Direct-Acting Antivirals For Chronic Hepatitis C Treatment

38 Pages·2017·0.22 MB·English

Viral Hepatitis
Chapter 1
Direct-Acting Antivirals For Chronic
Hepatitis C Treatment
Roberto Pontarolo1*, Helena Hiemisch Lobo Borba1,
Vinicius Lins Ferreira1, Maria Lucia Alves Pedroso2, Astrid
Wiens Souza1 and Fabiane Mateus Siqueira3
1Pharmaceutical Sciences Postgraduate Program, Universi-
dade Federal do Paraná, Brazil
2Gastroenterology Service, Hospital de Clínicas, Universidade
Federal do Paraná, Brazil
3Pharmaceutic Assistence Postgraduate Program, Universi-
dade Federal do Paraná, Brazil
*Corresponding Author: Roberto Pontarolo, Department of
Pharmacy, Universidade Federal do Paraná, Av. Pref. Lothario
Meissner, 632, Jardim Botânico, 80210170 - Curitiba, PR, Bra-
sil, Tel: + 55 41 33604094; Email: [email protected]
First Published June 16, 2017
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Viral Hepatitis
Copyright: © 2017 Roberto Pontarolo, et al.
This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to
the original author(s) and the source.
Abstract
Chronic hepatitis C currently affects 71 million peo-
ple worldwide. The chronic phase of the disease can re-
sult in serious health conditions such as cirrhosis, hepa-
tocellular carcinoma and liver-related deaths. Most of the
patients infected with hepatitis C virus (HCV) need to
receive drug treatment to cure the disease (i.e., achieve
the sustained virological response—SVR). Chronic hepa-
titis C treatments have changed over the last few decades.
Therefore, this chapter aims to perform a review of the
historical treatment for chronic hepatitis C. Interferon
(IFN; and later the pegylated interferon) associated with
ribavirin was the first combined therapy for hepatitis C
treatment, used in combination in a dual therapy regimen
for many years. However, treatment response was less
than that expected, and was related to several side effects.
In 2011, pegylated IFN and ribavirin started to be used in
combination with the first-generation direct-acting anti-
virals (DAAs; boceprevir and telaprevir), in a triple ther-
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apy regimen, for patients with genotype 1, who were the
most difficult to respond to treatment. Albeit the increase
in SVR rates observed with the new treatment approach,
the side effects have become even more serious. In this
sense, second-generation DAAs were developed (elbasvir
+ grazoprevir; sofosbuvir + ledipasvir; paritaprevir/rito-
navir + ombitasvir; paritaprevir/ritonavir + ombitasvir +
dasabuvir; sofosbuvir + simeprevir; daclatasvir + sofos-
buvir; sofosbuvir + velpatasvir; sofosbuvir + ribavirin) to
be used for all hepatitis C genotypes in combination with
or without pegylated IFN (IFN-free therapies). These new
treatments for chronic hepatitis C provide higher rates
of SVR, with a better safety profile. Hence, they are very
promising therapies for HCV-infected patients.
Introduction
The term hepatitis was introduced by Bianchi, J. B.
only in the 18th century [1]. Originally, viral hepatitis were
classified as infectious hepatitis (also termed short-incu-
bation), and as serum hepatitis (described as long-incuba-
tion) [2,3]. It was only in 1947 that the names hepatitis A
(referring to the short-incubation) and hepatitis B (denot-
ing the long-incubation) were introduced by MacCallum,
when differences between the clinical profiles of patients
affected by each type of virus were verified [4]. The second
half of the 20th century was then marked by the identifica-
tion of several types of hepatitis viruses [2,5,7].
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Currently, six different types of viral hepatitis are rec-
ognized: A, B, C, D (delta), E and G [8]. Chronic hepatitis
C is presently considered the leading cause of end-stage
liver disease worldwide [9]. Due to its severity, which
promotes a great impact in terms of public health, new
therapies have been recently developed, with very promis-
ing results [10]. Hence, this chapter addresses the charac-
terization of hepatitis C, highlighting new treatments ap-
proaches that emerged during the last few years.
