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Evaluation
General Care
For supportive care, consider hospitalization if there is vomiting,
dehydration, or signs of hepatic decompensation. Evaluate for advanced fibrosis
or other conditions that may hasten liver fibrosis (eg HBV and HIV infections, genotype
3, MASLD) to help guide in the treatment. Monitor for hepatocellular carcinoma with
alpha-fetoprotein (AFP) and liver ultrasound every 6 months in those with
advanced fibrosis. Screen for other sexually transmitted diseases in cases of
sexually acquired hepatitis or if otherwise appropriate. Identify extrahepatic
manifestations and treat comorbidities appropriately. Test for HIV infection, past
or current HBV infection, and for HAV immunity, and search for other causes of
liver comorbidities.
Clinical Decision
Antiviral therapy is currently widely accepted for the following
hepatitis C patient groups: ≥18 years of age, elevated serum alanine
aminotransferase (ALT) levels, liver biopsy showing chronic hepatitis with
significant fibrosis or cirrhosis (stage F1 or above), hepatitis C virus
genotype 2 or 3 regardless of stage, compensated liver disease, acceptable
hematological and biochemical indices, and those who are willing to be treated and
conform to patient requirements.
Therapy should be individualized in patients with any of the
following: Failed prior treatment of either Interferon given alone or
in combination with Ribavirin or Peginterferon given alone; current alcoholic
or person who injects drugs (PWID) but willing to participate in an alcohol
support program or substance abuse program; acute hepatitis C; coinfected with
HIV; individuals <18 years of age; chronic renal disease; known
hypersensitivity to drugs used to treat hepatitis C virus; decompensated
cirrhosis; liver transplant recipient; pregnant or unwilling/unable to comply with
adequate contraception; severe concurrent disease (eg hypertension, heart
failure, diabetes mellitus [DM], etc); and hepatic decompensation.
Factors to be Considered Before Treatment Initiation
The factors to be considered before treatment initiation are the history
of prior treatment and response to previous treatment; stage of fibrosis;
hepatitis C virus genotype, especially in patients with known cirrhosis or
relapse after antiviral therapy; and comorbidities that may affect therapy.
Factors Associated with Accelerated Fibrosis Progression
The non-modifiable host factors associated with accelerated fibrosis
progression are the fibrosis stage, inflammation grade, male sex, older age at
the time of infection, and organ transplant. The modifiable host factors associated
with accelerated fibrosis progression are alcohol consumption, insulin
resistance, metabolic dysfunction-associated steatotic liver disease (MASLD),
and obesity. The viral factors are coinfection with HBV or HIV and genotype 3.
Principles of Therapy
Goals of Treatment
The clinical objective of treatment of hepatitis C is to achieve
virologic cure. Antiviral treatment for acute hepatitis C aims to prevent
progression to chronic hepatitis C. Antiviral treatment of chronic hepatitis C
aims to prevent the occurrence of liver-related complications and prevent the
development of extrahepatic manifestations (eg B cell lymphoma, essential mixed
cryoglobulinemia, leukocytic vasculitis, membranoproliferative
glomerulonephritis, neuropathy, porphyria cutanea tarda, renal disease). Hepatitis
C virus therapy reduces the decompensation rate and hepatocellular carcinoma
risk in patients with cirrhosis. Hepatitis C virus therapy reduces the risk of
cardiovascular disease (CVD), diabetes mellitus and insulin resistance. The prevention
of transmission of hepatitis C virus is also a goal of treatment.
