The revolutionary changes in hepatitis C treatment: A concise review

Issue: BCMJ, vol. 61 , No. 2 , March 2019 , Pages 72-77 Clinical Articles

ABSTRACT: Since hepatitis C was discovered in 1989, the pharmacological management of infections caused by the virus has undergone revolutionary changes, significantly improving cure rates and reducing patient morbidity and mortality. Early treatment options included interferon and ribavirin, which were associated with significant side effects and poor efficacy. In 2011 the first direct-acting antiviral agents were introduced and since have continued to improve both the efficacy and tolerability of treatment. The development of the direct-acting antiviral agents has reduced disease burden, expanded treatment options for patients with different hepatitis C genotypes or other pre-existing comorbidities, and significantly improved cure rates, which now exceed 95% with newer antiviral agents. Barriers to using this therapy in British Columbia include suboptimal population screening and diagnosis, variable patient and physician knowledge, high drug costs, lack of insurance coverage for some antivirals, and difficulty accessing coverage under Pharmacare. Re-infection is also an ever-present risk. Using the antiviral therapies currently available and ensuring patients have better access to care would make eliminating hepatitis C possible in British Columbia, especially if health care providers, patient communities, and government agencies all strive to achieve this goal.


The replacement of interferon-based therapy with highly effective and well-tolerated direct-acting antiviral therapy makes eliminating hepatitis C infections in British Columbia a realistic goal.


Worldwide, hepatitis C is a major public health concern, with an estimated 71 million people being chronically infected with the virus (www.who.int/news-room/fact-sheets/detail/hepatitis-c). Individuals with untreated hepatitis C infection have an approximate fivefold increase in all-cause mortality and a twentyfold increase in liver-related mortality.[1] Acute hepatitis C infections can present asymptomatically, and approximately 85% of acute infections will develop into chronic disease.[2] Chronic hepatitis C infections can cause significant liver damage, including the development of cirrhosis and hepatocellular carcinoma.[3,4] In addition to the hepatic manifestations, acute and chronic hepatitis C can have extra-hepatic manifestations, including disease processes associated with the virus and more specific immune-related end-organ effects.[5] Disease processes associated with hepatitis C infection include renal insufficiency, type 2 diabetes, and insulin resistance, while more specific hepatitis C immune-related manifestations include sicca syndrome, arthralgia, myalgia, and mixed cryoglobulinemia.[5] The hepatic and extra-hepatic manifestations contribute to the huge burden of disease that negatively impacts patient well-being and quality of life.

In British Columbia, more newly reported hepatitis C cases are reported than elsewhere in Canada,[1] with the Metro Vancouver area having an alarmingly high incidence rate of 37.3 per 100 person-years among young injection drug users.[6] In a recent study of more than 1.1 million individuals in BC tested for hepatitis C, a prevalence rate of 5.8% was reported.[1] While high incidence rates are associated with sex-trade work, incarceration, and injection drug use, high prevalence rates in British Columbia are associated with the following: male gender, a birthdate from 1945 to 1964, HIV or hepatitis B co-infection, a mental health condition, a substance and/or alcohol abuse disorder, and low socioeconomic status.[1]

Despite advances in management and better understanding of viral genotypes,[7] hepatitis C infection continues to pose a threat to public health in Canada and other countries.[2]

Screening

A high proportion of Canadians with chronic hepatitis C infection remain undiagnosed,[8] making it important for physicians and other health care providers to understand screening recommendations that will help with diagnosis and, ultimately, eradication of hepatitis C. The Canadian Association for the Study of the Liver released updated guidelines in 2018 that include recommendations on the assessment, evaluation, and management of hepatitis C.[8] The 2018 guidelines recommend taking a risk-based and population-based approach to screening.[8] Chronic hepatitis C infection is prevalent in individuals born from 1945 to 1975.[8] Despite the high prevalence of hepatitis C infection in this birth cohort, screening rates are low[8] and the guidelines recommend one-time screening in all individuals in the 1945 to 1975 birth cohort, independent of individual risk factors.[8] For those with risk factors, testing for hepatitis C infection is recommended.

Some notable risk factors for hepatitis C are:

  • A history of injection drug use.
  • Having received a blood transfusion, blood products, or an organ transplant in Canada before 1992.
  • A history of or current incarceration.
  • Having received chronic hemo-dialysis.
  • HIV infection.

