References

  1. World Health Organization (WHO). Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. July 2018. Available at: https://www.who.int/hepatitis/publications/hepatitis-c-guidelines-2018/en/ (accessed November 2018).
  2. American Association for the Study of Liver Diseases (AASLD). HCV Guidance: recommendations for testing, managing, and treating hepatitis C. Sept 21, 2017. Available at: hcvguidelines.org (accessed November 2018).
  3. European Association for the Study of the Liver (EASL). EASL recommendations on treatment of hepatitis C 2018. J Hepatol 2018;69:461-511.

Treatment goals

The main goal of antiviral therapy in chronic HCV is to achieve viral eradication. In HCV, viral eradication is defined by the achievement of a sustained virological response (SVR}.

SVR = undetectable plasma HCV RNA at 12 weeks (SVR12) after the completion of therapy.4-6

Once achieved, SVR is considered a cure of the infection as late relapses are uncommon.9-10 HCV cure is associated with numerous health benefits, including:

  • improvement in quality of life,11-12
  • loss of infectivity,8
  • regression of liver fibrosis and cirrhosis,13
  • a reduction in the risk of liver failure and hepatocellular carcinoma (HCC),14 and
  • a reduction in the risk of liver-related and all-cause mortality.14-16

 

All these goals can be achieved in a significant proportion of patients with the currently available therapies. Preferably, treatment should be initiated early in the course of HCV infection before the development of severe liver disease and other complications.5

 

Clinical considerations

Prior to commencing DAA therapy, patients should undergo a thorough pre-treatment evaluation.6 The WHO HCV treatment guidelines list the following factors for consideration:1

  • Assessment of cirrhosis
  • Drug-drug interactions
  • Is hepatitis B virus (HBV) or human immunodeficiency virus (HIV) coinfection present?
  • What is the renal function [i.e. estimated glomerular filtration rate (eGFR)]?
  • Patients with tuberculosis (TB)/HCV coinfection

Cirrhosis

The presence or absence of cirrhosis can influence the duration of treatment with some regimens (eg., sofosbuvir/daclatasvir). As such, the WHO recommends a fibrosis assessment prior to treatment using non-invasive tests such as the aminotransferase/platelet ratio index (APRI) score or Fibrosis-4 (FIB-4) test.1 For more information on fibrosis testing, please refer to the Assessment and diagnosis section of the website.

Drug-drug Interactions

In the presence of potential drug-drug interactions, current therapy may require optimisation before antiviral therapy can begin. Discontinuation of, or alternatives to, certain medications such as macrolide antibiotics, St John’s wort and certain antiepileptics, such as carbamazepine or phenytoin, is critical.4 The University of Liverpool’s Hepatitis Drug Interactions website (https://www.hep-druginteractions.org/checker) is a useful resource with information that is updated regularly.18

DISCLAIMER: This link will take you to an external website. Gilead Sciences, Inc is not responsible for the content on this website.
Although Gilead makes every effort to ensure the links provided are accurate, up-to-date and relevant, we cannot take responsibility for pages maintained by external providers. Gilead does not routinely screen, approve, review or endorse the contents of or use of any of the products or services that may be offered by these external sites.

HIV and/or HBV coinfection

HCV treatment outcomes with DAAs are comparable in patients with HIV/HCV coinfection compared to those with HCV monoinfection.19 Furthermore, because DAAs are well-tolerated and effective for patients with HIV/HCV, there is no longer any need to consider them as a special or difficult-to-treat population.8

HBV/HCV coinfection is more likely among people who inject drugs (PWID) and persons living in areas where both viruses are endemic.20 According to the WHO:

  • Patients with HBV/ HCV coinfection may be assessed for eligibility for HBV treatment and, if needed, started on HBV treatment before starting HCV treatment.5,6
  • The risk of reactivation among patients who are anti-HBc positive but HBsAg negative is very low.21-23

Renal function

Many DAAs and their metabolites are renally cleared, and as such, their use in patients with severe renal impairment (e.g., creatinine clearance <30 ml /min/1.73 m2) should be handled with care and patients should be closely monitored.17

TB/HCV coinfection

The clinical evaluation of patients being considered for HCV treatment should include screening for active TB. TB can be reasonably excluded in the absence of any one of the following: current cough, fever, weight loss or night sweats. If any of the symptoms listed are present, patients must undergo further investigations.8  

Concurrent treatment of HCV infection and TB must be avoided. Since there are limited data on the management of patients coinfected with HCV and TB, specialist referral is warranted.