Principles of Treatment
Hepatitis C_Management 1Treatment of hepatitis C is indicated for both treatment-naive and treatment-experienced patients with compensated and decompensated cirrhosis. Treatment-naive patients are those who have never been treated for hepatitis C virus infection. Treatment-experienced patients are those who were previously treated with Interferon or Peginterferon with or without Ribavirin, or Sofosbuvir plus Ribavirin with or without Peginterferon. Interferon-free, Ribavirin-free, direct-acting antiviral (DAA)-based regimens are the recommended treatment options: NS3/4A (protease) inhibitors such as Asunaprevir, Glecaprevir, Grazoprevir, Paritaprevir, Simeprevir, Voxilaprevir; NS5A inhibitors such as Daclatasvir, Elbasvir, Ledipasvir, Ombitasvir, Pibrentasvir, Velpatasvir; NS5B polymerase inhibitor (nucleotide analogue) such as Sofosbuvir; and NS5B polymerase inhibitor (non-nucleoside analogue) such as Dasabuvir. Boceprevir, an NS3/4A protease inhibitor, may be used in addition to standard therapy if with partial or no response to standard therapy. Treatment is generally not recommended in patients with short life expectancy that cannot be resolved with hepatitis C virus therapy, liver transplantation, or another directed therapy.
The choice, course, and duration of therapy are influenced by the hepatitis C virus genotype as well as the severity of liver disease, which must both be identified before starting treatment. Patients with confirmed hepatitis C should be treated with direct-acting antivirals without awaiting spontaneous resolution. Hepatitis C virus genotyping should be considered in patients with cirrhosis. In areas where virological tests are unavailable or are costly, or to simplify therapeutic regimen, pangenotypic therapy may be considered. Assess the risk for a drug-drug interaction before starting hepatitis C virus therapy or other medications during therapy in patients receiving direct-acting antivirals and monitor for side effects during treatment. Patients initiating direct-acting antiviral therapy should also be assessed for HBV or HIV coinfection and for the presence of resistance-associated substitutions (RASs).
Treatment responses are usually characterized by HCV RNA testing. Eradication of infection is considered when there is sustained virologic response (SVR). Sustained virologic response is defined as the absence of HCV RNA in serum or plasma by a sensitive test at least 12 weeks after completing treatment. If HCV RNA assays are unavailable, an undetectable hepatitis C virus core antigen in serum or plasma 24 weeks after completing treatment can be an alternative endpoint of therapy. The end of treatment response is defined as a continued absence of detectable virus at the end of treatment. Relapse is considered when HCV RNA becomes undetectable on treatment but is detected after discontinuation of therapy. Reinfection happens when HCV RNA or hepatitis C virus core antigen reappears after a sustained virologic response in patients who have risk factors for infection, and when the infection is caused by a different genotype or a related strain of the same genotype from the prior infection.
Virological responses in patients with hepatitis C virus infection treated with Interferon-based therapy can be defined as follows: Rapid virologic response (RVR) is achieved when HCV RNA becomes undetectable (<50 IU/mL) in serum after 4 weeks of therapy; early virologic response (EVR) is defined as a 2-log drop or loss of HCV RNA 12 weeks into therapy; and patients in whom HCV RNA levels remain stable while on treatment are considered non-responders, while those whose HCV RNA levels decline but never become undetectable are referred to as partial responders.
Individualize treatment based on the following: Severity of liver disease, previous therapy, potential of serious side effects or drug-drug interactions with concomitant medications, likelihood of treatment response, and presence of comorbid conditions (in patients with HIV/HCV coinfection, antiretroviral therapy (ART) is suggested to be initiated first before direct-acting antiviral, however, if the patient is ineligible for ART, direct-acting antiviral can be initiated if there are no contraindications; in patients with hemoglobinopathies, the European Association for the Study of Liver (EASL) guidelines recommend direct-acting antiviral for hepatitis C virus infection; patients with HCV-associated cryoglobulinemia should be treated with direct-acting antiviral; and patients with renal impairment [eGFR <30 mL/min/m2] or those on hemodialysis, Sofosbuvir-free treatment regimen is preferred).
Recommended Management of Direct-acting Antiviral (DAA) Treatment Interruptions for Treatment-Naive Patients
Interruptions before receiving 28 days of direct-acting antiviral therapy should be done in the following: When patients missed ≤7 days of treatment, direct-acting antiviral therapy is restarted immediately and must be completed for a planned duration of 8-12 weeks; and when patients missed ≥8 days of treatment, direct-acting antiviral therapy is restarted immediately and an HCV RNA test must be obtained as soon as possible preferably on the same day as therapy is restarted. HCV RNA-negative patients should complete the original planned duration of therapy (8-12 weeks). HCV RNA-negative patients with genotype 3 and/or with compensated cirrhosis and HCV RNA-positive patients (>25 IU/L) or if not obtained should extend direct-acting antiviral treatment for an additional 4 weeks from the original planned duration of therapy.
