Book on hepatitis from page 248 to 257
248 Hepatology 2012
boceprevir Phase III studies have revealed a rapid decline of resistant variants below
the limit of detection (>20% of quasispecies) of population sequencing techniques
(Barnard 2011, Sherman 2011). However, telaprevir- and boceprevir-resistant
variants were detectable by a clonal sequencing approach several years after
treatment in single patients who had been treated with telaprevir or boceprevir
within smaller Phase Ib studies (Susser 2011).
NS5B polymerase inhibitors
Molecular biology
HCV replication is initiated by the formation of the replication complex, a highly
structured association of viral proteins and RNA, of cellular proteins and cofactors,
and of rearranged intracellular lipid membranes derived from the endoplasmic
reticulum (Moradpour 2007). The key enzyme in HCV RNA replication is NS5B,
an RNA-dependent RNA polymerase that catalyzes the synthesis of a
complementary negative-strand RNA by using the positive-strand RNA genome as
a template (Lesburg 1999) (Figure 6). From this newly synthesized negative-strand
RNA, numerous RNA strands of positive polarity are produced by NS5B activity
that serve as templates for further replication and polyprotein translation. Because
of poor fidelity leading to a high rate of errors in its RNA sequencing, numerous
different isolates are generated during HCV replication in a given patient, termed
HCV quasispecies. It is reasoned that due to the lack of proofreading of the NS5B
polymerase together with the high replication of HCV, every possible mutation is
generated each day.
NS5B RNA polymerase inhibitors can be divided into two distinct categories.
Nucleoside analog inhibitors (NIs) like valopicitabine (NM283), mericitabine
(R7128), R1626, PSI-7977, PSI-938 or IDX184 mimic the natural substrates of the
polymerase and are incorporated into the growing RNA chain, thus causing direct
chain termination by tackling the active site of NS5B (Koch 2006). Because the
active centre of NS5B is a highly conserved region of the HCV genome, NIs are
potentially effective against different genotypes. Single amino acid substitutions in
every position of the active centre may result in loss of function or in extremely
impaired replicative fitness. Thus, there is a relatively high barrier in the
development of resistances to NIs.
In contrast to NIs, the heterogeneous class of non-nucleoside inhibitors (NNIs)
achieves NS5B inhibition by binding to different allosteric enzyme sites, which
results in conformational protein change before the elongation complex is formed
(Beaulieu 2007). For allosteric NS5B inhibition high chemical affinity is required.
NS5B is structurally organized in a characteristic “right hand motif”, containing
finger, palm and thumb domains, and offers at least four NNI-binding sites, a
benzimidazole-(thumb 1)-, thiophene-(thumb 2)-, benzothiadiazine-(palm 1)- and
benzofuran-(palm 2)-binding site (Lesburg 1999) (Figure 6). Because of their
distinct binding sites, different polymerase inhibitors can theoretically be used in
combination or in sequence to manage the development of resistance. Because NNIs
bind distantly to the active centre of NS5B, their application may rapidly lead to the
development of resistant mutants in vitro and in vivo. Moreover, mutations at the
NNI binding sites do not necessarily lead to impaired function of the enzyme.
Figure 7 shows the structure of selected nucleoside and non-nucleoside inhibitors.
Hepatitis C: New Drugs 249
Figure 6. Structure of the HCV NS5B RNA polymerase and binding sites.
Figure 7. Molecular structure of selected NS5B polymerase inhibitors.
Nucleoside analogs
Valopicitabine (NM283, 2'-C-methylcytidine/NM107), the first nucleoside inhibitor
investigated in patients with chronic hepatitis C, showed a low antiviral activity
250 Hepatology 2012
(Afdhal 2007). Due to gastrointestinal side effects the clinical development of
NM283 was stopped.
The second nucleoside inhibitor to be reported in patients with chronic hepatitis C
was R1626 (4'-azidocytidine/PSI-6130). A Phase 1 study in genotype 1-infected
patients observed a high antiviral activity at high doses of R1626 in genotype 1-infected patients (Pockros 2008). No viral breakthrough with selection of resistant
variants was reported from monotherapy or combination studies with pegylated
interferon ± ribavirin (Pockros 2008). Due to severe lymphopenia and infectious
disease adverse events further development of R1626 was stopped.