History and Characterization of Hep-
atitis C
In the mid-1970s, with the advent of serological tests
for the identification of hepatitis A and B viruses, it was
found that the majority of cases of post-transfusional hep-
atitis were non-A, non-B hepatitis [11]. Subsequently, in
1989, Choo et al identified the hepatitis virus C (HCV),
and it was proved that most cases of non-A and non-B
hepatitis were due to HCV. This virus is an RNA that be-
longs to the Flaviviridae family [12,13].
HCV presents seven genotypes (classified from 1 to
7) and 67 subtypes (classified as 1a, 1b, 2a, 2b, among oth-
ers) [14]. The virus is distributed all over the globe, with
a higher prevalence in Asia and Africa. However, a lower
prevalence of HCV is observed in more industrialized re-
gions such as North America and Europe [15]. Genotypes
1, 3 and 4 are the most prevalent in the world [14].
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The virus is formed by RNA and an envelope, which
surrounds the nucleocapsid of the HCV. RNA is responsi-
ble for translation of important proteins for virus survival,
including three structural proteins and seven proteins that
are non-structural. The structural proteins compose the
envelope (E1 and E2 proteins) and the nucleocapsid (core
protein) [16-22]. However, the non-structural proteins are
necessary for virus replication that includes p7, NS2, NS3,
NS4A, NS4B, NS5A and NS5B proteins [16,23,24].
Hepatitis C may present two stages of the disease
viz., acute and chronic, although the acute form is hardly
recognized as hepatitis C is usually asymptomatic. Acute
hepatitis C is characterized as the period right after the
infection, i.e., the first six months after the initial con-
tamination with the virus. About 15–45% of infected per-
sons spontaneously clear the virus within six months of
infection without any treatment. The remaining 55–85%
of persons will develop chronic HCV infection. Of those
with chronic HCV infection, the risk of liver cirrhosis cor-
responds to 15–30% within 20 years [2,25,26].
It is estimated that there are more than 71 million
people chronic infected with HCV and it causes 399,000
deaths per year. Eastern Mediterranean and European Re-
gions present the highest number of infected individuals
[27].
The main routes through which HCV is transmitted
involves direct contact with contaminated blood, includ-
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ing the use of injectable illicit drugs, blood transfusions
and transplantation from donors infected with the virus
[28]. Vertical and sexual transmission, as well as proce-
dures performed without proper safety (such as tattoos
and piercings), were also described as possible routes for
HCV infection [16].
Hepatitis C is considered the leading cause of end-
stage liver disease and liver transplantation worldwide
[29,30]. Due to epidemiological aspects (i.e., wide global
distribution, high rate of infected individuals, significant
potential of chronification), hepatitis B and C are un-
doubtedly the most relevant from the perspective of the
public health system [31-33].
HCV infected patients, highlighting chronified, need
to receive drug treatment to cure the disease. As explained
in the following sections, hepatitis C treatment improved
significantly during the last few decades, especially in
the last few years, when antiviral therapy for hepatitis C
reached a level that a higher number of infected patients
could be cured [34,35].
History of Chronic Hepatitis C Treat-
ment
The main goal of antiviral therapy for chronic hepa-
titis C treatment is the eradication of the virus, in order
to prevent disease progression and its associated com-
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plications (e.g., cirrhosis and hepatocellular carcinoma)
[36,37]. Treatment success is measured in terms of sus-
tained virological response (SVR) achievement, defined as
undetectable HCV RNA at 12 or 24 weeks after the end of
the treatment [38]. The response to antiviral therapy may
be influenced by several elements such as, HCV genotype,
severe fibrosis and cirrhosis stage. All these elements are
associated with lower SVR rates. It is important to high-
light, though, that patient adherence to treatment is an
important predictor of SVR. Hence, selection of an appro-
priate drug and establishment of the best treatment ap-
proach are essential to maximize the therapeutic response
[39-41].
This section addresses the progress of hepatitis C
treatments, as therapies without DAAs, until the interfer-
on-free treatments.
Standard Dual Therapy
The treatment of chronic hepatitis C improved signif-
icantly in the recent years. Formerly, monotherapy with
interferon (IFN) alfa, an immunomodulator, was used,
promoting very low SVR rates (approximately 20%). Sub-
sequently, the antiviral medication ribavirin, a synthetic
guanosine analogue, was added to the therapy, increasing
SVR rates to 40%. The addition of ribavirin also reduced
the rates of relapse after treatment cessation [42-44].
