Liver International ISSN 1478-3223
REVIEW ARTICLE
A brief history of hepatitis milestones
Christian Trepo
Hepatology Unit, CROIX ROUSSE Hospital and INSERM U1052, Lyon, France
Keywords
Antivirals – Hepatitis B – Hepatitis C – Liver –
HAV – HCV – HDV – History – Interferon –
Nucleoside analogs – Vaccine
Correspondence
Christian Trepo, Hepatology Unit, CROIX
ROUSSE Hospital and INSERM U1052, Lyon,
France
Tel: +33 4 26 10 93 47
Fax: +33 4 26 73 27 34
e-mail: christian.trepo@chu-lyon.fr
DOI:10.1111/liv.12409
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 discov-
ery 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 achieve-
ment 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 carci-
noma 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
Liver International (2014)
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Abstract
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 car-
riers 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%. Suc-
cessful 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 mole-
cules) for 3 to 6 months which will cure over 90% of patients. This unpre-
cedented 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.
molecular approach, without tissue culture, electron
microscopy or serology. Innumerable new viruses have
been discovered this way since.
Remarkably, HCV explained most of post-transfu-
sion, 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 discov-
ery saga now evolving towards full blessed achievements
was a blend of genius thinking, team work, rivalry and
serendipity.
29
History of hepatitis milestones
From the disease to the viral alphabet (A TO E)
Jaundice at the dawn of medicine 5000 years ago
For centuries, hepatitis was a mystery and understand-
ing came in waves until its origin was finally unraveled.
The first description was found in Sumeria (3rd millen-
nium 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 ful-
minant 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 rec-
ommended 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 esti-
mated death toll from hepatitis was 16 million cases.
The US Army identified 150 000 cases whereas 4 mil-
lion 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 L€uhrman, who studied a Bremen shipyard epi-
demic. He observed that only victims who had been vac-
cinated 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
30
Trepo
gold salts or bismuth, providing further support of par-
enteral 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 sug-
gested 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 ‘volun-
teers’ performed in Germany, England and the USA
confirmed the transmissibility of viral hepatitis A and B
and defined their clinico-epidemiological characteris-
tics.
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 hepa-
titis often with successive episodes. After careful authori-
zation from the institution and the parents he performed
two well- controlled inoculations which generated dis-
tinct 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
Australia antigen (Ag) and HBV structure
In 1963, Baruch Blumberg, a geneticist working at the
National Institute of Health (NIH) on the polymor-
phism of lipoproteins, observed an unusual reaction
between the serum of a poly-transfused haemophiliac
and that of an Australian aborigine in an immunodiffu-
sion gel. He thought that he had identified a new lipo-
protein. 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
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Trepo History of hepatitis milestones

Advances in HBV treatment

1990
2008
PMEA anti-HBV 2001 Tenofovir
activity discovered Telbivudine anti-HBV approved for HBV
activity discovered
1991
1957 3TC anti-HBV and 1998
Interferon anti-HIV activity Entecavir anti-HBV
discovered discovered activity discovered

2002 2006
1991
Adefovir dipivoxil Telbivudine
Interferon alfa-2b
(PMEA prodrug) approved for HBV
approved for HBV
approved for HBV
1998 2005
Lamivudine (3TC) Entecavir and From 2010
approved as first peginterferon alfa-2a Lamivudine patent
nucleoside approved for HBV expires in Europe
analogue for HBV

Fig. 1. Advances in HBV treatment.

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 correla-
tion 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 detec-
tion became mandatory, but fortunately, most of the
blood centers in leading institutions had been screening
since the 1970s. The protective role of anti-HBs immu-
noglobulins was documented for the prophylaxis of
exposed healthcare workers and needle stick exposure.
Blumberg soon developed the principle of the first gen-
eration 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 demon-
strated in chimpanzees and Blumberg was awarded the
Nobel Prize in Medicine in 1976 for both the descrip-
tion of HBV and the notion of this revolutionary first
generation HBV vaccine. The vaccine was soon devel-
oped (13).
In France, the pioneer work of Philippe Maupas was
behind the first generation vaccine developed at the Pas-
teur 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 hepati-
tis B vaccine by genetic engineering. This also led to fine
molecular studies to identify 8 genotypes and high sen-
sitivity HBV DNA testing.
HBeAg-negative mutants
Careful clinico-virological studies soon identified a sub-
group of HBV carriers who were negative for the HBe
antigen and positive for anti-HBe but with active ongo-
ing 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 pre-
core region of the genome with a stop codon preventing
production of the HBe antigen (16). This precore muta-
tion 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