Mericitabine (RG7128) is still in development and the most advanced nucleoside
polymerase inhibitor. Mericitabine is safe and well-tolerated, effective against all
HCV genotypes, and thus far no viral resistance against mericitabine has been
observed in clinical studies. Interim results of current Phase II clinical trials in HCV
genotype 1-, 2-, 3-infected patients of R7128 in combination with pegylated
interferon and ribavirin revealed superior SVR rates of mericitabine-based triple
therapy compared to PEG-IFN α alone (Pockros 2011). In an all oral regimen,
administration of R7128 in combination with the protease inhibitor
R7227/ITMN191 for 14 days, a synergistic antiviral activity of both drugs was
observed (Gane 2010). No viral breakthrough with selection of resistant variants has
been reported.
Very promising clinical data have been published recently for PSI-7977, a
nucleoside analog NS5B inhibitor effective against all HCV genotypes. In HCV
genotype 2- and 3- infected patients, PSI-7977 (400 mg once daily) in combination
with ribavirin for 12 weeks + PEG-IFN α for 4-12 weeks resulted in 100% RVR and
100% week 12 SVR rates (Gane 2011). No PSI-7977-associated side effects have
been reported, and no virologic breakthrough has been observed. A second study
evaluated PSI-7977-based triple therapy in treatment-naïve HCV genotype 1-infected patients. In this study, PSI-7977 was administered for 12 weeks, together
with PEG-IFN α and ribavirin for 24 or 48 weeks in total, according to whether
HCV RNA was below the limit of detection at treatment weeks 4 and 12 or not,
respectively (Lawitz 2011). Most patients were eligible for the shortened treatment
duration of 24 weeks, and SVR was achieved in approximately 90% of all patients.
Other nucleoside analogs (e.g., PSI-938 and IDX184) are at earlier stages of
clinical development (Sarrazin 2010).
Overall, the newer nucleoside analogs (PSI-7977, PSI-938) also demonstrate high
antiviral activities that, together with their high genetic barrier to resistance, suggest
that they are optimal candidates for all-oral combination therapies (see below).
Non-nucleoside analogs
At least 4 different allosteric binding sites have been identified for inhibition of the
NS5B polymerase by non-nucleoside inhibitors. Currently, numerous non-nucleoside inhibitors are in Phase I and II clinical evaluation (e.g., NNI site 1
inhibitor BI207127; NNI site 2 inhibitors filibuvir (PF-00868554), VCH-759, VCH-916 and VCH-222; NNI site 3 inhibitor ANA598, NNI site 4 inhibitors HCV-796,
and ABT-333) (Ali 2008, Cooper 2007, Erhardt 2009, Kneteman 2009). In general,
these non-nucleoside analogs display a low to medium antiviral activity and a low
genetic barrier to resistance, evidenced by frequent viral breakthrough during
monotherapy studies and selection of resistance mutations at variable sites of the
Hepatitis C: New Drugs 251
enzyme. In line with these experiences in Phase I studies, a Phase II triple therapy
study with filibuvir in combination with pegylated interferon and ribavirin showed
high relapse and relative low SVR rates (Jacobson 2010). In contrast to nucleoside-analogs, non-nucleoside analogs in general do not display antiviral activity against
different HCV genotypes (Sarrazin 2010). Due to their low antiviral efficacy and
low genetic barrier to resistance, non-nucleoside analogs will probably not be
developed as part of triple therapy but rather as components of quadruple or all-oral
regimens (see below).
NS5A inhibitors
The HCV NS5A protein seems to play a manifold role in HCV replication,
assembly and release (Moradpour 2007). It was shown that NS5A is involved in the
early formation of the replication complex by interacting with intracellular lipid
membranes, and it initiates viral assembly at the surface of lipid droplets together
with the HCV core (Shi 2002). NS5A may also serve as a channel that helps to
protect and direct viral RNA within the membranes of the replication complex
(Tellinghuisen 2005). Moreover, it was demonstrated that NS5A is able to interact
with NS5B, which results in an enhanced activity of the HCV RNA polymerase.
