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Published on 11 April 2011

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Role of protease inhibitors in treatment of chronic hepatitis C

teaser

Tarek Saadi
Liver and Gastroenterology Units
Division of Medicine
Rambam Health Care Campus
Haifa

Rifaat Safadi
Liver and Gastroenterology Units
Division of Medicine
Hadassah Medical Center
Jerusalem
Israel

Chronic hepatitis C is among the leading causes of chronic liver disease worldwide, with approximately 170 million people infected. It is a leading cause of cirrhosis and hepatocellular carcinoma and is the major indication for liver transplantation in the USA.1 In patients infected with HCV genotype 1, the most common genotype worldwide, the standard combination of pegylated interferon alpha and ribavirin for 48 weeks results in 40–50% sustained virologic response rates only. Specifically targeted antiviral therapy for HCV (STAT-C) represents a new treatment paradigm with improved patient outcomes.

There are six major genotypes for HCV according to genomic sequence variation and these can be further classified into subtypes (eg, 1a or 1b). Each genotype/subtype varies in its geographical distribution and has different responses to currently available anti-HCV therapy. In the USA, genotype 1 is the most predominant, especially in HIV-HCV co-infected and the African-American population.2

The current treatment for HCV infection is peginterferon alpha (PEG-IFN) combined with ribavirin and administered for 24 weeks (for HCV genotype 2 or 3) or 48 weeks (for HCV genotype 1, the most prevalent genotype in Europe and North America). Sustained virologic response (SVR) is the desired and optimal response for HCV therapy that improved risk for progression of liver disease and reduced viral transmission. SVR is defined as an undetectable serum HCV RNA level 24 weeks after cessation of therapy. The SVR rates in naive HCV genotype 1 patients range in different studies between 38 and 46%. There are many risk factors that affect antiviral response and outcome. SVR is 19% among black patients1 and 30–40% in HIV-HCV co-infected patients.2

Due to the limited success rates of current treatment, there is an evident need for novel, directly acting treatments.3 The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases. All the HCV enzymes – NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RdRp – are essential for HCV replication, and are therefore potential drug discovery targets.4 Specifically targeted antiviral therapy for HCV (STAT-C) represents a new treatment paradigm with improved patient outcomes. There are several STAT-C agents at various stages of clinical development, including protease inhibitors (PIs) and nucleoside/non-nucleoside polymerase inhibitors. Other agents under investigation include novel analogues of ribavirin, modified interferons, cyclophilin B, a-glucosidase inhibitors, oligonucleotides and immune modulators.1,3,5–7 The recent published treatment results of protease inhibitors that are in late stage clinical development are discussed according to peer-reviewed reports.

Protease inhibitors
The HCV NS3 gene encodes a serine protease and NTPase/helicase. The NS4A gene encodes a protein that serves as a cofactor for the serine protease. The NS3-NS4A complex plays an important role in the final steps of the HCV replication cycle, specifically the maturation step. In addition, the NS3-NS4A complex is believed to block the activation of interferon regulatory factor 3 (IRF-3), resulting in host immune evasion.2 One of the first HCV protease inhibitors developed, BILN-2061, showed promising Phase I results but was cardiotoxic to animals, so further development of the drug was discontinued.8 However, there are two protease inhibitors, telaprevir and boceprevir, that have advanced to late stage Phase II trials and will be discussed in this review.2

Telaprevir
Telaprevir is an anti-protease NS3-NS4A drug antiviral agent (DAA). In a Phase I trial in 34 patients with genotype 1, at a dose of 750 mg, three times a day, a marked reduction in the viral load of four to five logs has been observed.9 When this anti-protease is used in combination with PEG-IFN, a reduction in the viral load of more than four logs has been observed at day 14. Resistant variants to HCV emerge rapidly during telaprevir monotherapy. However, when telaprevir is combined with PEG-IFN alpha-2a plus ribavirin, the antiviral activity is improved and the incidence of resistance is greatly reduced.4 The most frequent side effects were headache, flatulence, diarrhoea, frequent urination, dry mouth, fatigue and dry skin and were similar across all dosage groups.2 The Prove-1 trial,1,10 included 250 treatment-naïve genotype 1 chronic HCV patients in the USA. Participants were randomly assigned to one of four regimens:

