EDITORIAL VIRAL HEPATITIS C IN 2014 THE BEGINNING OF THE END?

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1 Rev. Med. Chir. Soc. Med. Nat., Iaşi 2014 vol. 118, no. 2 EDITORIAL VIRAL HEPATITIS C IN 2014 THE BEGINNING OF THE END? Annual advances in the management of chronic viral hepatitis C occur at an astounding pace. In our 2013 editorial we presented the new standard of care for the management of chronic viral hepatitis C using Boceprevir and Telaprevir with Pegylated Interferon (Peg) and Ribavirin (R). In 2014, these guidelines are already out-dated. Currently, over 35 new antiviral agents offer excellent results (95% eradication irrespective of genotype, fibrosis or previous therapy), transforming chronic viral hepatitis C in a condition that is both manageable and potentially curable. The current editorial aims to outline new therapeutic regimes, with or without interferon, which have already become goldstandards in the USA and Western Europe. Unfortunately, at present (June 2014) the National Insurance programme in Romania provides only pegylated interferon and ribavirin therapy. The hepatitis C virus (HCV) (Flaviviridae family; Hepacivirus genus) affects around 185 million people globally according to the World Health Organisation estimates, representing 2.8% of the world s population. The average prevalence worldwide of chronic viral hepatitis C varies between 1.2% and 3.8% (1). The HCV has 7 genotypes (1-7) with multiple subtypes and a variable global distribution. It contains three non-structural proteins that are essential for viral replication: NS3/4A protease, NS5B polymerase and NS5A protein. The most frequently occurring global genotype is type 1, with over 95% of Romania s population being infected with genotype 1b (2, 3). The majority of patients have a slow, paucisymptomatic or asymptomatic disease evolution. The signs of chronic hepatic or extrahepatic disease can occur after years from the initial infection. Consequently chronic hepatitis accounts for up to 27% of liver cirrhosis, 25.5% of hepatocellular carcinomas and annual deaths. Extrahepatic diseases (diabetes, lymphoma, crioglobulinaemias and glomerulonephrites) add further complexity to the therapeutic management and quality of life of chronic viral hepatitis C patients. HISTORY OF STANDARD OF CARE IN CHRONIC VIRAL HEPATITIS C The HCV was discovered in 1989 by Choo and was initially treated empirically with simple interferon (3 million units three times per week) with a sustained viral response (SVR) in 6% of cases. Subsequently, in 1991 the introduction of ribavirin improved the SVR through unknown mechanisms to 40-45%. This increased by 10% with the advent of pegylated interferon administered weekly (4). In the USA and Western Europe, double therapy with Peg and R has remained the standard of care until the summer of These are administered in naive chronic viral hepatitis C patients for 48 weeks in those with genotype 1, 4, 5 and 6 and for 24 weeks in those with genotype 2 and 3 (4). The SVR is 40-50% in type 1 genotype, 55-65% in type 4 and 85% in types 2 and 3 (4). Retreatment with double therapy has been recommended in genotype 1 patients with disease recurrence (negative viraemia at the end of initial therapy, but 272

2 Viral hepatitis C in 2014 the beginning of the end? detectable viraemia subsequently), partial responders (2 log lower viraemia at the end of week 12, but present at any point prior to the end of therapy). Selected nonresponders (viraemia decrease by less than 2 log at 12 weeks of treatment) may benefit from treatment, but with a very low SVR (5, 6). In Romania, the SVR percentage is similar with that reported in literature both in naive and previously treated individuals. The therapy costs in Romania are free of charge and covered by the National Insurance System. Early and dynamic monitoring of RNA -HCV allows targeted therapy based on the virological response. In cases where there is a rapid viral response (RVR), based on undetectable viral load at 4 weeks, treatment can be stopped at 24 weeks in patients with mild fibrosis and initial viraemia under IU leading to similar SVR as in patients with standard therapy of 48 weeks. The lack of adequate viral response at 12 and 24 weeks (decrease in viraemia by 2 logs and undetectable