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Thereafter, a polyethylene glycol molecule was bonded
to an IFN molecule, originating the pegylated interferon
(PEG-IFN). This process improved the therapeutic regi-
men, as the IFN alfa concentrations could be maintained
after single weekly injections. Hence, instead of three times
a week injections, as occurred with IFN, PEG-IFN could
be administered once a week. In addition, this new mol-
ecule increased SVR rates to 50-60% in HCV genotype 1
infections. SVR improved significantly for genotypes 2, 3,
5 and 6, with rates of approximately 80%. However, SVR
improved moderately in genotypes 1 and 4 [39,43-48].
Both IFN and ribavirin exhibit immunomodulatory
action in addition to antiviral activity, i.e., during the
course of virus elimination these drugs regulate patient’s
immune response [42]. IFN alfa presented potent antivi-
ral properties and was capable of inducing a rapid initial
decline in HCV RNA titers. The addition of ribavirin pro-
moted the improvement in the second-phase HCV RNA
decline elicited by the previously mentioned drug, accel-
erating the viral clearance of the infected cells [49].
IFN or pegylated IFN associated with ribavirin for
chronic hepatitis C treatment was associated to several ad-
verse events, highlighting neutropenia and thrombocyto-
penia. It was also observed to promote alopecia, anorexia,
cough, depression, injection site reaction, fatigue, myal-
gia, nausea and pruritus [50,51]. Ribavirin was associated
to frequent hemolytic anemia due to its permanence in the
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red blood cells and consequent damage to them. Hence,
patients with baseline anemia or other hemoglobin-re-
lated dysfunctions are contraindicated to the use of this
antiviral [42].
Standard dual therapy regimen dictated by the pa-
tient’s weight and viral genotype. IFN was used in the
dose of 5 million units, subcutaneously, three times a
week. PEG-IFN alfa 2b (PEG-Intron) was administrated
in a dose of 1.5 mcg per kg subcutaneously, once weekly.
PEG-IFN alfa 2a (Pegasys) was given in a dose of 180 mcg
subcutaneously, once weekly. When treating HCV geno-
type 1 infection, the associated ribavirin was given in the
regimen of three 200 mg capsules twice daily (a total daily
dose of 1,200 mg) for patients weighting 75 kg or greater;
and two 200 mg capsules every morning and three 200
mg capsules every evening (a total daily dose of 1,000
mg) for patients weighting less than 75 kg. For genotypes
2 and 3, ribavirin was given in the regimen of two 200
mg capsules twice daily (a total daily dose of 800 mg) for
all patients’ weights. For ribavirin and both types of PEG-
IFN, treatment length was 48 weeks for viral genotype 1
and 24 weeks for viral genotypes 2 and 3. The common-
est adverse events observed with the use of standard dual
therapy included alopecia, anorexia, cough, depression,
injection site reaction, fatigue, myalgia, nausea and pru-
ritus [50,51].
Considering the long period of treatment, as well as
the adverse events promoted by these antiviral therapies,
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it was highly necessary the adequate medical support and
long-term patient follow-up, in order to improve SVR
achievement [45].
Triple Therapy with First-Generation DAAs
Boceprevir and telaprevir were the first DAAs devel-
oped for chronic hepatitis C treatment, to be used in as-
sociation with PEG-IFN and ribavirin in a triple thera-
py regimen. The Food and Drug Administration (FDA)
approved these two protease inhibitors in May 2011 for
HCV genotype 1 treatment, the most difficult genotype to
respond to dual therapy at this time [52]. Triple therapy
with the first-generation DAAs promoted a significant in-
crease in SVR rates, reaching 75% of response in clinical
trials with treatment-naïve patients [39].
Boceprevir and telaprevir prevent viral assembly and
replication by targeting the serine protease NS3/4A, a
non-structural protein of HCV that plays an important
role in viral replication, as it is responsible for cleaving the
virus polyprotein at four sites. Despite the high antiviral
efficacy exhibited by the protease inhibitors, they were
prone to the development of resistance. This was due to
the configuration of the active site of NS3/4A serine pro-
tease, which is composed of three highly conserved amino
acid residues. Hence, when DAA therapy was started, the
amount of drug-resistant virus (mutated variants preex-
isting in small quantities within the patient’s quasispecies)
overcomed the wild-type virus, once they gained replica-
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