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Emerging Therapeutic Options in Hepatitis C Virus Infection
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The current standard of care for patients with chronic hepatitis C virus (HCV) infection is pegylated interferon alfa in combination with ribavirin. Treatment duration and efficacy depend heavily on HCV genotype. A sustained virologic response (SVR) is achieved only in approximately 40% of patients. Side effects of the current standard of care often make adherence to therapy difficult, further reducing the chance for an SVR. Numerous patient-related and virus-related factors can determine response to treatment. Nonresponders are a large proportion of the current HCV-infected population, and the number of patients with HCV infection is growing, necessitating newer therapies with higher efficacy and potentially fewer side effects. A new era of direct acting antiviral (DAA) compounds has emerged. The first 2 protease inhibitors for HCV infection, telaprevir and boceprevir, are coming to market in 2011. Other protease compounds in development include TMC-435, vaniprevir, BI-201335, BMS-650032, and danoprevir. The numerous other therapies that have potential in the treatment of HCV infection include nucleoside inhibitors, non-nucleoside inhibitors, NS5A inhibitors, DAA combinations, therapeutic vaccines, human monoclonal antibodies, immune modifiers, and interferon lambda.
(Am J Manag Care. 2011;17:S123-S130)
Growing Epidemic and Limitations of Current Therapies
Chronic hepatitis C virus (HCV) infection affects approximately 170 million people. The average period between infection and the development of complications from cirrhosis is 20 to 30 years. Chronic HCV infection is becoming an increasingly significant health burden in the United States. The disease often leads to cirrhosis and sometimes hepatocellular carcinoma.1,2
Since the early 1990s, interferon has been the backbone of HCV infection therapy, initially as monotherapy 3 times a week. Later, it was combined with ribavirin (RBV), and finally, a pegylated form was developed and given once weekly. The current standard of care for patients with HCV infection is pegylated interferon alfa (PEG) in combination with RBV. Two forms of pegylated interferon, pegylated interferon alfa-2a and pegylated interferon alfa-2b, are currently approved by the US Food and Drug Administration (FDA) for the treatment of HCV infection. Treatment duration and efficacy depend heavily on HCV genotype. Genotype 1, the most common in the United States, is the most difficult to treat and usually requires 48 weeks of therapy. A sustained virologic response (SVR) is achieved only in approximately 40% of patients. The 3000-patient IDEAL (Individualized Dosing Efficacy versus flat dosing to Assess optimaL pegylated interferon therapy) study, a multicenter, US trial in patients with genotype 1 HCV infection, showed comparable efficacy (approximately 40% with an SVR) between pegylated interferon alfa-2a and alfa-2b when combined with ribavirin.3 While this is a reasonable SVR, it does not serve the majority of patients. Genotypes 2 and 3 comprise 30% of US infections, usually require 24 weeks of therapy, and have SVR rates of 80% to 85%.4
Side effects of the current standard of care often make adherence to therapy difficult, further reducing the chance for an SVR.5 Interferons can also exacerbate autoimmune conditions. Assessing predictors of response prior to treatment, including the use of IL-28B gene testing, can help to minimize risks, select patients most appropriate to receive therapy, and guide management. Patient-related factors that can determine response to treatment include ethnicity, sex, body mass index, and the presence of metabolic syndrome.6 Virus-related factors include HCV genotype, baseline viral load, degree of liver fibrosis, the presence of steatosis, and coinfection with HIV.7 A single nucleotide polymorphism near the IL28B gene on chromosome 19, coding for interferon-lambda-3, is associated with a 2-fold difference in SVr rates among patients. Patients with genotype cc, cT, or TT are more likely to achieve an SVr than others.8
Up to 60% of patients with hcV genotype 1 infection do not clear the virus despite currently available therapy.9 up to 80% of black patients with hcV genotype 1 do not respond to the current standard of care.10 Nonresponders are a large proportion of the current hcV-infected population, and the number of patients with hcV infection is growing, creating the need for newer therapies with higher efficacy and potentially fewer side effects vital.
