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Keywords:

  • Antivirals;
  • Hepatitis B;
  • Hepatitis C;
  • Liver;
  • HAV;
  • HCV;
  • HDV;
  • History;
  • Interferon;
  • Nucleoside analogs;
  • Vaccine

Abstract

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

Hepatitis has been a major plague of mankind. The history of the discovery of causative viruses is one of the most fascinating scientific adventures of this half century. Individualization of several types of hepatitis only emerged after world war two. Their identification has been associated with milestones which revolutionized medicine and public health. The discovery of HBV brought the first ever vaccine not prepared by tissue culture but initially directly from plasma and soon the first vaccine produced by genetic engineering. HBV vaccine proved to be the first “anti-cancer” vaccine by preventing hepatocellular carcinoma and practically eradicating it from childhood in Taiwan. Successful vaccines became also available for HAV and more recently HEV. The discovery of HCV in 1989 opened a new era since it was the first virus was identified by a direct molecular approach. Two billion people are infected with HBV and 350 million are chronic carriers of the virus. The extraordinary effectiveness of HBV vaccination was best illustrated in Taiwan and Singapore where in less than 2 decades HBs Ag carriers dropped from 9,1% to 2,7% and HCC from 27% to 17%. Successful development of nucleos(t)ides analogs make it now possible to fully control disease progression with a daily pill long term therapy. The progress in HCV therapy has been even more spectacular and successful treatment jumped from 6 % with interferon alone in 1986 to more than 80% in 2013 with triple combination therapies. Remarkably chronic hepatitis C is the only chronic disease which is curable. It will be soon possible to eradicate HCV infection with, an all oral, daily single pill (containing several molecules) for 3 to 6 months which will cure over 90% of patients. This unprecedented therapeutic victory benefiting hundred millions of people matches the triumphs over small pox, polio and tuberculosis. The next 10 years should undoubtedly witness cure or full control over all forms of acute and chronic hepatitis.

The history of the discovery of hepatitis viruses is one of the most fascinating scientific adventures of the last 50 years. Their identification has been associated with unique cognitive milestones and breakthroughs which revolutionized medicine and public health. The discovery of HBV started the process by bringing the hepatitis B vaccine, the first ever vaccine not prepared by tissue culture but directly from plasma. This unique achievement was soon followed by a new leap to become the first vaccine produced by genetic engineering. The implementation of HBV vaccine proved to be the first ‘anti-cancer’ vaccine by preventing hepatocellular carcinoma and practically eradicating it from childhood in Taiwan.

Since then universal HBV vaccination has been adopted by most of the countries.

The discovery of HCV in 1989 opened a new era since it was the first virus which was identified by a direct molecular approach, without tissue culture, electron microscopy or serology. Innumerable new viruses have been discovered this way since.

Remarkably, HCV explained most of post-transfusion, intravenous drug users and nosocomial hepatitis and proved to be the first cause of chronic liver diseases, cirrhosis, transplantation and HCC in western and many developing countries.

The discovery of HBV made it possible to explain the pathogenesis of polyarteritis nodosa and the HCV the etiology of cryoglobulinaemia and to unravel a link between HCV and non-Hodgkin lymphoma but also with autoimmunity as well as lipidoglucidic alterations responsible for diabetes type II.

As often with scientific ventures, this hepatitis discovery saga now evolving towards full blessed achievements was a blend of genius thinking, team work, rivalry and serendipity.

From the disease to the viral alphabet (A TO E)

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

Jaundice at the dawn of medicine 5000 years ago

For centuries, hepatitis was a mystery and understanding came in waves until its origin was finally unraveled. The first description was found in Sumeria (3rd millennium B.C.) with the first description of jaundice on clay tablets that were the first handbook of medicine. The etiological agent was a devil name Ahhazu who attacked the liver, which in those days was the home of the soul. [1, 2] (Hippocrates 460 to 375 B.C.) described the first clinical features of epidemic jaundice including a fulminant course in patients who died within 11 days. The recommended treatment was a diet of honey and water [3]. The word icterus was first found in the Hippocratic corpus [4].

