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INTRODUCTION — Hepatitis C virus (HCV) can cause both acute and chronic hepatitis. The acute process is self-limited, rarely causes hepatic failure, and usually leads to chronic infection. Chronic HCV infection often follows a progressive course over many years and can ultimately result in cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)
This topic addresses the general management of patients with chronic HCV infection. Patient selection for treatment and specific treatment regimens are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection" and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults" and "Direct-acting antivirals for the treatment of hepatitis C virus infection".)
GUIDELINES — Guidelines for the diagnosis and management of hepatitis C virus (HCV) infection were released jointly by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in 2014, are continuously updated, and can be accessed at www.hcvguidelines.org . The discussion in this topic is generally consistent with those guidelines.
Other guidelines include treatment recommendations from the European Association for the Study of the Liver (EASL), which was updated in 2015 , and United Kingdom consensus guidelines, which were updated in 2014 . World Health Organization (WHO) also released guidelines in 2014 on screening and treatment of HCV, intended primarily for clinicians and policy-makers in low- and middle-income countries .
PATIENT EVALUATION — The objectives of the evaluation of patients diagnosed with chronic hepatitis C virus (HCV) include the following:
●Assessment of the extent of liver disease. Specifically, identification of advanced fibrosis or cirrhosis informs the need for additional monitoring and management.
●Assessment of viral and host factors that inform the optimal antiviral selection. These factors include viral genotype, liver fibrosis stage (and signs of decompensated disease in those with cirrhosis), history of prior antiviral treatment, renal function, and concurrent medication use.
●Identifying comorbidities associated with HCV infection. These include extrahepatic manifestations of chronic HCV infection, such as cryoglobulinemia, HCV-associated renal disease, porphyria cutanea tarda, and autoimmune disorders.
Additionally, HCV-infected patients should also be tested for human immunodeficiency virus (HIV) and hepatitis B virus (HBV) given the common modes of transmission and the association of these coinfections with more rapid disease progression.
The evaluation of patients with chronic HCV infection is discussed in detail elsewhere. (See "Diagnosis and evaluation of chronic hepatitis C virus infection", section on 'Additional evaluation' and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Evaluation to guide management decisions'.)
Psychosocial issues — Although most patients with chronic hepatitis C virus (HCV) infection are asymptomatic at the time of diagnosis, the potential sequelae of chronic HCV infection are significant, and this possibility can have important emotional and physical consequences. Counseling and screening for depression should be a major consideration, both at diagnosis and during subsequent follow-up. Many patients benefit from participation in a support group. (See "Patient education: Hepatitis C (Beyond the Basics)".)
HCV-infected individuals may also have issues with ongoing illicit drug use. Such patients should be counseled on substance use treatment, including psychiatric services or opioid substitution therapy (see "Continuing care for addiction: Implementation" and "Pharmacotherapy for opioid use disorder"). Active injection drug use is not a contraindication to antiviral therapy, as long as the patient wishes to be treated and is willing and able to adhere to close monitoring during treatment.
Transmission risk — Transmission of HCV is primarily through exposure to infected blood. Counseling should include discussions about the specific routes of HCV transmission and advice on measures to decrease the risk of transmission to other individuals (table 1). Women of childbearing age may also be concerned about the risk of perinatal transmission. These issues are discussed in detail elsewhere. (See "Epidemiology and transmission of hepatitis C virus infection", section on 'Transmission' and "Vertical transmission of hepatitis C virus".)
Diet and behaviors — Patients should be informed about the natural history of HCV infection and counseled on potentially modifiable factors that are associated with accelerated liver disease, including alcohol use, obesity and insulin resistance, and marijuana use. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)
Because of the association with more rapid progression of liver disease, we suggest complete avoidance of alcohol for HCV-infected individuals. In addition, we encourage weight loss in obese patients and cessation of cigarettes and marijuana. (See "Hepatitis C and alcohol", section on 'How much alcohol is too much?' and "Obesity in adults: Overview of management" and "Treatment of cannabis use disorder".)
We also advise patients that two to three cups of coffee daily can be beneficial to liver health. Coffee consumption (more than two cups per day) has been associated with a reduced risk of hospitalization and mortality from a number of chronic liver diseases including chronic viral hepatitis, nonalcoholic steatohepatitis (NASH), and alcoholic liver disease [5,6].