Besides its regulatory impact on HCV replication, NS5A has been shown to
modulate host cell signaling pathways, which has been associated with interferon
resistance (Wohnsland 2007). Furthermore, mutations within the NS5A protein have
been clinically associated with resistance / sensitivity to IFN-based antiviral therapy
(Wohnsland 2007).
BMS-790052 was the first NS5A inhibitor to be clinically evaluated. Even low
doses of BMS-790052 display high antiviral efficacy against all HCV genotypes in
vitro. Monotherapy with BMS-790052 led to a sharp initial decline of HCV RNA
concentrations, though its genetic barrier to resistance is relatively low (Gao 2010).
According to an interim analysis of a Phase IIb clinical trial in treatment-naïve HCV
genotype 1 and 4 patients, treatment with 20 or 60 mg BMS-790052 once daily in
combination with PEG-IFN α and ribavirin for 24 or 28 weeks, 54% of all patients
achieved an extended RVR, compared to 13% in the control group (Hezode 2011).
SVR rates of this study are awaited.
During monotherapy, rapid selection of variants resistant to BMS-790052
occurred (Nettles 2011). The most common resistance mutations in HCV genotype
1a patients were observed at residues M28, Q30, L31, and Y93 of NS5A. In HCV
genotype 1b patients, resistance mutations were observed less frequently,
predominantly at positions L31 and Y93. These resistance mutations increased the
EC50 to BMS-790052 moderately to strongly (Fridell 2011). However, no cross-resistance between BMS-790052 and other DAA agents has been reported.
Collectively, BMS-790052 is a highly promising agent for both triple therapy as
well as all-DAA combination therapy approaches.
Other NS5A inhibitors (e.g., BMS-824393, PPI-461, GS-5885) are in early
clinical development.
252 Hepatology 2012
Compounds targeting viral attachment and entry
The tetraspanin protein CD81, claudin-1, occludine, scavenger receptor class B type
1 (SR-B1), the low-density lipoprotein (LDL) receptor, glycosaminoglycans and the
dendritic cell- /lymph node-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN/L-SIGN) have been identified as putative ligands for E1 and E2
in the viral attachment and entry steps (Moradpour 2007). HCV entry inhibition
might enrich future hepatitis C treatment opportunities, in particular in the
prevention of HCV liver graft reinfection. HCV entry inhibition can be theoretically
achieved by the use of specific antibodies or small molecule compounds either
blocking E1 and E2 or their cellular receptors. So far, only results from clinical
trials using polyclonal (e.g., civacir) (Davis 2005) or monoclonal (e.g., HCV-AB
68) (Schiano 2006) HCV-specific antibodies are available. The clinical benefit of
these antibodies has been poor, however. The development of small molecule entry
inhibitors is in a preclinical stage and is complicated by difficulties in the
crystallographic characterization of HCV envelope proteins.
Host factors as targets for treatment
Cyclophilin B inhibitors
HCV depends on various host factors throughout its life cycle. Cyclophilin B is
expressed in many human tissues and provides a cis-trans isomerase activity, which
supports the folding and function of many proteins. Cyclophilin B enhances HCV
replication by incompletely understood mechanisms, like the modulation of NS5B
activity. Debio-025 (alisporivir) is an orally bioavailable cyclophilin B inhibitor
exerting an antiviral impact on both HCV and HIV replication. In clinical trials in
HIV- and HCV-coinfected patients, treatment with 1200 mg Debio-025 twice daily
for two weeks led to a mean maximal log10 reduction of HCV RNA of 3.6 and of
HIV DNA of 1.0 (Flisiak 2008). Debio-025 was well-tolerated and no viral
breakthrough occurred during the 14 days of treatment.