Emergence of transmissible hepatitis

Epidemic jaundice was reported by the Greeks and Romans but poorly described and probably confused with malaria and leptospirosis etc. During the middle ages, jaundice was well recognized and blamed on a divine malediction. Patients were considered ‘impure’ and were therefore to be ‘avoided’ and isolated. This was best formulated by Pope Zackary who clearly recommended isolation as the best approach in dealing with an epidemic of jaundice. Following the discovery of the New World by Christopher Columbus in 1492 and awareness that syphilis had indeed been introduced by the Conquistadors, the notion of transmissibility and contagion was confirmed.

Indeed in the 18th century, many epidemics were reported during military campaigns and in particular at the Siege of Saint-Jean-d'Acre in 1799 and Paris in 1870. The American Civil War (1861–1865) was also plagued by 52 000 cases of hepatitis. In World War 2, the estimated death toll from hepatitis was 16 million cases. The US Army identified 150 000 cases whereas 4 million were ‘the census data’ in the German military and civil population [3].

Individualization of two types of hepatitis

Identification of syringe/vaccine/serum hepatitis

With all these cases, careful descriptions helped identify specific epidemiological aspects of this disease.

The most remarkable group of cases was published in 1885, by Lührman, who studied a Bremen shipyard epidemic. He observed that only victims who had been vaccinated against smallpox developed hepatitis but none of the employees who did not receive the vaccine. He concluded that the source of infection was probably human lymph administrated with the smallpox vaccine. The incubation period was from to 1 to 7 months. Many outbreaks were reported following IV injections of arsenic for syphilis or intramuscular injections of gold salts or bismuth, providing further support of parenteral transmission. Finally, in 1942, there was a major outbreak of hepatitis in the US Navy when 56 000 patients [1-3] were infected following administration of the yellow fever vaccine contaminated with normal human plasma [5]. Based on this, Mac Callum suggested the first historical distinction between two forms of hepatitis in 1947 [6]: epidemic hepatitis with a short incubation and serum hepatitis with a long incubation (100-day fever).

Confirmation of the existence of two distinct forms of hepatitis A and B

From 1942 to 1950, a series of experiments in ‘volunteers’ performed in Germany, England and the USA confirmed the transmissibility of viral hepatitis A and B and defined their clinico-epidemiological characteristics.

The ultimate experimental confirmation of the two distinct forms of viral hepatitis was provided by Saul Krugman between 1964 and 1967 at the Willowbrook School (for mentally retarded children) in New York State. All the residents in this institution developed hepatitis often with successive episodes. After careful authorization from the institution and the parents he performed two well- controlled inoculations which generated distinct plasma incubation pools called MS1 and MS2 which were infectious and could transmit either hepatitis A with a short incubation period (30 to 45 days/MS1) or long incubation hepatitis (60–90 days/MS2). In the 1950s and 1960s, human experimentation was relatively common and generally accepted. Remarkably, JAMA Editorial comments can be found on line [7, 8].

The big bang: the discovery of the hepatitis B virus

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

Australia antigen (Ag) and HBV structure

In 1963, Baruch Blumberg, a geneticist working at the National Institute of Health (NIH) on the polymorphism of lipoproteins, observed an unusual reaction between the serum of a poly-transfused haemophiliac and that of an Australian aborigine in an immunodiffusion gel. He thought that he had identified a new lipoprotein. However, the red staining of this reaction was different [9]. The new antigen was called the Australia antigen (Au). In 1967, the serendipity of a lab technician who got jaundice and follow-up studies prompted Blumberg to suggest that the Au antigen was linked to viral hepatitis [10]. Soon afterwards, in 1968, Alfred Prince at the New York Blood Center used the immuno-electrophoretic technique and described a serum antigen that was specifically associated with post-transfusion hepatitis that he called the serum hepatitis antigen (SH antigen) [11]. The Au antigen and the SH antigen were soon found to be identical and electron microscopic density gradient experiments of Au SH positive serum demonstrated virus like particles. In 1970, David Dane [12] identified the famous eponym 42 nm particle, hallmark of the HB virion, and progress was exponential thereafter. Several determinants of the Au antigen were identified and the two major subtypes AY and AD were reported, suggesting the diversity of HBV.