Initial screening includes a test for hepatitis C antibodies.[8] If test results are positive, active infection should be confirmed with an RNA screen for hepatitis C.[8] Subsequently, patients should be referred to practitioners with experience in hepatitis C management to optimize treatment and outcomes.[8]

The 2018 guidelines also recommend that patients with confirmed hepatitis C infections undergo further testing to help establish a baseline and individualize treatment.[8] Suggested testing includes routine blood work with a complete blood count, liver enzymes (alanine transaminase, aspartate transaminase, alkaline phosphatase), liver function (bilirubin, INR, albumin), and creatinine.[8] Additionally, serology is recommended to exclude other infections (HIV, hepatitis B) and common liver diseases (transferrin saturation for hemochromatosis evaluation, IgG for autoimmune hepatitis).[8] Furthermore, all patients with hepatitis C should undergo staging of their liver disease, including a baseline ultrasound and evaluation for fibrosis.[8]

Other recommendations include resistance testing, if indicated, and genotype testing.[8] Six hepatitis C genotypes have been identified based on nucleotide differences. In turn, these numbered genotypes have been further classified by letter (1a, 2b, 3c, etc.).[7] Geographic differences are seen in the prevalence of some variants, with genotypes 1, 2, and 3 being common throughout the world, genotype 4 being common in the Middle East, and genotype 1 being overwhelmingly dominant in North America. Knowing a patient’s genotype can help select the most effective treatment.

Early treatment options

The first pharmacological regimen for hepatitis C was introduced in the 1990s and consisted of non-pegylated interferon alpha-2a or alpha-2b mono-therapy.[9] The treatment duration was 24 or 48 weeks, depending on the hepatitis C genotype, and required thrice weekly injections.[9] As well as being cumbersome to patients and having significant side effects, the treatment was not very successful in achieving viral clearance as measured by the sustained virological response—undetectable hepatitis C RNA levels at 12 weeks or 24 weeks following the end of therapy. To increase the rates of sustained virological response, ribavirin was added to the interferon alpha treatment regimen, which improved outcomes and increased the response rates to approximately 30% to 40%.[9] However, treatment response was heavily dependent on the hepatitis C genotype, with relatively poor cure rates reported in cases of genotype 1 and 4.[9]

In the latter half of the 1990s, pegylated interferonalpha formulations were introduced. Pegylation slows down the rate of drug absorption, reduces distribution, and decreases the rate of elimination.[10] With pegylation, ideal plasma concentrations for inhibiting viral replication are better maintained, improving drug efficacy and increasing rates of sustained virological response.[10] However, response rates for pegylated interferon were found to be heavily dependent on patient-specific characteristics: body mass index, degree of pretreatment hepatic damage (specifically, cirrhosis), IL-28B genotype, and hepatitis C RNA viral load. In cases of patients with treatment experience, the response to previous treatment (i.e., relapse vs nonresponse) was also a factor.[11,12] Although patients treated with pegylated interferon plus ribavirin required only one rather than multiple injections per week, the therapy had a number of side effects.[10] Adverse effects associated with interferon therapy included neutropenia, thrombocytopenia, alopecia, hypothyroidism, hyperthyroidism, flu-like symptoms, nausea, vomiting, and weight loss.[13] Interferon therapy was also associated with neuropsychiatric side effects, namely impaired memory and concentration, depression, and irritability.[13] Additional side effects associated with ribavirin specifically included anemia, respiratory complications, and teratogenicity.[13] Due to the many potential systemic toxicities and complications, interferon therapy was contraindicated in many patients. For genotype 1, the most common genotype in Canada, the likelihood of achieving a sustained virological response was a disappointing 40%, at best, in noncirrhotic patients after 48 weeks of therapy.[14] For the combined genotype 2 and 3 patients, 24 weeks of pegylated interferon and ribavirin yielded a sustained virological response of 76%.[15] Cirrhotic patients in general responded less well to any interferon-based therapy, and those with advanced cirrhosis requiring a liver transplant tolerated the therapy poorly and experienced significant adverse side effects, including worsening decompensation and death.[16] In short, interferon-based therapies were associated with significant side effects and suboptimal treatment success rates, and the use of interferon was contraindicated in patients with advanced liver disease.

Current treatment options

In 2011 the first direct-acting antiviral agents were developed and approved for the treatment of hepatitis C infection.[17] These novel antiviral medications include the following classes of drugs: NS3/4A protease inhibitors, NS5A replication complex inhibitors, and NS5B polymerase inhibitors. As shown in the Figure,[18] direct-acting antiviral agents were developed to target the products of the nonstructural coding sequence of hepatitis C, thus directly impairing the replicative machinery of the virus rather than relying on the nonspecific antiviral effects of pegylated interferon and ribavirin.[7] The Table shows a list of the currently available products and their pivotal registration clinical trials.[19-53] Each product uses a combination of drugs to achieve an additive or synergistic effect. The cure rates with these extremely well tolerated antiviral formulations is 95% to 99%.

