Stefanovich 1

Vlad Stefanovich
Dr. Porter
Microbiology 201H-Section 001
18 April, 2016
Zepatier as an Improved Drug Treatment for Hepatitis C Genotypes 1 and 4
Hepatitis C is an infectious disease that is caused by the hepatitis C virus (HCV) and is
estimated to affect 130-200 million people worldwide .1 The virus replicates mainly in the
hepatocytes of the liver, where it is thought that each infected cell produces approximately fifty
virions daily. As the disease is hepatic, those with a chronic hepatitis C infection typically
exhibit liver damage that can progress to cirrhosis , liver cancer, and eventual liver failure that
requires a liver transplant for survival. This disease is difficult to detect early-on; a trait which
facilitates the high mortality rates that are often seen in populations with poor access to quality
medical care and effective pharmaceuticals. Of those infected with hepatitis C, approximately
343,000 died due to liver cancer and 358,000 due to cirrhosis in 2013 .2 These astonishingly high
numbers reflect the need for more comprehensive and available treatment programs for a viral
infection with no known vaccine. However, what seems to be an incredibly effective treatment
has been cleared by the US Food and Drug Administration (FDA) for sale as of February of this
year. Known as Zepatier, it boasts high efficacy rates for curing hepatitis C and few adverse side
effects. But before the molecular mechanisms of Zepatier can be explored, some foundation must
be laid concerning the morphology of the HCV and how it propagates virions in order to achieve
maximum understanding.

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The hepatitis C virus is a small (5565 nm in size), enveloped, positive-sense singlestranded RNA virus of the family Flaviviridae.3 Based on genetic differences between HCV
isolates, the hepatitis C virus species is classified into seven genotypes (numbered 17) with
several subtypes within each genotype that are represented by lowercase letters . Subtypes are
further broken down into quasispecies based on the inherent genetic diversity that occurs due to
random mutations. HCV mutates rapidly due to a high error rate on the part of the viral RNAdependent RNA polymerase. This mutation rate produces so many variants of the virus that it is
considered a quasispecies rather than a conventional virus species . Genotypes differ by 3035%
of the nucleotide sites over the complete genome with differences in genomic composition of
subtypes usually 2025%. Genotypes 1 and 4 are less responsive to interferon-based treatment
than the other genotypes while subtypes 1a and 1b are found worldwide and cause about 55% of
all cases.4 These facts highlight the need for a therapy that can effectively address these issues.
The hepatitis C virus consists of an RNA core, surrounded by an icosahedral protective
shell of capsid proteins to form the nucleocapsid , and further encased in a lipid envelope. Some
important features to highlight include two glycoproteins , E1 and E2, that are embedded in the
lipid envelope on the viral membrane and function to mediate entry into host cells . Both
envelope proteins are highly glycosylated , with E1 serving as the fusogenic subunit and E2
acting as the host-receptor binding protein.5 Elsewhere, NS5A is a hydrophilic phosphoprotein
which plays an important role in viral replication , regulation of cell signaling pathways, and
inhibiting the host-bodys interferon response. It is known to bind to endoplasmic reticulum (ER)
- anchored human VAP proteins, which play a key part in the regulation of lipid transport ,

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membrane trafficking and homeostasis.6 The NS5B protein is the viral RNA-dependent RNA
polymerase which has the key function of replicating the HCV s viral RNA by using the viral
positive RNA strand as its template and catalyzing the polymerization of ribonucleoside
triphosphates (rNTP) during RNA replication.7
There are varying degrees of severity in hepatitis C cases, with acute HCV infection
occurring in 15% of instances. Acute symptoms are generally mild and too vague to associate
with hepatitis C specifically - including a decreased appetite, fatigue, nausea, muscle or joint
pains, and weight loss. Most cases of acute infection typically do not exhibit jaundice and rarely
does acute liver failure result. The infection resolves spontaneously in 1050% of cases, a
majority of whom are young and female .8 Chronic hepatitis infections are significantly more
common with about 80% of those exposed to the virus developing one . This is defined as the
presence of detectable viral replication for at least six months . As with acute hepatitis C, chronic
patients experience minimal or no symptoms during the initial few decades of the infection .9
Liver enzymes are normal in 753% of patients - which after several years often leads to
dangerous complications such as cirrhosis or liver cancer. Furthermore, fatty changes to the liver
occur in about half of those infected and are usually present before cirrhosis develops . About
80% of the time, this change affects less than a third of the liver and increases the chance of
cirrhosis in the patient.10 In certain cases, persons who have been infected with hepatitis C may
appear to clear the virus but remain infected. The virus is not detectable with conventional
testing in this case but can be found with ultra-sensitive tests . The original method of detection