A new era of direct acting antiviral (dAA) compounds is now beginning, with the first 2 protease inhibitors coming to market in 2011. The dAA therapies will be the biggest development since the addition of rBV to interferon and the pegylation of interferon. Adding an oral antiviral to the current standard of care (Peg/rBV) may double the SVr rate in patients with genotype 1 hcV infection. The NS3-4A protease inhibitors and NS5B ribonucleic acid (rNA)-dependent rNA polymerase inhibitors have received the most attention (Figure). Beyond the initial 2 agents, several more are likely to be approved, although combinations of dAAs will likely be the next phase of therapy, perhaps without interferon in some cases. Table 1 outlines the currently proposed combination therapies with 2 or more dAAs.
Protease Inhibitors
The serine protease NS3-NS4A is used by the hcV for post-translational processing and viral replication. inhibitors of this protein lead to rapid viral decline, but cannot be used as monotherapy due to rapidly developing resistance.11 Hence, combinations with Peg/rBV have been studied. Table 2 outlines the various protease inhibitors currently in clinical development, and details those which have been assessed in phase 3 trials. Table 3 compares the protease inhibitors with Peg/rBV. The first dAAs will be the linear serine protease inhibitors, telaprevir and boceprevir.
Boceprevir
Boceprevir was studied in the SPriNT (Serine Protease inhibitor Therapy)-2 trial with 1100 treatment-naïve patients. The overall SVr rate was 66% (68% in non-black patients and 53% in blacks compared with controls [40 and23%, respectively]; P = .004 and P = .044) with a regimen that used a 4-week lead-in of PEG/RBV followed by the addition of boceprevir for 24 weeks.12 A response-guided therapy paradigm was then used to determine ultimate length of PEG/RBV of 28 weeks or 48 weeks based on viral negativity at and beyond week 8. Overall, approximately 50% of patients qualified for the shortened duration (28 weeks of therapy), and approximately 25% required 24 weeks of boceprevir and 48 weeks of PEG/RBV. The remaining 25% of patients discontinued due to futility at week 24 or side effects.13
In the 404 patient nonresponder trial called RESPOND (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peginteron/Rebetol)-2 trial, SVR rates were 66% in the 48-week arm and 59% in the response-guided arm, both significantly better than the control (21%) (P <.0001). The study included previous relapsers and those who had some interferon responsiveness, having achieved at least a 2-log decline of virus with PEG/RBV. Interestingly, 25% of patients demonstrated very little interferon response during the 4-week lead-in, having less than a 1-log decline in virus prior to beginning boceprevir. These patients had SVR rates of only 34% compared with 73% to 79% in patients with some interferon response at the end of lead-in. Most importantly, the lead-in appears to be an excellent predictor of risk of resistance-associated variants (RAVs), with fewer than 10% of patients developing variants if they had PEG/RBV responsiveness compared with 32% developing RAVs if they did not. The predominant adverse event in both of the phase 3 trials was anemia, defined as hemoglobin (Hb) below 10 g/dL, which occurred in 50% of patients given boceprevir. Discontinuations due to anemia, however, occurred in less than 2% of patients. The majority of patients with anemia were treated with an erythropoietic stimulating agent (ESA) at the discretion of the investigator to maintain Hb between 10 and 12 g/dL.14
Telaprevir
ADVANCE (A New Direction in HCV Care: A Study of Treatment-naïve Hepatitis C Patients with Telaprevir), a phase 3 trial in treatment-naïve patients, studied telaprevir in combination with PEG/RBV. Patients received 12 weeks of telaprevir, with 24 or 48 weeks of PEG/RBV, based on response-guided parameters of viral negativity between weeks 4 and 12 (extended rapid virology response [eRVR]), with almost 60% of patients qualifying for the shorter duration. SVR rates of 75% were achieved (compared with 44% with control). The predominant adverse event of rash occurred in 56% of patients; however, only 7% discontinued telaprevir due to rash. Anemia occurred at a rate of 40%. ESAs were not allowed in this study.15 A companion study in treatment-naïve patients called the ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir) revealed an SVR of 72%, high SVR rates in those achieving an eRVR, and no benefit of extending PEG/RBV beyond 24 weeks in those achieving eRVR.16
The REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial assessed telaprevir in patients who previously received treatment. Results were recently presented and revealed SVR rates of 64% compared with 17% with control. Although a 4-week lead-in arm did not reveal differences in SVR rates, complete data regarding the predictability of SVR and resistance based on PEG/RBV response has not been presented. Patients with a previous relapse had an SVR rate of 86% (24% with control), partial responders had an SVR rate of 57% (15% with control), and null responders 31% (5% with control).17
Dosing With Boceprevir and Telaprevir
Both boceprevir and telaprevir are dosed 3 times daily, with anemia rates of 40% to 50%; rash is common with telaprevir, and dysgeusia with boceprevir. Both were associated with significantly higher SVR rates compared with controls, and both can be used with either PEG/RBV regimen on the market. Patient compliance with the dosing scheduleand the high rates of anemia (and rash with telaprevir) are concerns.
TMC-435
Other protease compounds in development are further behind boceprevir and telaprevir. Phase 3 trials with TMC-435, however, are starting in treatment-naïve and relapsed patients at a dose of 150 mg daily. Results of the phase 2b PILLAR (Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen) study reveal SVR rates in those relegated to a response-guided duration of 24 weeks of therapy (approximately 80% of patients) to be approximately 90%. SVR results in the 48-week control arm are not yet available, but are expected to be higher than that of other studies based on week 24 on-treatment response rates of over 80%. The appeal of this compound beyond the expected high efficacy is its once daily dosing, and no apparent risk of rash or anemia.18
MK-7009 (Vaniprevir)
A phase 2, randomized, placebo-controlled, double-blind study of MK-7009 (a non-covalent competitive inhibitor of HCV NS3/4A protease) in combination with PEG/RBV was performed in treatment-naïve patients with HCV infection. MK-7009 was given for 28 days with PEG/RBV in 1 of 5 regimens: placebo, 300 mg twice daily, 600 mg twice daily, 600 mg once daily, or 800 mg once daily; all patients continued PEG/RBV for an additional 44 weeks. The primary end point was undetectable HCV RNA at day 28 (a rapid viral response [RVR]). RVR rates were 1/18 (5.6%), 12/16 (75%), 15/19 (78.9%), 11/16 (68.8%), and 14/17 (82.4%), respectively.19 No serious adverse events and no discontinuations due to adverse events were reported. The most common adverse events reported were nausea, headache, and flu-like symptoms.
BI-201335
BI-201335 is a specific HCV NS3/4A protease inhibitor studied in chronic HCV genotype 1 infection. It was administered as 14-day monotherapy in treatment-naïve patients followed by combination PEG/RBV for an additional 14 days. It has also been studied in treatment-experienced patients for 28 days as combination therapy with PEG/RBV.20 A median viral load reduction of at least 3 log10 was achieved in all dose groups. On-treatment viral rebound was noted in most patients on monotherapy, but only in 3 of 19 treatment-experienced patients receiving triple combination therapy with lower dosages of BI-201335. A recent study revealed that HCV NS3 variants that confer resistance to the medication were selected during treatment. The variants do not alter sensitivity to PEG/RBV, as the treatment-naïve patients with resistant virus did display antiviral responses during combination therapy.
BMS-650032
BMS-650032 is an HCV NS3 protease inhibitor with demonstrated antiviral activity in single and multiple ascending dose studies in patients with chronic HCV genotype 1 infection. In healthy patients, BMS-650032 was well tolerated at doses up to 1200 mg once daily and up to 600 mg twice daily for 14 days. A mean decline in HCV RNA of 2.5 log10 at 24 hours after a single 600 mg dose was noted. No deaths or discontinuations due to adverse events were reported.
