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Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection
Authors:
Sanjiv Chopra, MD, MACP
Sanjeev Arora, MD, MACP, FACG
Section Editor:
Adrian M Di Bisceglie, MD
Deputy Editor:
Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Jan 25, 2018.

INTRODUCTION — We are at a major inflection point in our long term effort to control the silent epidemic of chronic hepatitis C virus infection (HCV). With the advent of new medicines, the vast majority of patients with HCV infection who have access to them can be cured with treatment. Newer treatments are of shorter duration, have fewer side effects, and have higher cure rates. The goal of treatment of chronic HCV infection is a sustained virologic response (SVR), defined as absence of virus in the blood 12 weeks after the cessation of treatment. Patients achieving an SVR are considered cured, as studies show that 99 percent of patients who achieve a SVR remain free of detectable virus during long term follow up [1].

This topic will review patient selection for antiviral therapy in the context of the availability of all oral HCV regimens, as well as peginterferon and ribavirin-based regimens. The treatment of acute HCV and detailed information on the use of specific treatment regimens for chronic HCV infection are discussed separately:

(See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

(See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults".)

(See "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults".)

(See "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)

GUIDELINES — Guidelines for the diagnosis and management of 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 [2]. The discussion in this topic is largely consistent with these guidelines.

Other guidelines include treatment recommendations from the European Association for the Study of the Liver (EASL) [3]. 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 [4].

Links to these and other guidelines can be found below. (See 'Society guideline links' below.)

RATIONALE FOR TREATMENT — HCV is a serious systemic infection which causes substantial morbidity and mortality worldwide. Treatment is safe and effective, and can mitigate the serious consequences of this disease, and thus all patients, with the exception of those with life expectancy limited to <12 months due to non-related conditions, should be considered for treatment [2].

Safety and virologic efficacy of treatment — In locations where combination direct-acting antiviral regimens are available, these highly effective, well-tolerated, interferon-free regimens can result in sustained virologic response (SVR) in over 90 percent of HCV-infected patients [5]. Thus, achieving a cure of HCV, which results in improved survival, reduced morbidity, and higher quality of life in the vast majority of patients, has become more likely and much easier with the availability of newer agents. For this reason, all patients should be considered for treatment. (See 'Deciding when to treat' below.)

The selection of specific treatment regimens is discussed in detail elsewhere. (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".)

Reduction in liver-related morbidity and mortality — The main risk of HCV infection is progression to cirrhosis and its attendant complications. Curing HCV prior to the development of decompensated cirrhosis results in decreased all-cause mortality, liver-related death, need for liver transplantation, hepatocellular carcinoma rates, and liver-related complications [6-21].

After acute infection with HCV, about 55 to 80 percent of patients remain chronically viremic; ie, they develop chronic infection. In a systematic review of 111 studies analyzing the natural history of chronic HCV the estimated prevalence of cirrhosis 20 years after infection was 16 percent (95% CI 14 to 90 percent) [22]. This wide variation in fibrosis progression rates probably reflects host factors, study design, referral bias, and geographic differences. Even though we have identified many factors associated with rate of fibrosis progression, it is very difficult to predict the rate of fibrosis progression in an individual patient. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Natural history' and "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Factors associated with disease progression'.)

Additionally, many patients acquire HCV as young adults and often live with infection for 30 or more years, and the likelihood of developing cirrhosis continues to increase as the patient ages. As a result of such long standing infection in large numbers of patients, the burden of HCV has grown. As an example, in the United States, HCV is a major cause of cirrhosis, end stage liver disease, and liver cancer, and complications of chronic HCV are the most common indication for liver transplantation, accounting for more than 40 percent of transplants in adults [23-25]. After an orthotopic liver transplant, 95 percent of patients develop recurrent HCV infection of the new graft, which is the leading cause of graft failure in these patients [26].

Achieving SVR through successful antiviral treatment can dramatically reduce HCV-related morbidity for the individual, even when advanced fibrosis (bridging fibrosis or cirrhosis) has already developed [9,18,20,27]. In a meta-analysis of 26 observational studies that assessed long-term outcomes of HCV-infected patients with advanced fibrosis after treatment, those who did not attain an SVR had a liver-related mortality rate of 2.7 percent per year. In contrast, those who did achieve an SVR had a much lower risk of liver-related mortality (relative risk [RR] 0.19; 95% CI 0.10-0.37) and were significantly less likely to develop HCC (RR 0.32) or hepatic decompensation (RR 0.13) [27]. Similarly, in a prospective study of patients with advanced fibrosis who underwent antiviral treatment and were followed for a median of 79 to 86 months, morbidity and mortality rates were lower among the 140 patients who achieved SVR (2 and 3 percent, respectively) compared with the 209 patients who had no response to therapy (21 and 27 percent morbidity and mortality, respectively) [9].