GENERAL MANAGEMENT — Antiviral therapy is the cornerstone of treatment of chronic hepatitis C virus (HCV) infection (see 'Antiviral therapy' below). With current antiviral therapies, HCV is relatively easily treated and can be eliminated in almost all patients. Other general measures in the management of patients with chronic HCV include symptom management, dose adjustment of medications, and preventing complications of cirrhosis if present.
Fatigue — Many patients with HCV infection complain of fatigue. The cause is uncertain and may be difficult to ascribe to liver disease alone rather than other comorbidities such as depression. Fatigue and overall quality of life improve in some patients who have a sustained virologic response (SVR) following antiviral therapy, although the improvements may be modest [7,8]. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Symptom alleviation'.)
Dose adjustments of medications — Prescription and over-the-counter medications usually do not require a dose adjustment in HCV-infected patients who have normal hepatic function. Many patients voice concern about taking acetaminophen due to its association with liver injury when taken in high doses. Patients do not need to avoid acetaminophen, but we suggest that the dose of acetaminophen not exceed 2 g per 24 hours. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis".)
However, for HCV-infected patients with advanced liver disease or cirrhosis, dose adjustments or avoidance of certain medications may be warranted (table 2 and table 3). In particular, nonsteroidal anti-inflammatory drugs can be hepatotoxic and should be avoided in patients with advanced liver disease.
While statins are frequently withheld from patients with chronic liver disease, available data fail to show an increased risk of adverse effects in patients with compensated chronic liver disease, suggesting that statin use is safe in patients with stable HCV infection [9,10]. In addition, there are some data that suggest statin use is associated with lower fibrosis progression rate and decreased risk of progression to cirrhosis and hepatic decompensation [11-13].
Certain medications, including over-the-counter agents, have interactions with various direct-acting antivirals and may need to be adjusted during therapy. These are discussed in detail elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)
Vaccination — In addition to standard adult vaccinations, HCV-infected patients who are not immune to hepatitis A or B virus should be vaccinated against these viruses. HCV-infected patients with chronic liver disease should also receive pneumococcal vaccination. Details on these vaccinations are discussed elsewhere (figure 1). (See "Immunizations for patients with chronic liver disease".)
Patients with advanced liver fibrosis or cirrhosis — HCV-infected patients who are found to have advanced fibrosis should be monitored for the development of complications. This includes evaluating for clinical signs of liver failure (including ascites, hepatic encephalopathy, or bleeding from gastroesophageal varices) as well as laboratory testing to identify hepatic dysfunction (hypoalbuminemia, hyperbilirubinemia, or hypoprothrombinemia). Additionally, patients with cirrhosis should be screened for the presence of gastroesophageal varices by upper endoscopy. Patients with advanced liver fibrosis or cirrhosis should undergo surveillance for hepatocellular carcinoma (HCC) because HCC occurs at a rate of 1 to 4 percent per year. Liver ultrasonography every six months is the recommended method for HCC surveillance. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Preventing and identifying complications' and "Clinical features and diagnosis of primary hepatocellular carcinoma", section on 'Screening and surveillance'.)
Goals of therapy — The goal of antiviral therapy in patients with chronic hepatitis C virus (HCV) is to eradicate HCV RNA, which is predicted by attainment of a sustained virologic response (SVR), defined as an undetectable RNA level 12 weeks following the completion of therapy.
An SVR is associated with a 97 to 100 percent chance of being HCV RNA negative during long-term follow-up and can therefore be considered cure of the HCV infection . Attaining an SVR has been associated with decreases in all-cause mortality, liver-related death, need for liver transplantation, hepatocellular carcinoma rates, and liver-related complications, even among those patients with advanced liver fibrosis [15-24]. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Rationale for treatment'.)