  1. 
PEG-IFN alpha-2a (180 μg per week) and ribavirin (1,000 or 1,200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (the control group)
  2. 
Telaprevir (1,250mg on day one and 750mg every eight hours thereafter) for 12 weeks, as well as PEG-IFN alpha-2a and ribavirin (at the same doses as described above) for the same 12 weeks
  3. 
The same regimen but PEG-IFN alpha-2a and ribavirin for a total of 24 weeks
  4. 
The same regimen but PEG-IFN alpha-2a and ribavirin for a total of 48 weeks.

The rate of SVR was 41% in group A, as compared with 61% in group C, 67% in group D and 35% in group B. Rates of rapid virologic response (RVR), early virologic response (EVR) and end of treatment response (ETR) were higher with telaprevir-based therapy as compared to the standard PEG-IFN alpha and ribavirin conventional therapy. Viral breakthrough occurred in 7% of patients receiving telaprevir. Only 2% of patients in group C had an evidence of relapse (undetectable HCV RNA at the time of completion of treatment but detectable levels during the follow-up period), whereas relapse rates were 6% of patients in group D, 23% of patients in group A and 33% in group B. The discontinuation rate was higher in the three telaprevir-based groups (21% vs 11% in the control group) because of adverse events; with rash the most common reason for discontinuation. Serious adverse events in more than one patient, which occurred only in the telaprevir-based groups, included rash, anaemia, ocular events (retinal detachment and scotoma) and depression.1

The Prove-2 trial5,11 included 334 patients who had chronic HCV genotype 1 and had not been treated previously. The patients were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1,250mg on day one, then 750mg every eight hours), PEG-IFN alpha-2a (180 μg weekly) and ribavirin (dose according to body weight):

  1. 
Telaprevir, PEG-IFN alpha-2a and ribavirin for 12 weeks, followed by PEG-IFN alpha-2a and ribavirin for 12 more weeks
  2. 
Telaprevir, PEG-IFN alpha-2a and ribavirin for 12 weeks
  3. 
Telaprevir and PEG-IFN alpha-2a without ribavirin for 12 weeks
  4. 
The control group (82 patients) received PEG-IFN alpha-2a and ribavirin for 48 weeks.

The SVR rates of B and C groups combined were 48%, similar to 46% in the control group (p=0.89). The rate was 60% in group B (p=0.12 for the comparison with the control group), as compared with 36% in group C (p=0.003). The rate was significantly higher in group A than in the control group. RVR, EVR and ETR were significantly higher in all telaprevir-based groups than in the control group. By week 12, a viral breakthrough had been observed in 1% of patients in the control group, 24% in group C, 1% in group B and 5% in group A. Relapse occurred in 14% in group A, 30% in group B, 48% in group C and 22% in the control group. The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash and anaemia.5

For patients in whom SVR is not achieved with standard therapy, retreatment options are limited to re-exposure to the same medications, with potential modification of the dose or duration of the regimen. These retreatment strategies are associated with clinically significant morbidity and generally have a very limited chance of resulting in a successful outcome.12 Recently, a study by McHutchison et al12 randomly assigned patients with HCV genotype 1 who had not had SVR after standard of care (SOC) to four treatment groups:

  1. 
Telaprevir (1,125 mg loading dose, then 750 mg every eight hours) for 12 weeks. PEG-IFN alpha-2a (180 μg per week) and ribavirin (1,000 or 1,200 mg per day, according to body weight) for 24 weeks
  2. 
Telaprevir for 24 weeks and PEG-IFN alpha-2a and ribavirin for 48 weeks (at the same doses as described above)
  3. 
Telaprevir and PEG-IFN alpha-2a for 24 weeks (at the same doses)
  4. 
PEG-IFN alpha-2a and ribavirin for 48 weeks (at the same doses) as a control.

The SVR rates in the three telaprevir groups were significantly higher than the rate in the control group (14%). SVR rates were 51% in group A, 53% in group B and 24% in group C. Response rates were higher among patients who had previously had relapses than among non-responders. One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of patients, with severe rash in 5%). Discontinuation of study drugs because of adverse events was more frequent in the telaprevir groups than in the control group (15% vs 4%).