Antiviral therapy

Interferon-based regimens

For many years, the most effective therapy for all HCV genotypes was a combination of once-weekly subcutaneously administered pegylated-IFN (PEG-IFN) plus twice-daily oral ribavirin for between 24 and 72 weeks.23 In patients with HCV genotype 2 and 3, the combination was associated with SVR rates of 70-80% after 24 weeks of therapy. The degree of success was lower in people with HCV genotype 1: only 50% achieved an SVR after 12 months of therapy.26,27

PEG-IFN therapy was also complicated by a wide range of potential side effects (e.g., weight loss, insomnia, vomiting, depression and anxiety, mild hair loss, rash, and myelosuppression) with the need for close monitoring of patients undergoing treatment. Given the efficacy and markedly improved tolerability of DAAs, regimens containing IFN are no longer recommended for treatment-naïve patients with HCV.5

Direct-acting antiviral agents

The introduction of DAA agents, first licensed in 2011, has improved treatment responses rates and heralded a new era of HCV treatment.25

Figure 1: The evolution of care for HCV and improvements in SVR rates25

Adapted from Webster PD, et al. Lancet seminar – Hepatitis C. Lancet. 2015;385:1124–1135.

DAA agents target multiple intracellular steps in the HCV replication life cycle:28

  • The NS5B polymerase involved in replication
  • The NS3/4A protease involved in protein production
  • The NS5A domain involved in assembly and release
  • Some regimens also include ribavirin

In addition, different classes of DAAs have been combined to overcome drug resistance. Currently approved DAAs are listed in Table 3.

Table 3. DAAs according to class8

NS3/4A (protease) inhibitors

NS5A inhibitors

NS5B polymerase inhibitor (nucleotide analogue)

NS5B polymerase inhibitor (non-nucleoside analogue)

Glecaprevir

Daclatasvir

Sofosbuvir

Dasabuvir

Voxilaprevir

Velpatasvir

 

 

Grazoprevir

Ledipasvir

 

 

Paritaprevir

Ombitasvir

 

 

Simeprevir

Pibrentasvir

 

 

 

Elbasvir

 

 

Adapted from WHO. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. July 2018.

 

 

On-treatment monitoring for toxicity and response

In contrast to IFN-based regimens, intense monitoring of patients undergoing DAA therapy is usually unnecessary. The WHO propose that the frequency of routine laboratory monitoring be limited to a baseline and end-of-treatment blood specimen.8

Table 5: On-treatment monitoring for virologic response in patients with HCV infection receiving DAAs8

Time

DAA alone

DAA + RBVa

 

Full blood count, renal, liver function

Full blood count, renal, liver function

Baseline

Xb

X

Week 4

 

X

Week 12 after end of treatment

X

X

Adapted from WHO. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. July 2018.

a Recommended treatment for adolescents with genotypes 2 and 3 HCV infection.

b If haemaglobin >10 g/dL then no need to check again at week 4.

DAA, direct-acting antiviral; RBV, ribavirin.

Additional monitoring is necessary in patients treated with ribavirin. Similarly, more frequent monitoring may be required in patients with HIV and/or HBV coinfection, cirrhosis, renal impairment, those with potential drug-drug interactions and other medical conditions that warrant close observation.8

Long-term patient management

Successful clearance of HCV does not protect against reinfection. In population cohorts at high risk, such as people who inject drugs (PWIDs) or men who have sex with men (MSM), rates of reinfection are in the order of 1–8% per year. The risk of reinfection should be explained to all patients, to positively modify risk behaviour.6

Patients with ongoing risk factors and patients with pre-existing cofactors for liver disease (e.g., history of excessive alcohol drinking, obesity and/or type 2 diabetes) should be periodically assessed. Similarly, patients with cirrhosis should be screened for HCC with six-monthly ultrasound and α-fetoprotein estimation and should have endoscopy every 1–2 years to exclude oesophageal varices.4-6,8

Table 6. Recommendations for long-term follow-up in patients who achieve an SVR6

Patient population

Recommendation

No to moderate fibrosis and no ongoing risk behaviour (F0-F2)

Patients can be discharged provided they have no other comorbidities

Advanced fibrosis (F3) or cirrhosis (F4)

Surveillance for HCC every 6 months by ultrasound, continued indefinitely

Cirrhosis with oesophageal varices present at pre-treatment endoscopy

Surveillance for oesophageal varices by endoscopy should be performed

PWIDs, MSM with ongoing risk behaviour

Monitoring for HCV reinfection ideally through bi-annual or at least annual HCV RNA assessment

Adapted from EASL. EASL recommendations on treatment of hepatitis C 2018. J Hepatol 2018;69:461-511.