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was by demonstrating the viral genome within liver biopsies, but newer methods include an
antibody test for the virus' core protein and the detection of the viral genome after first
concentrating the viral particles via ultracentrifugation. A form of infection, known as a
cryptogenic occult infection, with perpetually elevated serum liver enzymes but without
antibodies to hepatitis C has also been reported. Several clinical pictures have been associated
with this type of infection, with cases found in people with anti-hepatitis-C antibodies but with
normal serum levels of liver enzymes; in antibody-negative people with ongoing elevated liver
enzymes of unknown cause; in healthy populations without evidence of liver disease; and in
groups at risk for HCV infection including those on hemodialysis or family members of people
with occult HCV.11
Although a variety of drug cocktails have been synthesized and tested for the treatment of
Hepatitis C, Zepatier boasts the highest efficacy of any treatment yet seen . The FDA approval of
Zepatier was based on six studies in 1,373 patients with chronic HCV Genotype 1 (GT1) or
Genotype 4 (GT4) infection. The clinical development program for Zepatier enrolled diverse
groups of HCV GT1- and GT4-infected patients, including treatment-nave patients and those
who had failed prior therapy with peginterferon alfa (PegIFN) and ribavirin (RBV) , as well as
patients suffering with meaningful comorbidities and health complications , such as compensated
cirrhosis and HIV-1/HCV co-infection. GT1-infected patients with severe renal impairment on
hemodialysis and those who previously failed therapy with PegIFN and RBV in combination
with a HCV NS3/4A protease inhibitor such as simeprevir , boceprevir, or telaprevir were also
studied. Throughout the studies, subjects receiving Zepatier achieved high rates of sustained

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virologic response (SVR) ranging from 94-97% in GT1-infected patients , and 97-100% in GT4infected patients. In terms of HCV, a cure is defined as a sustained virological response
following a period of time of about 12 weeks after which the virus rarely returns.12
In principle, a single pill of Zepatier contains two drugs: elbasvir and grazoprevir.
Elbasvir is a highly potent and selective inhibitor of the hepatitis C virus NS5A replication
complex. This multifunctional protein is essential for replication and assembly of HCV and is a
perfect target for therapeutics as inhibitors of NS5A can block viral production at an early stage
of assembly.13 A great feature of elbasvir is that is is very potent and incredibly selective .
Potency means that it inhibits NS5A very effectively even at smaller dosages - a major reason
why Zepatier contains only 50 mg of elbasvir . Selectivity is also crucial as elbasvir inhibits
NS5A and only NS5A which this means that it does not alter other important processes . Both of
these qualities are very important when it comes to Zepatiers side effects. Namely, Zepatiers
side effects are mild because the high cure rate can be achieved with small dosages of the
selective elbasvir molecule. Grazoprevir is a hepatitis C virus protease inhibitor acting at the
NS3/4A protease targets which prevents viral replication by selectively binding to them and
blocking proteolytic cleavage of protein precursors that are necessary for the production of
infectious viral particles.14 As research into virology shows, the best way to overcome a viral
infection is to use more than one antiviral drug simultaneously in order to dramatically decrease
the chance of antiviral resistance and virus survival. The same is true for HCV as prior to the
release of Zepatier, experimental trials were performed by pairing elbasvir with grazoprevir in a
set of hepatitis C patients.15 Results showed similar efficacy back then and it is likely that Merck

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Industries were directly influenced by what can be considered a landmark study for the improved
treatment of Hepatitis C.
In terms of adverse side effects , they are minor for a life-saving treatment with Zepatier
proving much easier on the body than previously used drug therapies . Zepatier is typically
available as a fixed-dose combination that is administered once a day with or without ribavirin
depending on the presence of resistance-associated polymorphisms (RAPs) and patient
characteristics. Because of lower SVRs in GT1a patients with baseline NS5A polymorphisms ,
these patients would receive elbasvir/grazoprevir plus ribavirin for 16 weeks. No dosage
adjustment is required in patients receiving elbasvir/grazoprevir with mild, moderate or severe
renal impairment including hemodialysis. In patients receiving elbasvir/grazoprevir without coadministration of ribavirin for 12 weeks, the most common adverse reactions (5%)
were fatigue, headache and nausea. In patients receiving elbasvir/grazoprevir co-administered
with ribavirin for 16 weeks, the most common adverse reactions of moderate and
severe intensity (5%) were anemia and headache .15 In subjects treated with
Zepatier who reported an adverse reaction , 73% had adverse reactions of mild severity . The type
and severity of adverse reactions in subjects with compensated cirrhosis were comparable to
those seen in subjects without cirrhosis. No subjects treated with Zepatier or placebo had serious
adverse reactions, with the proportion of subjects treated with Zepatier or placebo who
permanently discontinued treatment due to adverse reactions being less than 1% in each group .
However, in those participants, liver enzymes exceeded five times the upper limit of normal ,
generally at or after 8 weeks of treatment . Accordingly, clinicians should conduct liver-related