Improvement or prevention of extrahepatic complications — Even patients with chronic HCV who have no evidence for advanced fibrosis (bridging fibrosis or cirrhosis) are still at significant risk for developing extrahepatic manifestations of HCV, some of which can be life threatening. A cure of HCV prevents the development of extrahepatic manifestations.

In a prospective, multicenter study of 321 patients with chronic HCV, 122 of them (38 percent) had at least one extrahepatic manifestation [28]. Extrahepatic manifestations that are associated with, and in most cases caused by, HCV include essential mixed cryoglobulinemia, B cell lymphoma, renal disease, membranoproliferative glomerulonephritis, neuropathy, leukocytoclastic vasculitis, and porphyria cutanea tarda. (See "Extrahepatic manifestations of hepatitis C virus infection".)

HCV is also associated with insulin resistance and diabetes mellitus. In a meta-analysis of 34 observational studies, HCV-infected patients had a significantly higher risk of developing diabetes mellitus than control populations (hazard ratios 1.67 [95% CI 1.28-2.06] among prospective studies and odds ratio 1.68 [95% CI 1.15-2.20] among retrospective studies) [29]. Achievement of SVR results in a lower incidence of diabetes and decreased insulin resistance among HCV infected patients [30-32]. (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Diabetes mellitus'.)

Symptom alleviation — Although chronic HCV infection is typically minimally symptomatic, some patients do complain of generalized symptoms, most commonly fatigue. Fatigue and overall quality of life improve in some patients who have a SVR following antiviral therapy, although the improvements may be modest [33-39]. In one study evaluating this issue, fatigue improved in 29 of 83 patients who responded to antiviral therapy versus 75 of 348 nonresponders (35 versus 22 percent) [33].

EVALUATION TO GUIDE MANAGEMENT DECISIONS — All patients should be considered for treatment. The urgency with which to treat chronic HCV infection and which regimen to use is based upon several factors, including the infecting genotype, the natural history and stage of the disease, the expected efficacy of therapy, prior treatment history, potential side effects of and ability to tolerate the appropriate treatment regimen. Evaluation prior to management decisions should focus on these factors.

HCV genotype — Regimen selection, dosing, and duration of therapy all depend on the HCV genotype, and thus determination of the genotype is essential to making decisions about treatment. (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".)

The HCV family of viruses is extremely heterogeneous, and at least six genotypes and numerous subtypes have been identified [40]. A variety of methods are available to identify genotypes. The commonly used method of genotyping is the line probe assay (INNO-LiPA HCV II, Siemens Healthcare Diagnostics), which provides genotype and subtype. Currently, only genotype (not subtype) is used in making clinical decisions regarding treatment. (See "Characteristics of the hepatitis C virus", section on 'Genotypes'.)

Viral resistance testing — In certain populations, testing for pre-existing resistance-associated substitutions (RASs) is warranted prior to the use of certain regimens. As examples, patients with genotype 1a infection should be tested for NS5A RASs if elbasvir-grazoprevir is being considered, and patients with genotype 3 infection who have cirrhosis or prior treatment failure should be tested for NS5A RASs if sofosbuvir-velpatasvir or daclatasvir plus sofosbuvir are being considered. The presence of RASs impacts the regimen duration and/or whether ribavirin should be added. This is discussed in detail elsewhere. (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".)

Testing for NS3 and/or NS5A RASs is also important in determining appropriate treatment regimens for individuals who have failed prior treatment with interferon-free regimens.

History of prior treatment — Patients should be asked about any prior exposure to HCV antiviral treatment and their response, as future management decisions depend on specific aspects of the treatment history.

Patients who have never received any treatment for HCV infection are considered treatment–naïve.

For patients who had failed prior treatment (ie, treatment-experienced patients), it is important to clarify what the failing regimen was, as the approach to regimen selection is different for those who failed peginterferon and ribavirin alone compared with those who failed a direct-acting antiviral regimen.

