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Hepatology Research 32 (2005) 146–153
Emerging drugs for chronic hepatitis C
Girish Mahadeorao Bhopale∗, Rabindra Kumar Nanda
Research and Development Division, Hindustan Antibiotics Limited, Pimpri, Pune 411018, India
Received 27 January 2005; received in revised form 18 April 2005; accepted 12 May 2005
Abstract
HepatitisCvirus(HCV)isa major cause ofchronic hepatitis, livercirrhosis and hepatocellular carcinoma worldwide. A combinationtherapy
comprising pegylated interferon and ribavirin currently represents the most effective therapy for chronic HCV infection. The limitations of
this current therapy mainly its efficacy and significant side effects have prompted the development of new drugs. Few categories of therapeutic
agents appear promising for future therapy, e.g. novel interferons, ribavirin analogs, antisense oligonucleotides, short interfering RNAs,
ribozymes, enzyme inhibitors, immunomodulatory agents, antifibrotic agents, therapeutic vaccines and antibodies. Few drugs belong to afore-
mentioned categories have already reached the different clinical phases of development. The present article highlights the status of current
available therapies and emerging drugs for the treatment of hepatitis C.
© 2005 Elsevier B.V. All rights reserved.
Keywords: Hepatitis C virus; Interferon; Ribavirin analogs; Antiviral therapy
1. Introduction
Hepatitis C virus (HCV) is a major cause of chronic hep-
atitis, liver cirrhosis and hepatocellular carcinoma worldwide
[1]. Currently, the most effective therapy for the treatment
of HCV is the combination of pegylated interferon and rib-
avirin. However, the therapy is effective nearly 40–50% in
genotype 1 infected patients with high viral load and about
80–90% in genotypes 2 and 3 infected patients [2,3]. Fur-
ther, the therapy is costly and associated with significant
side effects. Therefore, improvements in current therapies
and/or new drug are needed to treat hepatitis C patients.
The article highlights the status of current available ther-
apies and emerging drugs for the treatment of hepatitis
C.
∗Corresponding author. Tel.: +91 20 2742511;
fax: +91 20 27425327.
E-mail address: girishbhopale@rediffmail.com
(G.M. Bhopale).
2. Hepatitis C virus
2.1. Structure
HCV is a positive stranded RNA virus with a genome of
9.6kilobase [4]. The genome encodes a large polyprotein of
about 3000 amino acids (Fig. 1). Both 5and 3untranslated
regions (UTR) bear highly conserved RNA structures essen-
tial for polyprotein translation and genome replication. At
the 5UTR resides the internal ribozyme entry site (IRES),
which is highly conserved and represents a site for devel-
opment of translation inhibitors such as antisense oligonu-
cleosides and ribozymes. The polyprotein is proteolytically
cleaved into structural and nonstructural proteins. The struc-
tural proteins include the core (C) protein which forms the
viral nucleocapsid and the envelope glycoproteins E1 and E2.
P7 is a small hydrophobic protein. Although it seems to be
located mainly in endoplasmic reticulum membranes, it can
beexportedto the plasma membrane and may havefunctional
roles in the secretary pathway. These properties make it an
attractive candidate target for new anti-HCV drugs. The non-
structural proteins (NS) are NS2, NS3, NS4a, NS4b, NS5a
1386-6346/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.hepres.2005.05.005
G.M. Bhopale, R.K. Nanda / Hepatology Research 32 (2005) 146–153 147
Fig. 1. Schematic representation of hepatitis C virus genome.
and NS5b. The NS3 has both helicase and protease activities
while NS5 contains the RNA dependent RNA polymerase
(RdRp) activity. These enzymatic activities are essential for
HCV replication and are currently considered as promising
targets for the development of new anti-HCV agents [5–7].
2.2. Genotypes
HCV is a heterogeneous virus composed of at least six
major genotypes and multiple subtypes [8]. Genotypes dif-
fer from each other by approximately 30% in amino acid
sequence, whereas subtypes vary by only 5–10% within
genotypes [8]. Genotype is an important predictor of the
response to anti-HCV therapy and its determination is cur-
rently used to tailor treatment indications. Additional vari-
ants, known as quasispecies, may be present within indi-
viduals. Genotypes have distinct geographic distribution. In
WesternEuropeand the United States, the predominant geno-
types are 1, 2 and 3. In most Asian countries genotype 1b is
most common whereas genotype 4 is mostly found in the
Middle East and Africa. Genotypes 5 and 6 seem to be con-
fined to Middle East Africa and Hong Kong, respectively.
