Munir et al. Virology Journal 2010, 7:296
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REVIEW
Open Access
Hepatitis C Treatment: current and
future perspectives
Saira Munir†, Sana Saleem†, Muhammad Idrees*, Aaliyah Tariq, Sadia Butt, Bisma Rauff, Abrar Hussain
, Sadaf Badar, Mahrukh Naudhani, Zareen Fatima, Muhmmad Ali, Liaqat Ali, Madiha Akram, Mahwish Aftab,
Bushra Khubaib, Zunaira Awan
Abstract
Hepatitis C virus (HCV) is a member of Flaviviridae family and one of the major causes of liver disease. There are
about 175 million HCV infected patients worldwide that constitute 3% of world’s population. The main route of
HCV transmission is parental however 90% intravenous drug users are at highest risk. Standard interferon and
ribavirin remained a gold standard of chronic HCV treatment having 38-43% sustained virological response rates.
Currently the standard therapy for HCV is pegylated interferon (PEG-INF) with ribavirin. This therapy achieves 50%
sustained virological response (SVR) for genotype 1 and 80% for genotype 2 & 3. As pegylated interferon is
expensive, standard interferon is still the main therapy for HCV treatment in under developed countries. On the
other hand, studies showed that pegylated IFN and RBV therapy has severe side effects like hematological
complications. Herbal medicines (laccase, proanthocyandin, Rhodiola kirilowii) are also being in use as a natural and
alternative way for treatment of HCV but there is not a single significant report documented yet. Best SVR
indicators are genotype 3 and 2, < 0.2 million IU/mL pretreatment viral load, rapid virological response (RVR) rate
and age <40 years. New therapeutic approaches are under study like interferon related systems, modified forms of
ribavirin, internal ribosome entry site (HCV IRES) inhibitors, NS3 and NS5a inhibitors, novel immunomodulators and
specifically targeted anti-viral therapy for hepatitis C compounds. More remedial therapies include caspase
inhibitors, anti-fibrotic agents, antibody treatment and vaccines.
Background
Hepatitis C virus (HCV) is a meticulous factor of liver
disease and one of the most important health issues
worldwide [1,2]. Hepatitis C has approximately 175 million Global Disease Burden which represent almost 3%
of the whole population in the world, each year 3 to 4
million new patients with HCV are diagnosed. HCV
remains endemic in many countries of the world [3-5].
Statistics based on general healthy population revealed
that HCV has 5.3% seroprevalence in Pakistan, 2.2% in
Turkey and 7.7% in Zimbabwe [6-8]. Hepatitis C virus
infection is not a main factor of mortality in the first
decade of infection [9]. Even though, the biological
aspects of HCV are revealed to a great extent in recent
years, an absolute therapy of hepatitis C remains
* Correspondence: idrees.khan96@yahoo.com
† Contributed equally
Division of Molecular Virology & Molecular Diagnostics, National Centre of
Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
problematic in a large majority of patients [10] and
about 50% HCV patients does not attain sustained virological Responses [11-13].
A few years back, it was not easy to study HCV in
invitro because there was no proficient system present
but fortunately Heller et al got success in establishing in
vitro model of HCV virions. This system proves good
for high level production and secretion of HCV virions
hence this system expands the scope of tools present for
HCV study [14,15]. Many patients remain asymptomatic
for years and are only detected on health screening or
at the time of blood transfer [16]. Peg. INF and ribavirin
therapy is still the therapy of choice for HCV patients
besides having many side affects [17,12]. As HCV is
mainly a chronic disease and progress very slowly therefore persistent infection is a typical characteristic of disease which can be found in approximately 75% patient
at primarily stage. Prospective studies conducted on natural history suggest that HCV take almost 20 years to
© 2010 Munir et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Munir et al. Virology Journal 2010, 7:296
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develop cirrhosis and only 20% of cirrhotic patient can
develop Hepatocellular Carcinoma (HCC) after 40 years
of preliminary infection [18,10].
HCV genotypes and treatment response
Patients with different HCV genotypes react in a different way to alpha interferon because genotype is one of
the strongest prognostic aspects of sustained virological
response [19,20]. This clinical importance of HCV genotype was revealed by clinical studies based on interferon
treatment response account [5]. Patients show more sustained virological response when suffered from HCV
genotype 2 and 3 as compared to HCV infected persons
of genotype1 [6]. Patients infected with HCV genotype 2
and 3 show 65% SVR and patients with HCV genotype
1 show 30% Sustained Virological Response (SVR) [7,8].