Assessment of fibrosis stage — The presence of advanced fibrosis (bridging fibrosis or cirrhosis) guides certain decisions regarding treatment, including optimal regimen and duration, and is a key factor that determines urgency of treatment. Fibrosis stage can be assessed indirectly through history, physical examination, laboratory tests, and other noninvasive studies (such as the FibroSure and ultrasound-based transient elastography). Although some practitioners still utilize liver biopsy for assessment of fibrosis stage, we do not routinely biopsy patients with HCV. (See 'Role of liver biopsy' below.)

The history should include questions regarding nonspecific symptoms (eg, anorexia, weight loss, weakness) or complications that could suggest underlying cirrhosis (eg, a history of jaundice, ascites, hematemesis, and mental status changes). A directed physical examination should assess for signs consistent with cirrhosis (eg, spider angiomata, palmar erythema, gynecomastia, firm liver on palpation, and splenomegaly). (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Important laboratory testing includes a complete blood count, serum aminotransferase activity and measures of synthetic function (bilirubin, prothrombin time, and albumin). Common laboratory abnormalities in cirrhosis include elevated serum bilirubin, abnormal aminotransferases, elevated alkaline phosphatase, a prolonged prothrombin time/elevated international normalized ratio (INR), low albumin, and thrombocytopenia. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Laboratory findings'.)

Various noninvasive markers of liver fibrosis can be very helpful to assess to the degree of liver fibrosis present. Some of these, such as the AST/ALT ratio, the AST to platelet ratio index (APRI) (calculator 1), and the FIB-4 (calculator 2), can be calculated from results of routine laboratory tests. Other specialized noninvasive diagnostic tests include the FibroSure and ultrasound-based transient elastography. Potential benefits of these noninvasive markers are ease of administration and lower cost compared with liver biopsy. Also, they can be repeated over time to monitor progress of liver disease and may predict clinical outcomes better than liver biopsy [41]. A detailed discussion on noninvasive tests to assess hepatic fibrosis is found elsewhere. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic and radiographic tests".)

Of note, knowledge of the presence of bridging fibrosis and cirrhosis is also important for assessing prognosis and indications for additional surveillance. As an example, patients with advanced fibrosis should undergo routine screening for hepatocellular carcinoma, and patients with established cirrhosis 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). (See "Prevention of hepatocellular carcinoma and recommendations for surveillance in adults with chronic liver disease" and "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

Role of liver biopsy — We do not routinely perform liver biopsy in patients with chronic HCV infection. Liver fibrosis has historically been the gold standard for assessing the liver stage and thus predicting the prognosis of the disease. However, it is not a reliable gold standard, noninvasive markers of fibrosis (such as the FibroSure test and ultrasound-based transient elastography) are becoming more widely available, and as treatment for HCV continues to become less toxic and more effective, there is less need to precisely stage the patient’s liver disease through biopsy.

Limitations of liver biopsy include [42,43]:

Sampling error, which leads to misinterpretation in 10 to 15 percent of patients. Thus, the diagnosis of cirrhosis can be missed, leading to false assurance for the clinician and the patient.

Significant interobserver variability in the interpretation of liver biopsies.

Expense and risk of complications, given its invasive nature.

However, unlike noninvasive markers of fibrosis, a liver biopsy can establish the presence of concomitant diseases (such as hemochromatosis, alcoholic hepatitis, nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, and hepatic sarcoidosis) and the degree to which these conditions contribute to the patient's liver disease.

We base our decision to treat HCV on history, physical exam, laboratory tests, and noninvasive assessment of liver fibrosis (such as FibroSure or ultrasound-based transient elastography). We perform liver biopsy only in select patients with HCV infection, including those with a liver transplant, suspected autoimmune liver disease, drug induced liver disease, and in those for whom the diagnosis is in doubt.

Another proposed strategy, if resources are available, is to use two types of noninvasive tests for fibrosis (ie, biomarker test and transient liver elastography) and reserve biopsy for those patients who have discordant results on these two tests [2,44].

Evaluation for conditions that might affect therapy — Prior to initiating antiviral therapy, a thorough evaluation for other types of liver disease should be obtained, and other medical conditions should be investigated as they may have a bearing on the treatment plan, depending on the planned regimen. The specific workup depends on the planned regimen.