2.3. Pathogenesis
HCV enters into susceptible host mainly through either
directly, through needle (injection or transfusion of contami-
natedblood products) or sexually.Acutehepatitis C is marked
by appearance of HCV RNA in serum within 1–2 weeks of
exposure.The pathogenesis of liverdamage is most likelydue
to a combination of direct cytopathic effects of viral proteins
and of immune mediated mechanism. Studies are needed to
understand better the implication of HCV genotypes and qua-
sispecies in pathophysiology of HCV infection.
Both humoral and cell mediated immune responses partic-
ipate in limiting the spread of HCV in early stage of infection
[9]. The HCV may escape from humoral immune response
if the kinetics of infection and viral replication do not allow
complete neutralization of the virus by specific antibodies
[10]. Further, the emergence of viral mutants or quasispecies
with sequence variations in T cell epitopes may contribute
to the apparent ineffectiveness of cell mediated immune
response [11]. Approximately, 85% of cases of acute hepati-
tis become chronic hepatitis C patients [12]. Hepatic fibrosis
is the principal complication of chronic HCV infection lead-
ing to the development of cirrhosis. Studies are needed to
define rates of progression of fibrosis in patients with pro-
longed duration of HCV infection. Approximately, 20–30%
patients progress to cirrhosis during their lifetime with atten-
dant risks of the development of hepatocellular carcinoma
[13].
3. Status of current therapies
3.1. Monotherapy and combination therapy of
interferon and ribavirin
The HCV treatment has evolved from the use of interferon
(IFN) alone to the combination of IFN plus ribavirin. The
effectiveness of IFN monotherapy is unsatisfactory. It varies
withthe duration oftherapyand HCVgenotypes[14,15]. Rib-
avirin monotherapy is also ineffective in inducing sustained
viral clearance. A recent study conducted in Japan to com-
pareIFNplusribavirin with IFN therapy for 24 weeks [16].In
combinationtreatment groups, the percentageof patients who
were HCV negative with 4 weeks decreased with increase
in base line viral levels. In IFN monotherapy groups, the
response rates were lower. Disappearance of virus within 12
weeks after the start of combination was indicative of higher
probability of sustained viral response. The risk of relapse
was more highly correlated with the timing of initial viral
disappearance than base line HCV level; it was 4–10 times
higher in patients who become HCV negative at 4–12 and
13–24 weeks compared with in those who were HCV nega-
tive with 4 weeks.
The IFN potently inhibits the replication of HCV and has
immunomodulatory properties that probably accelerate the
clearance of infected cells [17]. The mode of action of rib-
avirin is less well understood. Further, the mechanism by
which ribavirin enhances IFN efficacy in combination ther-
apy remains unknown. Therefore, it is an obvious need for
greater understanding of the mechanism of action of these
drugs.
148 G.M. Bhopale, R.K. Nanda / Hepatology Research 32 (2005) 146–153
The IFN and ribavirin combination therapy produces a
number of well described side effects that are dominated by
fatigue, influenza like symptoms, hematological abnormal-
ities and neuropsychiatric symptoms [18]. Ribavirin accu-
mulates in red blood cells and causes a dose development
hemolytic anemia of moderate severity [18].
3.2. Combination therapy of pegylated interferon with
ribavirin
Recently, pegylated forms of IFNs (PEG-IFNS) have been
developed with the aim of prolonging the halflife of IFN alfa-
2b and IFN alfa-2a. In the PEG-IFN, the IFN molecule is
linked to a polyethylene glycol (water soluble nontoxic mod-
ular polymer) (PEG) molecule. PEG-IFN alfa-2b utilize a
12KDa PEG linked with a non-covalent bond. This PEG
size results in more rapid subcutaneous absorption, wider
volume of distribution and predominantly renal clearance
[19]. PEG-IFN alfa-2a utilizes 40KDa PEG molecule cova-
lently bound to IFN alfa-2a. The larger PEG results in slower
absorption,primarilyintravascular and organdistribution and
largely hepatic clearance [20].
PEG-IFNalfa monotherapy is more effectivethanIFNalfa
monotherapy but less than the combination of IFN alfa and
ribavirin [3,21–24]. The addition of ribavirin to PEG-IFN
alfa-2a or PEG-IFN alfa-2b has improved efficacy [3,24].
