Approach
The goal of treatment is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma by achieving a virological cure (evidenced by a sustained virological response).[66] Direct-acting antivirals (DAAs) are the standard of treatment. The use of DAAs has substantially improved the treatment of hepatitis C virus (HCV) and made virological cure possible in most patients.[82]
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Acute infection
Treatment should be initiated in all patients with acute HCV infection with viraemia without awaiting spontaneous resolution. The same regimens that are used for chronic infection are recommended for acute infection.[66]
Chronic infection
The American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) guidelines recommend antiviral treatment for all patients with chronic HCV infection, except those with a short life expectancy that cannot be re-mediated by HCV therapy, liver transplantation, or another directed therapy. Studies demonstrate that treating at an earlier stage of disease is associated with improved outcomes compared with waiting for more advanced disease to develop. Patients with a short life expectancy should be managed by a specialist. If treatment is deferred for any reason, ongoing assessment of liver disease is recommended.[66]
The rapid development of DAAs has resulted in changes to treatment guidelines, with recommendations being updated regularly by the AASLD, and readers are advised to review the website for changes to recommendations.[66] Different guidelines may be used in different countries and cost factors are a major determinant of management decisions in some countries.
The AASLD recommendations are sometimes considered controversial as they may differ from the approved label indications for some drugs.
Drug regimen components include:
Elbasvir/grazoprevir
Glecaprevir/pibrentasvir
Ledipasvir/sofosbuvir
Sofosbuvir/velpatasvir
Sofosbuvir/velpatasvir/voxilaprevir.
Ombitasvir/paritaprevir/ritonavir with or without dasabuvir, daclatasvir plus sofosbuvir, and sofosbuvir plus simeprevir regimens are no longer recommended by the AASLD guidelines, but may still be used in other countries.
The specific regimens used primarily depend on the genotype and the presence or absence of cirrhosis. Although rare, genotyping assays may indicate the presence of a mixed infection (e.g., genotype 1a and genotype 2). Pangenotypic regimens that exhibit activity against genotypes 1 to 6 (e.g., sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, and glecaprevir/pibrentasvir) should be considered in these patients.[66] Pangenotypic regimens require relatively shorter treatment durations and have greatly simplified the treatment of HCV infection.
Simplified treatment regimens
AASLD guidelines recommend simplified treatment regimens in patients who are eligible. To be eligible for simplified treatment, patients must be adults with chronic hepatitis C infection (any genotype) who do not have decompensated cirrhosis and have not previously received treatment for their condition. Any patients with end-stage renal disease and compensated cirrhosis, a current or prior episode of decompensated cirrhosis, known or suspected hepatocellular carcinoma, or a history of liver transplant are not eligible for simplified treatment. In addition to this, pregnant women and patients who are hepatitis B surface antigen (HBsAg) positive are also not eligible. In patients with HIV co-infection, the simplified approach should not be used in those on tenofovir disoproxil-containing regimens if their eGFR is <60 mL/minute due to the need for additional monitoring.[66]
The recommended simplified regimens are glecaprevir/pibrentasvir for 8 weeks (all genotypes) or sofosbuvir/velpatasvir for 12 weeks (all genotypes except genotype 3, who require baseline NS5A resistance-associated substitution testing first).[66]
The simplified treatment algorithms provide clear, concise guidance on pre-treatment assessment, on-treatment monitoring, assessment of response, and follow-up. It is thought that these simplified regimens may expand the number of healthcare professionals who prescribe antiviral therapy, and therefore increase the number of patients who are treated.[66]
Efficacy of DAAs