Interruptions after receiving ≥28 days of direct-acting antiviral therapy should be done in the following: When patients missed ≤7 days of treatment, direct-acting antiviral therapy is restarted immediately and must be completed for a planned duration of 8-12 weeks; when patients missed 8-20 consecutive days of treatment, direct-acting antiviral therapy is restarted immediately and an HCV RNA test must be obtained as soon as possible preferably on the same day as therapy is restarted. HCV RNA-negative patients should complete the original planned duration of therapy (8-12 weeks). HCV RNA-negative patients with genotype 3 and/or with compensated cirrhosis should extend direct-acting antiviral treatment for an additional 4 weeks from the original planned duration of therapy. HCV RNA-positive patients (>25 IU/L) or if not obtained should stop treatment and treatment should be restarted. Interruptions after receiving ≥28 days of direct-acting antiviral therapy should also be done when patients missed ≥21 consecutive days of treatment; direct-acting antiviral therapy should be stopped and sustained virologic response 12 weeks after the completion of treatment (SVR12) should be assessed. Retreatment is recommended in patients who have not achieved SVR12.
Spontaneous Resolution in Acute Infection
Patients with acute hepatitis C should be treated according to the simplified approach without awaiting spontaneous resolution. Patient education focusing on the reduction of viral transmission should be done. The chance of spontaneous resolution is greater in female patients and those with hepatitis C virus genotype non-1 infection. This is less likely to happen if infection lasts >12 weeks.
Pharmacological therapy
Acute Hepatitis C
The treatment for acute hepatitis C may be delayed for 8-12 weeks as
there is a 20-50% chance of spontaneous resolution. Consider pharmacotherapy to
prevent progression to chronic hepatitis C, or to minimize transmission or loss
to follow-up. Direct-acting antiviral therapy was shown to be cost-effective and
improved clinical outcomes in comparison to delaying treatment until the
chronic phase. Measure HCV RNA prior to starting therapy and sustained
virologic response at 12 and 24 weeks after therapy.
Pending further data that will establish the start time of the ideal
treatment regimen and its duration, acute hepatitis C patients may be treated with
the following antiviral regimens: Sofosbuvir/Velpatasvir for 12 weeks (all
genotypes); Glecaprevir/Pibrentasvir for 8 weeks (all genotypes); Sofosbuvir/Ledipasvir
for 8-12 weeks (genotypes 1, 4, 5 and 6); and Grazoprevir/Elbasvir for 12 weeks
(genotypes 1b and 4). Interferon (high-dose) or Peginterferon may also be used.
Treat hepatitis C virus genotype 1 for 24 weeks, and genotype 2, 3, or 4 for 12
weeks. Patients who are unresponsive to monotherapy should be given
Peginterferon/Ribavirin or a protease inhibitor-based triple therapy.
Chronic Hepatitis C
Simplified Pangenotypic Hepatitis C Virus Treatment for
Treatment-Naive Adults without Cirrhosis
The recommended regimens are Glecaprevir/Pibrentasvir for 8 weeks and
Sofosbuvir/Velpatasvir for 12 weeks.
Patients with any of the following are eligible for simplified hepatitis
C virus treatment: Chronic hepatitis C virus infection, including persons
living with HIV with infection of any genotype, without previous hepatitis C
virus treatment, and without cirrhosis or with compensated cirrhosis
(Child-Pugh A).
Patients with any of the following characteristics are ineligible for
the simplified treatment: HBsAg-positive; previous hepatitis C treatment; prior
episode of decompensated cirrhosis; current pregnancy; known or suspected hepatocellular
carcinoma; and prior liver transplantation.
Simplified Pangenotypic HCV Treatment for Treatment-Naive Adults with
Compensated Cirrhosis
The recommended regimens are Glecaprevir/Pibrentasvir for 8 weeks (all
genotypes) and Sofosbuvir/Velpatasvir for 12 weeks (all genotypes except
genotype 3).