viraemia, respectively) warrants therapy cessation. Relatively recently, a genetic marker has been identified which can predict response to double antiviral therapy in chronic viral hepatitis C. The polymorphism of Interleukin 28B (lambda 3 interferon on chromosome 19) has predictive value for SVR in dual therapy with R and Peg. The position of the C (cytosine) and T (thymine) alleles with a CC sequence compared to a CT or TT sequence, leads to an SVR that is twice as high (69% compared to 33% and 27% respectively) (7). Dual therapy has many limitations, ranging from a poor SVR to the many know severe side effects of interferon and ribavirin. Knowledge of the life cycle of HCV has led to the development of new antiviral agents which include drugs with direct action (DAA direct acting agents) and those against host factors needed in viral replication (HTA host targeting agents). These can be used in association with classical therapy (Peg and R) or interferon-free, in order to reach a cure rate of over 90% irrespective of genotype or severity of fibrosis. In , the standard treatment in the USA and Western Europe consisted of triple therapy in genotype 1 both in naïve patients and in previously treated individuals, consisting of associating Peg/R with DAA-protease inhibitors (Boceprevir or Telaprevir). The addition of these agents raises the SVR by 25-31% in naïve individuals and by 40-46% in those with recurrence, by 33-45% in partial responders and by 24-28% in non-responders (8). The advantage of triple therapy consists of a significant improvement in SVR with the possibility to reduce the duration of treatment by a half to two thirds. Patients with advanced hepatic fibrosis (F4 compensated hepatic cirrhosis) have a lower SVR, both with double and triple therapy (9). If the SVR rises significantly, the side effects of triple therapy with Boceprevir / Telaprevir are additive and cumulative with those known for Peg and R, but are reversible with cessation of treatment. In addition to the known side effects, new adverse effects may occur such as dysgeusia (Boceprevir), ano-rectal symptoms and advanced exanthema (Telaprevir). It is important to note that any reduction in the dose of DAA or administration of monotherapy leads to viral resistance. Consequently, patients who develop side effects or intolerance must discontinue treatment and the dose of DAA must not be modified. Similarly, both Boceprevir and Telaprevir are metabolised by the cytochrome p

3 Cristina Cijevschi Prelipcean et al. pathway and a wide variety of drug interactions must be taken into consideration in patients with multiple comorbidities. Triple therapy can be considered to be successful in patients with chronic viral hepatitis C with genotype 1 due to the significant rise in SVR in naïve and previously treated patients, compared to those with dual therapy. Despite this, triple therapy is far from the ideal treatment option. Treatment costs are high ($ $ for Boceprevir / Telaprevir) to which additional costs are added (monitoring, viraemia levels, management of side effects, specialist medical follow-up). There are groups of patients who do not respond adequately to treatment (advanced fibrosis, nonresponders with cirrhosis, intolerance or contraindication to treatment with Peg / R). Furthermore, treatment outcomes in patients with genotypes other than type 1 or other clinical entities (transplant, renal failure, HIV co-infection) have not been determined. Research advances, especially in the field of viral kinetics, have led to the creation of new DAA and HTA, benefiting from targeted activity for different viral genotypes and different barriers to resistance; their combination in different therapeutic regimes is imperative in order to prevent viral resistance and achieve synergistic effects. The main DAA are already approved and are in phase II and Phase III trials (10, 11): - Inhibitors of NS3-4A protease: first generation - first wave : Boceprevir, Telaprevir; second wave : Simeprevir, Faldaprevir, Asunaprevir, ABT-450r, Danoprevir, Sovaprevir, Vedroprevir, IDX320, Vaniprevir; second generation: MK-5172, ACH RNA Inhibitors RNA polymerase-dependent (RdRp): nucleotide analogues (Sofosvubir, Vx-135); nucleoside analogues (Mericitabin); non-nucleoside inhibitors RdRp: BMS , TMC647055, Lomibuvir, GS-9669, Dasabuvir, ABT-072, Setrobuvir; - NS5A Inhibitors: first generation: Daclatasvir, Ledipasvir, Ombitasvir, PPI- 668, PPI-461, ACH-2928, GSK , BMS824393, Samatasvir; second generation: MK-8742, ACH3102, GS5816. The HTA family includes ciclophilin A inhibitors (Alisporivir, SCY-635) and microrna 122 inhibitors (Miravirsen). Two new DAA were approved in 2013 in the USA and in 2014 in Europe for the treatment of chronic hepatitis C infection: Simeprevir and Sofosfubir. The addition of Simprevir (150mg, once daily) to standard treatment (Peg/R) leads to a SVR of 85% in naïve patients with genotype 1b, as demonstrated by data from the QUEST-1 and QUEST-2 (12, 13) studies. In genotype 1a, the SVR is low (58%) in patients with Q80K mutation in the sequence of the NS3 protease. It is recommended Q80K mutation screening before Simeprevir treatment. The SVR is also affected by the severity of hepatic fibrosis 58-65% in patients with F4; 83-85% in those with F0-2. In patients previously treated with Peg/R with disease recurrence, the addition of Simeprevir leads to a SVR of 86% in genotype 1b and 78% in genotype 1a without the Q80K mutation (14). The side effects of adding Simeprevir were no different from those in standard therapy. These include mild pruritus, rash and transient hyperbilirubinaemia. Sofosfubir (400mg, once daily) added to Peg/R leads to an SVR of 89% in naïve patients with genotype 1 after just 12 weeks of triple therapy (NEUTRINO study) (15). No significant differences were 274

4 Viral hepatitis C in 2014 the beginning of the end? found between genotype 1a and 1b, whilst the severity of the fibrosis did not significantly impact on the SVR (92% in noncirrhotic patients vs. 80% in those with cirrhosis). The combination of Sofosfubir and ribavirin is not effective in patients with genotype 1, with the exception of those awaiting liver transplantation. In contrast, in genotype 2 patients the SVR at 12 months is 95% in naïve patients and 82% in previously treated one (better results were obtained in non-cirrhosis patients compared to those with cirrhosis). The effectiveness of therapy in those with genotype 3 is lower compared to those with genotype 2: 56% in naïve patients and only 30% in in those previously treated (16). In the Valence study, the SVR in genotype 2 patients at 12 weeks was 97% in naïve non-cirrhosis patients; 100% in naïve cirrhosis patients; 91% in previously treated non-cirrhosis patients; 88% in previously treated cirrhosis patients. For genotype 3 the SVR after 24 weeks of treatment was 93%, 92%, 87% and 60%, respectively (17). The combination between Simeprevir (150mg once daily) and Sofosubir (400mg once daily) in genotype 1 is effective both in naïve and non-responding patients, irrespective of the level of fibrosis, with the exception of patients with genotype 1a and Q80K mutation (18). The WHO guidelines recommend the following therapy at present (19): Patients with genotype 1 and 4: 12 weeks of triple therapy with Sofosfubir / R / Peg. Those with contraindications or intolerance to interferon, can be treated with Sofosfubir / R for 24 weeks of therapy, leading to a SVR that is significantly lower compared to triple therapy with interferon. In genotype 1 Simprevir combined with Peg / R is administered for 12 weeks followed by another 12 weeks of double therapy with Peg / R in all naïve patients or in those with recurrence, including those suffering from cirrhosis. Previously treated patients who are partial or non-responders require 48 weeks of treatment (12 weeks of Simeprevir / Peg / R and 36 weeks of Peg / R). Patients with genotype 1a should be tested for Q80K mutation before therapy with Simeprevir. Patients with genotype 2 should have 12 weeks of Sofosfubir /R therapy. Those with genotype 3 (currently representing the most difficult to treat viral genotype) should have Sofosfubir /R for 24 weeks or Peg / R / Sofosfubir for 12 weeks. Currently there are a number of studies looking at other therapeutic regimes with or without interferon, which could become the standard of care in Regimens based on interferon: studies have looked at the outcomes of using standard therapy (Peg / R) in association with Faldaprevir, Asunaprevir, Daclatasvir, MK-5172, Alisporivir as well as quadruple regimens