Indications — All patients with virologic evidence of chronic HCV infection (ie, detectable HCV viral level over a six-month period) should be considered for treatment. The introduction of direct-acting antivirals (DAAs), drugs that target specific nonstructural proteins of HCV and thus disrupt viral replication and infection (figure 2 and table 4), has revolutionized therapy of HCV infection. Highly effective, well-tolerated, all-oral regimens are now the treatment of choice for the vast majority of HCV-infected patients who have access to these agents. The evaluation and selection of patients for antiviral therapy is discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)
In the United States, the high prices of these all-oral antiviral regimens have garnered substantial attention among medical and lay communities. Several studies have suggested that these regimens, even at their introductory high cost, are cost-effective for many populations, including those with genotype 1 infection or advanced fibrosis, because of their superior efficacy in clinical trials [25-29]. Availability of additional agents has made most DAA therapies more affordable to patient and third party payers, and thus more patients have access to them.
Regimen selection — Antiviral therapy of HCV has been rapidly evolving with the introduction and proliferation of DAAs that offer the potential for highly effective, interferon-free (and in many cases, ribavirin-free) regimens for the majority of HCV infected individuals. Regimen selection varies by genotype and other patient factors, such as the presence of cirrhosis and treatment history (algorithm 1 and algorithm 2 and algorithm 3 and algorithm 4), and is discussed separately:
Regimen selection for patients who are human immunodeficiency virus (HIV)/HCV-coinfected is generally the same as for monoinfected patients, although it is also constrained by the potential for drug interactions between DAAs and antiretroviral agents. (See "Treatment of hepatitis C virus infection in the HIV-infected patient", section on 'HCV regimen selection'.)
Severe renal impairment (ie, estimated glomerular filtration rate <30 mL/min per 1.73 m2) also constrains the choice of HCV antivirals. Regimen selection in such patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with renal impairment", section on 'Regimen selection'.)
MONITORING DURING ANTIVIRAL THERAPY
Interferon-free regimens — Clinical assessment during treatment with an interferon-free, direct-acting antiviral (DAA) regimen focuses on adherence to the regimen and identification of adverse effects. DAAs are generally well tolerated. Specific side effects are discussed in detail elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)
Viral monitoring — Monitoring viral levels during treatment with interferon-free regimens has minimal prognostic value, as almost all patients without cirrhosis in the large clinical trials of interferon-free regimens achieve an undetectable hepatitis C virus (HCV) viral level by four weeks of treatment and failure to achieve that threshold does not accurately predict failure to achieve a sustained virologic response (SVR) [30,31]. Thus, the main reasons to check viral levels during therapy are to assess adherence to the regimen and to document the treatment course and virologic response in case patients relapse and warrant retreatment. Given the expense of the medicines and the potential risk of viral resistance with inappropriate use, we check HCV RNA quantitative testing at week 4 in clinical practice. The joint guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) additionally recommend rechecking HCV RNA quantitative testing at week 6 if the week 4 level is detectable and discontinuing therapy if the level has increased by >1 log . Although there are no direct clinical data to support this practice, we agree that this is an appropriate approach.
The clinical value of a week 12 (or end of treatment) viral level is uncertain, and most providers do not routinely check it. It is undetectable in the vast majority of treated patients, even among those who have subsequent viral relapse. Furthermore, in one study, all six patients with quantifiable but low level (<65 international units/mL) viremia at the end of DAA-based treatment nevertheless achieved SVR . In the large registration trials of ledipasvir-sofosbuvir, 12 of 22 patients with detectable HCV at the end of treatment still achieved SVR .
Virologic response to treatment should be assessed by checking the viral load at 12 weeks following the cessation of therapy. (See 'Follow-up after antiviral therapy' below.)
Other monitoring — Drug toxicity with interferon-free DAA combinations is uncommon, although intermittent laboratory monitoring is warranted during treatment, particularly with certain regimens and for patients who have evidence of prior or current HBV infection.
In the absence of data to suggest otherwise, we agree with the AASLD/IDSA recommendations to check basic laboratory tests (complete blood count, creatinine with eGFR calculation, and liver enzyme and bilirubin levels) at week 4 of treatment with any regimen, with more frequent monitoring for concerning results or trends .
Additional indications for laboratory testing are regimen specific:
●Elbasvir-grazoprevir – Additionally, checking liver enzyme and bilirubin levels at week 8 (and week 12, if treatment duration is 16 weeks) is recommended. If an increase in the alanine aminotransferase exceeds 10-fold the baseline level or is accompanied by symptoms or hyperbilirubinemia, treatment should be discontinued.
