The NEW ENGLA ND JOURNAL of MEDICINE

Perspective December 10, 2020

His tory of Medicine

The Discovery of Hepatitis C — The 2020 Nobel Prize

in Physiology or Medicine
Jay H. Hoofnagle, M.D., and Stephen M. Feinstone, M.D.​​

N
ews that Drs. Harvey J. Alter, Michael Hough- chronic infection was also often
The Discovery of Hepatitis C

ton, and Charles M. Rice were recipients of asymptomatic but usually accom-
panied by chronic hepatitis that
the 2020 Nobel Prize in Physiology or Medi- could result in cirrhosis, end-
cine for their roles in the discovery of the hepatitis C stage liver disease, and hepato-
cellular carcinoma, typically after
virus (HCV) was met with both of Health (NIH) reported that decades of infection. Alter and
enthusiasm and pride by the hep- cases of post-transfusion hepati- his coworkers showed that non-
atitis and liver disease research tis that were not caused by hepa- A, non-B hepatitis was transmis-
communities. The prize recogniz- titis B were also not caused by sible to chimpanzees and had
es not just the contribution of hepatitis A.1 This report led to characteristics of an enveloped
these three outstanding scientists, global efforts first to define the virus. Without a specific test,
but also the critical importance clinical features, complications, however, it remained a diagnosis
of hepatitis C in world health. and epidemiology and second to of exclusion: defined not by what
The discovery of HCV was a ma- discover the cause of what the it was, but by what it was not.
jor milestone in 20th-century authors termed “non-A, non-B Finding the virus was a great-
medicine, and the awardees rep- hepatitis.” The clinical features er challenge than defining its
resent three critical periods of were soon defined by many stud- clinical characteristics. Worldwide
research on this important virus, ies, but most clearly by those by efforts, using the approaches to
whose discovery has led to elimi- Alter at the NIH Clinical Center, viral discovery and detection that
nation of post-transfusion hepa- which were based on his prospec- were successful for hepatitis A
titis and a means to cure and tive, long-term studies of post- and B (immunodiffusion, immu-
possibly eradicate hepatitis C. transfusion hepatitis. Alter showed nofluorescence, radioimmunoas-
The existence of a third form that acute hepatitis C was often say, enzyme-linked immunoassay,
of viral hepatitis was revealed asymptomatic and rarely severe immune electron microscopy, and
when investigators (including Har- or fatal but that it led to chronic cell culture) were unsuccessful or
vey Alter) at the National Institutes infection in most patients. The led to promising but ultimately