The combination of PEG IFN alfa and ribavirin is now the
besttherapyfor the treatment of chronic hepatitis C [25]. This
therapydepends on theHCV genotype. Ingeneral,genotype 1
requires 12-months therapy with PEG-IFN once a week sub-
cutaneously in combination with 1000 mg ribavirin (patients
>75kg 1200 mg) orally per day. In case of genotypes 2 and
3, 6-months therapy with PEG-IFN and 800mg ribavirin is
sufficient. The relative virological response rates to therapy
for genotypes 4–6 are less well defined but they probably
more closely resemble genotype 1 rather than genotypes 2
and 3.
Despite these improvements in current therapy, less sat-
isfactory results have been obtained in certain patient pop-
ulations. Several virus and host factors are associated with
significantly lower virological response rates to the therapy
[26,27]. Viral response to therapy differs among genotypes.
Sustained virological response rates in patients with geno-
type 1 are only half of these in patients with genotype 2
or 3 [3,21,23,24,28]. Patient related factors include previ-
ous nonresponders to IFN therapy, the presence of cirrhosis,
African–American ethnicity, older age contraindications to
therapy and possibly obesity [27]. An important cause of
therapy failure is poor adherence or nonadherence to ther-
apy. Another risk factor is addictive behavior such as active
alcohol or intravenous drug use.
Asan increasing number of chronichepatitisC patients are
treated, the number of nonresponders to currently available
therapies will also rise. The growing numbers of these non-
responder patients highlights the need for the development
of more efficacious anti-HCV therapies.
4. Emerging drugs
4.1. Novel interferon’s and interferon delivery systems
Beyond PEG-IFN, few novel parenteral IFNs such as
Omega, Multiferon and Albuferon are in clinical phase II
(Table 1)[7]. Recent study showed that Albuferon reduces
significant viral load in patients who have failed prior IFN
therapy [29]. Oral agents that can stimulate the production of
IFN are also under clinical phase of evaluation. ANA 245, a
low molecular weight nucleoside analog that induces multi-
ple cytokines including IFN showed significant reduction of
viral load [7]. Resiquimod is currently in phase II studies for
chronic viral hepatitis [7].
Novel delivery system for sustained IFN release into
circulation, viz. disposable infusion pumps (hold 3 days
reservoir of drug) controlled release injectables (using a
polymer matrix) delivered either intramuscular or sub-
cutaneous, a polyamino acid based oral delivery system
and encapsulation in liposomes, are under development
[30].
4.2. Ribavirin analogs
Hemolytic anemia is a frequent side effect that lim-
its ribavirin dosing, emphasizing the need for alternative
molecules. Levovirin (l-isomer of ribavirin) has similar
immunomodulatory activity as ribavirin. It is not phospho-
rylated in RBCs and therefore is less toxic [31]. In a clinical
phase 1 study, it was safe and well tolerated when admin-
istered as a single doses of 200–1200mg range [32].A
second ribavirin analogue currently under clinical phase III
is viramidine, the amidine inversion of ribavirin. This pro-
drug is rapidly converted into ribavirin by enzyme adenosine
deaminase, as the liver is exposed to the first pass effect of
oral dosing of the drug [33]. In first phase of clinical trial,
doses up to 1200mg viramidine are safe and well tolerated
[3]. Recent study showed that no significant differences in
antiviral activity were found between Viramidine and rib-
avirin treated patients [34]. However, the incidence of anemia
was significantly lower among patients treated with virami-
dine as compared with ribavirin.
4.3. Antisense oligonucleotides, short interfering RNAs
and ribozymes
Antisense drugs block the synthesis of disease caus-
ing proteins by preventing translation of viral RNA. In
case of HCV, an antisense oligodeoxynucleotide directed
against specific HCV sequence effectively inhibits viral gene
expression [35]. A potential antisense drug ISIS-14803 (a
20 nucleotide phosphorothioate oligonucleotide), is comple-
mentary to highly conserved region of the HCV IRIES [36].