Barriers to overcome

Treatment of hepatitis C has undergone revolutionary changes since the early 1990s. The introduction of direct-acting antivirals in particular has improved cure rates and reduced patient all-cause and liver-specific mortality and morbidity. Treatment has gone from being cumbersome and ineffective to being well tolerated and highly effective. But although good treatment options exist, the complete eradication of the disease in British Columbia will require overcoming some barriers. These include suboptimal population screening and diagnosis, variable patient and physician knowledge, high drug costs, lack of insurance coverage for some antivirals, and difficulty accessing coverage under Pharmacare. In addition, direct-acting antivirals do not work for a small but real minority, and reinfection is an ever-present risk.[54]

The World Health Organization has declared that eliminating hepatitis C globally by 2030 is feasible.[55] Using the antiviral therapies currently available and ensuring patients have better access to care would make eliminating hepatitis C a realistic goal in British Columbia, especially if health care providers, patient communities, and government agencies all strive to achieve this goal.

Competing interests

Over the past 22 years Dr Yoshida has been an investigator in hepatitis C clinical trials sponsored by Gilead Sciences, Merck (previously Schering-Plough), Janssen, AbbVie, Vertex, Hoffmann-La-Roche, Boerhinger Ingel-heim, Pfizer, Human Genome Sciences, and Novartis. In the past 2 years he has received honoraria for CME/Ad Board lectures from Gilead Sciences Canada, Merck Canada, and AbbVie Canada.


This article has been peer reviewed.


References

1.    Janjua NZ, Yu A, Kuo M, et al. Twin epidemics of new and prevalent hepatitis C infections in Canada: BC Hepatitis Testers Cohort. BMC Infect Dis 2016;16:334.

2.    Blackard J, Shata MT, Shire NJ, Sherman KE. Acute hepatitis C infection: A chronic problem. Hepatology 2008;47:321-331.

3.    Wook Kim C, Chang KM. Hepatitis C virus: Virology and life cycle. Clin Mol Hepatol 2013;19:17-25.

4.    Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci 2006;3:47-52.

5.    Cacoub P, Comarmond C, Domont F, et al. Extrahepatic manifestations of chronic hepatitits C virus infection. Ther Adv Infect Dis 2016;3:3-14.

6.    Miller CL, Johnston C, Spittal PM, et al. Opportunities for prevention: Hepatitis C prevalence and incidence in a cohort of young injection drug users. Hepatology 2002;36:737-742.

7.    Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 2000;13:223-235.

8.    Shah H, Bilodeau M, Burak KW, et al. The management of chronic hepatitis C: 2018 guideline update from the Canadian Association for the Study of the Liver. CMAJ 2018;190:E677-E687.

9.    Burstow NJ, Mohamed Z, Gomaa AI, et al. Hepatitis C treatment: Where are we now? Int J Gen Med 2017;10:39-52.

10.    Medina J, Garcia-Buey L, Moreno-Monteagudo JA, et al. Combined antiviral options for the treatment of chronic hepatitis C. Antiviral Res 2003;60:135-143.

11.    deLemos AS, Chung RT. Hepatitis C treatment: An incipient therapeutic revolution. Trends Mol Med 2014;20:315-321.

12.    Pearlman BL. Hepatitis C treatment update. Am J Med 2004;117:344-352.

13.    Andronescu D, Diaconu S, Tiuca N, et al. Hepatitis C treatment & management. J Med Life 2014;7:31-36.

14.    McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580-593.

15.    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982.

16.    Crippen JS, McCashland T, Terrault N, et al. A pilot study of the tolerability and efficacy of antiviral therapy in hepaitits C virus-infected patients awaiting liver transplantation. Liver Transpl 2002;8:350-355.

17.    Alexopoulou A, Karayiannis P. Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals. Ann Gastroenterol 2015;28:55-65.

18.    FDA. Drugs@FDA: FDA Approved drug products. Accessed 4 April 2018. www.accessdata.fda.gov/scripts/cder/daf.

19.    Keating GM. Ledipasvir/sofosbuvir: A review of its use in chronic hepatitis C. Drugs 2015;75:675-685.

20.    Gritsenko D, Hughes G. Ledipasvir/sofosbuvir (Harvoni): Improving options for hepatitis C virus infection. P T 2015;40:256-259.

21.    Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370:1889-1898.

22.    Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483-1493.

23.    Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370:1879-1888.

24.    Kohli A, Kapoor R, Sims Z, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: A proof-of-concept, single-centre, open-label phase 2a cohort study. Lancet Infect Dis 2015;15:1049-1054.

25.    Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 2015;149:649-659.

26.    Gane EJ, Hyland RH, An D, et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015;149:1454-1461.

27.    Abramowicz M, Zuccotti G, Pflomm JM, et al. Sofosbuvir/velpatasvir (Epclusa) for hepatitis C. JAMA 2017;317:639-640.

