Direct acting antivirals for hepatitis C: new developments

Published in Health News and Evidence

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Current standard of care for people with HCV genotype 1 includes the first generation direct acting antivirals (DAAs), telaprevir or boceprevir, combined with peginterferon/ribavirin. However, second generation DAAs have emerged, with higher sustained virologic response and shorter and less-complicated treatment regimens, but with similar safety profiles to currently approved therapies. Second generation DAAs offer the possibility of a shift towards interferon-free therapies which could be managed by primary care health professionals.

Key points

  • Rate of treatment uptake for chronic HCV is low despite a high rate of chronic hepatitis C diagnosis.
  • Two first generation direct acting anti-virals (DAAs), the protease inhibitors telaprevir and boceprevir, are PBS listed (S100 Highly Specialised Drugs) for treatment of HCV genotype 1.
  • Telaprevir and boceprevir have a high pill burden, and are associated with a high risk of drug–drug interactions and low barrier to resistance.
  • Second generation DAAs appear to be more effective at achieving sustained virologic response  with shorter, less-complicated treatment regimens, and they have safety profiles that are equivalent to or better than currently recommended peginterferon/ribavirin-based treatments.

Low treatment uptake

In 2013 it was estimated that hepatitis C virus (HCV) affected around 1.4% of the Australian population,1 but of these it has been estimated that less than 2% of people with chronic HCV infection are receiving treatment.2,3

In Australia, of the six known chronic HCV genotypes, genotype 1 accounts for around 50% of people infected with chronic HCV, and genotypes 2 and 3 combined account for a further 40%.4,5

Reasons behind the low HCV treatment uptake include:3

  • Concern over the adverse effects associated with interferon-based therapies, such as anaemia, rash, cough and neuropsychiatric problems.6
  • High rates of co-morbidities in people with HCV infection including substance abuse and psychiatric disease.
  • Relatively low overall treatment efficacy and long treatment duration for pegylated interferon alfa 2a and 2b (peginterferon) and ribavirin treatments.
  • Lack of infrastructure available to administer these therapies, which are required to be undertaken through specialist hepatitis and liver disease clinics.7

Approval of DAAs in Australia

Until recently, the standard of care for all genotypes of chronic HCV included non-specific antiviral treatment with injectable peginterferon and oral ribavirin (with or without the protease inhibitors telaprevir or boceprevir depending on the genotype).4,8

The first generation DAAs boceprevir and telaprevir were listed on the PBS for chronic genotype 1 hepatitis C infection under Section 100 Highly Specialised Drugs Program arrangements in April 2013.9,10 Under PBS listing restrictions treatment with these agents is currently required to be undertaken in hospitals with access to appropriate specialist facilities, specialists and liver disease clinics.11

More recently, sofosbuvir (Solvadi), daclatasvir (Daklinza)A and the fixed-dose combination of ledipasvir and sofosbuvir (Harvoni) received positive recommendations for the treatment of chronic HCV from the PBAC at its March 2015 meeting.12

A. In combination with sofosbuvir.

Current HCV treatment guidelines

The current standard of care for people infected with HCV genotype 1 is now triple therapy with boceprevir or telaprevir, peginterferon and ribavirin.8 The standard of care for people infected with all other HCV genotypes (2–6) still involves only peginterferon with or without ribavirin and does not include any approved first generation DAA.4,8

Limitations with telaprevir and boceprevir

DAAs work by interfering with the various stages of the HCV life cycle.6,8,13,14 Telaprevir and boceprevir work by inhibiting the NS3/NS4A serine protease, which is required for replication of HCV.6,14Treatment with telaprevir or boceprevir involves multiple daily doses,15-19and complex response-guided regimens, often with lead-in phases to potentially reduce the rates of viral resistance.16-20

In addition, as telaprevir and boceprevir inhibit the cytochrome P450 enzyme, treatment with either of these agents is limited by drug–drug interactions.15,21-23

Concerns with adverse effects

Adding boceprevir and telaprevir to peginterferon/ribavirin therapy in treatment naive patients with chronic disease due to HCV genotype 1 significantly improves the sustained virologic response compared with peginterferon/ribavirin alone. However, it has been reported that their use exacerbates the adverse effects normally seen with peginterferon/ribavirin therapy.16,18,19

Adding boceprevir and telaprevir to peginterferon/ribavirin treatments for HCV genotype 1 infections increased the incidence of adverse events such as anaemia, dysguesia and neutropenia with boceprevir17,19 and nausea, vomiting, diarrhoea, haemorrhoids, skin problems (pruritus, rash, alopecia) and anaemia with telaprevir, compared with peginterferon/ribavirin treatments alone.16,18