MSM, men who have sex with men; PWID, people who inject drugs.

In all cases, retreatment should be made available, if reinfection is identified during post-SVR follow-up.8

Hepatitis C

HCV

Introduction to hepatitis C, treatment regimens and ongoing care. 

Assessment and diagnosis

HCV

Identifying high-risk individuals, prevention, screening and treatment. 

Expert insights

HCV

Expert opinions and thought leadership on key issues around HCV. 

Disclaimer:

While this information is considered to be true and correct at the date of publication (May 2020), changes in circumstances after the time of publication may impact the accuracy of the information.

This page will be updated regularly.

References

  1. World Health Organization (WHO). Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. July 2018. Available at: https://www.who.int/hepatitis/publications/hepatitis-c-guidelines-2018/en/ (accessed November 2018).
  2. American Association for the Study of Liver Diseases (AASLD). HCV Guidance: recommendations for testing, managing, and treating hepatitis C. Sept 21, 2017. Available at: hcvguidelines.org (accessed November 2018).
  3. European Association for the Study of the Liver (EASL). EASL recommendations on treatment of hepatitis C 2018. J Hepatol 2018;69:461-511.
  4. Khoo A and Tse E. A practical overview of the treatment of chronic hepatitis C virus infection. AFP 2016;45:718-20.
  5. The University of Liverpool, Hepatitis Drug Interactions website. Available at: hep-druginteractions.org(accessed November 2018).
  6. Maylin S, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008;135:821-9.
  7. Swain MG, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593-601.
  8. Younossi ZM, et al. Quality of life in adolescents with hepatitis C treated with sofosbuvir and ribavirin. J Viral Hepat. 2018;25:354–62.
  9. Younossi ZM, et al. Health-related quality of life in adolescent patients with hepatitis C genotype 1 treated with sofosbuvir and ledipasvir. J Pediatr Gastroenterol Nutr. 2018;66:112–6.
  10. Poynard T, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122:1303-1313.
  11. Morgan RL, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158(5 Pt 1):329-337.
  12. Bang CS, Song IH. Impact of antiviral therapy on hepatocellular carcinoma and mortality in patients with chronic hepatitis C: systematic review and meta-analysis. BMC Gastroenterol. 2017;17:46.
  13. Kobayashi M, et al. Sustained virologic response by direct antiviral agents reduces the incidence of hepatocellular carcinoma in patients with HCV infection. J Med Virol. 2017;89:476–83.
  14. Sikavi C, et al. Hepatitis C and human immunodeficiency virus co-infection in the era of direct-acting antiviral agents: no longer a difficult to treat population. Hepatology. 2018;67:847–57.
  15. Jamma S, et al. Current concepts of HBV/HCV coinfection: coexistence, but not necessarily in harmony. Curr Hepat Rep. 2010;9:260–9.
  16. Serper M, et al. Rare clinically significant hepatic events and hepatitis B reactivation occur more frequently following rather than during direct-acting antiviral therapy for chronic hepatitis C: data from a national US cohort. J Viral Hepat. 2018;25:187–97.
  17. Belperio PS, et al. Evaluation of hepatitis B reactivation among 62,920 veterans treated with oral hepatitis C antivirals. Hepatology. 2017;66:27–36.
  18. Sulkowski MS, et al. No evidence of reactivation of hepatitis B virus among patients treated with ledipasvir-sofosbuvir for hepatitis C virus infection. Clin Infect Dis. 2016;63:1202–4.
  19. World Health Organization (WHO). Web Annex 5 to Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. July 2018. Available at: http://apps.who.int/iris/bitstream/handle/10 665/277217/WHO-CDS-HIV-18.39-eng.pdf?sequence=1&isAllowed=y (accessed May 2020).
  20. Webster PD, et al. Lancet seminar – Hepatitis C. Lancet. 2015;385:1124–1135.
  21. Manns MP, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-65.
  22. Fried MW, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-82.
  23. Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;436(Suppl):933–8.
  24. Gilead Sciences. Epclusa SmPC. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/epclusa (accessed February 2019).
  25. Gilead Sciences. Vosevi SmPC. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/vosevi (accessed November 2018).
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  28. AbbVie Viekirax SmPC. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/viekirax (accessed February 2019).
  29. AbbVie Exviera SmPC. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/exviera (accessed February 2019).
  30. Merck Sharp & Dohme B.V. Zepatier SmPC. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/zepatier (accessed November 2018).
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