Combination therapy of Debio-025 200 mg, 600 mg or 1000 mg and PEG-IFN α-2a was evaluated in a double-blind placebo-controlled Phase II trial in treatment-naïve patients monoinfected with HCV genotypes 1, 2, 3 or 4. Treatment was
administered for 29 days. Mean log10 reductions in HCV RNA at day 29 were 4.75
(1000 mg), 4.61 (600 mg) and 1.8 (200 mg) in the combination therapy groups
compared to 2.49 (PEG-IFN α-2a alone) and 2.2 (1000 mg Debio-025 alone) in the
monotherapy groups. No differences in antiviral activity were observed between
individuals infected with the different genotypes. Debio-025 was safe and well
tolerated but led to a reversible bilirubin increase in some of the patients treated
with 1000 mg Debio-025 daily (Flisiak 2009). A high genetic barrier to resistance of
Debio-025 and a broad HCV genotypic activity highlight the potential of drugs
targeting host proteins.
In a Phase II clinical trial in treatment-naïve HCV genotype 1 patients,
combination therapy with Debio-025, PEG-IFN α-2a and ribavirin for 24-48 weeks
resulted in SVR rates of 69-76% compared to 55% in the control group (Flisiak
2011).
Hepatitis C: New Drugs 253
Nitazoxanide
Nitazoxanide with its active metabolite tizoxanide is a thiazolide antiprotozoal
approved for the treatment of Giardia lamblia and Cryptosporidium parvum
infections. In vitro studies have revealed an essential inhibitory impact on HCV and
HBV replication by still unknown mechanisms.
Results of two Phase 2 studies evaluating 500 mg nitazoxanide twice daily for 12
weeks followed by nitazoxanide, PEG-IFN α-2a ± RBV for 36 weeks yielded
conflicting results with SVR rates of 79% in treatment-naïve genotype 4 patients,
but of only 44% in HCV genotype 1 patients (Rossignol 2009). Additional studies
are warranted to determine the role of nitazoxanide in the treatment of chronic
hepatitis C.
Silibinin
Silymarin, an extract of milk thistle (Silybum marianum) with antioxidant activity,
has been empirically used to treat chronic hepatitis C and other liver diseases.
Silibinin is one of the six major flavonolignans in silymarin. Surprisingly, recent
reports demonstrated that silibinin inhibits HCV at various steps of its life cycle
(Ahmed-Belkacem 2010, Wagoner 2010). In addition, intravenous silibinin in non-responders to prior IFN-based antiviral therapy led to a decline in HCV RNA
between 0.55 to 3.02 log10 IU/ml after 7 days and a further decrease after an
additional 7 days in combination with PEG-IFN α-2a/RBV in the range of 1.63 and
4.85 log10 IU/ml (Ferenci 2008). Ongoing studies will clarify the role of silibinin in
the treatment of chronic hepatitis C, including HCV liver graft reinfection.
Miravirsen
MicroRNA-122 (miRNA-122) is a liver-specific microRNA that has been shown to
be a critical host factor for HCV (Landford 2010). MiRNA-122 binds to the 5´NTR
region of the HCV genome, which appears to be vital in the HCV replication
process. Miravirsen is a modified antisense oligonucleotide that targets miRNA-122
and thereby prevents binding of miRNA-122 to the HCV genome. In a Phase IIa
proof-of-principle study, weekly subcutaneous injections of miravirsen led to a
reduction of HCV RNA serum concentration of up to 2.7 log10 IU/mL, indicating
that an antisense oligonucleotide-based approach of miRNA-122 inhibition could be
a promising modality for antiviral therapy (Janssen 2010). No relevant side effects
were seen in this study.
Newer combination therapies
The approval of the HCV protease inhibitors telaprevir and boceprevir in 2011
constitutes a milestone in the treatment of chronic HCV genotype 1 infection.
Nevertheless, telaprevir- or boceprevir-based triple therapy has certain limitations.