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History of hepatitis milestones
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 func-
tion as a shield to protect the virus against immune
responses. The first identification test by immunopre-
cipitation 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 immunosup-
pression (18, 19).
Hepadnaviruses
Hepatitis B virus (HBV) was only transmissible to chim-
panzees. 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 hepato-
tropic 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 repli-
cation, antivirals and therapeutic vaccines studies.
Identification of hepatitis delta virus (HDV)
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 anti-
gen particle in the liver was a first hint. Since this anti-
gen 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 chimpan-
zees performed at the NIH in a collaboration between
32
Trepo
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 simi-
lar to plant viroids, and is the smallest human virus
identified so far (23). HDV is endemic in certain pop-
ulations 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 pop-
ulations 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 nec-
essary for replication and this may be the target of spe-
cific antiviral therapy. Indeed, at present treatment of
hepatitis Delta is only based on interferon alpha. Unfor-
tunately, 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 hep-
atitis 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)
As early as 1979, Fritz Deinhardt in Chicago success-
fully transmitted well documented clinical and histo-
logical 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 ro-
taviruses, 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)
Identification of non-A non-B hepatitis
In 1974, soon after the identification of HAV, the Pur-
cell 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.
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Trepo
These cases of post-transfusion hepatitis were because of
unidentified agents. They were called non-A non-B hep-
atitis 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 con-
firmed cases of transfusion hepatitis but also, anti-
haemophilic Factor VIII and IX which were readily
infectious and helped fully characterize the post-transfu-
sion 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 identi-
fied 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 collabora-
tion 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 molec-
ular 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 epi-
tope, characteristic of the HCV envelope in 1989 (30).
HCV and its nucleic acid structure were rapidly identi-
fied. 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 encepha-
litis (TBE) flavirirus and the International Taxonomy
Committee classified HCV in the new genus of hepaci
viruses in the family of Flaviride.
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History of hepatitis milestones
Discovery of HEV
Studies of large epidemics in India and China, in par-
ticular, 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 virolo-
gist, 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 hepati-
tis 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 caliciviri-
dae, the taxonomic virology committee reclassified it
into the Hepeviridae family genus Hepevirus as its
sole member. HEV is the only hepatitis virus with ani-
mal reservoirs, mainly pigs. HEV should now be con-
sidered a zoonosis as confirmed by phylogenic studies
that have traced uncooked pork and deer meat to
human outbreaks.
Vaccine and treatments
This section focuses on HBV and HCV since vaccines.
HBV Vaccine
Soon after the identification of hepatitis B and its anti-
gens, immunization was being investigated on both
sides of the Atlantic. The first attempt at immunization
was made by Saul Krugman as early as 1971, document-
ing heat inactivation of HBV and confirming the pre-
vention of hepatitis B by immunoglobulins, while JP
Soulier in France, also performed similar studies (36,
37). Confirmation came from chimpanzees further sup-
porting the visionary concept of Blumberg on the feasi-
bility of a plasma-derived HBs antigen vaccine.
Collaborative performed in the US with Robert Purcell
at the NIH and Maurice Hilleman with MSD progressed
33
History of hepatitis milestones Trepo

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. per-
formed large clinical efficacy studies of the HB vaccine
in the New York homosexual community (38). Follow-
ing 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 land-
mark studies by Beaseley in Taiwan confirmed its signif-
icant 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 land-
mark 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 ste-
roids 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 hep-
atitis in Z€
urich 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 test-
ing 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 wood-
chuck 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 introduc-
tion 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 lymphoblas-
toid interferon. All three were indicated for chronic hep-
atitis B. Several controlled studies confirmed the benefit
of interferon for 3 to 6 months in HBeAg positive hepa-
titis 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

Potential Evolution of HCV Therapy for GT 1

Small Molecules will be Added in an Effort to Improve
SVR Rates
Estimated Estimated
60-70% 85-90%
Interferon
42-50%

Peg-Interferon
35% Estimated
+/- 85-90%
Ribavirin
10%
Nucleoside +/-
polymerase OR
Inhibitor 6th Stage
+/- +/-
1st Stage 2015+
1989-1998
Protease Inhibitor
2nd Stage
1998-2001
Other Direct
Antivirals 3rd Stage
2001 - present
5th Stage
All Oral Therapy 4th Stage
2011-2015
2009-2010

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

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Trepo
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 intro-
duction of acyclovir to treat herpes simplex. However,
acyclovir had a too weak activity against HBV and famci-
clovir 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 sero-
conversion after 48 weeks of therapy in 12% of patients.
Fortunately, the new generation of nucleoside/nucle-
otide 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 resis-
tance has been described even after long-term adminis-
tration 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 revers-
ible 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 treat-
ment is often lifelong.
One situation has illustrated the potential for a cure
for chronic HBV infection with frequent HBsAg clear-
ance and seroconversion associated with cure. This is
polyarteritis nodosa (45) in which the use of a patho-
physiological approach using the triple sequential com-
bination 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).
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History of hepatitis milestones
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 Wei-
land from Stockholm then showed the activity of ribavi-
rin, 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 pro-
vided a new breakthrough and the sustained virological
response (SVR) with the combination pegylated inter-
feron 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 gener-
ation 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. More-
over, like HBV, viral clearance is associated with regres-
sion of fibrotic and inflammatory lesions (Fig. 2).
Conclusion
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 epi-
demics of HEV occurred and mysterious mortality of
women in late pregnancy persisted in developing coun-
tries until recently. Successful HAV and now HEV vac-
cine 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 manipulat-
ing innate and adaptive immunity combined with antiv-
iral 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
35
History of hepatitis milestones
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.
Acknowledgements
We thank Dr. Jean Louis Payen for most precious
sources of information, Dr. Pierre Pradat for precious
help on documentation and Ms. Anna Foukia for her
assistance.
Disclosure
The author does not have have any disclosures to
report.
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