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PERS PE C T IV E
unsubstantiated claims for speci-
ficity. During this 15-year period,
Alter led the effort for objective
assessment of claims for identifi-
cation of the viral agent by pre-
paring a panel of documented
infectious blood samples and con-
trols, which he provided (under
code) to investigators for assess-
ing the specificity of their experi-
mental assays. He expressed the
scientific community’s frustration
at the time in one of his inimi-
table poems: “I think that I shall
never see / this virus called non-
A, non-B.”
The breakthrough in identifi-
cation of the agent of non-A,
non-B hepatitis came when Mi-
chael Houghton and his cowork-
ers at Chiron Corporation report-
ed finding a viral RNA fragment
in the plasma of a chimpanzee
that was a known carrier of the
virus.2 The technique they used
combined the power of molecu-
lar biology with the specificity of
antigen–antibody reactions. Using
random oligonucleotide primers,
they created a cDNA library repre-
senting all DNA and RNA found
in pellets made from infected
chimpanzee plasma by high-speed
ultracentrifugation. The cDNAs
were then ligated into a bacterio-
phage expression system, and the
resulting clones were screened
with serum from patients with
chronic non-A, non-B hepatitis
that they postulated would have
antibody to the virus. More than
a million clones were screened
before they found one that ap-
peared specific for non-A, non-B
hepatitis. The specificity was
clinched when serologic assays
using the phage-expressed poly-
peptide were applied to Alter’s
collection of samples from post-
transfusion hepatitis.3 The anti-
body arose in patients who devel-
oped non-A, non-B hepatitis, was
2298
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
not present in pretransfusion blood
samples, and did not arise in pa-
tients with other forms of hepati-
tis. Most patients could be shown
to have received at least one unit
of blood that also tested positive
for antibody. The term non-A,
non-B hepatitis was retired for
what finally could be called hep-
atitis C.
The Houghton group extended
their cDNA clones and analyzed
the resulting sequence, demon-
strating that the virus had a
positive-sense RNA genome with
a flavivirus-like structure. Enter
Charles Rice, who was at Wash-
ington University at the time (be-
fore moving to Rockefeller Uni-
versity in 2001) and had built a
career in the basic virology of al-
phaviruses and flaviviruses, includ-
ing yellow fever, Sindbis, and
dengue viruses. The medical im-
portance of this new member of
the Flaviviridae family was not
lost on Rice, and he promptly ap-
plied his molecular and virologic
expertise to hepatitis C. He was
instrumental in unraveling the
structure and functions of the
different genetic regions of HCV
and ultimately constructed a com-
plete cDNA clone of the viral ge-
nome. Its function was proved
when, with no cell culture system
available, RNA transcribed from
the cDNA clone was inoculated
directly into a chimpanzee liver
and resulted in a typical HCV in-
fection. These and subsequent
studies of a cell-culture–adapted
strain of HCV provided a corner-
stone for the understanding of
the genomic structure and repli-
cative cycle of this important
pathogen.4 During this period,
Rice, always respecting the canons
of research ethics, freely shared
his reagents and clones with the
HCV research community.
The consequences of the dis-
n engl j med 383;24  nejm.org  December 10, 2020
The New England Journal of Medicine
The Discovery of Hepatitis C
covery of HCV and elucidation of
its structure and replicative cycle
have been immense. Screening
blood donations with the new
serologic and molecular assays
quickly resulted in the elimina-
tion of post-transfusion hepati-
tis C. Serologic assays allowed for
better understanding of the epi-
demiology of hepatitis C, which
helped to direct public health
measures to reduce its incidence
in the United States and around
the world. The ability to diag-
nose acute and chronic hepatitis
C was critical to more precisely
defining its natural history, risk
factors for progression, role in
causing cirrhosis and hepatocel-
lular carcinoma, as well as extra-
hepatic manifestations of HCV in-
fection, including essential mixed
cryoglobulinemia and some B-cell
lymphomas. Most important, how-
ever, these breakthroughs ulti-
mately allowed for innovative,
direct approaches to therapy.
Delineation of the structure
and function of HCV polypeptides
and the viral replication cycle led
to development of assays for test-
ing molecules that might disrupt
these functions and block repli-
cation. Using these tools, several
orally available, direct-acting anti-
viral agents were developed, com-
binations of which have proved to
be safe, well tolerated, and high-
ly effective. Currently, oral anti-
viral regimens given for 8 to 12
weeks successfully eradicate HCV
and result in a cure of the chron-
ic infection in more than 95% of
patients. Indeed, the ease and ef-
ficacy of HCV therapy led to the
proposal from the World Health