In particular, treatment success still depends on the interferon-sensitivity of
individual patients because a slow decline of HCV viral load during triple therapy is
associated with a high risk of antiviral resistance development. Consequently, viral
breakthrough of drug resistant variants was observed in a significant number of
patients with partial or null response to previous treatment with PEG-IFN α and
ribavirin, in patients with limited decline of HCV viral load during lead-in treatment
with PEG-IFN α and ribavirin alone, or in difficult to cure populations like Blacks
254 Hepatology 2012
or patients with advanced liver fibrosis. In addition, triple therapy is not an option
for patients with contraindications to PEG-IFN α or ribavirin, such as patients with
decompensated liver cirrhosis or liver transplant failure.
To overcome these limitations, numerous trials have been initiated to investigate
the potential of combination therapies with different DAA agents alone (Table 3).
As is well established in the treatment of HIV infection, combining DAA agents
with different antiviral resistance profiles should result in a substantially decreased
risk of viral breakthrough of resistant variants. Nucleoside analog NS5B inhibitors
plus drugs targeting host factors such as the cyclophilin inhibitor alisporivir display
a high genetic barrier to resistance development and may therefore be key agents for
effective DAA combination therapies (Sarrazin 2010). In contrast, NS3-4A and
NS5A inhibitors display a low genetic barrier to resistance development, but in view
of their high antiviral efficacy they appear to be promising combination partners for
nucleoside analogs or cyclophilin inhibitors. Due to their low antiviral efficacy and
low genetic barrier to resistance development, the role of non-nucleoside analog
NS5B inhibitors is currently less clear. A potential advantage of non-nucleoside
analogs is their binding to multiple target sites that may allow simultaneous
treatment with several non-nucleoside analogs.
Currently, DAA combination treatment regimens can be classified according to
the usage of PEG-IFN α into quadruple therapy regimens and all-oral therapy
regimens. Quadruple therapy approaches are based on therapy of PEG-IFN α and
ribavirin plus combination of two DAA agents from different classes. In contrast,
all-oral treatment comprises interferon-free regimens including combinations of
various DAA compounds with or without ribavirin.
Quadruple therapy
Preliminary SVR data of a small but highly informative trial serves as a proof-of-concept for the potential of quadruple therapy approach for patients with previous
null response to PEG-IFN α + ribavirin (Lok 2011). In this Phase II study, 11 HCV
genotype 1 patients with prior null response were treated with a combination of the
NS5A inhibitor BMS-790052 and the protease inhibitor BMS-650032 together with
PEG-IFN α and ribavirin for 24 weeks. Quadruple therapy resulted in 100% SVR 12
weeks after treatment completion in both HCV genotype 1a- and 1b-infected
patients. Even though the number of patients included in this trial was very limited,
this high SVR rate after quadruple therapy seems impressive compared to SVR rates
of ~30% that were achieved with telaprevir-based triple therapy in prior null
responders (Zeuzem 2011).
A Phase II clinical trial assessed quadruple therapy with the non-nucleoside NS5B
inhibitor tegobuvir in combination with the NS3-4A inhibitor GS-9256 + PEG-IFN
α and ribavirin for 28 days in treatment-naïve HCV genotype 1 patients (Zeuzem
2011). The primary endpoint of this study was rapid virologic response (RVR),
which was achieved in 100% of patients. After 28 days of quadruple therapy,
treatment with PEG-IFN α and ribavirin was continued, which led to complete early
virologic reponse (cEVR) in 94% of patients (Zeuzem 2011).
Another Phase II clinical trial investigated a response-guided approach during
quadruple therapy containing the non-nucleoside NS5B inhibitor VX-222 (100 mg
or 400 mg) in combination with the NS3-4A inhibitor telaprevir + PEG-IFN α and
ribavirin in treatment-naïve HCV genotype 1 patients (Nelson 2011). Quadruple
Hepatitis C: New Drugs 255
treatment was administered for 12 weeks. All treatment was stopped after 12 weeks
in patients who were HCV RNA-negative at treatment weeks 2 and 8. Patients in
whom HCV RNA was detectable at treatment week 2 or 8 received an additional 12
weeks of PEG-IFN α and ribavirin alone. Up to 50% of patients met the criteria for
the 12-week treatment duration. Of those, 82-93% achieved an SVR 12 weeks after
treatment completion. In patients who were treated with an additional 12 weeks of
PEG-IFN α and ribavirin, the end-of-treatment response was 100%.
