This section provides an overview of the treatment approach for HCV infection in the community setting. More specifically, the information covered here refers to the management of treatment-naïve patients with chronic HCV.

Please note that guidelines for the management of HCV infection continue to evolve. Clinicians are advised to refer frequently to the most recent recommendations from the European Association for the Study of the Liver (EASL) at:4 http://www.easl.eu/research/our-contributions/clinical-practice-guidelines

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Indications for treatment

In 2018, the World Health Organization (WHO) issued new recommendations for the treatment of patients with chronic HCV infection. The recommendations, corresponding grade and quality of evidence are presented in Table 1.6

Table 1. WHO recommendations for the treatment of patients with chronic HCV6

Recommendation

Grade of recommendation/quality of evidence

When to start treatment in adults and adolescents

All individuals with HCV, who are 12 years of age or older,* should be offered treatment, irrespective of disease stage.

Strong recommendation, moderate quality of evidence

What treatment to use for adults and adolescents

The use of pangenotypic DAA regimens for the treatment of patients with chronic HCV infection aged 18 years and above.

In HCV-infected patients without cirrhosis, suitable regimens include:

  • glecaprevir/pibrentasvir for 8 weeks
  • sofosbuvir/daclatasvir for 12 weeks
  • sofosbuvir/velpatasvir for 12 weeks

Conditional recommendation, moderate quality of evidence

In adolescents aged 12–17 years or weighing at least 35 kg, suitable regimens include:

  • sofosbuvir/ledipasvir for 12 weeks in genotypes 1, 4, 5 and 6
  • sofosbuvir/ribavirin for 12 weeks in genotype 2
  • sofosbuvir/ribavirin for 24 weeks in genotype 3.

Strong recommendation, very low quality of evidence

Treatment of children 0–12 years of age

Treatment should be deferred until 12 years of age

Conditional recommendation, very low quality of evidence

Treatment with interferon-based regimens should no longer be used

Strong recommendation, very low quality of evidence¥

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

* With the exception of pregnant women.

The Guidelines Development Group defined pangenotypic regimens as those leading to a sustained virological response (SVR) rate >85% across all six major HCV genotypes.

Patients with HCV genotype 3 infection who have received interferon and/or ribavirin in the past should be treated for 16 weeks.

¥ Prior to approval of DAAs for children aged <12 years of age, exceptional treatment with interferon + ribavirin may be considered for children with genotype 2 or 3 infection and severe liver disease. This may include children at higher risk of progressive disease, such as with HIV coinfection, thalassaemia major and survivors of childhood cancer.

For treatment recommendations in patients with compensated and decompensated cirrhosis please refer to the:

WHO Guidelines

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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 therapy2-4

Once achieved, SVR is considered a cure of the infection as late relapses are uncommon.7,8 HCV cure is associated with numerous health benefits, including:

  • improvement in quality of life,9,10
  • loss of infectivity,6
  • regression of liver fibrosis and cirrhosis,11
  • a reduction in the risk of liver failure and hepatocellular carcinoma (HCC),12 and
  • a reduction in the risk of liver-related and all-cause mortality.13,14

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.3

Clinical considerations

Prior to commencing DAA therapy, patients should undergo a thorough pre-treatment evaluation.4 The WHO HCV treatment guidelines list the following factors for consideration:6

  • 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 pangenotypic regimens (eg., sofosbuvir/daclatasvir and glecaprevir/pibrentasvir). As such, the WHO recommends a fibrosis assessment prior to treatment using noninvasive tests such as the aminotransferase/platelet ratio index (APRI) score or Fibrosis-4 (FIB-4) test.6 For more information on fibrosis testing, please refer to the Assessment and diagnosis section of the web site.