Thus genotype of patients must not be over looked
when giving standard interferon therapy. Different ethnic groups respond differently to standard therapy of
HCV and hence there is variation in Early Treatment
Response (ETR) and SVR rates [21].
Mechanism of Pathogenesis and interferon resistance
Now a number of mechanisms associated with escape of
the pathogen from the host’s immune response, hepatocyte damage and molecular oncogenesis of hepatocellular carcinoma have been elucidated. Inefficient clearance
of virus from patient’s body is basically due to the
hyper-variability of virus envelope protein that enables
HCV to neutralize antibody [22,23]. Once the virus
enters the hepatocytes through receptor mediated endocytosis and starts replication, it initiate damaging of
hepatocyte, the major component of which is through
the host’s own immune response [24,23]. Interferon is
the most potent natural weapon of the host against
intra-cellular viral infection. HCV, however, owing to
intricate actions of its genomic proteins is equipped
with ability to evade the natural interferon-mediated
clearance. HCV core protein has been reported to
decrease the robustness of the host’s immune response
by decreasing transcription of interferon induced antiviral genes [25,23]. HCV NS3/4A protease also has been
concerned in inhibiting the interferon amplification loop
which otherwise results in suppression of HCV replication. Inhibition of HCV protease can reverse the effects
of HCV infection that make protease inhibitors one of
the most noteworthy potential therapeutic agents for
HCV [26,25].
Route of transmission and treatment response
At first, it was believed that most frequent route of
transmission of HCV was blood transfusion and intravenous drug abuse. But recent epidemiological studies
suggest further routes of transmission [27]. The main
Page 2 of 6
route of HCV transmission is parental. However 90%
intravenous drug users are at highest risk of getting
HCV infection such as those who require multiple
blood transfusions and blood products (hemophiliacs) or
those who go through major surgery [28,29]. Unlike
HBV, HCV infection transfer less frequently by sexual
or intimate contact (0.4 to 3%). Domestic contacts are
also at low risk [30]. Almost 5% HCV infections are
caused by needle stick injury [29,30]. 3% to 5% infants
acquire HCV from infected mother by perinatal transmission [31]. HCV is present in saliva and milk but
transfer of HCV infection through breast milk has not
been reported [32,33].
Community barbershops also play a key role in HCV
transmission in under development countries [27].
Some other reported risk factors of disease transmission are dental and surgical treatments, circumcision,
ear piercing, tattooing and dialysis [34-36]. In a study
conducted on 3351 patients of HCV in Pakistan it has
been documented that more than 70% hepatitis C
infections are spread in hospitals by the use of same
needle several times and major or minor operations
that are extremely frequent in Pakistan. Globally reuse
of needles is also common source of transmission [37].
Studies show that RVR and SVR are independent of
transmission routes of HCV.
Base line diagnosis
Detection of anti HCV by ELISA is the initial step in
diagnosis of HCV infection and it is more than 99% sensitive and specific [38]. PCR is the second main step in
the analysis of chronic HCV infection and exposure of
virus is usually detectable within 7 to 21 days [39,40].
Liver biopsy is also an important parameter in diagnosis
of chronic HCV infection but as persons infected with
genotype 2/3 respond well to standard therapy, treatment can be started without liver biopsy [40].
Therapy for HCV infection
Chronic HCV is treated with a glycoprotein commonly
known as interferon (INF) alpha and it is considered
the backbone of therapy because it efficiently increases
the immune response against virus [41]. Afterward
interferon plus ribavirin become a gold standard (3
MIU thrice weekly along with ribavirin 800 to1200 mg
per day). This treatment enhances SVR rate up to 3843%. As SVR greatly depend on HCV genotype so genotype 1 needs treatment for 48 weeks to achieve SVR of
29% and genotype 2 and 3 needs treatment up to 24
weeks to attain SVR rate of 66% [42]. Currently the regular treatment of HCV is pegelated interferon (PEGINF) in combination with ribavirin. This therapy
achieves SVR of about 50% for genotype 1 and 80% for
genotype 2 & 3 [43].