Other Protease Inhibitors
Danoprevir (600 mg twice daily) has been shown to have good efficacy and safety in HCV infection. It is currently being assessed in an ongoing phase 2 study. ACH-1625 is a potent, nearly pangenotypic compound that is dosed once daily and has a good safety profile. However, mild hyperbilirubinemia is a concern. Similarly, ABT-450 is a once-daily compound dosed with ritonavir, and showed good week-4 efficacy. Several other protease inhibitors are in development, either in combination with other DAAs or with PEG/RBV.
Polymerase Inhibitors
Polymerase inhibitor agents bind to the NS5B RNAdependent RNA polymerase. This class can be divided into 2 classes, based on which part of the protein they bind to. Compounds that bind to the active site are nucleoside analog inhibitors (NI), and those that bind to various other sites are called non-nucleoside inhibitors (NNI). Table 4 outlines the polymerase inhibitors.
Nucleoside Inhibitors
PSI-7977
PSI-7977, a uridine nucleotide analog, is one of the most potent compounds in this class. In a phase 2b study in 125 treatment-naïve patients, PSI-7977 100 mg, 200 mg, and 400 mg was given once daily with PEG/RBN for 4 weeks followed by PEG/RBV for 36 more weeks. Efficacy rates at day 28 and week 12 were very high, achieving 75% to 94% viral negativity. A genotype 2/3 study with 12 weeks of PSI-7977 therapy is underway because this compound is pangenotypic in its coverage. Results look encouraging up to week 12, with most patients having undetectable viral levels at the end of dosing.21
RG7128
Another similar compound, RG7128, an oral cytidine NI, is dosed twice daily and demonstrated efficacy in HCV infection. In a phase 2b trial of 408 patients with HCV genotypes 1 and 4, dosing of 500 mg and 1000 mg twice daily for 8 to 12 weeks and PEG/RBV for 24 to 48 weeks produced week-12 viral negativity rates of 68% to 88%, revealing efficacy in both genotype 1 subtypes and genotype 4.22 When given in conjunction with a protease inhibitor (R7227/ITMN-191) over a 2-week period, a proof of concept was achieved, revealing that potent viral suppression can be achieved with no viral breakthrough when combing 2 DAAs that act on different targets.
PSI-938
PSI-938 is a guanine nucleoside analog that is dosed daily. It is currently being studied in a phase 1 trial. Interim results showed potent antiviral activity with daily doses of 100, 200, and 300 mg.
These compounds appear to have tremendous potential with a high barrier to resistance, and reasonable safety profiles.
IDX-184 and INX-189
IDX-184 is a nucleotide prodrug. The clinical development program for this agent was put on hold due to observations of elevated liver enzymes when used in combination with a protease inhibitor. The clinical development program is set to resume in 2011. INX-189 is a methylguanosine analog, and it is currently being evaluated in a phase 1b trial.23
Toxicities With NI Compounds
Toxicities have been observed with NI compounds. R1626 has been associated with significant toxicity issues, including neutropenia and ocular toxicity. Prior to that, NM283 was discontinued due to gastrointestinal toxicity.
Non-Nucleoside Inhibitors
This heterogeneous class of compounds can bind to at least 4 different sites, and has a lower potency compared with other therapies. However, as a part of combination regimens with other DAAs, they may be of value. Table 4 lists several compounds currently being explored. These agents may be best used in combination, rather than as part of a regimen withPEG/RBV alone.