Collectively, the quadruple therapy approach appears to be highly promising in
patients with limited sensitivity to interferon-α, even in patients with HCV subtype
1a.
All-oral therapy without ribavirin
A first interferon-free clinical trial (the INFORM-1 study) evaluated the
combination of a polymerase inhibitor (R7128) and an NS3 inhibitor
(R7227/ITMN191). In this proof of principle study, patients were treated with both
compounds for up to 2 weeks (Gane 2010). HCV RNA concentrations decreased by
up to 5.2 log10 IU/ml, viral breakthrough was observed in only one patient (although
no resistant HCV variants were identified), and HCV RNA was undetectable at the
end of dosing in up to 63% of treatment-naïve patients. However, the fundamental
question of whether an SVR can be achieved with combination therapies of
different DAA compounds without PEG-IFN α and ribavirin was not answered by
this trial.
SVR data are available for a Phase II clinical trial investigating therapy with the
NS5A inhibitor BMS-790052 in combination with the NS3-4A protease inhibitor
BMS-60032 for 24 weeks in 10 HCV genotype 1 patients with a previous null
response to PEG-IFN α and ribavirin (Lok 2011). 36% of patients achieved an SVR
24 weeks after treatment completion. All patients with viral breakthrough were
infected with HCV genotype 1a, and in all of them HCV variants with resistance
mutations against both agents were detected. Although data of longer follow-up
periods are needed, this trial constitutes a proof-of-principle that SVR can be
achieved via all-oral regimens, even in patients infected with HCV subtype 1b. This
was confirmed with a 100% SVR rate in a small study evaluating the same agents
(BMS-790052 and BMS-60032) in Japanese HCV genotype 1b previous null
responders (Chayama 2011).
Another trial has investigated 12 weeks of PSI-7977 monotherapy (400 mg once
daily) in HCV genotype 2- and 3-infected patients (n=10). 100% of patients
achieved an RVR and EOTR, which translated into an SVR in 60% of patients
(Gane 2011).
All-oral therapy with ribavirin
Two trials evaluated all-oral DAA combination therapies with ribavirin. In one of
them, combination therapy of the NS3-4A inhibitor BI-201335, the non-nucleoside
NS5B inhibitor BI-207127 (400 or 600 mg TID) and ribavirin for 4 weeks was
assessed (Zeuzem 2011). Virologic response rates in patients treated with 600 mg
TID of BI-207127 were 82%, 100% and 100% at treatment days 15, 22, and 29,
respectively (Zeuzem 2011). In patients who received the lower dose of BI-207127,
virologic response rates were significantly lower, and in these patients lower
256 Hepatology 2012
virologic response rates were observed for patients infected with HCV subtype 1a
compared to subtype 1b.
Another trial compared tegobuvir (a non-nucleoside NS5B inhibitor) + GS-9256
(a NS3-4A inhibitor) with or without ribavirin in treatment-naïve HCV genotype 1
patients (Zeuzem 2011). Importantly, tegobuvir + GS-9256 + ribavirin led to a
higher HCV RNA decline after 28 days of treatment compared to tegobuvir + GS-9256 alone (-5.1 log10 vs. -4.1 log10, respectively), indicating that ribavirin might be
an important component of interferon-free DAA combination therapies. SVR data
of these and additional combination therapy regimens are expected in the near
future.
Additional trials investigated all-oral combination regimens with ribavirin in
HCV genotype 2 and 3 patients. 12 weeks of PSI-7977 plus ribavirin resulted in
100% RVR, EOTR, and SVR rates in a small number of treatment-naïve patients
(n=10) (Gane 2011). In contrast, during treatment with the cyclophilin A inhibitor
alisporivir in combination with ribavirin, only approximately 50% of HCV genotype
2 and 3 patients became HCV RNA-negative at treatment week 6 (Pawlotsky 2011).
Nevertheless, these data highlight the impressive potential of all-oral regimens,
when agents with little risk of antiviral resistance development such as nucleoside
analog NS5B inhibitors are used in combination with ribavirin.