It demonstrated dose dependent anti-HCV activity in vitro
and in vivo models [36]. Clinical phase I or II trial of it indi-
cated significant reduction of HCV RNA in some patients
G.M. Bhopale, R.K. Nanda / Hepatology Research 32 (2005) 146–153 149
Table 1
Drugs for hepatitis C in current clinical development
Drug category Drug name Clinical phase Comments
Interferon Omega Interferon II Genetically engineered Interferon, plan to develop oral prodrug
formulation
Multiferon II Natural alfa interferon, produced from human white blood cells
Albuferon II Interferon alfa fused to albumin molecules, albumin fusion extend
the half life up to 157 h
ANA 245 I/II Low molecular weight nucleoside analog that induces multiple
cytokines including IFN alpha
Resiquimod II Induced number of cytokines including IL-12, IL-1, IL-6 IFN alpha,
TNF alfa and neopterin
Ribavirin analogs Levovirin I l-isomer of ribavirin, associated with lesser degrees of hemolytic
anemia
Viramidine III Prodrug which gets rapidly converted into ribavirin in vivo
Antisense oligonucleotides ISIS-14803 II Genetically inhibits translation (production) of disease-causing
proteins, clinical trials combining with pegylated/ribavirin are
underway
Ribozymes Heptazyme II Cleaves RNA at a point to interrupt life cycle of virus, trials
temporarily halted because of animal toxicity
Enzyme inhibitors BILN 2061 II Serine protease inhibitor, further clinical trials on hold due to
potential toxicities in monkeys
VX-950 I Protease inhibitor, Clinical evaluation underway
NM-283 II RpRd polymerase inhibitor, oral nucleoside analogue, a novel drug
that after absorption metabolized to form that inhibits HCV RNA
JTK 003 I/II RpRd polymerase inhibitor, a nonnucleoside
Merimebodib (VX-497) II IMPDH inhibitor, studies awaited to confirm efficacy in combination
with IFN
Mycophenolate mofetil I IMPDH inhibitor an Immunosuppressive drug, evaluation of efficacy
combined with IFN in progress
Immunomodulatory agents Histamine dihydrochloride II Exhibits immunomodulatory effects. Evaluation of efficacy in
combination with PEG-INF is in progress
Thymosin alfa-1 III Stimulate the immune system, use in combination with IFN is in
progress
Amantadine IV Antiflu agent, studies are needed to confirm its benefits in HCV
treatment
Antifibrotic agents Interferon gamma II Reversal of liver fibrosis as determined by histological scoring
system, studies for milder disease is pending
Interleukin-10 II Reduces fibrosis. However in 12-months follow up study, there was
an increase in HCV RNA levels
Interleukin-12 II Minimal efficacy in virological and histological response with
significant toxicity
Therapeutic vaccine Envelope protein 1 II Improvement in liver fibrosis
Peptide IC41 II Capable of inducing both IFN gamma secreting cytotoxic and helper
T cells
Antibodies Monoclonal antibodies I/II Reduce viral level, use to prevent reinfection in CHV associated liver
transplant patients
Immunoglobulin II Inactivated pooled immunoglobulin, prevent hepatitis C disease in
HCV positive liver transplant patients
[37]. Further clinical trials with pegylated IFN/reibavirin are
currently underway.
Small interfering RNAs (siRNAs) drugs inhibit gene
expression by blocking specific mRNA [38]. Stabilized
siRNA drugs are under preclinical evaluation for their poten-
tial activity against HCV.
Ribozymes are catalytic RNA molecules that cleave spe-
cific RNA sequence and disrupting the viral lifecycle of
HCV. Heptazyme (a synthetic ribozyme) [39] is an HCV spe-
cific ribozyme designed to target and cleave the HCV IRES.
Although phase 1 studies suggested a good safety profile, pri-
mate toxicological studies have halted current drug studies.
4.4. Enzyme inhibitors
Thenonstructural proteins encode proteases,helicasesand
polymerases. These enzymes are novel targets for develop-
ment of anti-HCV drug. Inhibition of either enzyme would
disrupt HC RNA strand synthesis prevention the produc-
tion of genomic HV RNA for new virions. BILN 2061 is
150 G.M. Bhopale, R.K. Nanda / Hepatology Research 32 (2005) 146–153
a potent and specific inhibitor of serine protease [40]. The
results of three exploratory studies indicate that BILN 2061,
administered twice daily over a 2-days period, is effective
and well tolerated in patients infected with HCV [41]. Fur-
ther studies would be needed to determine if prolonged
therapy with either as monotherapy or in combination with
other anti-HCV drugs, leads to a longer lasting effects. Fur-
ther clinical trials halted due to toxicity concerns. Another
promising NS3 protease inhibitor is VX950 [7]. It is orally
bioavailable in several species with favorable pharmacoki-
netic profile. The uptake of drug is characterized by first
pass hepatic extraction resulting in high concentrations of
drug in the liver, which should be advantageous for the treat-
ment of chronic HCV. Further, studies expected to begin
shortly.
Theprimary function ofNS3 helicase istounwind the viral
genomic RNA during HCV replication. In vitro activity of
few NS3 helicase inhibitors has been reported [7]. However,
efficacy of viral helicase inhibitors in clinical trials remains
to be established.