Based on the studies by Okochi in Japan, the correlation between the Au/SH antigen in blood donors and post-transfusion hepatitis was established in 1972. The new antigen was renamed the HBs antigen and its detection became mandatory, but fortunately, most of the blood centers in leading institutions had been screening since the 1970s. The protective role of anti-HBs immunoglobulins was documented for the prophylaxis of exposed healthcare workers and needle stick exposure. Blumberg soon developed the principle of the first generation vaccine, which he predicted could be obtained from high titer HBs antigen plasma. He filed the patent to protect this very new concept of a vaccine which, for the first time, would not be derived from tissue culture. The proof of concept and its feasibility was demonstrated in chimpanzees and Blumberg was awarded the Nobel Prize in Medicine in 1976 for both the description of HBV and the notion of this revolutionary first generation HBV vaccine. The vaccine was soon developed [13].

image

Figure 1. Advances in HBV treatment.

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In France, the pioneer work of Philippe Maupas was behind the first generation vaccine developed at the Pasteur Institute.

Following the identification of the ultrastructure of the HB virion with its HBsAg coat and its inner core (HBc antigen), a new soluble antigen was identified and called the HBe antigen by Magnius [14]. This protein turned out to be a subcomponent of the HBc antigen. The HBc antigen-antibody system complementing HBs serology was studied by Jay Hoofnagle. Finally, HBV was cloned by Pierre Tiollais at the Pasteur Institute in Paris opening the way to mass production of the hepatitis B vaccine by genetic engineering. This also led to fine molecular studies to identify 8 genotypes and high sensitivity HBV DNA testing.

HBeAg-negative mutants

Careful clinico-virological studies soon identified a subgroup of HBV carriers who were negative for the HBe antigen and positive for anti-HBe but with active ongoing viral replication as shown by significant HBV DNA levels [15]. This prompted the discovery of specific mutations occurring in one of the two sites in the precore region of the genome with a stop codon preventing production of the HBe antigen [16]. This precore mutation was consecutive to a selection process and variants were escape mutants from the host immune response HBc/HBe antigen [17].

This clinico-virological form that was historically referred to as a Mediterranean variant since it was described in Italy and Greece, has now become the most prevalent form of HBV hepatitis in the world and is spreading fast.

Virological assays and occult hepatitis B

One of the unique features of HBV is its unprecedented infectivity although the virus itself is still outnumbered by massive production of subviral particles, which function as a shield to protect the virus against immune responses. The first identification test by immunoprecipitation as well as the first plasma vaccine production was only possible because of this massive production of proteins.

Thanks to the understanding of viral structures, highly sensitive diagnostic tools have been developed, especially the exquisitely sensitive real time PCR with its large dynamic range enabling optimal monitoring of antiviral therapy. This led to the identification of a new form of hepatitis B called occult hepatitis B, which was characterized by HBsAg negativity in the presence of HBV DNA in the liver and in serum. This cryptic hepatitis B form is relevant since it favours oncogenicity, but is also susceptible to reactivation into full-blown infection and potentially fulminant hepatitis especially in patients receiving immunosuppression [18, 19].

Hepadnaviruses

Hepatitis B virus (HBV) was only transmissible to chimpanzees. The probability of its transmission to small primates is a recent breakthrough [20, 21]. The absence of a true animal model was fortunately compensated by the existence of a whole animal family of parent hepatotropic DNA viruses where HBV is the prototype of this new class of hepadnavirus. The woodchuck hepatitis virus (WHV) was the first to be identified in 1978 by Jessy Summers. Many species of mammals followed including tupaias but also birds (ducks, herons, geese), and finally bats. WHV has been the most useful model to study liver cancer and duck hepatitis B virus (DHBV) for viral replication, antivirals and therapeutic vaccines studies.