Table 3. Selected trials evaluating DAA combination therapies.
DAAs combined Additional medication Phase
BMS-650032 (NS3-4A inhibitor) + / - PEG-IFN α
and ribavirin
II
+ BMS-790052 (N5A inhibitor)
BI-201335 (NS3-4A inhibitor) + ribavirin
+ / - PEG-IFN α
II
+ BI-207127 (non-nuc. NS5B inhibitor)
GS-9190 (non-nuc. NS5B inhibitor) + / - ribavirin
+ / - PEG-IFN α
II
+ GS-92568 (NS3-4A inhibitor)
Danoprevir (NS3-4A inhibitor) followed by PEG-IFN α
and ribavirin
II
+ RG-7128 (nuc. NS5B inhibitor)
Telaprevir (NS3-4A inhibitor) + / - ribavirin
+ / - PEG-IFN α
II
+ VX-222 (non-nuc. NS5B inhibitor)
PSI-938 (purine nuc. NS5B inhibitor)
- II
+ PSI-7977 (pyrimidine nuc. NS5B inhibitor)
Novel interferons
Over the last years, attempts have been made to reduce side effects and treatment
discomfort of PEG-IFN α. However, interferons with longer half-life and sustained
plasma concentrations (e.g., albinterferon, a fusion protein of IFN α 2b with human
albumin) have so far shown no overall benefit with respect to SVR rates (Zeuzem
2010). Still promising is the development of pegylated interferon lambda 1 (PEG-IFN lambda 1). Like other type 3 interferons, IFN lambda 1, which is also called
interleukin-29 (IL-29), binds to a different receptor than IFN α, but downstream
signaling pathways of IFN lambda and IFN α are largely comparable. The IFN
lambda receptor is predominantly expressed in hepatocytes. Thus, interferon-related
side effects may be less frequent during PEG-IFN lambda treatment. A Phase I
clinical trial evaluating pegylated interferon lambda with or without ribavirin was
completed (Muir 2010). Interferon lambda was well-tolerated and the majority of
Hepatitis C: New Drugs 257
patients achieved a greater than 2 log10 decline of HCV RNA by 4 weeks.
According to an interim analysis of a subsequent Phase II clinical trial, PEG-IFN
lambda (240 ug, 180 ug, or 120 ug once weekly) was compared to PEG-IFN α-2a.
PEG-IFN lambda at doses of 240 or 180 ug resulted in approximately 10% higher
RVR and approximately 20% higher cEVR rates, a lower frequency of flu-like
symptoms, but with more frequent aminotransferase and bilirubin elevations than
PEG-IFN α-2a (Zeuzem 2011).
Conclusions
Telaprevir- and boceprevir-based triple therapy of treatment-naïve and treatment-experienced HCV genotype 1 patients results in substantially increased SVR rates
compared to PEG-INF-α and ribavirin alone. The approval of these agents
represents a major breakthrough in the treatment of chronic hepatitis C. However,
successful use of these drugs will require a precise classification of response
patterns to previous treatment, careful on-treatment monitoring of HCV viral load
and emergence of antiviral resistance as well as of additional side effects and
numerous possible drug-drug interactions. Next-generation NS3-4A protease
inhibitors and NS5A inhibitors may have even more favorable properties than
telaprevir and boceprevir in terms of HCV genotype coverage, safety profiles, less
pronounced drug-drug interactions, or possible once-daily administration. However,
the triple therapy approach has several limitations. First of all, concomitant IFN α
and ribavirin are necessary to avoid the development of antiviral resistance.
Consequently, the efficacy of triple therapy was limited in prior null responders to
PEG-IFN α and ribavirin, and triple therapy cannot be administered to patients with
contraindications to PEG-IFN α or ribavirin. Recent data indicate that the
development of DAA combination therapies in all-oral or quadruple treatment
regimens will likely be a very potent option for these patients. In such DAA
combination regimens, the inclusion of drugs with a high genetic barrier to
resistance such as nucleoside NS5B inhibitors or drugs targeting host factors such as
alisporivir may be important.
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