Notable compounds in this category include ANA598, currently being assessed in a phase 2 study. ANA598 200 and 400 mg is given twice daily following a loading dose of 800 mg. Undetectable virus at week 12 was achieved in 75% of patients, with good tolerability.24
Two compounds, ABT-333 and ABT-072, are being studied in phase 2 trials. In patients with genotype 1 HCV infection, they are being dosed once or twice daily in conjunction with PEG/RBV for 12 weeks followed by PEG/RBV for another 36 weeks.25,26
NS5A Inhibitors
Compounds that inhibit the NS5A protein are now being assessed as pangenotypic agents that can be used with PEG/RBV, or in combinations with other DAAs. The first-in-class BMS-790052 is given at doses of 3, 10, and 60 mg with PEG/RBV for 12 weeks followed by PEG/RBV therapy. Preliminary data from the phase 2a study indicate good antiviral effects and good tolerability. A phase 2b study is planned. In nonresponders, combination with a protease inhibitor will be examined. Several other NS5A agents are also in development and appear to be a promising partner compound in combination regimens. Table 5 outlines the NS5A inhibitors.
Vaccines
Currently, no vaccine exists for the prevention or management of HCV infection. Therapeutic vaccines boost the immune system and may be effective in the treatment of HCV. IC41 is a synthetic peptide vaccine with 7 relevant HCV T-cell epitopes and the T-helper cell (Th)1/Tc1 adjuvant poly-L-arginine.27 In healthy volunteers, IC41 induces HCV-specific interferon-gamma secreting CD4 and CD8 T cells.28 A total of 35 patients received 6 vaccinations with IC41. It did not prevent HCV relapse in patients with ongoing interferon treatment, but HCV-specific T-cell responses were inducible and associated with lower relapse rates.29
The induction of neutralizing antibodies is a key feature of most vaccines. Infusion of neutralizing antibodies is also used for postexposure prophylaxis. Recombinant E1E2 glycoproteins with MF59 containing a CpG oligonucleotide elicited strong CD4 T helper responses but no CD8 T cell responses. Recombinant nonstructural proteins 3, 4, and 5 also stimulated strong CD4 T helper responses when adjuvanted with Iscomatrix containing CpG. A single immunization regimen was shown to elicit broad T cell responses and neutralizing antibodies.30
GI-5005 is a whole, heat-killed Saccharomyces cerevisiae therapeutic vaccine expressing HCV NS3 and core antigens that elicits antigen-specific responses to improve the rate of immune-mediated elimination of HCV-infected hepatic cells.23 Triple therapy with GI-5005, PEG, and RBV improved EVR, compared with PEG and RBV alone. No new toxicities were noted with triple therapy.
In a proof of concept trial, 133 patients with HCV genotype 1 infection were randomized to triple therapy with the GI-5005 vaccine, designed to elicit a T-cell response specific to HCV plus PEG and RBV or standard PEG/RBV therapy alone. Overall, the difference in SVR rates between the vaccine and control group was statistically significant, with SVR rates of 47% and 35%, respectively (P = .037). Currently, a phase 2 trial is evaluating GI-5005 triple therapy. Triple therapy and novel combination strategies with GI-5005 and other HCV inhibitory agents will be useful in the future.31
Human Monoclonal Antibodies
Chronic HCV infection is characterized by a high turnover of infected cells and de novo infection of target cells. A potential target for antiviral therapy is de novo infection. The envelope protein E2 is a target to block de novo infection, and this can be achieved by entry inhibitors. MBLHCV1, a fully humanized monoclonal antibody to a linear epitope of HCV E2 glycoprotein, was developed and neutralizes pseudoviruses from multiple HCV genotypes. The antibody completely neutralizes infectious HCV particles in cell culture. Based on in vitro studies, the monoclonal antibody anti-E2 was investigated to prevent HCV infection in uninfected chimpanzees.32 Three chimpanzees each received a single dose of the anti-E2 antibody intravenously, then weregiven a challenge with HCV 1a strain H77. No HCV RNA was detected in the serum of the chimpanzees who received 250 mg/kg of MBL-HCV1 through week 20, while the 0 mg/ kg and 50 mg/kg group became infected by day 14. A phase 1 study in humans is planned.