Organization for nation-by-nation
efforts to eliminate this disease
globally.5 At present, chronic HCV
infection is estimated to affect 71
million persons worldwide and to
account for 440,000 deaths each
 PE R S PE C T IV E
year. With efforts to identify per-
sons with hepatitis C and connect
them with treatment, a major de-
cline in the morbidity and mor-
tality of this disease is possible.
Meanwhile, HCV vaccine re-
search continues, but multiple
An audio interview virologic and immu-
with Dr. Hoofnagle nologic factors have
is available at NEJM.org made vaccine devel-
opment an elusive goal. Never-
theless, the consequences of the
discovery of HCV three decades
ago have provided the knowl-
edge and tools to achieve global
control and elimination of this
Broken Promises
Broken Promises — How Medicare Part D Has Failed
to Deliver Savings to Older Adults
Stacie B. Dusetzina, Ph.D., Benyam Muluneh, Pharm.D., Nancy L. Keating, M.D., M.P.H.,
and Haiden A. Huskamp, Ph.D.​​
D rug prices in the United
States are high, particularly
for innovative drugs used to treat
rare and life-threatening condi-
tions. In some cases, a reason-
able defense of high prices for
brand-name drugs is that they
are temporary — historically, the
prices paid by plans and patients
for most small-molecule drugs
have decreased substantially soon
after patents expired. Rapid price
reductions rely on competition
among generics manufacturers,
with large reductions typically
achieved after multiple generic
products become available.1 For
the growing number of expensive
specialty drugs, including those
for rare diseases, it’s unclear
whether and how quickly this
level of price competition can be
achieved.1 Furthermore, even if
generic specialty drugs have far
lower list prices than their brand-
name counterparts, savings that
accrue to Medicare beneficiaries
n engl j med 383;24  nejm.org  December 10, 2020
The New England Journal of Medicine
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
disease within the next three
decades.
The Nobel committee has
rightly acknowledged the impor-
tance of the discoveries made by
these three outstanding and gen-
erous scientists.
Disclosure forms provided by the authors
are available at NEJM.org.
From the Liver Disease Research Branch
and Liver Diseases Branch, National Insti-
tute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health,
Bethesda, MD.
This article was published on December 5,
2020, at NEJM.org.
are limited by the design of the
Medicare Part D benefit.
Nearly two thirds of new med-
icines approved between 2011
and 2015 and covered by Medi-
care Part D were specialty drugs.2
Although most of these products
are still under patent protection,
market entry of generic versions
is anticipated for many specialty
drugs during the next decade.
The introduction of generic com-
petitors for Gleevec (imatinib)
highlights critical policy failures
that should be addressed to en-
sure rapid adoption of generic
products and savings for Medi-
care beneficiaries who use ge-
neric specialty drugs.
As one of the first targeted
cancer therapies, imatinib has
revolutionized the treatment of
chronic myeloid leukemia (CML)
and other hematologic and solid
tumors. By targeting the BCR-ABL
mutation, imatinib has trans-
formed diseases with universally
The Discovery of Hepatitis C
1. Feinstone SM, Kapikian AZ, Purcell RH,
Alter HJ, Holland PV. Transfusion-associated
hepatitis not due to viral hepatitis type A
or B. N Engl J Med 1975;​292:​767-70.
2. Choo QL, Kuo G, Weiner AJ, Overby LR,
Bradley DW, Houghton M. Isolation of a
cDNA clone derived from a blood-borne
non-A, non-B viral hepatitis genome. Sci-
ence 1989;​244:​359-62.
3. Alter HJ, Purcell RH, Shih JW, et al. De-
tection of antibody to hepatitis C virus in
prospectively followed transfusion recipi-
ents with acute and chronic non-A, non-B
hepatitis. N Engl J Med 1989;​321:​1494-500.
4. Lindenbach BD, Rice CM. Unravelling
hepatitis C virus replication from genome to
function. Nature 2005;​436:​933-8.
5. Thomas DL. Global elimination of chron-
ic hepatitis. N Engl J Med 2019;​380:​2041-50.
DOI: 10.1056/NEJMp2031110
Copyright © 2020 Massachusetts Medical Society.
The Discovery of Hepatitis C
fatal outcomes into chronic dis-
eases that have a limited effect
on people’s life expectancies. List
prices were high when Gleevec
was approved in 2001 ($30,000
per year) and tripled within 10
years. At the time of generic en-
try in 2016, point-of-sale spend-
ing on Gleevec (excluding rebates
obtained by health plans and
pharmacy benefits managers af-
ter the point of sale) for people
covered by Medicare Part D ex-
ceeded $120,000 per patient per
year (see figure). For people with
CML, high cost remains an im-
portant barrier to medication ac-
cess and adherence as well as to
clinical outcomes, since high lev-
els of adherence (above 90%) are
needed to achieve optimal out-
comes.
Given the high price of Gleevec
and its long-term use by people
with CML, generic entry was eager­
ly anticipated in the United States.
Prices for generic imatinib were
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