2% in the general population in most other settings.3 4 Likewise, although HEV infection has been reported worldwide, the incidence is much higher in Asia and sub-Saharan Africa.5 6

There are also important similarities and differences in the clinical expressions of hepatitis viruses and the probability that they cause chronic infection. While all viruses can cause acute hepatitis and jaundice, symptoms are more common with acute HAV and HEV infections than with acute HCV infection. In contrast, chronic infection is common following HCV infection and rare or non-existent with HAV and HEV. With HBV, age plays a major influence in the likelihood of symptoms and chronic infection. HBV infection in children usually occurs without symptoms but often becomes chronic. In contrast, with HBV infection in adults, symptoms are more likely but chronic infection occurs in <5%.7 Most of the mortality attributed to viral hepatitis is believed to occur from the long-term consequences of chronic hepatitis, and in particular, cirrhosis or hepatocellular carcinoma (HCC).8

Global burden of viral hepatitis

An estimated 1 million people die of chronic hepatitis each year, making it one of the leading causes of mortality worldwide. Although precise estimates are difficult, much of the hepatitis-related morality comes from the approximately 350 million people with chronic hepatitis B and 130–170 million with chronic hepatitis C.9 In a recent review, Weiss and McMichael ranked viral hepatitis with HIV, tuberculosis and malaria as one of the top five preventable causes of global mortality (figure 1).10

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Relative importance of preventable causes of death as determined by their estimated impact on mortality (from Weiss and McMichael10). HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papillomavirus; SARS, severe acute respiratory syndrome; TB, tuberculosis; vCJD, variant Creutzfeldt-Jakob disease.

These global estimates are based on weak primary data and may significantly underestimate the global burden of chronic hepatitis. One of the foremost future challenges in the field is to characterise better the global burden and ongoing transmission patterns. Accordingly, on 21 May 2010, the World Health Assembly passed a resolution that called for WHO to develop a comprehensive approach to surveillance and control of chronic hepatitis.9

Although improved understanding of the burden of viral hepatitis is essential, reducing that burden will require novel methods of implementing prevention and treatment programmes. Safe, effective vaccines exist to prevent HAV, HBV (and HDV) and HEV infections, and use of the HBV vaccination has in some areas already reduced HBV-related mortality.11 However, vaccine update is extremely low in other regions of the world, including many of those with the largest burden of chronic infection. Likewise, although there have been rapid advances in the therapy of chronic hepatitis, there is little evidence these treatments have penetrated beyond 5–10% of all those with chronic hepatitis.12 Thus, another major future challenge is developing global programmes to diagnose and treat chronic hepatitis infections, as has already occurred with HIV, tuberculosis and malaria.

Hepatitis A virus

Approximately 1.4 million cases of acute infection are reported each year, and the true incidence is probably 3–10 times higher. These statistics are regrettable since safe, effective vaccines have been available to prevent HAV infection since 1992. Although questions remain about the durability of that vaccine-related protective immunity, mathematical modelling suggests those who seroconvert to the vaccine will be protected for at least 20 years.13 In addition, a recent study of 306 persons vaccinated in 1996 with three doses of the combined HAV and HBV vaccine demonstrated that all had anti-HAV titres >15 mIU/ml 15 years later.14 Thus, given the safety and durability of HAV vaccination, clearly the major future challenge is coupling vaccination with other methods of preventing HAV infection to eliminate HAV from humans.

Hepatitis B virus

Prevention of HBV infection is one of the most significant developments of modern medicine. In 1976, Dr Baruch Blumberg was awarded the Nobel prize for discovering HBV and providing insights leading to its transmission and ultimately the development of the HBV vaccine. Widespread use of the HBV vaccine has already markedly reduced HBV-related morbidity and mortality, including the prevention of HCC in countries like Taiwan where nearly all infants are vaccinated.11 Nonetheless, new HBV infections continue to occur worldwide, in part because of the lack of knowledge of the general population on the mode of HBV transmission (including sexual transmission) and the difficulty to deliver the HBV vaccine in remote regions of the world.

A key future challenge is to fill gaps in the public health infrastructure to deliver vaccine and educate about prevention. Additional work is also needed to protect special populations such as those with HIV or on haemodialysis who are not able to produce robust antibody responses but remain at risk for HBV infection.15 Likewise, although HBV transmission by transfusion or organ transplantation can be prevented by testing for HBsAg and HBV DNA by PCR,16 much more work is needed to allow resource-poor areas of the world to implement these technologies.

Although there have also been major breakthroughs in the treatment of chronic hepatitis B, major challenges remain.17–19 Compelling evidence connects high levels of viral replication to and an increased incidence of cirrhosis, HCC and liver-related mortality. Thus, the choice of potent first-line therapy is important to achieve sustained suppression of viral replication, preventing the progression of liver disease and prolonging survival. Most patients will need long-term treatment to meet these goals and the development of antiviral resistance is a major concern in these cases.20 The correct choice of first-line treatment also reduces the need for salvage therapy, which can be affected by cross resistance.21 For economically challenged countries with a high burden of disease, there is a need for inexpensive virological monitoring and drugs to expand accessibility of antiviral treatment.