In all patients, the following should be assessed:

Renal function (see 'Kidney disease' below)

Complete blood count and differential (see 'Contraindications/precautions with anti-HCV agents' below)

Concurrent alcohol or drug use (see 'Active drug use' below and 'Ongoing alcohol use' below)

Extrahepatic manifestations of HCV infection (see 'Extrahepatic manifestations of HCV infection' below and "Extrahepatic manifestations of hepatitis C virus infection")

HIV coinfection (see 'HIV coinfection' below)

HBV coinfection (with HBV surface antigen [sAg], surface antibody [sAb], and core antibody [cAb] followed by HBV DNA testing for those who have a positive sAg or who have only cAb positive; HBV DNA testing is not necessary for those who have a positive sAb alone or positive sAb and cAb) (see 'HBV coinfection' below)

Presence of severe co-morbidity (eg, cardiac disease) (see 'Contraindications/precautions with anti-HCV agents' below)

Potential for drug interactions (see 'Contraindications/precautions with anti-HCV agents' below)

In patients whose regimen is to contain ribavirin, the following should be assessed:

Pregnancy test (for women) and contraceptive plan in patients of child-bearing potential (see 'Ribavirin' below)

In patients whose regimen is to contain interferon, the following should be assessed:

Psychiatric history (see 'Interferon' below)

Presence of underlying autoimmune disorders (such as autoimmune hepatitis) (see 'Interferon' below and "Principles of interferon therapy in liver disease and the induction of autoimmunity")

Thyroid function, fasting glucose, funduscopic exam (see "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection")

DECIDING WHEN TO TREAT — As above, a cure of HCV results in improved survival, reduced morbidity, and higher quality of life in the vast majority of patients (see 'Rationale for treatment' above). Thus, all patients with virologic evidence of chronic HCV infection (ie, detectable HCV viral level over a six month period), except for those with limited life expectancy (<12 months) due to non-related conditions, should be considered for treatment. Candidacy for treatment is limited mainly by the presence of contraindications to the available regimens. (See 'Contraindications/precautions with anti-HCV agents' below.)

Before the introduction of direct-acting antivirals (DAAs), antiviral treatment of HCV infection with peginterferon and ribavirin was variably effective for different patient populations, was associated with numerous contraindications and adverse effects, and in some cases required prolonged duration of therapy. In order to optimize administration of a difficult treatment regimen, management decisions focused on identifying patients who would be most likely to respond to therapy or who were most likely to suffer liver-related morbidity and mortality without successful treatment. With the increasing availability of DAAs, treatment regimens that achieve very high SVR rates, have more favorable adverse effect profiles and greater ease of administration than earlier regimens, and have relatively short treatment durations are possible for many patients. Thus, curative, all-oral regimens are possible for the vast majority of patients who have access to these agents. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

Nevertheless, if financial resources preclude more widespread delivery of antiviral therapy, it can be prioritized for those who would be most likely to benefit in the near-term, as recommended by the joint guidelines from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) [2]. The highest priority patients include those who are at highest risk of substantial morbidity and mortality from untreated HCV infection, namely those with advanced fibrosis or compensated fibrosis, transplant recipients, and those with severe extrahepatic manifestations of HCV infection. High priority patients include those at high risk of fibrosis progression, such as patients with substantial fibrosis (eg, Metavir stage F2), HIV coinfection, coexisting liver disease, and diabetes mellitus. Symptomatic HCV infection (eg, with debilitating fatigue or other less severe extrahepatic manifestations) and the potential for transmission of HCV are additional considerations that might prioritize treatment in a given patient.

If interferon-free regimens are not yet available for the patient, but are expected to be in the near future, we favor deferring therapy until that time, unless there is a compelling reason to initiate treatment earlier. Such reasons may include the presence of advanced fibrosis, severe extrahepatic complications, or patient preference. (See 'Bridging fibrosis and compensated cirrhosis' below and 'Extrahepatic manifestations of HCV infection' below.)

For patients who do defer antiviral treatment to wait for future regimens, liver wellness (eg, alcohol abstinence, maintaining a healthy weight, control of diabetes mellitus) and close monitoring of clinical status are warranted.

CONTRAINDICATIONS/PRECAUTIONS WITH ANTI-HCV AGENTS — Direct-acting antivirals are well tolerated by the vast majority of patients, although some comorbidities preclude certain regimens. Additional precautions should be taken into account if the addition of ribavirin to the regimen is warranted.