28.    Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5 and 6 infection. N Engl J Med 2015;373:2599-2607.

29.    Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015;373:2608-2617.

30.    Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015;373:2618-2628.

31.    Wyles D, Brau N, Kottilil S, et al. Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunodeficiency virus type 1: An open-label, phase 3 study. Clin Infect Dis 2017;65:6-12.

32.    Keating GM. Elbasvir/grazoprevir: First global approval. Drugs 2016;76:617-624.

33.    Vallet-Pichard A, Pol S. Grazoprevir/elbasvir combination therapy for HCV infection. Ther Adv Gastroenterol 2017;10:155-167.

34.    Zeuzem S, Ghalih R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, 4, or 6 infection. Ann Intern Med 2015;163:1-13.

35.    Kwo P, Gane E, Peng CY, et al. Efficacy and safety of grazoprevir/elbasvir ± ribavirin (RBV) for 12 or 16 weeks in patients with HCV G1, G4, or G6 infection who previously failed peginterferon/RBV: C-EDGE treatment-experienced trial. Gastroenterology 2015;148:S1194-S1195.

36.    Lawitz E, Poordad F, Gutierrez JA, et al. Short-duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: A randomized trial. Hepatology 2017;65:439-450.

37.    Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): A randomised, open-label phase 2 trial. Lancet 2015;385(9973):1087-1097.

38.    Rockstroh JK, Nelson M, Katlama C, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): A non-randomised, open-label trial. Lancet HIV 2015;2:319-327.

39.    Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): A combination phase 3 study. Lancet 2015;386(10003):1537-1545.

40.    Dore GJ, Atlice F, Litwin AH, et al. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: A randomized trial. Ann Intern Med 2016;165:625-634.

41.    Heo YA, Deeks ED. Sofosbuvir/velpatasvir/voxilaprevir: A review in chronic hepatitis C. Drugs 2018;78:577-587.

42.    Gilead Sciences Inc. Vosevi (sofosbuvir/velpatasvir/voxilaprevir) tablets 400 mg/100 mg/100 mg. Product monograph. 18 April 2018. Accessed 3 June 2018. www.gilead.ca/application/files/3215/2589/3935/Vosevi_English_PM_e192340-GS-001.pdf.

43.    Bourliere M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017;376:2134-2146.

44.    Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology 2017;153:113-122.

45.    AbbVie Inc. Mavyret (glecaprevir/pibrentasvir 100 mg/40 mg tablets). Highlights of prescribing information. 2017. Accessed 3 June 2018. www.rxabbvie.com/pdf/mavyret_pi.pdf.

46.    Abutaleb A, Kottilil S, Wilson E. Glecaprevir/pibrentasvir expands reach while reducing cost and duration of hepatitis C virus therapy. Hepatol Int 2018;12:211-214.

47.    Kwo PY, Poordad F, Asatryan A, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol 2017;67:263-271.

48.    Asselah T, Kowdley KV, Zadeikis N, et al. Efficacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol 2018;16:417-426.

49.    Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): A single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017;17:1062-1068.

50.    Rockstroh J, Lacombe K, Viani RM, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: The EXPEDITION-2 study. Clin Infect Dis 2018;67:1010-1017.    

51.    Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017;66:389-397.

52.    Reau N, Kwo PY, Rhee S, et al. MAGELLAN-2: Safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1-6 infection. J Hepatol 2017;66:90-91.

53.    Gane E, Lawitz E, Pugatch D, et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment. N Engl J Med 2017;377:1448-1455.

54.    Konerman MA, Lok ASF. Hepatitis C treatment and barriers to eradication. Clin Transl Gastroenterol 2016;7:e193.

55.    World Health Organization. Combating hepatitis B and C to reach elimination by 2030. 2016. Accessed 18 June 2018. www.who.int/hepatitis/publications/hep-elimination-by-2030-brief/en/.


Ms Dahiya is a student in the MD Undergraduate Program at the University of British Columbia. Dr Hussaini is a pharmacotherapy specialist in liver transplantation at Vancouver General Hospital and a clinical assistant professor in the Faculty of Pharmaceutical Sciences at UBC. Dr Yoshida is a professor in the Department of Medicine and past head of the Division of Gastroenterology at UBC. He is also head of the BC Hepatitis Program.

Monica Dahiya, BSc, Trana Hussaini, PharmD, Eric M. Yoshida, OBC, MD, MHSc, FRCPC. The revolutionary changes in hepatitis C treatment: A concise review. BCMJ, Vol. 61, No. 2, March, 2019, Page(s) 72-77 - Clinical Articles.



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