There are few HCV RdRp polymerase inhibitors. NM283
isa novelanti-HCVdrug that, afterabsorption,is metabolized
toaformthat inhibits the HCV RNA polymerase [7]. In phase
I or II clinical trial, it demonstrated consistent dose related
anti-HCV effects with satisfactory safety profile. Phase II
clinical trials of NM283 have demonstrated reduction in viral
load when used as a monotherapy or in combination, with
pegilated IFN [42]. JTK 003 is also a promising candidate
currently in phase II clinical trials in Japan [7].
Merimepodib (VX-497) is an enzyme inosine monophos-
phate dehydrogenase (IMPDH) inhibitor. IMPDH inhibition
leads to a reduction in intracellular guanosine triphosphate
(GTP),amoleculerequired for DNA and RNAsynthesis. The
results of multicenter trials of it with IFN showed no signif-
icant additive reduction in HCV RNA [43]. Phase II clinical
study showed that Merimepodib enhanced the antiviral effect
of peginterferon/ribavirin combination therapy without exac-
erbating ribavirin associated anemia [44]. Mycophenolate
mofetil, another IMPDH inhibitor alone does not appear to
have significant antiviral effect [45]. A combination of it with
PEG-IFN is currently under investigation.
4.5. Immunomodulatory agents
Several parenterally administered immunomodulatory
drugs are currently being used in combination with IFN or
PEG-IFNin clinical trials. Histamine dihydrochloride (HDC)
exhibits various immunomodulatory effects by way of T cells
and natural killer cells and inhibits phagocyte derived oxida-
tive stress and inflammation. A phase II clinical trials showed
that HDC treatment combined with IFN-alpha-2b yielded
sustained virological responses between 31 and 38% depend-
ing on HDC dosing regimen [46]. Clinical trials evaluating
the safety and efficacy of the triple combination of PEG-IFN-
alpha, ribavirin and histamine in HCV infected patients are
going on.
Thymosin-alfa 1 (synthetic 28 amino acids nonglyco-
sylated peptide derived from thymus gland extracts) has
immunoregulatory activity. It seems to stimulate the produc-
tionof IFN-gamma, interleukin(IL)-2and IL-3. Combination
treatment of it with IFN showed significant higher efficacy
than monotherapy [47]. It is currently being evaluated in
phase II or III trials with pegylated IFN alfa in HCV infected
patients who did not respond to current effective therapy.
Amantadine is an antiviral agent successfully used against
influenza A virus infection. A higher sustained response was
reported with IFN and amantadine than the IFN treatment
alone[48].Triple therapy with PEG-IFN, ribavirinand aman-
tadine may lead to a higher SVR in HCV patients after
virologic relapse; however, data remain controversial [49].
Further studies are needed to confirm the benefit of amanta-
dine.
4.6. Antifibrotic agents
The most effective way to eliminate hepatic fibrosis is
to clear the primary injury of liver disease. Therefore, cura-
tiveantiviraltherapyremains the best ‘Antifibroticapproach’.
Gamma IFN has activity both as an immunomodulator and
as an antifibrotic cytokine. A clinical trial is in progress to
test recombinant gamma 1b to improve histological fibro-
sis in chronic hepatitis patients with advanced fibrosis. IL-
12 indicated minimal efficacy in virological and histologi-
cal response with significant toxicity [50]. IL-10 treatment
reduces fibrosis, but there was an increase in HCV RNA lev-
els in patients during 12-months follow up study [51].
4.7. Therapeutic vaccines
Recent data on immune responses in the chronic phase
of infection suggest that a therapeutic vaccine of stimulating
functional CD4+ and CD8+ T cell responses in the chronic
carrier may benefit [52,53]. Targets for DNA vaccine devel-
opments are mainly envelope glycoprotein (E1 or E2), core
antigen and nonstructural proteins (NS3, NS4, NS5) [54].
A vaccine, based on purified versions of envelope protein 1
(E1) showed improvement in liver fibrosis [7]. Vaccination
with synthetic HCV peptides induces IFN gamma secreting
cytotoxic and helper T cells when administered with the T
ell adjuvant poly-l-arginine. The new synthetic peptide IC41
vaccine is capable of inducing both IFN gamma secreting
cytotoxic and helper T cells in patients that are not respond-
ing or relapsing from standard therapy [55].