For those who do not have access to interferon-free regimens, the adverse effects associated with interferon should be accounted for when determining candidacy for and timing of antiviral treatment. In some patients, interferon treatment is contraindicated due to the risk of side effects, whereas in others, treatment should be undertaken with extreme caution.

Direct-acting antivirals — There are generally few contraindications or precautions with the use of direct-acting antiviral agents. The main precaution with direct-acting antivirals are drug interactions; these are more significant for regimens that contain HCV protease inhibitors (eg, simeprevir, paritaprevir, grazoprevir) but affect use of all direct-acting antiviral agents. Potential drug interactions with specific regimens are discussed in detail elsewhere and can be evaluated through the Lexi-Interact program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

Additional precautions include the following:

For patients with severe renal impairment (estimated GFR <30 mL/min per 1.73 m2 or on dialysis), sofosbuvir-containing regimens should be avoided if possible, because of the paucity of evidence supporting their safety. If such regimens are the only reasonable option, they should be used only by or in consultation with an expert in the treatment of HCV infection. (See "Treatment of chronic hepatitis C infection in adults with renal impairment", section on 'Regimen selection'.)

For patients with decompensated cirrhosis (Child-Pugh classes B and C), simeprevir, elbasvir-grazoprevir, and ombitasvir-paritaprevir-ritonavir-based regimens should be avoided.

Ribavirin — The main adverse effect of ribavirin is hemolysis. This effect is generally only clinically relevant among patients with pre-existing anemia (eg, hemoglobin <12 g/dL for men and <11 g/dL for women), renal insufficiency (estimated glomerular filtration rate <60 mL/min per 1.73 m2), and coronary artery disease, and so ribavirin should be used with caution in such patients [45]. In addition, ribavirin is excreted renally and may accumulate to toxic levels in patients with impaired renal function or on hemodialysis, which thus warrants significant dose reductions and careful monitoring when used in such patients. (See 'Kidney disease' below.)

Because of the risk of hemolysis, ribavirin should also be only used with caution, dose reduction, and frequent monitoring in patients with hemoglobinopathies.

Additionally, ribavirin is pregnancy category X due to significant teratogenic and embryocidal effects and is contraindicated in pregnant women. It also should not be used in individuals of child-bearing potential (men and women) who cannot or will not use contraception.

Ribavirin generally does not have many interactions with other agents. Its use is contraindicated with didanosine; however this HIV antiretroviral is rarely used anymore.

Interferon — Interferon is generally only used in locations that do not have access to interferon-free regimens. Conditions that may be complicated or worsened by side effects of interferon treatment include significant anemia (eg, hemoglobin <12 g/dL for men and <11 g/dL for women) or leukopenia (eg, absolute neutrophil count <1500 cells/microL or, if of African descent, <1000 cells/microL), severe depression or other psychiatric conditions, cardiac disease, poorly controlled diabetes, seizure disorders, and autoimmune or potentially immune-mediated diseases. Use of an interferon containing regimen is not recommended if some of these conditions are present and not treated or well controlled.

Additionally, interferon may be associated with an excess of side effects in certain populations, such as those with advanced fibrosis or decompensated cirrhosis and the elderly. Consideration of use of interferon in these groups is discussed elsewhere. (See 'Bridging fibrosis and compensated cirrhosis' below and 'Decompensated cirrhosis' below and 'Older adults' below.)

Specifically, contradictions to the use of interferon include:

Significant and uncontrolled depressive illness, bipolar disease, or schizophrenia (such patients are at risk for exacerbation and potential suicide during treatment). Stably treated psychiatric conditions are not a contraindication to interferon use. (See "Neuropsychiatric side effects associated with interferon plus ribavirin for treatment of hepatitis C: Recognition and risk factors" and "Neuropsychiatric side effects associated with interferon-alfa plus ribavirin therapy: Treatment and prevention".)

A kidney, heart, or lung transplant.

Autoimmune hepatitis or other severe autoimmune conditions known to be exacerbated by interferon. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection", section on 'Autoimmune disease exacerbation'.)

Untreated thyroid disease. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection", section on 'Thyroid dysfunction'.)

Severe concurrent disease, such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, obstructive pulmonary disease.

Known hypersensitivity to interferon.

SPECIAL SITUATIONS — Certain clinical characteristics should be taken into account when making decisions about antiviral treatment for HCV infection.