using Peg / R / Daclatasvir / Asunaprevir (SVR 95%) or Peg / R / Danoprevir / Mericitabin (SVR 100%) in genotype 1b non-responders (11). Interferon-free regimens: Sofosfubir and Ledipasvir have been used for 8-24 weeks (a single tablet per day) with a SVR of over 95% without significant side effects both in naïve and previously treated patients with or without cirrhosis. This may well become the gold standard therapy for 2015 (20). The same encouraging results were obtained using Sofosfubir and Daclatasvir for genotype 1, as well as genotypes 2 and 3. The use of ABT-450 boosted with Ritonavir (first generation, second wave non-nucleoside inhibitor), ABT-267 (NS5A inhibitor), ABT-333 (RdRp nonnucleoside inhibitor) and R for 12 weeks 275

5 Cristina Cijevschi Prelipcean et al. demonstrated a SVR of 95-98% in naïve and previously treated patients with genotype 1 (10). A number of other combinations of DAA and HTA in double or triple therapy are currently being studied. FACTORS INFLUENCING DECISION-MAKING IN ANTIVIRAL TREATMENT Ideally, any patient infected with hepatitis C virus must benefit from antiviral treatment. In order to obtain a SVR and to cure hepatitis in a high proportion (>95%) all the factors that can or cannot be affected by antiviral therapy must be know (10). Factors that cannot be changed are virus-related, such as genotype, subtypes, mutations (such as Q80K) and patientrelated (Il28 genetic polymorphism, degree of fibrosis and comorbidities). Factors that can be changed are related to the type of treatment, antiviral agents combinations, duration of treatment and associations with or without ribavirin (20). Theoretically, the treatment of hepatitis C viral infections is easy if two essential conditions are fulfilled: 1. the antiviral activity of the therapeutic regime must effectively and rapidly block the production of virus in the infected cells (the viraemia sharply decreases in the first 3 days of treatment); 2. the blocking activity must be sustained with on-going therapy (the choice of antivirals for the prevention of resistance or breakthrough in the second phase of decreasing the viraemia). In order to prevent recurrence treatment must be continued until the last infected cell is eliminated failure to achieve this can lead to on-going virus production (11). Patients with advanced fibrosis, cirrhosis, genotype 1a or 3 non-cc sequence have a poorer response to therapy, having a longer second phase of viraemia decrease and requiring a longer duration of therapy. The addition of ribavirin accelerates the second phase of viraemia decrease, optimising the SVR even in interferon free regimens, although the mechanism of action is yet unknown in This is well tolerated in the absence of interferon. LIMITATIONS OF ANTIVIRAL TREATMENT Currently (June 2014) there is limited data regarding the safety, effective dose, duration of treatment for patients with genotypes 5, 6 and 7, genotype 1a with Q80K mutation (30% of studied patients), decompensated cirrhosis, renal failure and liver or other organ transplant. In genotypes 1 and 4 the association of DAA with Peg/R as a standard therapy is difficult to accept. The treatment of infected children with vertical transmission from infected mothers (>5 million worldwide) is not standardised. This is particularly relevant in countries with a high prevalence of hepatitis C. Another limitation is the development of viral resistance. The first generation of NS3-4A protease inhibitors, NS5A inhibitors and HCV RdRp nonnucleoside inhibitors have a reduced genetic barrier to viral resistance. In double treatment regimens it is recommended the addition of a DAA or HTA with a high genetic barrier or triple therapy regimens with a low genetic barrier. New therapies are not widely available worldwide, especially in underdeveloped countries with a high disease prevalence (41% of infected patients live in countries without medical compensation for the treatment of chronic hepatitis B or C). Whilst 7 11% of infected individuals in the USA and 16% in the European Union benefit from treatment, only 1.5% of patients in China have similar access to care. Currently, double therapy (Peg / R) in 276

