Also See;How are the different types of hepatitis transmitted?
Gut2012;61:i1-i5 doi:10.1136/gutjnl-2012-302122
New challenges in viral hepatitis
David Thomas1,Fabien Zoulim2,3
+
Author Affiliations
1Division of Infectious Diseases, Johns Hopkins School of Medicine,
Baltimore, Maryland, USA
Contributors I have read the article and attest to its accuracy and
originality.
Revised 16 February 2012
Accepted 17 February 2012
http://gut.bmj.com/content/61/Suppl_1/i1.full
Abstract
Over the past few decades there has been remarkable progress in
viral hepatitis. Beginning with discovery of the viral agents,
we now have reliable methods to diagnose and monitor all hepatitis
virus infections, as well significant advances in treatment and prevention.
Nonetheless, important challenges remain. This supplement to Gut looks
forward to the next generation of challenges in the field of viral hepatitis, and this
introductory article highlights several key issues.
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
View this table:
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Table 1 Key clinical features of viral hepatitis agents
Key clinical features of viral hepatitis agents
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
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
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
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.28To 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 inhealthcare 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 effectivenessof 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 infectionare not currently diagnosed.12 39
Of the estimated 170 million with HCV infectionworldwide, no more than 10% are under care.40
Thus, curing all of those under care still has little impact without expandingaccess 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
modelfor HCV infection may pave the way towards the development of new prophylactic
vaccines or innovative medicines for the treatment of chronic HCV infection.41
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).
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
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.28To 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 inhealthcare 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 effectivenessof 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 infectionare not currently diagnosed.12 39
Of the estimated 170 million with HCV infectionworldwide, no more than 10% are under care.40
Thus, curing all of those under care still has little impact without expandingaccess 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
modelfor HCV infection may pave the way towards the development of new prophylactic
vaccines or innovative medicines for the treatment of chronic HCV infection.41
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 susceptibilityof
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
References
http://gut.bmj.com/content/61/Suppl_1/i1.full
Footnotes