Patients with any of the following are eligible for simplified HCV
treatment: Chronic HCV infection, including persons living with HIV with
infection of any genotype, without previous HCV treatment, and without
cirrhosis or with compensated cirrhosis (Child-Pugh A).
Patients with any of the following characteristics are ineligible for
the simplified treatment: HBsAg-positive; current or prior episode of
decompensated cirrhosis; previous hepatitis C treatment; end-stage renal
disease (eGFR <30 mL/min/m2); current pregnancy; known or
suspected hepatocellular carcinoma; and prior liver transplantation.
Genotype-specific Therapy
Identify the hepatitis C virus genotype and genotype 1 subtype (eg 1a
or 1b) before initiating treatment to determine the choice and duration of
therapy. The genotype and subtype should be determined in areas or settings
where subtypes of hepatitis C virus are resistant to NS5A inhibitors (eg
subtypes 1l, 3b, 3g, 4r, 6u, 6v).
| Regimen | Genotype | Treatment Experience | Duration (weeks) |
| Daclatasvir plus Sofosbuvir with or without weight-based Ribavirin | 1a, 1b | Treatment-naive and treatment experienced, without cirrhosis | 12-24 |
| 2, 3 | Treatment-naive without cirrhosis or with compensated cirrhosis, treatment experienced without cirrhosis | 24 | |
| Elbasvir/Grazoprevir | 1a, 1b, 4 | Treatment-naive, without cirrhosis or with compensated cirrhosis | 12 |
| Glecaprevir/Pibrentasvir | 1a, 1b, 2, 3, 4, 5, 6 | Treatment-naive without cirrhosis or with compensated cirrhosis | 8 |
| 1a, 1b, 2, 3, 4, 5, 6 | Treatment-naive without cirrhosis or with compensated cirrhosis if coinfection of HIV/HCV is present | 12 | |
| Ledipasvir/Sofosbuvir | 1a, 1b, 4, 5, 6 (except 6e) |
Treatment-naive, without cirrhosis or with compensated cirrhosis | 12 |
| 1a, 1b, 4, 5, 6 | Treatment-naive with decompensated cirrhosis who are not qualified for Ribavirin therapy | 24 | |
| Ledipasvir/Sofosbuvir with weight-based Ribavirin | 1a, 1b, 4, 5, 6 | Treatment-naive with decompensated cirrhosis | 12 |
| Sofosbuvir/Velpatasvir | 1a, 1b, 2, 3*, 4, 5, 6 | Treatment-naive, without cirrhosis or with compensated cirrhosis |
12 |
| 1a, 1b, 2, 3, 4, 5, 6 | Treatment-naive with decompensated cirrhosis who are not qualified for Ribavirin therapy | 24 | |
| Sofosbuvir/Velpatasvir with weight-based Ribavirin | 3* | Treatment-naive, with compensated cirrhosis and baseline NS5A Y93 RAS | 12 |
| 1a, 1b, 2, 3, 4, 5, 6 | Treatment-naive with decompensated cirrhosis | 12 | |
| Sofosbuvir/Velpatasvir/Voxilaprevir | 3* | Treatment-naive and PEG/RBV experienced, with compensated cirrhosis and baseline NS5 Y93 RAS |
12 |
| *If resistance testing is performed at baseline, patients with NS5A Y93H RAS for Velpatasvir should be treated with Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvir plus Ribavirin for 12 weeks; patients without the Y93H RAS should be treated with Sofosbuvir/Velpatasvir only for 12 weeks. References: Bhattacharya D, Aronsohn A, Price J, et al. Hepatitis C guidance 2023 update: American Association for the Study of Liver Diseases – Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Clin Infect Dis. 2023 May:ciad319; European Association for the Study of the Liver (EASL). EASL recommendations on treatment of hepatitis C. 2020. |
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Retreatment for Patients with Failure of Prior Therapy
Hepatitis C_Management 2Sofosbuvir-based treatment failure without cirrhosis or with compensated cirrhosis: Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks for all genotypes. An addition of weight-based Ribavirin is recommended in patients with genotype 3 infection with compensated cirrhosis. Glecaprevir/Pibrentasvir for 16 weeks as an alternative regimen for genotypes 1, 2, 4, 5 and 6. This is not recommended in patients with previous exposure to an NS5A inhibitor plus hepatitis C virus non-structural protein 3-4a (NS3/4A) protease inhibitor regimen (eg Elbasvir/Grazoprevir).