Immune Modifiers and Others
New therapeutic approaches for patients who have a low SVR with traditional therapies are underway, including immune modifiers and other drugs.
Nitazoxanide
Nitazoxanide is a thiazolide approved for diarrhea from cryptosporidiosis. In a double-blind, placebo-controlled study in 13 US centers, 125 treatment-naïve patients with HCV genotype 1 infection were randomized to receive nitazoxanide (n = 75) or placebo (n = 37) twice daily over a 4-week lead-in followed by 48 weeks of nitazoxanide or placebo, plus peginterferon 180 μg weekly and weight-based RBV. In those with HCV RNA levels greater than 600,000 IU/mL, complete EVR and EVR rates were higher in the nitazoxanide group compared with placebo (57% vs 39%, and 79% vs 61%, respectively).33 Based on current data, it is unlikely that this compound will have a role in treating HCV infection when combined with PEG/RBV.
Cyclophilin Inhibitors
Debio 025
Debio 025 is a non-immunosuppressive cyclosporine A (CsA) derivative that selectively inhibits cyclophilins. Host cell cyclophilins are essential for efficient HCV replication in hepatocytes. Combination therapy with interferon alfa-2b and Debio 025 for 24 weeks produced an SVR in 42% of patients with HCV genotype 1b infection and high viral loads.34
NIM811
Another cyclophilin inhibitor called NIM811 was administered in 40 healthy volunteers. No further development of this compound is expected.
Celgosivir (MX-3253)
Celgosivir is an alpha-glucosidase I inhibitor, an oral prodrug of castanospermine. It is not intended for use as monotherapy in HCV, but has a synergistic effect with PEG/RBV.35
Vitamin D
Low serum vitamin D levels are related to severe fibrosis and low responsiveness to interferon-based therapy in patients with genotype 1 infection.36
Albumin Interferon
Phase 3 clinical trials with albumin interferon alfa-2b, the fusion protein of human serum albumin and interferon alpha, are complete. Human serum albumin is made in the liver and has a half-life of 20 days. Albumin interferon alfa-2b has a longer half-life and a duration of antiviral activity that allows for dosing intervals of 2 to 4 weeks. In a phase 3 trial, albumin interferon alfa-2b 900 μg administered every 2 weeks showed comparable efficacy to PEG in patients with HCV genotype 1 infection. SVR rates were 51%, 48%, and 47% in the PEG, albumin interferon alfa-2b 900 μg, and 1200 μg groups, respectively.37 Safety concerns over pulmonary toxicity, however, will prevent approval of this compound based on current data.
Interferon Lambda
Interferon lambda is a novel type III interferon, which binds to a unique cell surface receptor, induces an intracellular antiviral response, and efficiently inhibits HCV replication in vitro. Researchers hope that interferon lambda will have comparable antiviral activity to PEG, but with a better tolerability profile. Studies are ongoing.
Author Affiliation: Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA.
Funding Source: Financial support for this work was provided by Merck & Co, Inc.
Author Disclosure: Dr Poordad reports being a consultant or a member of the advisory board for Abbott, Achillion, Anadys, Gilead, Merck, Novartis, Pfizer, and Vertex. He also reports being a member of the speakers’ bureau for Gilead, Roche, and Vertex. He has received grants from Abbott, Achillion, Anadys, Bristol-Myers Squibb, Gilead, Merck, Novartis, Pfizer, Pharmasset, and Vertex. Dr Khungar has nothing relevant to disclose.
Authorship Information: Concept and design (FP, VK); drafting of the manuscript (FP, VK); and critical revision of the manuscript for important intellectual content (FP, VK).
Address correspondence to: Fred Poordad, MD, Department of Medicine, Cedars-Sinai Medical Center, 8635 W Third St, Ste 1060, Los Angeles, CA 90048. E-mail: fred.poordad@cshs.org.
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