●Paritaprevir-ritonavir-ombitasvir-based regimens – For those patients who have compensated cirrhosis, close monitoring for hepatic decompensation is warranted during therapy with these regimens. This includes assessment for clinical signs of decompensation (eg, ascites, encephalopathy) throughout the treatment course and testing liver enzyme and bilirubin levels at week 2 in addition to week 4, at weeks 12 and 24 for those who are on a longer duration of therapy, and for any concerning signs or symptoms. Clinical evidence of decompensation or significant increases in these laboratory values should prompt treatment discontinuation.
●Ribavirin-containing regimens – We check the complete blood count at weeks 4, 8, and 12 to evaluate for anemia. For those who develop anemia, the dose of ribavirin can be adjusted based on the severity and comorbidities. For patients with no cardiac disease, ribavirin can be reduced to 600 mg daily for hemoglobin levels between 8.5 and 10 g/dL and can be held for levels <8.5 g/dL. For with a history of cardiac disease, ribavirin can be reduced to 600 mg daily for a ≥2 g/dL decrease during any four-week period and can be held for hemoglobin <12 g/dL despite four weeks at a reduced dose. Gradual titration up of the ribavirin dose by 200 mg a day can be attempted if patients have a subsequent increase in the hemoglobin.
For women of childbearing-age taking a ribavirin-containing regimen, assessment of contraception use and pregnancy testing should be performed during and for six months after treatment. Men taking a ribavirin-containing regimen should be counseled on contraceptive use for sex with a woman of childbearing-age during and for six months after treatment.
Patients with evidence of prior or current HBV infection (ie, those with positive HBV core antibody [HBcAb]) who are not on HBV antiviral therapy warrant specific monitoring because of the risk of HBV reactivation during HCV treatment [1,35].
●For those who are HBV surface antigen (HBsAg)-positive, the following should be performed:
•Obtain a baseline HBV DNA prior to HCV therapy.
•For those who meet criteria for antiviral treatment of HBV (table 5), initiate HBV treatment prior to or at the same time as HCV therapy.
•For those who do not meet criteria for HBV therapy, monitor HBV DNA levels at regular intervals (usually not more frequently than every four weeks) during HCV therapy. Initiate HBV therapy for those whose HBV DNA levels meet criteria for treatment (table 5).
●For those who are HBsAg-negative but HBcAb-positive, there are no data to inform optimal monitoring. We suggest monitoring for HBV reactivation in these patients by checking liver enzymes at four week intervals during HCV therapy. In the event of unexplained increases in liver enzymes and during and/or after completion of HCV therapy, repeat HBsAg testing and HBV DNA should be performed. HBV reactivation is suggested by conversion from an undetectable to a detectable HBV DNA or a rise in HBV DNA level by >2 log international units and may warrant antiviral therapy for HBV infection.
Indications for and regimen selection for HBV antiviral therapy are discussed elsewhere. (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.)
Following identification of this association between HCV treatment and HBV reactivation, a review of adverse hepatic events associated with DAAs that were reported to the US Food and Drug Administration (FDA) identified 524 cases of liver failure in the course of one year, with an estimated 250,000 individuals treated over a similar time frame . It is unclear what proportion of these represent cases of HBV reactivation or complications in patients with existing advanced liver disease (including inappropriate use of protease inhibitors in patients with decompensated disease), situations in which the risk of liver failure is higher than the general population. Patients should understand that this risk is overall very low and that further data are needed to more clearly define it.
Adherence counseling — It is important to have a discussion about adherence at each clinic visit. Patients should be interviewed regarding medication adherence in a nonjudgmental manner. It is sometimes useful to discuss medication schedules with patients to help them link pill-taking behaviors to other daily activities, such as brushing teeth. If the patient admits to difficulties with adherence, potential barriers could involve the timing of doses, sizes of pills, and treatment-limiting side effects.
For ribavirin-containing regimens, if insomnia is a problem, the evening dose of ribavirin can be adjusted to earlier in the afternoon.