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There are two types of pegylated interferon; PEG-IFNalpha-2a and PEG-IFN-alpha-2b. These are dissimilar
only by size and configuration of the polyethylene glycol
molecules that has binding sites for interferon. The functioning of these two formulated interferon not compared
still but both are equally good for HCV treatment [44].
Current HCV therapy for genotypes 2a to 2b, 3a to
3d, 5a, 6a and mixed genotypes infected patients is 3
subcutaneous injections of 3 MU of recombinant interferon alpha and ribavirin (10 mg per day per kg body
weight) in one week for 6 months. Individuals infected
from HCV genotype 1a to 1c, 4 and mixture of 1 and 4
HCV genotypes should receive three 3 MU subcutaneous injections of recombinant IFN alpha and ribavirin
that are given orally (for individuals with ≤ 75 kg body
weight) require 1,000 mg per day, for patients with > 75
kg body mass require 1,200 mg per day) in a week for
total 48 weeks [45].
Conventional interferon (C-INF) therapy is used for
HCV treatment in poor countries because of financial
reasons and Pakistan Society of Gastroenterology and
GI Endoscopy also recommend the use of C-INF therapy for HCV genotype 3 in Pakistan [46,40]. In under
developed and developing countries including Pakistan,
pegylated interferon therapy is beyond the reach of
common poor patients [47,40]. In 2001, FDA permitted
two kinds of PEG-INF (i) PEG-INF Alpha 2a (40 KD)
and (ii) PEG-INF Alpha 2b (12 KD). These are administered only once a week because they have long half life
of plasma (almost 10 times) in comparison with conventional INF. Liver primarily metabolizes PEG-INF Alpha
2a and kidney excretes out PEG-INF Alpha 2b. Recent
studies and clinical trials confirmed that SVR rates
could be increased by the using mono therapy with
PEG-INF 2a or PEG-INF 2b in comparison with conventional interferon [48,40].
Limitations of Recent HCV Therapy
It has been reported that 40% to 50% patients with HCV
genotypes 1 and or 4 early attain SVR in comparison
with 80% patients infected with genotypes 2 and or 3
[4,49]. However PEG-IFN and ribavirin treatment has
severe side effects. Major complications of standard
interferon and ribavirin therapy are anemia, cytopenias,
neutropenia and thrombocytopenia as elucidated in
table 1.
Novel types of interferon alpha (albinterferon) are
under study; these might be very suitable anti-viral therapy because these can be given just once or twice a
month as compared to standard PEG-IFN therapy [4,49].
Taribavirin, a recently introduced drug, is tested in various randomized trials that show low efficacy but also has
a few complains of anemia and the side effects are easily
manageable [50,4]. There are also several side affects
Page 3 of 6
associated with conventional interferon and ribavirin
therapy including Influenza like sign and symptoms. For
example headache, myalgias or arthralgias, fever, anorexia, nausea or vomiting, fatigue, abdominal pains,
insomnia, suicide attempt, pruritis, anaemia, redness at
injection site, dry skin, leucopoenia, irritability, thrombocytopoenia, anxiety, psychosis and laryngitis [51].
Herbal treatment
There is no effective vaccine developed or excellent drug
available for the treatment of HCV. Standard INF therapy in combination with ribavirin show sustained virological response with efficacy of not more than 50%,
therefore most of the patients try herbal medicine and
conventional medicine all over the world particularly in
poor countries. Laccase are largely used as herbal medicine that is extracted from oyster mushroom (Pleurotus
ostreatus). Studies showed that laccase is proficient in
inhibiting the HCV replication rate [52] however the
mechanism of action of this medicine is not known.
Herbal treatment can open a natural and alternative
way for treatment of HCV. As Hepatitis C virus infects
liver and this infection requires two or more decades to
extend into substantial disease, a nutritional supplement
might facilitate to decrease or stop disease development.
More recent studies regarding herbal treatment provoke
a hope for HCV patient that is based on a chemical
known as proanthocyandin, extracted from blueberry
leaves. It has been reported that proanthocyandin can
stop HCV replication in infected patients [53]. According to another study rhizomes of the Chinese medicinal
herb Rhodiola kirilowii may also act as possible inhibitor
of HCV [54].
Factors affecting treatment response
Treatment response is better in patient of less than 40
years of age in comparison with elderly. Young females
respond well to the treatment. High intensity of viremia is related with deprived response. Immunodeficiency, excessive use of alcohol and co-infection with
HIV or HBV, all harmfully cause the result to HCV
infection [55,16].