Identification of hepatitis delta virus (HDV)

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

While studying immunohistological patterns of Italian patients infected with HBV, Mario Rizetto in Torino identified a new nuclear antigen distinct from the HBc antigen in 1977 by liver immunostaining. The surprising discordance between strong nuclear staining and an absence of the characteristic ultra-structural core antigen particle in the liver was a first hint. Since this antigen was distinct from the HBc and HBe antigens, it was called the Delta antigen. Although it was always restricted to HBV carriers, this marker was associated with specific clinical forms of the disease [22].

Thanks to elegant transmission studies in chimpanzees performed at the NIH in a collaboration between John Gerin and Robert Purcell, the new agent was identified as a defective virus requiring the helper function of HBV for its replication. This new defective RNA virus, named hepatitis D virus (HDV) was similar to plant viroids, and is the smallest human virus identified so far [23]. HDV is endemic in certain populations and has mysteriously spread in the Great Equatorial Forests of the Amazon and Central Africa where it is still responsible for outbreaks of fulminant hepatitis [24].

HDV spread rapidly in Europe in drug addicted populations especially in certain areas of eastern Europe. HDV is still an enigma, and mysterious in many ways from its origin to its replication and high infectivity.

An isoprenylation step was recently found to be necessary for replication and this may be the target of specific antiviral therapy. Indeed, at present treatment of hepatitis Delta is only based on interferon alpha. Unfortunately, even the most powerful nucleoside analogues, failed to improve disease outcome. Fortunately, HDV can be prevented by immunization for HBV since this infection is a prerequisite.

Although it affects 25 million people worldwide hepatitis D is a neglected disease. At the same time, because of massive immigration and uncontrolled parenteral injection in the developing countries, interest has been renewed in this disease.

Identification of hepatitis A virus (HAV)

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

As early as 1979, Fritz Deinhardt in Chicago successfully transmitted well documented clinical and histological short incubation hepatitis to marmosets [25]. The absence of the HBs antigen in cases of short incubation hepatitis helped to identify the agent of epidemic hepatitis, which was characterized clinically and epidemiologically as a highly contagious orofecal infection.

In 1977, Stephen Finestone at the NIH, who was working with Kapikian who had just developed the immune-electron microscopy technique to look for rotaviruses, successfully identified a new agent in stool specimens from acute hepatitis A outbreaks [26]. Soon after the identification of HAV on electron microscopy, specific serology for HAV antigen in stools and HAV antibody in serum (IgM and IgG) was developed. The virus was then grown in tissue cultures and a vaccine was rapidly developed.

Hepatitis C virus (HCV)

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

Identification of non-A non-B hepatitis

In 1974, soon after the identification of HAV, the Purcell and Finestone groups at the NIH and Prince at the New York Blood Center independently noted that most cases of post-transfusion hepatitis were HBs negative and therefore were neither HAV nor HBV infections. These cases of post-transfusion hepatitis were because of unidentified agents. They were called non-A non-B hepatitis since they could be related to several agents and there was optimism at the time could that they would soon be identified. As we will see, this was not the case at all [27, 28].

Several groups successfully transmitted the disease to chimpanzees with well characterized inocula from confirmed cases of transfusion hepatitis but also, anti-haemophilic Factor VIII and IX which were readily infectious and helped fully characterize the post-transfusion hepatitis chimpanzee model, its long incubation and mild histology. One of the key emerging features was identification by electron microscopy of a double membrane and tubular structures of the endoplasmic reticulum [29]. It was rapidly shown that chloroform inactivated non-A non-B hepatitis confirming that it was an enveloped virus. Further filtration studies identified the size of 45–60 nm in diameter. All cultivation attempts and classic serological and electron microscopy approaches failed. Investigators were frustrated for many years. In fact, it almost 15 years passed between the identification of the non-A non-B post-transfusion hepatitis entity and the etiologic agent.

Identification of HCV: the revolution in molecular virology

HCV was finally identified thanks to the close collaboration between the private scientific teams at Chiron Corp. (Emeryville – California) led by Michael Houghton and the team led by Daniel Bradley at the Center for Disease Control (CDC) in Atlanta Georgia. In fact, this discovery introduced a new dimension in viral research: the molecular virology revolution, resulting in the identification of numerous viruses including certain orphan viruses such as hepatitis G virus and the transfusion transmitted virus (TTV) which are still in search of a disease.