A Cochrane review of 138 randomised clinical trials (25,232 patients) comparing DAAs with no intervention or placebo, alone or with co-interventions, found that DAAs have mainly been studied short-term, with sustained virological response (SVR) as a surrogate outcome, and few or no data are available yet about the effect of DAAs on hepatitis C-related morbidity or mortality.[83] The AASLD/IDSA disagreed with the conclusions of the review and released a response, urging the authors of the review to retract or revise their conclusions.[84] The European Association for the Study of the Liver also published a response statement to the review expressing serious concerns about the review's conclusions.[85] The conclusions of the review were updated in September 2017, with the authors now concluding that they were unable to determine the effect of long-term treatment with DAAs, were uncertain as to how treatment with DAAs affects morbidity and mortality, and, although DAAs may reduce the number of people with detectable virus in their blood, that SVR (as an outcome) still requires proper validation.[83][86]
A large retrospective cohort study of over 245,000 adult participants in the US found that DAAs were independently associated with a lower risk of mortality, as well as liver (e.g., hepatocellular carcinoma) and non-liver (e.g., chronic kidney disease, cardiovascular disease, diabetes, cancer) outcomes compared with no treatment. The all-cause mortality rate was 36.5 deaths per 1000 person-years for those treated with DAAs compared with 64.7 deaths per 1000 person-years in those who were not treated.[87]
A large cohort study found that treatment with DAAs is associated with a reduced risk of all-cause mortality and hepatocellular carcinoma after adjustment for potential confounding factors (e.g., age, sex, fibrosis score, HCV genotype). Post-entry follow-up information was available for 9895 patients, and 31% of these patients had cirrhosis. Interestingly, a lower risk of non-liver-related death was also noted in this study.[88]
A prospective cohort study of 1760 patients found that the overall SVR was 96.6% in patients with HCV infection treated with DAAs, and that DAAs significantly reduced the risk of new liver-related complications such as hepatic decompensation, development of hepatocellular carcinoma, need for liver transplant, and death.[89]
Despite the successful use of DAAs, a population-based cohort study of 21,790 patients found that those who completed successful treatment had a high mortality rate compared to the general population (between 3 and 14 times higher, depending on stage of liver disease), with drug- and liver-related causes of death being the main drivers of excess mortality. Therefore, continued support and follow-up are necessary after the completion of successful treatment in order to ensure maximal impact treatment.[90]
Assessments before starting treatment
Before starting treatment, the following assessments are recommended:[66]
Staging of hepatic fibrosis
FBC (within 6 months prior to starting treatment)
INR (within 6 months prior to starting treatment)
Hepatic panel (within 6 months prior to starting treatment)
Estimated glomerular filtration rate (within 6 months prior to starting treatment)
HCV genotype and subtype
Quantitative HCV RNA (HCV viral load)
History of decompensated liver disease and liver disease severity using the Child-Pugh score (in patients scheduled to receive a NS3 protease inhibitor)
Presence of resistance-associated substitutions AASLD/IDSA: HCV resistance primer Opens in new window
HIV co-infection
Serum pregnancy test (in women of child-bearing age who are starting a ribavirin-containing regimen).
The introduction of DAAs into HCV treatment regimens means that there is an increased risk of drug interactions with other medications the patient may be taking concomitantly (e.g., antiretrovirals, anticonvulsants, antifungals, corticosteroids, statins, antibiotics, herbal medicines). Potential drug interactions should be assessed before starting an antiviral regimen, particularly in patients with hepatitis C/HIV co-infection who are on antiretroviral therapy, as certain drugs may be contraindicated with these medications or a dose adjustment may be necessary.