Interferon-containing regimens — For patients who are treated with a regimen that contains peginterferon and ribavirin, side effects can be substantial. These most commonly are flu-like symptoms, fatigue, neuropsychiatric symptoms, and hematologic effects. Patients should thus be evaluated regularly for toxicity during the course of therapy with such regimens. This is discussed elsewhere. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)
FOLLOW-UP AFTER ANTIVIRAL THERAPY — Virologic response to treatment should be assessed by checking the viral load at 12 weeks following the cessation of therapy. Sustained virologic response (SVR) is defined by an undetectable viral level at this time point, which is generally maintained through 24 weeks following the cessation of therapy and beyond. However, a very small proportion of patients (less than 1 percent in studies of direct-acting antivirals) experience virologic relapse between weeks 12 and 24, and some of those cases may be reinfection rather than true relapse [37-39]. Thus, some practitioners also check the viral load at 24 weeks to ensure maintenance of SVR. Although SVR reflects effective cure of hepatitis C virus (HCV) infection, it does not confer immunity to HCV, and patients should be counseled that they are at risk for reinfection with future exposure.
Patients who achieve an SVR and do not have bridging fibrosis or cirrhosis do not require any specific follow-up for their HCV infection, though some will check an HCV viral load one year after the completion of treatment to confirm that the viral load remains undetectable.
Patients who fail to achieve an SVR should continue to be followed for signs of progression of liver disease and assessed for retreatment of HCV infection. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection" and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and 'General management' above.)
Patients with advanced fibrosis or cirrhosis, regardless of whether they attain an SVR, require ongoing monitoring (including liver ultrasonography every six months) because they continue to be at risk of hepatocellular carcinoma and other complications. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'General management'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hepatitis C (The Basics)" and "Patient education: Treatment for hepatitis C (The Basics)")
●Beyond the Basics topic (see "Patient education: Hepatitis C (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The evaluation of patients with chronic hepatitis C virus (HCV) infection involves assessing the extent of liver disease, assessing other viral and host factors (including viral genotype, liver fibrosis stage, history of prior antiviral treatment, renal function, and medication use) that inform optimal antiviral selection, and identifying comorbidities associated with HCV infection (including extrahepatic manifestations of HCV infection as well as human immunodeficiency virus [HIV] and hepatitis B virus [HBV] infection). (See "Diagnosis and evaluation of chronic hepatitis C virus infection", section on 'Additional evaluation' and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Evaluation to guide management decisions'.)
●HCV-infected patients should be counseled on measures to decrease the risk of transmission (table 1) and correcting factors associated with accelerated liver disease, including alcohol use, obesity and insulin resistance, and marijuana use. Substance use treatment is also an important element of care in patients who have ongoing illicit drug use. (See 'Counseling' above.)
●Additional management is warranted for patients who are found to have advanced fibrosis or cirrhosis, including dose modification or avoidance of certain medications (table 2 and table 3), twice yearly ultrasonography for hepatocellular carcinoma screening, and upper endoscopy screening for esophageal varices. (See 'Patients with advanced liver fibrosis or cirrhosis' above and "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'General management'.)
●All patients with virologic evidence of chronic HCV infection (ie, detectable HCV viral level over a six-month period) should be considered for antiviral treatment. The goal is to eradicate HCV RNA, which is associated with decreases in all-cause mortality, liver-related death, need for liver transplantation, hepatocellular carcinoma rates, and liver-related complications. (See 'Antiviral therapy' above and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)
●Where direct-acting antivirals are available, highly effective, interferon-free (and in many cases, ribavirin-free) regimens are appropriate options for the majority of HCV infected individuals. Regimen selection varies by genotype and other patient factors (algorithm 1 and algorithm 2 and algorithm 3 and algorithm 4). (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)
●With interferon-free regimens, the purpose of viral level monitoring during treatment is primarily to assess adherence and document the treatment course. We typically check a quantitative HCV RNA test at week 4 of therapy. Virologic response to treatment should be assessed by checking the viral load at 12 weeks following the cessation of therapy. Sustained virologic response (SVR) is defined by an undetectable viral level at this time point. (See 'Monitoring during antiviral therapy' above and 'Follow-up after antiviral therapy' above.)
●Patients who fail to achieve an SVR should continue to be followed for signs of progression of liver disease and assessed for retreatment of HCV infection. Patients with advanced fibrosis or cirrhosis, regardless of whether they attain an SVR, warrant ongoing monitoring because they continue to be at risk of hepatocellular carcinoma and other complications. (See 'Follow-up after antiviral therapy' above.)
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