As mentioned earlier, Daniel Bradley at the CDC and Harvey Halter at the NIH, identified high titer plasma infectious inoculums for non-A non-B hepatitis.

Thanks to an original direct molecular approach, nucleic acid extracted from plasma was cloned in an expression vector (GT11), which generated a library of clones allowing the Chiron team to identify the first epitope, characteristic of the HCV envelope in 1989 [30]. HCV and its nucleic acid structure were rapidly identified. HCV is a single strand positive RNA of 9,6 kb. A new paradigm for the identification of infections agents was born since this was the first time in history that a pathogenic agent was identified with a straightforward molecular biology approach without tissue culture, serology or immune-electron microscopy. Finally, the assembly model and the envelope protein display of HCV was found to be similar to the tick borne encephalitis (TBE) flavirirus and the International Taxonomy Committee classified HCV in the new genus of hepaci viruses in the family of Flaviride.

Discovery of HEV

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

Studies of large epidemics in India and China, in particular, suggested the existence of a peculiar water borne hepatitis with a short incubation period among non-A non-B hepatitis that was not HAV or HCV. One of the clinical hallmarks of this form of hepatitis was the high mortality (20%) in women in the third trimester of pregnancy. A unique massive water borne epidemic attracted major attention in December, 1955 when 29 300 residents of a New Delhi suburb [31] developed acute hepatitis. Epidemiologically it was surprising to have so many patients who were not immunized against HAV in a developing country, thus, it had to be a distinct agent [32]. Other small outbreaks were studied by Mohamed Sultan Khuroo in Cashmere [33]. The same year, the Russian virologist, Mikhail Balayan of the Poliomyelitis Institute in Moscow, reported his self-inoculation prompted by an outbreak in Tashkent. After ingesting stool extracts Balayan developed acute hepatitis and used his own feces to look for the virus by immune-electron-microscopy. He observed 27–32 virus like particles [34]. Daniel Bradley and his team soon successfully transmitted the virus to Marmosets, chimpanzees and then cynomolgus macaques. Then, using the same approach as for HCV, the CDC team successfully identified an antigen [35] characteristic of the hepatitis E virus: a non-enveloped virus with isocahedric symmetry and 27–34 nm in diameter. The genome is a positive single stranded RNA of 7,2 kb. After being initially classified in a separate genus of the caliciviridae, the taxonomic virology committee reclassified it into the Hepeviridae family genus Hepevirus as its sole member. HEV is the only hepatitis virus with animal reservoirs, mainly pigs. HEV should now be considered a zoonosis as confirmed by phylogenic studies that have traced uncooked pork and deer meat to human outbreaks.

Vaccine and treatments

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

This section focuses on HBV and HCV since vaccines.

HBV Vaccine

Soon after the identification of hepatitis B and its antigens, immunization was being investigated on both sides of the Atlantic. The first attempt at immunization was made by Saul Krugman as early as 1971, documenting heat inactivation of HBV and confirming the prevention of hepatitis B by immunoglobulins, while JP Soulier in France, also performed similar studies [36, 37]. Confirmation came from chimpanzees further supporting the visionary concept of Blumberg on the feasibility of a plasma-derived HBs antigen vaccine. Collaborative performed in the US with Robert Purcell at the NIH and Maurice Hilleman with MSD progressed rapidly. The efficacy and inocuity of this first generation vaccine was confirmed and reported simultaneously in the USA and France in 1975–1976. Szmuness et al. performed large clinical efficacy studies of the HB vaccine in the New York homosexual community [38]. Following the cloning of HBV and this wave of first generation plasma derived vaccines, the recombinant vaccine was soon developed.

Administration of the vaccine and the famous landmark studies by Beaseley in Taiwan confirmed its significant efficacy in the reduction of hepatocellular carcinoma [39] (Fig. 1).