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.15 The University of Liverpool’s Hepatitis Drug Interactions website (www.hep-druginteractions.org ) is a useful resource with information that is updated regularly.16

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HIV and/or HBV coinfection

Patients with HIV/HCV coinfection have more rapid disease progression than monoinfected patients and should be prioritised for treatment.6 However, HCV treatment outcomes with DAAs are comparable in patients with HIV/HCV coinfection compared to those with HCV monoinfection.17 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.6

HBV/HCV coinfection is more likely among people who inject drugs (PWID) and persons living in areas where both viruses are endemic.18 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.3,4
  • The risk of reactivation among patients who are anti-HBc positive but HBsAg negative is very low.19-21

Renal function

Many DAAs and their metabolites are renally cleared, and as such, their use in patients severe renal impairment (e.g., creatinine clearance <30 mL/min/1.73 m2) cannot be supported.15

Table 2. Summary of available non-pangenotypic DAA regimens and their use in patients with renal insufficiency22

Regimen

Genotype coverage

Can be used in patients with renal insufficiency

Sofosbuvir/Ledipasvir

1,4,5,6

NO

Grazoprevir/Elbasvir

1,4

YES

Paritaprevir/Ritonavir/ Ombitasvir + Dasabuvir

1

YES

Simeprevir/ Sofosbuvir

1,4

NO

Adapted from WHO. Web Annex 5 to Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. July 2018.

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.6

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.24,25

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.3

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.23

Figure 1: The evolution of care for HCV and improvements in SVR rates23

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:26

  • 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 class6

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.

For each HCV genotype, multiple approved regimens are available in Europe.

Table 4. Approved direct-acting antiviral regimens for treatment naïve patients with HCV infection – 20184,27-33

Regimen

HCV genotype

Pills per day

Duration (wks)

Comments

Pangenotypic drugs or drug combinations

Sofosbuvir/ velpatasvir

1-6

1

12

Addition of RBV may be considered for GT3 with compensated cirrhosis

Sofosbuvir/ velpatasvir/ voxilaprevir

1-6

1

8

 

Glecaprevir/ pibrentasvir

1-6

3

8-12

No cirrhosis, 8 wks

Cirrhosis, 12 wks

Genotype-specific drugs or drug combinations

Sofosbuvir/ ledipasvir

1a, 1b, 4, 5, 6

1

8-24

Untreated without cirrhosis, 8 wks

Compensated cirrhosis, ± RBV (12-24 wks)

Paritaprevir/ ombitasvir/ ritonavir

4

2

12

Addition of RBV

Paritaprevir/ ombitasvir/ ritonavir/ dasabuvir

1a, 1b

4

8-24

G1b, 12 wks; 8 wks may be considered in untreated pts

G1a, addition of RBV, 12 wks

G1a with compensated cirrhosis, + ribavirin, 24 weeks

Grazoprevir/ elbasvir

1a, 1b, 4

1

12-16

G1a, 12 wks; 16 wks + RBV in pts with baseline HCV RNA level >800,000 IU/ml

G1b, 12 wks

G4, 12 wks; 16 wks + RBV in pts with baseline HCV RNA level >800,000 IU/ml

G, genotype; HCV, hepatitis C virus; IU, international units; pts, patients; RBV, ribavirin; RNA, ribonucleic acid; wks, weeks.

For additional information on the characteristics of individual DAAs, please refer to the relevant:

Summary of Product Characteristics

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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.6

Table 5: On-treatment monitoring for virologic response in patients with HCV infection receiving DAAs6

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.6

Drug resistance and salvage therapy

Detectable serum HCV RNA after DAA treatment is an indication of non-response. Non-adherence or an incomplete course of therapy can result in post-treatment failure. However, patients who have taken a complete course of therapy, non-response is generally due to the emergence of resistance-associated substitutions (RASs). RASs have been identified in vitro for all of the DAAs approved for clinical use. However, there is no clinical role for baseline HCV resistance testing in treatment-naive patients because such high SVR rates are achieved.2,4

Salvage therapy must be guided either by knowledge of which drugs were administered in previous treatment courses if no resistance test is available or, if resistance testing is performed, by probabilities of response according to the resistance profile observed.6

  • For patients who have failed to achieve SVR after an IFN-free, DAA-based treatment course, the triple combination of sofosbuvir/velpatasvir/voxilaprevir for 12 weeks is an option.34 However, it should be noted that sofosbuvir/velpatasvir/voxilaprevir cannot be used in patients with Child–Pugh Class B or C cirrhosis or renal failure.6
  • The combination of glecaprevir/pibrentasvir for 12 weeks has been approved for retreatment in patients who have failed sofosbuvir-containing regimens and those who have failed treatment with either a protease inhibitor or an NS5A inhibitor (but not both).6

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.4

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.2-4,6

Table 6. Recommendations for long-term follow-up in patients who achieve an SVR4

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.6

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. 

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LID/IHQ/18-12//1048b Date of preparation: January 2019