The US Food and Drug Administration (FDA) has issued a warning about the risk of hepatitis B reactivation in patients who are treated with DAAs and who have current or previous hepatitis B infection.[91] Although the risk is low, hepatitis B reactivation has resulted in severe liver problems (requiring liver transplant) or death. All patients should be screened for evidence of current or prior hepatitis B infection (i.e., by testing for HBsAg, antibody to hepatitis B surface antigen [anti-HBs], and antibody to hepatitis B core antigen [anti-HBc]) before initiating treatment with DAAs. Patients found or known to be HBsAg-positive should be assessed for whether their hepatitis B viral DNA level meets criteria for initiation of hepatitis B antiviral therapy. Hepatitis B vaccination is recommended for all susceptible individuals.[66]
Ribavirin is not recommended in women of child-bearing potential and their partners during or for at least 6 months prior to pregnancy. Women of child-bearing potential should be counselled not to become pregnant while receiving a ribavirin-containing regimen, and for at least 6 months after stopping the regimen. Male partners of women of child-bearing potential should be cautioned to prevent pregnancy while they are receiving a ribavirin-containing regimen, and for up to 6 months after stopping the regimen.[66]
Response to treatment
SVR is defined as undetectable HCV RNA in the serum 12 or more weeks after treatment completion, which correlates well with long-term absence of virus.[66]
A systematic review found high SVR rates for all FDA-approved regimens. SVR rates were >95% in patients with genotype 1 infection for most drug combinations and patient populations. Overall rates of serious adverse effects and treatment discontinuation were found to be low (<10%) across all patients.[92]
Patients who do not achieve an SVR (i.e., due to failure of treatment to clear infection or maintain clearance of infection with relapse after treatment completion) have the possibility of continued liver injury and transmission with ongoing infection. These patients should be monitored for progressive liver disease and considered for re-treatment when alternative treatments are available.[66] Recommended options for treatment-experienced patients depend on the patient's previous regimen that resulted in treatment failure.[66]
Unique patient populations
Management strategies and drug regimens may differ in some patient populations: for example, pregnant women, children, patients with renal impairment (or kidney transplant patients), HCV/HIV co-infection, decompensated cirrhosis, men who have sex with men, people who inject drugs, correctional settings, and those who develop recurrent HCV infection post liver transplant. The treatment of these patients is beyond the scope of this topic, and guidelines should be consulted.[66] US-based HIV guidelines recommend the treatment regimens in the AASLD guideline.[93]
Decompensated cirrhosis
Includes patients with moderate or severe hepatic impairment (Child-Pugh class B or C) who may or may not be candidates for liver transplantation, including those with hepatocellular carcinoma. These patients should be referred to a physician with experience in treating these patients, ideally in a liver transplant centre. Treatment regimen will depend on the genotype of the patient and eligibility to receive ribavirin.[66]
Some DAAs are contraindicated or not recommended in patients with moderate-to-severe hepatic impairment (Child-Pugh B or C). The FDA has received rare reports of worsening liver function or liver failure when these patients are treated with the following drugs:
Elbasvir/grazoprevir
Glecaprevir/pibrentasvir
Sofosbuvir/velpatasvir/voxilaprevir
Ombitasvir/paritaprevir/ritonavir ± dasabuvir.
These drugs are not indicated in patients with moderate-to-severe hepatic impairment, and most of the reported cases were in patients who should not have been prescribed these drugs because they had signs and symptoms of advanced liver disease (or other serious liver problems) prior to starting treatment. These adverse events typically occurred in the first 4 weeks of treatment. Resolution of symptoms (or improvement in worsening liver function) occurred in most patients after stopping the medication; however, some of these cases led to liver failure and death. When prescribing these drugs, assess the severity of liver disease at baseline and monitor the patient for clinical signs and symptoms of worsening liver function (e.g., increases in liver enzymes, ascites, jaundice, variceal haemorrhage, encephalopathy) during treatment. This is especially important in patients with pre-existing serious liver problems or risk factors that can contribute to clinical worsening of liver function during treatment (e.g., hepatocellular carcinoma, alcohol abuse). These drugs should not be prescribed in patients with a history of prior hepatic decompensation. Discontinue use of these drugs in patients who develop evidence of hepatic decompensation or as clinically indicated.[94][95] A specialist should be consulted when deciding on an appropriate antiviral regimen for patients with moderate-to-severe hepatic impairment.
Patients who develop recurrent hepatitis C infection post liver transplant should also be referred to a specialist for treatment.
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