Milestones in the treatment HBV

History

In the 1950s, treatment for acute hepatitis was strict/absolute bed rest. This was challenged in the landmark study by Thomas Chalmers during the Korean war [40] which showed that it was both unnecessary and detrimental (most cases were probably HAV). In early 1960s, hepatitis was normally treated with steroids since this normalized ALT and improved the patient well-being. This of course, turned out to be detrimental as shown in the classic study ‘Fortuitously controlled study of steroid therapy in acute viral hepatitis in Zürich en 1969′ [41]. This study ended the use of steroids in most but not all countries for acute hepatitis, but not for chronic cases and it was only in 1981 that a carefully controlled based on HBeAg testing showed that steroids were deleterious and should no longer be used to treat chronic active hepatitis B [42].

Treatment progressed thanks to the identification of the structure of the virus, its polymerase and replication and of access to animal models (especially the woodchuck and the duck).There were three phases to clinical development. The first was the approval of standard interferon alpha 2a/2b in 1992 followed by the introduction of lamivudine into clinical practice in 1998 and from 2002 to the present the third period of new drugs with high genetic barriers.

Interferon alpha

In 1980, recombinant technology made it possible to produce interferon alpha 2a/alpha 2b and lymphoblastoid interferon. All three were indicated for chronic hepatitis B. Several controlled studies confirmed the benefit of interferon for 3 to 6 months in HBeAg positive hepatitis B. Unfortunately results were disappointing in HBeAg negative hepatitis with a high relapse rate, although increased responses were observed after longer periods of treatment [43].

Pegylated interferon alpha 2a and alpha 2b were introduced in 2005 renewing interest in interferon as therapy with a potentially finite duration in HBeAg positive patients in whom seroconversion was obtained in approximately 30%. At the same time, the rate of HBsAg seroconversion remained low: 5–7% at 3 years and 10–12% at 5 years.

Oral antivirals: nucleoside analogues

Interferon remained the only treatment option until the mid-1990s.

The first breakthrough in oral antivirals was the introduction of acyclovir to treat herpes simplex. However, acyclovir had a too weak activity against HBV and famciclovir was discontinued. The first drug that was shown to be effective was vidarabine and in particular vidarabine monophosphate. Unfortunately, activity was limited by neurological side effects. Finally, in the mid-1990s the reverse transcriptase inhibitor lamivudine revolutionized the treatment of HBV. It was active in both HBeAg and HbeAg-negative patients, including those with advanced liver disease [44]. Nevertheless, it was soon clear that resistance developed within a few months and universally in patients co-infected with HIV.

Adefovir and its pro drug adefovir-dipivoxil belong to a new class of acyclic nucleosides. This agent was active in the retrovirus and herpes and HBV resistant lamivudine mutants. Unfortunately, its use is limited by nephrotoxicity. It was registered for HBV therapy in 2003 but like lamivudine, it only resulted in HBe seroconversion after 48 weeks of therapy in 12% of patients.

Fortunately, the new generation of nucleoside/nucleotide analogues with a high genetic barrier resolved the problems of resistance of both lamivudine and adefovir. Indeed, entecavir and tenofovir provide optimal viral suppression with limited side effects. So far, no resistance has been described even after long-term administration of more than 7 years, for tenofovir. Similar results have been found with entecavir except in patients who were previously resistant to lamivudine because of cross-resistance of YMDD mutants. It was found that long-term viral suppression was associated with reversible hepatic fibrotic lesions even in early stage cirrhosis with significant histological improvement. These potent drugs have also revolutionized the management of HBV liver transplantation by controlling HBV recurrence together with anti-HBs immunoglobulins.

Although HBV can now be fully controlled with one pill a day, like HIV, it cannot be eradicated, and treatment is often lifelong.

One situation has illustrated the potential for a cure for chronic HBV infection with frequent HBsAg clearance and seroconversion associated with cure. This is polyarteritis nodosa [45] in which the use of a pathophysiological approach using the triple sequential combination of short term steroid priming, followed by plasma exchange and antiviral therapy (vidarabine then interferon then lamivudine) resulted in a cure [46] and HBe and HBs Ag seroconversion and clearance of HBV in more than 60% of cases [47].

image

Figure 2. Potential Evolution of HCV Therapy for GT 1.