6 Viral hepatitis C in 2014 the beginning of the end? the majority of countries around the world costs for a 48-week course (without taking in account the need for erythropoietin therapy and medical costs of follow-up). First generation oral antiviral agents cost between $ ; second generation are even more expensive (e.g. Sofosbuvir costs $1000 per tablet; total treatment cost for 12 weeks being $ for Sofosbuvir and $66,000 for Simeprevir) (19). Despite this, due to the effectiveness, safety and simple administration modality, the decrease in treatment duration, prevention of complications and the increase in quality of life make these treatment modalities cost-effective. A sustained national and global campaign must be fought in order to allow all infected patients to have access to optimal therapies. The cure of viral infections is achievable in over 90% of patients using current therapies. However, this does not coincide with cure of the patient, as cirrhosis patients remain at risk of decompensating and exposed to associated risks, such as the development of hepatocellular carcinoma. CONCLUSIONS 25 years after the discovery of the HCV there are still no effective methods of immunisation. New therapies have however brought hope regarding the eradication of chronic viral hepatitis C. We hope that 2015 will bring a new editorial on a new gold standard of care (also applicable in Romania) using a Perfectovir an oral drug with no side-effects, administered as a once daily dose which can cure chronic viral hepatitis irrespective of genotype, degree of fibrosis, comorbidities, prior therapy or special conditions. REFERENCES 1. Mohd Hanafiah K, Groeger J, Flaxman AD. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatol 2013; 57(4): Rupp D, Bartenschlager R. Targets for antiviral therapy of hepatitis C. Semin Liver Dis 2014; 34: Grigorescu M. HCV genotype 1 is almost exclusively present in Romanian patients with chronic hepatitis C. J Gastrointestin Liver Dis 2009;18(1): Hadziyannis SJ, Sette HJ, Morgan TR et al. International Study Group. Peginterferon alfa 2 and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: Ghany MG, Nelson DR, Strader DB et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the AASLD. Hepatol 2011; 54 (4): EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2011; (55): Thompson AJ. Human and viral genomes: optimizing treatment algorithms for the future. Postgraduate course: Personalized medicine and the practice of hepatology. The Liver Meeting, Boston 2012: Alexopoulou A, Papatheodoridis G. Current progress in the treatment of chronic hepatitis C. World J Gastroenterol 2012; 18(42): Hezode C. Current treatment options for HCV genotype 1: what is available and who should receive triple therapies now? EASL Postgraduate Course 2014:

7 Cristina Cijevschi Prelipcean et al. 10. Pawlotsky JM. New hepatitis C virus drugs and the hope for a cure: concepts in anti-hcv drug. Semin Liver Dis 2014; 34 (1): Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterol 2014; 146: Jacobson I, Dore GJ, Foster GR et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-1, a phase III trial. J Hepatol 2013; 58: S Manns M, Marcellin P, Poordad et al. Simeprevir (TMC 435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-2, a phase III trial. J Hepatol 2013; 58: S Lawitz E, Forns X, Zeuzem S et al. Simeprevir (TMC 435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in patients who relapsed after previous interferon-based therapy: results from PROMISE, a phase III trial. Gastroenterol 2013; 144: S Lawitz E, Mangia A, Wyles D et al. Sofosvubir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: Jacobson IM, Gordon SC, Kowdley KV et al. Sofosfubir for hepatitis C genotype 2 or 3 in patients without treatment options. N Eng J Med 2013; 368: Zeuzem S, Dusheiko G, Salupere R et al. Sofosfubir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the Valence trial. Hepatol 2013; 58(Suppl 1): 733 A. 18. Jacobson I, Ghalib RH, Rodriguez-Torres M et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosvubir (GS 7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. Hepatol 2013; 58 (suppl 1): World Health Organization. Guidelines for the screening,care and treatment of persons with hepatitis C infection. April Feld J. Choosing the optimal HCV regimen. AGA Spring Postgraduate Course 2014: Cristina Cijevschi Prelipcean, P. Gogălniceanu, Cătălina Mihai 278