PERSPECTIVE
`
`Rationing Salt Water
`
`Accountability Office, February 10, 2014
`(http://www.gao.gov/assets/670/660785.pdf).
`4. Hanfling D, Altevogt BM, Viswanathan K,
`Gostin LO, eds. Crisis standards of care:
`a systems framework for catastrophic disaster
`response. Washington, DC: National Acade-
`
`mies Press, 2012 (http://www.iom.edu/
`Reports/2012/Crisis-Standards-of-Care-A
`-Systems-Framework-for-Catastrophic
`-Disaster-Response.aspx).
`5. Coping with and mitigating the effects of
`shortages of emergency medications. Arling-
`
`ton, VA: Association of State and Territorial
`Health Officials, December 2012 (http://
`www.ems.gov/pdf/2013/ASTHO_Shortages
`_of_Emergency_Meds.pdf).
`DOI: 10.1056/NEJMp1401833
`Copyright © 2014 Massachusetts Medical Society.
`
`Curing Chronic Hepatitis C — The Arc of a Medical Triumph
`Raymond T. Chung, M.D., and Thomas F. Baumert, M.D.
`
`Related articles, pages 1594 and 1604
`
`Chronic hepatitis C is a major
`
`cause of liver cirrhosis and
`hepatocellular carcinoma world-
`wide. Some 130 million to 170
`million people, or about 3% of
`the world’s population, are chron-
`ically infected with the hepatitis C
`virus (HCV). In the United States,
`chronic hepatitis C, the most com-
`mon cause of liver-related death
`and reason for liver transplanta-
`tion, recently eclipsed human
`immunodeficiency virus (HIV) in-
`fection as a cause of death. The
`development of direct-acting anti-
`viral agents (DAAs) has revolu-
`tionized HCV treatment by offer-
`
`ing genuine prospects for the first
`comprehensive cure of a chronic
`viral infection in humans. This
`success can be traced to impor-
`tant scientific, clinical, and reg-
`ulatory developments.
`The history of HCV’s discovery
`and antiviral-drug development
`offers a striking example of the
`effect of advances in biomedical
`research on disease outcome (see
`table). The discovery of HCV 25
`years ago showed the importance
`of new scientific approaches:
`whereas past virus discovery had
`relied on direct visualization of
`viral particles, the previously elu-
`
`sive HCV was isolated with the
`use of a new expression-cloning
`approach that generated a library
`of complementary DNA from in-
`fectious plasma.1
`The subsequent molecular char-
`acterization of the viral genome
`enabled several important discov-
`eries. First, it revealed HCV to be
`a positive-stranded RNA virus
`that replicates its genome direct-
`ly into RNA without traversing a
`DNA intermediate, so that unlike
`HIV or hepatitis B virus, it lacks
`a latent, nuclear form that defies
`ready immunologic clearance. In-
`stead, it requires continuous rep-
`
`Key Milestones and Their Effects on the Development of Curative Antiviral Treatment for Chronic Hepatitis C.*
`
`Key Milestone
`
`Scientific
`
`Expression cloning of HCV
`
`Model systems for viral replication in cell
` culture (replicons) and ultrastructural
` characterization of nonstructural proteins
`
`Effects
`
`Discovery of viral genome, genomic organization, and viral genotypes; diagnos-
`tic assays; safety of blood products
`
`Screening and discovery of direct-acting antiviral agents targeting the HCV
`NS3/4A protease, NS5B polymerase, and nonstructural protein NS5A
`
`HCV infectious-tissue culture model
`
`Entry and assembly inhibitors; host-targeting agents as adjunctive therapies
`
`Clinical
`
`Interferon-based treatment
`
`Successful HIV drug development
`
`Regulatory
`
`FDA policy
`
`Discovery that HCV infection is curable; starting point for initial add-on combi-
`nations with direct-acting antiviral agents
`
`Combination of potent agents from two or more classes with nonoverlapping resis-
`tance profiles produced effective viral suppression without resistance selection
`
`Enabled rapid clinical development of direct-acting antiviral agents by permitting
`phase 2 studies of all oral regimens without standard-of-care comparators
`
`* FDA denotes Food and Drug Administration, HCV hepatitis C virus, and HIV human immunodeficiency virus.
`
`1576
`
`n engl j med 370;17 nejm.org april 24, 2014
`
`The New England Journal of Medicine
`Downloaded from nejm.org on June 17, 2015. For personal use only. No other uses without permission.
` Copyright © 2014 Massachusetts Medical Society. All rights reserved.
`
`1
`
`GIL2002
`I-MAK, INC. V GILEAD PHARMASSET LLC
`IPR2018-00123
`
`

`

`PERSPECTIVE
`
`Curing Chronic Hepatitis C
`
`lication for its existence — an
`observation that would be lever-
`aged for the design of strategies
`to permanently clear the virus. In
`addition, molecular characteriza-
`tion resulted in an appreciation
`of viral genotypes, which led to
`critical epidemiologic discoveries
`and the development of appropri-
`ate genotype-specific therapeutic
`regimens.