Emerging HCV resistance to telaprevir and boceprevir

The effectiveness of first and second generation DAAs for treating HCV infection may be diminished by antiviral resistance.21 A retrospective analysis of phase three clinical trials showed that at treatment failure, telaprevir resistant variants were detected in 77% of patients infected with HCV genotype 1.24 Furthermore, resistant variants were detected in patients infected with HCV genotype 1 treated with boceprevir and peginterferon/ribavirin that exhibited viral breakthrough.17

Second generation DAAs: potential for interferon-free therapies

Following telaprevir and boceprevir, a second generation of DAAs has been developed that target different points in the pathway to formation of non-structural (NS) proteins required for viral RNA replication in the HCV virus.6

  • NS3/NS4 serine protease inhibitors: simeprevir and asunaprevir.
  • NS5A inhibitors: daclatasvir and ledipasvir.
  • NS5B polymerase inhibitor: sofosbuvir.

Whereas treatment with telaprevir or boceprevir may involve oral dosing every 8 hours,22,23 treatment with second generation DAAs involves less complicated treatment regimens administered as either once-daily oral doses (simeprevir, ledipasvir, daclatasvir and sofosbuvir)25-32or as twice-daily oral dose (asunaprevir).33

Clinical trials have reported sustained virologic response rates for peginterferon/ribavirin therapies at 38–49% in people infected with HCV genotypes 1–4.6,13 Adding first-generation protease inhibitors, telaprevir16,18 and boceprevir,17,19 improved the virologic response rates to 61–75% in treatment naive people infected with HCV genotype 1.B Treatment for HCV genotype 1 disease with simeprevir,13,25,30 asunaprevir,33 ledipasvir, 34 daclatasvir,31 or sofosbuvir,13,26,28 either with peginterferon/ribavirin or as part of an interferon- and ribavirin-free therapy, have resulted in virologic response rates of 68–100%.

B. The sustained virologic response rates for African American patients following treatment with boceprevir and peginterferon/ribavirin was lower at 42–53%.

Safety profile of second generation DAAs

Adding second generation DAAs to peginterferon and/or ribavirin-based therapies was often associated with mild to moderate adverse effects consistent with peginterferon and/or ribavirin use.25,26,28,30,31,33,34 These symptoms include fatigue, diarrhoea, nausea, vomiting, flu-like symptoms, headache, irritability, insomnia, moodiness, dizziness, and skin problems.25,26,28,30,31,33,34

While in most cases the incidence of these adverse effects was comparable to or lower than the incidence associated with peginterferon or ribavirin alone,25,28,30,31,34 it has been reported that adding asunaprevir to peginterferon/ribavirin therapy increased the incidences of diarrhoea, dry skin, myalgia and depression.33

Pan-genotypic activity of second generation DAAs

Because of the variability of the NS3/NS4A serine protease domain between HCV genotypes and the high specificity of telaprevir and boceprevir for NS3/NS4A serine proteases, these agents are more effective in HCV genotype 1.35 In contrast, second generation DAAs, such as daclatasvir and ledipasvir (NS5A inhibitors) and sofosbuvir (NS5B polymerase inhibitor), are able to suppress the replication of all HCV genotypes.6 However, in non-genotype 1 HCV, the efficacy between second generation DAAs may vary.6,36

Sofosbuvir is a nucleotide analogue, which means it mimics the natural substrate of the N5B polymerase (important for HCV replication), thus acting as a competitive inhibitor.6, 35Phase two and phase three clinical trials support the claim that sofosbuvir has a high barrier to resistance as no virological breakthrough or treatment-emergent resistance were detected.26,28

Second generation DAAs vs telaprevir and boceprevir

Clinical trial data have, thus far, compared the efficacy and safety of second generation DAAs with peginterferon- and/or ribavirin-based treatments and not with current standard of care treatment regimens involving telaprevir and boceprevir.13,25,27-33 However, a number of head-to-head clinical trials are underway that compare the safety and/or efficacy of telaprevir versus simeprevir ( number NCT01485991),37sofosbuvir ( number NCT01994486),38 and daclatasvir ( number NCT01492426),39 when combined with peginterferon/ribavirin.

Shift towards interferon-free therapies for chronic HCV

Improved efficacy, equivalent or better safety profiles, and shortened treatment duration associated with therapies that include second generation DAAs compared with peginterferon/ribavirin-based therapies may enable a shift to interferon-free therapies for people with chronic HCV.6,13 This may in turn allow more patients infected with HCV to be treated in primary care.40

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