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blood tests prior to starting therapy, and afterward as well because the drug is contraindicated for
patients with an already impaired liver.
A more recent set of clinical trials compared the efficacy of Zepatier side by side with
sofosbuvir paired with pegylated interferon/ribavirin (the most viable candidate for treatment
prior to Zepatiers emergence) and found that the combination of elbasvir and grazoprevir
resulted in an SVR12 of 99.2% (128/129) compared to 90.5% (114/126) in the
sofosbuvir/pegylated interferon/ribavirin group. Elbasvir and grazoprevir demonstrated superior
efficacy especially in subgroups of patients considered as hard-to-treat in the past (in cirrhotics,
patients with high initial viraemia, and in previous null-responders to pegylated interferon and
ribavirin). Furthermore, elbasvir and grazoprevir demonstrated a superior safety profile
compared to sofosbuvir/pegylated interferon/ribavirin.16 This is primarily due to the absence of
adverse effects commonly associated with pegylated interferon and/or ribavirin, including low
red blood cell count, low white blood cell count, flu-like illness, and pyrexia.
A major difference between this treatment and all the other Hepatitis C treatments that
boast a relatively high efficacy is their price. Zepatier only costs $54,600 per treatment in the US
which compared with Harvoni's price tag of $94,500 is quite a reduction .17 Since Zepatier is
cheaper, it is expected to add competition to the pharmaceutical market that will hopefully drive
down the prices of viable hepatitis C treatments . After all, it is one thing for an American citizen
to get hepatitis C and receive top-notch health care recommendations but it is entirely another
when the infection spreads to poor or medically underdeveloped areas of the world . These areas
exhibit fatalities more often than their medically developed counterparts and thus it is crucial for

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the maintenance of a universal standard of world healthcare to make available a cheap and
effective drug treatment or vaccine for the treatment of hepatitis C.
Although we have yet to see how Zepatier holds up on the world market , initial trials of
the drug administered to hepatitis C patients representing a variety of health demographics
showed promising results both in terms of effectiveness and relative safety . As the drug can only
treat Genotypes 1 and 4, a demographic which makes up about 55% of cases worldwide , future
studies must focus on either working to expand the range of Zepatiers treatment or to develop an
alternative drug that can effectively treat the remaining Genotypes. Regardless, with the
emergence of Zepatier, humanity is edging closer towards the comprehensive treatment of yet
another debilitating disease that was once considered untreatable.

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References
1

World Health Organization Hepatitis C Fact Sheet http://www.who.int/mediacentre/factsheets/fs164/en/

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Ferri, C. "HCV syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell
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4

Ohno O, Mizokami M, Wu RR, Saleh MG, Ohba K, Orito E, Mukaide M, Williams R, Lau JY; et al. "New
hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b,
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5

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6

Gupta G, Qin H, Song J; Qin; Song H. "Intrinsically unstructured domain 3 of hepatitis C Virus NS5A
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(2012). 7 (6): e39261.
7

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kinetic analysis of active RNA-dependent RNA polymerase elongation complex". Journal of Biological
Chemistry (2012). 287 (13): 1067483.
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Maheshwari, A; Ray S; Thuluvath PJ. "Acute hepatitis C". Lancet (2008).372(9635): 32132.

Springer V. Chronic Hepatitis C Virus Advances in Treatment, Promise for the Future. (2011). pp. 103
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10

El-Zayadi, AR. "Hepatic steatosis: a benign disease or a silent killer". World journal of
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11

Carreo, V; Bartolom, J; Castillo, I; Quiroga, JA. "New perspectives in occult hepatitis C virus infection.".
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12

Rosen, HR. "Clinical practice. Chronic hepatitis C infection". The New England Journal of Medicine
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13

Coburn, CA; Meinke, PT; Chang, W; Fandozzi, CM; Graham, DJ; Hu, B; Huang, Q; Kar gman, S;
Kozlowski, J; Liu, R; McCauley, JA; Nomeir, AA; Soll, RM; Vacca, JP; Wang, D; Wu, H; Zhong, B; Olsen,
DB; Ludmerer, SW. "Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity".
ChemMedChem (2013). 8 (12): 193040
14

Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway
MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer
SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S,
Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ.
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15
Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, Alric L, Bronowicki JP, Lester L,
Sievert W, Ghalib R, Balart L, Sund F, Lagging M, Dutko F, Shaughnessy M, Hwang P, Howe AY, Wahl J,
Robertson M, Barr E, Haber B. Efficacy and safety of 12 weeks versus 18 weeks of treatment with
grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1
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16

C-EDGE Head-to-Head Study: once daily oral combination of elbasvir and grazoprevir versus
sofosbuvir and pegylated interferon alpha 2b + ribavirin (2016).
17

Hepatitis C Society Esofosbuvir cost around the world http://esofosbuvir.com/harvoni-cost-in-usacanada-europe-egypt-india/