`Finally, it fostered the creation
`of several cell-culture systems to
`explicate the viral life cycle, virus–
`host interactions, and pathogene-
`sis.2 Because of initial difficulty
`in cultivating the virus, an impor-
`tant milestone was the construc-
`tion of subgenomic selectable
`replicons harboring the viral non-
`structural proteins (NS3–5) re-
`sponsible for genome replication.
`The use of replicons permitted ef-
`ficient screening, testing, or both
`of several classes of DAAs that
`blocked these proteins, whose
`structures were themselves suc-
`cessfully crystallized and eluci-
`dated. These include inhibitors
`of NS3/4A protease, NS5A, and
`both nucleoside and nonnucleo-
`side NS5B polymerase inhibitors.3
`The subsequent discovery of a
`viral isolate that efficiently in-
`fected a human hepatoma cell
`line enabled the expansion of the
`arsenal of therapeutic classes to
`include inhibitors of viral entry,
`translation, and assembly, as well
`as inhibitors that block host pro-
`teins or microRNAs that are es-
`sential for maintenance of the
`viral life cycle. Because replicons
`and tissue-culture models largely
`recapitulate in vivo viral-replica-
`tion behavior, researchers were
`able to develop DAA candidates
`rapidly by circumventing lengthy
`and costly efficacy studies in the
`chimpanzee, the only viable ani-
`mal model of HCV.
`
`In many ways, antiviral devel-
`opment in HCV was guided by the
`HIV therapeutic experience and,
`accordingly, quickly moved to
`more practicable paradigms. HCV
`encodes a highly error-prone RNA
`polymerase that generates extra-
`ordinary heterogeneity of the viral
`species within infected persons.
`Thus, it came as little surprise
`that initial monotherapy trials of
`
`was clinically effective. It amount-
`ed to a holding strategy, however,
`since its effectiveness was limit-
`ed by the side-effect profile of
`injected interferon regimens and
`first-generation protease inhibi-
`tors, which induce cytopenias, de-
`pression, autoimmunity, and rash;
`these toxic effects were particu-
`larly prominent in patients with
`cirrhosis.
`
`It may be possible to imagine the global
`eradication of HCV infection, but three
`major challenges remain: infection
`is often diagnosed at a late stage,
`the high cost of direct-acting antivirals
`may lead to selective use,
`and reinfection remains possible.
`
`the first HCV protease inhibitors
`were thwarted by rapid selection
`of preexisting resistant variants.
`Fortunately,
`the
`long-running
`standard of care, the broadly act-
`ing antiviral cytokine interferon
`alfa, which inhibits HCV replica-
`tion not by binding viral proteins
`but by inducing hundreds of host
`genes to produce an antiviral in-
`tracellular state, combined with
`ribavirin, an agent with both anti-
`viral and
`immunomodulatory
`properties, showed activity against
`both protease-inhibitor–resistant
`and wild-type virus. Thus, a key
`first step in the therapeutic revo-
`lution was the addition of a pro-
`tease inhibitor to the backbone of
`peginterferon and ribavirin. This
`strategy succeeded in boosting
`rates of sustained virologic re-
`sponse, or viral cure, from about
`45% to approximately 75% among
`patients with HCV genotype 1 in-
`fection and proved that a DAA
`
`Against this backdrop, the de-
`velopment of HCV nucleoside in-
`hibitors, nonnucleoside inhibitors,
`and NS5A inhibitors presented the
`opportunity to apply to HCV the
`HIV combination-therapy princi-
`ple, whereby a combination of
`potent agents from two or more
`classes with nonoverlapping resis-
`tance profiles could provide rapid
`and potent suppression of viral
`replication and prevent emergence
`of resistant variants. In theory,
`this regimen, applied for sufficient
`duration, could achieve the goal
`of high cure rates and freedom
`from dependence on interferon.
`But additional steps were re-
`quired to get from these inter-
`feron-tethered regimens to trials
`of investigational DAAs in com-
`bination. Traditional study designs
`had, until recently, used a stan-
`dard-of-care comparator for new
`agents, which in the case of HCV
`meant using an interferon-based
`
`n engl j med 370;17 nejm.org april 24, 2014
`
`1577
`
`The New England Journal of Medicine
`Downloaded from nejm.org on June 17, 2015. For personal use only. No other uses without permission.
` Copyright © 2014 Massachusetts Medical Society. All rights reserved.