Boceprevir
Boceprevir is a small molecule that is a specific inhibitor of the viral protease NS3-NS4A. Hepatitis C virus SPRINT-1 is a Phase II study in HCV genotype 1 patients evaluating boceprevir (800mg TID) in three treatment regimens.13 Interim results concluded that boceprevir, when combined with SOC, appears to be safe for use up to 48 weeks. Boceprevir and SOC combination substantially improves SVR rates with 28 weeks of therapy and can nearly double the SVR compared with the current SOC (48 weeks) in this trial. Use of a four-week lead-in with SOC before the addition of boceprevir appears to reduce the incidence of viral breakthrough. The most common adverse events reported in the boceprevir arms were fatigue, anaemia, nausea and headache.4

Protease inhibitors and HCV/HIV co-infection
Rapid progression to cirrhosis, end-stage liver disease and, ultimately, death is more common in patients co-infected with HCV/HIV. HCV viral loads may be higher in co-infected patients than those with mono HCV infection, and treatment outcomes in terms of SVR rates may be worse in co-infected patients, particularly with genotype 1 HCV infection. No significant difference in efficacy or safety has been reported in co-infected patients treated with PEG-IFN-2a plus ribavirin or PEG-IFN-2b plus ribavirin. HCV-associated liver failure is increasing significantly as a cause of death in HIV-positive patients in the post-highly active antiretroviral therapy (HAART) era in developed countries. It therefore follows that significant changes in HCV therapy could profoundly improve the treatment outcomes of this patient group. However, the addition of combination therapies, which include novel agents, for patients who are taking antiretroviral (ARV) regimens is unlikely to be without complication; clinically significant drug–drug interactions (DDIs) involving ARVs are common.3

The genetic variability of the protease encoding HCV NS3 gene was evaluated in 10 co-infected patients initiating ARVs (both before and after ARV initiation), and compared to the genetic variability in 10 patients on stable ARV therapy.13 No significant differences in sequence diversity or complexity at the nucleic acid or amino-acid levels were seen at baseline between groups. There was no significant development of amino-acid substitutions known to confer HCV PI resistance in either group. These results suggest ARV treatment for HIV would not affect the efficacy of HCV PI treatment.14

Conclusion
The combination of pegylated interferon (PEG-IFN) and ribavirin in chronic HCV infection led to an overall SVR in approximately 55% of cases. In genotypes 2 or 3, SVR rates reach 80%; in genotype 1 SVR rates are 50%. SVR appears to be long lasting, associated probably with a reduction in the risk of cirrhosis and hepatocellular carcinoma. Despite this progress, treatment failure still occurs in about half of the patients. Specifically targeted antiviral therapy for HCV (STAT-C) represents a new treatment paradigm with improved patient outcomes. According to the recent studies, the addition of a protease inhibitor to peginterferon alpha-2a and ribavirin in patients infected with HCV increased the rate of SVR in naïve patients as well as in non-responders and relapsers; this approach may allow for a substantial reduction in the duration of therapy in most patients.

References
1. McHutchison J, et al. N Engl J Med 2009;360:1827–28.
2. Liu-Young G, et al. AIDS Patient Care STDS 2008;22:449–55.
3. Seden K, et al. J Antimicrob Chemother 2010 [Epub ahead of print].
4. Asselah T, et al. Liver International 2009;29:57–67.
5. Hézode C, et al. N Engl J Med 2009;360:1839–50.
6. Arasappan A, et al. J Med Chem 2009;52:2806–17.
7. Berman K, et al. Clin Liver Dis 2009;13:429–39.
8. Lamarre D, et al. Nature 2003;426:186–89.
9. Reesink HW, et al. Gastroenterology 2006;131:997–1002.
10. McHutchison J, et al. J Hepatol 2008;4852:S4.
11. Zeuzem S, et al. Hepatology 2008;A243:AASLD.
12. McHutchison J, et al. N Engl J Med 2010;362:1292–1303.
13. Kwo P, et al. Hepatology 2008;LB16:AASLD.
14. Winters M, et al. J Med Virol 2010;82:791–98.



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