4.8. Antibodies
A novel therapeutic strategy is to use human monoclonal
antibodies to treat HCV. The results of first monoclonal
antibodies XTL-002 (human monoclonal antibody directed
against E2) in phase 1a study indicated that HCV viral RNA
levels were reduced in over half the patients after admin-
istration of different doses [56]. No serious adverse events
G.M. Bhopale, R.K. Nanda / Hepatology Research 32 (2005) 146–153 151
were reported. Further clinical trial is currently underway
to determine whether it can prevent recurrence of HCV
viremia in chronically infected patients undergoing liver
transplants. HCV-AB68 was also found to be safe and well
tolerated antibody which showed significant reductions in
HCV viral RNA levels [56]. A phase I/II multiple infusion,
dose escalating clinical study is currently underway. Sim-
ilarly, immunoglobulin (prepared from inactivated, pooled
HCV positive sera) is also in phase I or II [7].Itwas
well tolerated in liver transplant patients and produced a
trend toward a reduction in serum alanine aminotransferase
level.
4.9. Miscellaneous agents
The putative viroporin activity of HCV protein 7 (p7) may
provide another target for drug discovery. In vitro studies
show that amantadine can block p7 ability to form ion chan-
nels [57]. NN-DGJ is an imino sugar derivative appears to
interfere with viral replication by blocking the formation of
ion channels of p7 [58]. UT-231B entered into phase II trial
[7].
Herbal remedies, an alternative remedies including milk
thistle(activeagent silymarin), licorice root (activeagent gly-
cyrrhizin), thymic extract and traditional Chinese medicine
have also been proposed to have beneficial effects in chronic
HCV infection [59,60]. Data on the safety and efficacy of
these agents is limited and often ambiguous [61,62].
Recent reports suggested that cyclosporine A (CsA) can
inhibitHCV replication in vitro[63,64].This anti-HCV activ-
ity of CsA appeared to be independent of its immunosuppres-
sive function.
5. Future research needs
1. Thereisa need to develop reliable, reproducibleandeffec-
tive culture system for propagating the HCV. The system
willassistinnewdrug discovery as well as enhance under-
standing of the mechanism of development of resistance
to current and future anti-HCV therapies.
2. Characterization of HCV structure may define few novel
targets for drug design. Putative stem loops and ribonu-
clease P-sensitive sites have been identified in the coding
region of HCV positive strand RNA. The biological func-
tion of these structures is currently unknown but their
existence could be exploited for therapeutic purposes.
3. Studies are required to clarify the effect of host immune
response on IFN-∝therapy treatment outcomes, which
may provide therapeutic targets for improving its efficacy.
4. Available data indicated that nonstructural NS5a protein
likely plays a critical role in viral pathogenesis and may
allow to evade the host interferon system. Whether this
is a part by interacting with inhibiting interferon induced
protein kinase, GRB-2 or other unknown interactions is
yet to be determined.
5. Randomized controlled trials needed to be carried out in
different patient population to address the safety and effi-
cacy of future multi drug regimens. Further studies also
needed evaluation of pharmacologic interaction between
different classes of drug given in combination.
6. Investigations are needed into the role of fatty liver, obe-
sity,diabetesand hepatic iron storesin response to therapy.
7. Research is also needed to define the best approaches to
treat HCV in active drinkers, prisoners, those coinfected
with HIV and patients with concurrent renal disease.
6. Conclusions
It appears that the limitation of current standard therapies
for chronic HCV infection has prompted the development
of novel therapeutic agents. The development of effective
anti-HCV therapy has been hindered by several factors espe-
cially genetic heterogenecity of HCV, lack of available cul-
ture system or animal models, limited understanding of the
mechanisms of action of current therapies and the long delay
betweeninitiation of therapy and determinationofvirological
responses. Despite these limitations, progress has been made.
Few new HCV drugs are currently in clinical phase of devel-
opment. A large scale phase III clinical trials of Albuferon
willstart soon. Viramidineand thyroxin are currentlyinphase
IIIclinical trials forthe treatment ofchronichepatitis C. BILN
2061, NM283 and Merimepobid have demonstrated promis-
ing results. Monoclonal antibodies and immunoglobulin are
currently in phase I/II clinical trials for preventing reinfection
of transplanted organs. Each of these represents an important
advance in the treatment of HCV infection. It is clear that
only a few of these drugs will finally be approved for human
use.
Although, new drugs are clearly on the horizon, that hori-
zon still remains at a substantial distance. Until then, meticu-
lous attention to compliance and adherence to optimal dosing
regimensfor pegylated interferon andrivavirinisthe best way
to achieve the most propitious outcome.
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