HCV therapy is not suitable for people suffering from
severe HCV related cirrhosis, undergone organ transplant, children of <3 years and specific contraindication
to the medication. Interferon causes severe side effect
includes, anxiety, irritability personality changes, even
suicide, depression or acute psychosis. Ribavirin side
effect included anemia, renal dysfunction of coronary
artery. Fetal abnormality and fatality are important side
effects of ribavirin, a well-known teratogen.
Due to the distinctive character of the virus to develop
vaccine against HCV leftovers, a disappointment has
been seen due to its high mutation rate. It has already
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Table 1 Contraindications situations for pegylated interferon and ribavirin therapy
Contraindications levels
Situations
No more contraindications
- Regular alanine aminotransferase
- Methadone maintenance
- Anemia/thrombocytopenia and neutropenia
- Restricted seizure
- Age more than 65 years
- Excess use of alcohol
Virtual contraindications
- Depression
- Psychosis
- Autoimmune disorder
- Drug abuser
- Renal failure (with dialysis)
Tough although not general contraindications
-Alcohol use
-Coronary artery disorder
- Hepatic decompensation
- Transplantation of solid organ (except liver)
General contraindications
been reported that the rate of HCV reproduction is high
and the error-prone polymerase causes mutation continuously. The high HCV replication rate provides sufficient chance of mutation that occurs in the viral
population inside an infected person. Production of
virus has been estimated at 1012 (one trillion) new HCV
virions per day [56]. Studies on chronically infected
HCV patients show that rate of mutation in HCV genome has been approximately 0.001 substitutions per
genomic site in one year. Such high rate of mutation
could result into 8-18 mutations within the RNA of 9.6
kb genomic size. It has also been reported that envelop
protein E2 has highly mutated sites known as hypervariable region HVR1. High variation in E2 causes immune
escape mutants of the virus as of the neutralizing antibodies and therefore describes the constant viremia. In
addition to E2 gene, P7 region has also been shown
with increased variability [16].
Future perspectives
New therapeutic approaches are under study like interferon related systems, modified forms of ribavirin,
siRNA, internal ribosome entry site (IRES) inhibitors,
NS3 and NS5a inhibitors and novel immunomodulators.
These are particularly for those patients who show low
SVR rate by traditional therapies. More remedial therapies include antifibrotic agents, caspase inhibitors and
antibody treatment and vaccines. Particularly targeted
antiviral compounds like specifically targeted anti-viral
therapy for hepatitis C’ (STAT-C) compounds are now
under study by scientists that are used along with standard interferon therapy. Reports confirm improved SVR
rate at least in HCV genotype 1 patients. Further studies
are required to confirm its significance in the clearance
- Pregnancy
of HCV RNA if used as a single therapy without interferon and ribavirin [57,58].
Conclusion
Currently chronic HCV treatment consists of pegelated
interferon alpha and a nucleoside analogue ribavirin for
3 to 18 months. However several side effects are associated with this treatment. New therapeutic approaches
are under study and recent clinical trials are being
focused on inhibitors of HCV NS3 and NS5a RNA polymerase. Parameters that increase SVR rate for HCV are
genotype 2 and 3, age < 40 years and low viral load
before treatment.
Abbreviations
HCV: hepatitis C virus; PEG-INF: pegylated interferon; RVR: rapid virological
response; SVR: sustained virological response; RBV: ribavirin; ETR: end of
treatment response; ELISA: enzyme linked immunosorbant assay; PCR:
polymerase chain reaction; MIU: million international units; SDINF: standard
interferon; HVR: hiper variable region; IRES: internal ribosome entry site;
STAT-C: specifically targeted anti-viral therapy for hepatitis C.
Authors’ contributions
SM and SS reviewed the literature, and wrote the manuscript. MI edited the
manuscript. AT, SB, BR, AH, SB, ZA, MN, ZF, MA, LA, MA, MA, BK, helped SM
& SS in literature review. All the authors read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 22 September 2010 Accepted: 1 November 2010
Published: 1 November 2010
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doi:10.1186/1743-422X-7-296
Cite this article as: Munir et al.: Hepatitis C Treatment: current and
future perspectives. Virology Journal 2010 7:296.
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