Inactive HBV carriers who undergo immunosuppressive therapy have a significant risk of reactivation, which can be abated by pre-emptive antiviral therapy with nucleoside analogues. The benefits of preventive antiviral therapy justify systematic screening for HBV infection in all patients who start immunosuppressive therapy.22

The optimal timing of HBV treatment remains unclear for a very large group of immune tolerant patients for whom treatment is generally not recommended until they transition to more active disease stages. While the benefits of early intervention may take a decade or more to manifest, use of nucleoside analogues earlier in the course of disease may reduce the risk of developing HCC and irreversible liver damage.23

Another challenge is to diagnose HBV infection and deliver care. Most of the estimated 350 million people with chronic hepatitis B do not know they are infected, and it is estimated that 15–40% of these carriers will develop severe liver disease complications during their lifetime and thus need treatment.24 This problem is not limited to resource poor countries. For example, in France HBV prevalence is around 0.65% in the general population and around 4% in people born in highly endemic areas. Among those who tested positive, around 45% were aware of their status. It is estimated that out of the 300 000 chronically infected patients, only 15 000 are currently on therapy.24 25

In addition to new treatment models, we need new methods that can eradicate infection. HBV DNA persists in hepatocytes in a stable closed circular element (cccDNA) that can be transcribed to produce proteins like the HBsAg and also can reconstitute infection.26 Thus, while new oral medications such as tenofovir and entecavir potently suppress replication, if they are stopped, infection reoccurs from the cccDNA reservoir.

One of the most important future challenges in the field of viral hepatitis is developing a mechanism to bring about long-term control of HBV infection by elimination of cccDNA and/or stimulation of effective protective immunity. Elimination of cccDNA or the control of its epigenetic regulation will require identification of new targets and novel compounds,27 while the stimulation of specific antiviral immune responses in combination with nucleoside analogues will require the development of innovative immunotherapeutic approaches.28 To fulfil these objectives, relevant and accessible small animal models will also be necessary.29

Hepatitis C virus

There remain significant challenges to prevention of hepatitis C. Worldwide, unsafe medical injections probably account for the majority of HCV infections. Hauri and coworkers estimated that in the year 2000 alone contaminated injections caused 21 million HBV infections and 2 million HCV infections.30 Since many of these cases could be prevented with education about injection safety, future efforts have to be focused on education to prevent unnecessary injections and to improve injection safety in healthcare facilities in developing countries. Even in resource-rich regions of the world, HCV transmission continues to occur by injection drug use.31 Thus, strategies to reduce HCV risk among injection drug users must also be considered. Vaccines have been developed to prevent HCV infection,32 however no vaccine has yet been licensed for that use.

Arguably the most exciting developments in the entire field of viral hepatitis are occurring with HCV drug development. Indeed, HCV infections are the only known example of a chronic viral infection that can be completely cleared from an infected individual by treatment. HCV therapy has been based on interferon α and ribavirin. However, there are marked person-to-person and ethnic differences in responsiveness that were recently explained to a large extent by the DNA sequence around the genes for λ interferons.33 34 In addition, in the past 6 months two new compounds were approved in the USA and Europe for use with pegylated interferon and ribavirin.35 36 Scores of additional compounds from at least five different classes are in clinical development. When considered in light of the potential of HCV treatments to eradicate (cure) infection, these exciting developments provide a basis to anticipate the potential to cure nearly all HCV-infected persons by the end of this decade.

Nonetheless, as with other breakthroughs in viral hepatitis, there are many remaining challenges in the implementation of HCV treatments. Although new therapies are more effective, the addition of protease inhibitors to pegylated interferon and ribavirin bring added adverse events, such as rashes, anal burning, dysgusia and anaemia, in addition to interactions with other medications. The new adverse events caused by the protease inhibitors plus the effects of interferon and ribavirin make treatment of HCV infection challenging in many cases. New generations of protease inhibitors will be easier to tolerate. However, the next major step in HCV therapeutics is elimination of interferon α by using one or more direct acting compounds.37 38

Elimination of interferon α with its requirement for injections and myriad adverse events could transform the effectiveness of HCV treatment. People for whom interferon-based therapies did not work or who are intolerant will be the immediate beneficiaries. However, even in resource-rich nations like the USA and some European countries, more than half of those with HCV infection are not currently diagnosed.12 39 Of the estimated 170 million with HCV infection worldwide, no more than 10% are under care.40 Thus, curing all of those under care still has little impact without expanding access to HCV testing and treatment (figure 2). Given the high cost of existing treatments (US$50 000–80 000), clearly a partnership with industry will be required to bring these innovative treatments to regions of the world where they are most needed. However, the recent development of a genetically humanised mouse model for HCV infection may pave the way towards the development of new prophylactic vaccines or innovative medicines for the treatment of chronic HCV infection.41

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Global impact on breakthroughs in hepatitis C virus (HCV) treatment will be small without increasing HCV testing and treatment access (adapted from Thomas40).

Hepatitis E virus

One of the most significant advances related to HEV is the development of a safe, effective vaccination.42 That achievement is masked by the current limited availability of the vaccine to prevent HEV infection, and translation of HEV vaccination to licensure to realise its public health impact is one of the remaining challenges of the field.

There remain fascinating questions about the transmission of HEV. A family of related viruses has been characterised in animals and zoonotic transmission to humans reported.43 Nonetheless, there remain questions about differences in apparent susceptibility of children to HEV and the source of the seroreactivity in non-endemic countries.5 44 Although HEV infection is generally self-limited, there are also recent reports of HEV persistence in immunocompromised populations like those who have received organ transplantation.45 Additional investigation of the mechanisms may shed some light on the manner in which viruses establish persistence in liver. Persistent HEV has also opened the question of therapeutics and some early breakthroughs require further study.46