`
`2
`
`

`

`PERSPECTIVE
`
`therapy in the control group — an
`unappealing prospect for many
`patients. Buoyed by the success of
`combination HIV therapies and the
`knowledge that resistance vari-
`ants in HCV were not predicted to
`persist as they do in HIV, the
`Food and Drug Administration
`agreed to permit phase 2 trials to
`use new combinations of HCV
`DAAs without requiring a stan-
`dard-of-care comparator. This de-
`cision proved catalytic. Because of
`the short durations of, and rapid
`enrollment in, these studies, the
`pace of ensuing clinical drug de-
`velopment has been breathtaking.
`These trials have shown that
`the combination approach is not
`only viable in concept, but also
`capable of producing sustained
`virologic response rates exceeding
`90%, with the use of interferon-
`free, all-oral combinations. Just as
`impressively, several
`roads appear to be
`capable of leading
`to the same destina-
`tion; combinations of several dif-
`ferent classes have all yielded
`high rates of sustained virologic
`response in phase 2 studies.
`Phase 3 studies of many of these
`combinations are completed or
`under way, and approvals of the
`first of these regimens should be
`forthcoming within the year. Late-
`phase studies also show that DAA
`combinations are capable of bridg-
`ing most of the performance gap
`between more-conventional pop-
`ulations of previously untreated
`patients and populations that have
`historically been difficult to treat,
`including patients with cirrhosis,
`HIV-coinfected persons, and pa-
`tients who have not had a re-
`sponse to conventional interferon-
`based therapies.4
`
` An audio interview
`with Dr. Chung
`is available at NEJM.org
`
`Still, some drug-development
`hurdles lie ahead. Although they
`have achieved spectacular re-
`sponse rates in late-stage clinical
`trials, DAAs must fulfill their
`promise in the real world. Given
`historical trends in real-world pop-
`ulations, a minor but substantial
`fraction of some patient groups
`will probably need alternative ap-
`proaches; these include patients
`with coexisting conditions such
`as renal failure, hepatic decom-
`pensation, or a liver transplant,
`as well as those with previous
`failure of a DAA combination. For
`such patients, new treatments
`may be required, including host-
`targeting agents or inhibitors of
`viral entry or assembly.5
`It may now be possible to
`imagine the global eradication of
`HCV infection, but three major
`challenges remain. First, in the
`absence of effective screening
`programs, HCV infection is often
`diagnosed at a late stage (in high-
`income countries) or seldom diag-
`nosed at all (in low- or middle-
`income countries). Second, the
`high cost of DAAs will preclude
`their use in most infected patients
`in low- or middle-income coun-
`tries; in high-income countries,
`the need for payers to provide
`major resources for HCV treat-
`ment may lead to the selective
`use of DAAs for certain patient
`subgroups. Third, reinfection re-
`mains possible even after success-
`ful curative therapy.
`Ultimately, a preventive vaccine
`would be desirable for the global
`eradication of HCV, but the virus’s
`extraordinary sequence heteroge-
`neity and ability to evade host im-
`mune responses pose challenges
`for the development of a broadly
`protective vaccine. In the mean-
`
`Curing Chronic Hepatitis C
`
`time, effective HCV screening pro-
`grams, including full implemen-
`tation of birth-cohort screening
`in the United States, the estab-
`lishment of access to affordable
`treatment in low- and middle-
`income countries, and strategies
`for reducing the risk of transmis-
`sion (e.g., safe injection practic-
`es) will probably be needed to
`control HCV infection on a global
`scale. The introduction of DAAs
`represents a major breakthrough,
`but it is only a first step toward
`eliminating HCV globally.
`Disclosure forms provided by the authors
`are available with the full text of this article
`at NEJM.org.
`
`From the Liver Center, Gastrointestinal Divi-
`sion, and the Department of Medicine,
`Massachusetts General Hospital, and Har-
`vard Medical School — both in Boston
`(R.T.C., T.F.B.); and INSERM Unité 1110, In-
`stitut de Recherche sur les Maladies Virales
`et Hépatiques, Université de Strasbourg;
`and Institut Hospitalo-Universitaire, Pôle
`Hépato-digestif, Hôpitaux Universitaires
`de Strasbourg — all in Strasbourg, France
`(T.F.B.).
`
`This article was published on April 10, 2014,
`at NEJM.org.
`
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`Bradley DW, Houghton M. Isolation of a
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`2. Scheel TKH, Rice CM. Understanding the
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`3. Schaefer EAK, Chung RT. Anti-hepatitis C
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`perspectives and challenges. J Hepatol 2013;
`58:375-84.
`
`DOI: 10.1056/NEJMp1400986
`Copyright © 2014 Massachusetts Medical Society.
`
`1578
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`n engl j med 370;17 nejm.org april 24, 2014
`
`The New England Journal of Medicine
`Downloaded from nejm.org on June 17, 2015. For personal use only. No other uses without permission.
` Copyright © 2014 Massachusetts Medical Society. All rights reserved.
`
`3
`
`