Glecaprevir/Pibrentasvir treatment failure without cirrhosis or with compensated cirrhosis: Glecaprevir/Pibrentasvir plus Sofosbuvir and weight-based Ribavirin for 16 weeks for all genotypes. Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks for all genotypes. An addition of weight-based Ribavirin is recommended in patients with compensated cirrhosis.
Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir plus Glecaprevir/Pibrentasvir treatment failure without cirrhosis or with compensated cirrhosis: Glecaprevir/Pibrentasvir plus Sofosbuvir and weight-based Ribavirin for 16 weeks for all genotypes. The treatment duration should be extended to 24 weeks in extremely difficult cases (eg genotype 3 with compensated cirrhosis) or in patients with treatment failure under Sofosbuvir plus Glecaprevir/Pibrentasvir therapy. Sofosbuvir/Velpatasvir/Voxilaprevir plus weight-based Ribavirin for 24 weeks for all genotypes.
Peginterferon and Ribavirin with or without protease inhibitor treatment failure: Glecaprevir/Pibrentasvir for 16 weeks for genotype 3. Sofosbuvir/Velpatasvir for 12 weeks for patients with genotype 3 without cirrhosis and who do not have a Y93H variant. An addition of weight-based Ribavirin for 12 weeks is an alternative for patients with genotype 3 with compensated cirrhosis or Y93H variant. Sofosbuvir/Velpatasvir/Voxilaprevir for 12 weeks for patients with genotype 3 with compensated cirrhosis or Y93H variant. Sofosbuvir/Velpatasvir for 12 weeks in patients with genotypes 1, 2, 4, 5 or 6 and with or without compensated cirrhosis. Glecaprevir/Pibrentasvir for 8 weeks in patients with genotypes 1, 2, 4, 5 or 6 and without cirrhosis or protease inhibitor exposure. Administered for 12 weeks in patients with genotypes 1, 2, 4, 5 or 6 and with either cirrhosis or protease inhibitor exposure.
Decompensated Cirrhosis
Patients with genotypes 1 to 6 with decompensated cirrhosis and those with compensated cirrhosis with prior decompensation episodes should receive Sofosbuvir/Velpatasvir with weight-based Ribavirin for 12 weeks. Ribavirin can be initiated at 600 mg/day with subsequent dose adjustments based on the patient's tolerance. If the patient has contraindications to or is intolerant of Ribavirin, Sofosbuvir/Velpatasvir alone can be given for 24 weeks. Sofosbuvir/Velpatasvir with weight-based Ribavirin for 24 weeks is recommended as retreatment for patients with genotypes 1 to 6 with decompensated cirrhosis who failed treatment with a direct-acting antiviral (protease inhibitor and/or NS5A inhibitor)-containing regimen. Treatment regimens that include a hepatitis C virus protease inhibitor (eg Glecaprevir, Grazoprevir or Voxilaprevir) or Interferon-based regimens should not be given.
Hepatitis C virus Genotype 1, 4, 5 or 6
Those with decompensated cirrhosis who are Ribavirin eligible may take Ledipasvir/Sofosbuvir with low initial dose of Ribavirin (may be increased as tolerated) for 12 weeks. Those with decompensated cirrhosis who are Ribavirin ineligible may take Ledipasvir/Sofosbuvir for 24 weeks. Those with decompensated cirrhosis and in whom previous Sofosbuvir- or NS5A-based treatment has failed may take Ledipasvir/Sofosbuvir with low initial dose of Ribavirin (may be increased as tolerated) for 24 weeks.
Hepatitis C virus Genotype 2 or 3
Those with decompensated cirrhosis who are Ribavirin ineligible may take Sofosbuvir/Daclatasvir or Sofosbuvir/Velpatasvir for 24 weeks.