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Treatment of chronic hepatitis C

The first successful treatment of hepatitis C by Jay Hoofnagle preceded identification of the virus [48]. Despite the proof of concept, results remained poor since a durable normalization of transaminases occurred in less than 10% of patients without a relapse. Ola Weiland from Stockholm then showed the activity of ribavirin, a drug with some activity in Flaviviruses [49].

Although the exact mechanism was never identified, this activity was truly synergistic with interferon. Indeed, the combination of ribavirin with interferon alpha increased therapeutic responses from 17 to 40% [50, 51]. In 2000, the pegylated forms of interferon provided a new breakthrough and the sustained virological response (SVR) with the combination pegylated interferon and Ribavirin reached 60%.

Screening for antivirals was possible thanks to in vitro models of HVC replication. This, combined with the identification of the full cycle of HCV replication and its enzymes, made it possible to design optimal drugs [52].

The first generation of antiproteases, Boceprevir and Telaprevir increased the SVR by 30%. A SVR of over 85% is now being achieved with second and third generation direct antiviral combinations in all genotypes after only 3 months of treatment and IFN free regimens are now a reality.

Unlike HIV, these combinations eradicate the virus and are equivalent to a cure for most patients. Moreover, like HBV, viral clearance is associated with regression of fibrotic and inflammatory lesions (Fig. 2).

Conclusion

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References

Hepatitis viruses have been major plagues of mankind. Epidemics of hepatitis A crippled troops and assailed towns over the ages until the 19th century. Giant epidemics of HEV occurred and mysterious mortality of women in late pregnancy persisted in developing countries until recently. Successful HAV and now HEV vaccine will soon eliminate such tragedies.

Two billion people are infected with HBV and 350 million are chronic carriers of the virus. The extraordinary effectiveness of HBV vaccination was best illustrated in Taiwan and Singapore where in less than two decades HBsAg carriers dropped from 9.1 to 2.7% and HCC from 27 to 17%.

Pegylated recombinant interferon may sometime cure HBV in less than a year and successful development of nucleos(t)ides analogues make it now possible to fully control disease progression with a daily pill long-term therapy.

However, new immunotherapy approach manipulating innate and adaptive immunity combined with antiviral drugs must be imperatively developed to extend the benefit of treatment to millions of infected people living in resource limited countries of Asia and Africa.

Even more spectacular the progress in HCV therapy has been dramatic and successful eradication of the virus by antiviral treatment progressed from 6% with interferon alone in 1986 to more than 80% in 2013 with triple combination therapies.

Remarkably chronic hepatitis C is the only chronic viral infection which is curable and its lesions reversible. Last results do confirm that it will be soon possible to eradicate HCV infection with, an all oral, daily single pill (containing several molecules) for 3 to 6 months which will cure 90% of patients including advanced cases who previously failed therapy.

This unprecedented therapeutic victory benefiting hundred millions of people matches the triumphs over small pox, polio and tuberculosis.

References

  1. Top of page
  2. Abstract
  3. From the disease to the viral alphabet (A TO E)
  4. The big bang: the discovery of the hepatitis B virus
  5. Identification of hepatitis delta virus (HDV)
  6. Identification of hepatitis A virus (HAV)
  7. Hepatitis C virus (HCV)
  8. Discovery of HEV
  9. Vaccine and treatments
  10. Conclusion
  11. Acknowledgements
  12. Disclosure
  13. References
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    Payen JL. De la jaunisse à l'hépatite C, 5000 ans d'histoire. Editions EDK: Paris, 2002.
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    Oon GCJ. Viral hepatitis - The silent killer. Annals Academy of Medicine 2012; 41: 27980.
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    Tygstrup N. Viral Hepatitis. Clinics in Gastroenterology 1980; 3: 281.
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    Seeff LB, Beebe GW, Hoofnagle JH, et al. A serological follow-up of the 1942 epidemic of post-vaccination hepatitis in the United States Army. N Eng J Med 1987; 316: 96570.
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