Nonpharmacological
Patient Education
Hepatitis C_Management 3Provide the patients with a detailed explanation of their condition. Emphasize the disease's long-term implications (eg long-term medical therapy, continuous monitoring for liver disease progression) for their and their partners' health. Counsel regarding the importance of treatment adherence, proper dosing administration, and reporting of medication changes. Provide a clear, accurate, and written information. Advise the patient not to donate blood, semen or organs. Advise the patient to avoid sharing items of personal hygiene (eg toothbrushes, shaving equipment). Counsel the patient to stop using illicit drugs. Advise the patient regarding sexual transmission. Hepatitis C virus is not considered to be a sexually transmitted disease, but sexual promiscuity, HIV and herpes simplex virus (HSV-2) coinfections are associated with sexual transmission of hepatitis C. Avoid unprotected sex during menstruation. Advise the patient regarding the potential deleterious effect of alcohol especially in association with the development of hepatocellular carcinoma, the progression of liver fibrosis, and the increase in hepatitis C virus replication.
Partner Notification
Notify the partner for at-risk contacts. Contact tracing to include any sexual contact (penetrative vaginal or anal sex) or needle-sharing partners from 2 weeks before the onset of jaundice. If without acute infection, trace back to the likely time of infection (eg blood transfusion, first needle sharing).
Surgery
Liver
Transplantation
Liver transplantation is indicated in patients with end-stage liver
disease (cirrhosis), hepatocellular carcinoma, and acute liver failure (ie
caused by viruses, drugs and toxic agents). This is considered in patients with
expected survival of ≤1 year without transplantation or if quality of life is unsatisfactory
due to liver disease. Patients with hepatitis C virus infection can be treated
prior to or after transplant on a case-by-case basis. If there is hepatitis C
recurrence posttransplant, treatment with antivirals is done and is started
early in patients with significant graft damage. Hepatitis C virus replication
is not a contraindication for liver transplantation, though antiviral therapy
should be given after transplant.
Prevention
Primary
Prevention
At
present, there is no available vaccine for the hepatitis C virus. The
prevention of the hepatitis C virus would depend on the reduction of the risk
of exposure especially in patients in healthcare settings and those who are in
a high-risk population (eg IV drug use and through sexual contact). The HCV RNA
should be assessed at 6 or 12 months after sustained virologic response to
monitor for hepatitis C virus reinfection in the high-risk population.
The
recommended primary interventions are: Hand hygiene should include proper
surgical hand preparation, hand washing and use of gloves; appropriate and safe
use of healthcare injection; proper handling and disposal of sharp needles and
other objects and waste; comprehensive harm-reduction services should be
provided to persons who injects drugs including the use of sterile injecting equipment
and treatment of dependence; sterilization of equipment; all healthcare
personnel should be trained; donated blood should be tested for HBV, hepatitis
C virus, HIV, and syphilis; and proper and consistent use of condoms should be
promoted.
Hepatitis C_Management 4Secondary and Tertiary Prevention
Secondary and tertiary prevention recommendations for people who are infected with hepatitis C virus: Conduct an education and counseling program for patient care and treatment, including the risk of reinfection and prevention of hepatitis C virus transmission; immunization with hepatitis A and B vaccines is recommended to prevent coinfection and provide protection to the liver; early and appropriate medical management including the use of antiviral therapy; and routine laboratory, therapeutic and toxicity monitoring can be limited at the start and end of antiviral treatment. An HCV RNA 12 weeks post-DAA can be used to assess sustained virologic response; HCV core antigen 24 weeks post-DAA can be an alternative. Liver function tests and serum creatinine can be done during week 4 of antiviral therapy and 12 weeks post-treatment. A complete blood count monitoring should be done in patients treated with Ribavirin. Regular monitoring is the key to early diagnosis of chronic liver disease. Continue hepatocellular carcinoma surveillance every 6 months in patients with advanced fibrosis and cirrhosis, as a sustained virologic response will only reduce but not remove the risk of hepatocellular carcinoma.