Acute HCV — For patients who are diagnosed with acute HCV, there is still the possibility that they might clear the virus spontaneously, which would obviate the need for treatment. This is discussed in greater detail elsewhere. (See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

Treatment-experienced — With the availability of new direct-acting antivirals and the expectation of additional potent agents, most treatment-experienced patients can be retreated successfully. The selection of the precise treatment regimen may differ based on treatment history. This is discussed for each genotype separately. (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".)

Mild liver disease — As above, it is difficult to predict the rate of fibrosis progression in an individual patient and even patients without significant liver disease can develop extrahepatic complications; thus, patients with chronic HCV infection and mild liver disease can benefit from and should be considered candidates for therapy. (See 'Rationale for treatment' above.)

If highly effective interferon-free regimens are available for the patient and the patient is willing and able to proceed with treatment, there is no reason to delay therapy unless the patient has contraindications to the regimen (see 'Contraindications/precautions with anti-HCV agents' above). If financial resources are constrained, it is reasonable to prioritize treatment for those who have a higher risk of fibrosis progression (eg, those with Metavir stage F2 fibrosis, HIV coinfection, coexisting liver disease, diabetes mellitus, and debilitating fatigue), significant symptoms associated with HCV infection, and high potential for transmission of HCV infection [2].

However, if interferon-free regimens are not yet available for the patient, but are expected to be in the near future, we favor deferring therapy until that time, as these newer treatments have higher SVR rates and fewer adverse effects. Patients who do not have clinical or laboratory evidence of advanced fibrosis, with noninvasive tests and/or liver biopsy suggesting mild fibrosis and minimal necroinflammatory changes are likely to have slow progression of liver disease [27,46] while awaiting new therapies. Patient preference should be an important factor in the decision to treat such patients now or wait.

Bridging fibrosis and compensated cirrhosis — As above, patients with advanced fibrosis (bridging fibrosis and compensated cirrhosis) have a substantial reduction in morbidity and mortality following cure of HCV with successful therapy, and thus they stand to benefit the most from the newer antiviral agents for HCV (see 'Reduction in liver-related morbidity and mortality' above). However, certain patients with cirrhosis (particularly those who have failed previous treatment with interferon and ribavirin) appear to have lower SVR rates with the same regimen compared with those without cirrhosis [47-49]. Thus, the presence of underlying cirrhosis affects the selection of the specific treatment regimen. (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".)

If highly effective interferon-free regimens are available for the patient, and the patient is willing and able to proceed with treatment, there is no reason to delay therapy unless the patient has contraindications to the regimen. (See 'Contraindications/precautions with anti-HCV agents' above.)

For patients for whom interferon-free regimens are not yet available, management decisions are more difficult. On one hand, there is a risk that such patients may have progression of liver disease, potentially to decompensation, while awaiting the availability of newer therapies [50-52]. On the other hand, patients with cirrhosis have a substantial risk of adverse effects with interferon, and there appear to be some patients with apparently compensated cirrhosis who are at risk of decompensation when treated with an interferon-based regimen, although the risk factors for decompensation among these patients are not clear. In a study that included 455 patients with HCV genotype 1 and compensated cirrhosis who were treated with peginterferon, ribavirin, and telaprevir or boceprevir, serious adverse events occurred in 38 to 49 percent of patients, with 4 percent of patients developing hepatic decompensation [53]. Predictors of adverse events included albumin level <3.5 g/dL and platelet count <100,000/microL. It is unclear whether these adverse outcomes would be observed as frequently with a 12 week regimen of peginterferon, ribavirin, and sofosbuvir.

Thus, the decision on when to treat such patients must balance these opposing risks and depends how soon interferon-free agents are expected to become available for the patient.

If an interferon-based regimen is undertaken in a patient with underlying cirrhosis, it should be done with caution and close monitoring. In addition, the use of growth factors (such as erythropoietin and granulocyte macrophage colony-stimulating factor) may be helpful during treatment by limiting the need for excessive reductions in the dose of certain antiviral agents. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

Decompensated cirrhosis — Decompensated cirrhosis refers to a history of or the presence of, ascites, hepatic encephalopathy or jaundice (table 1). In addition, marked abnormalities in serum albumin, bilirubin, and prothrombin times are features of decompensation.

Hepatologists can consider antiviral therapy with direct-acting antiviral (DAA) combinations in patients with decompensated liver disease. Successful HCV treatment in such patients has been associated with improved survival, but interferon-based regimens were also associated with substantial side effects and drop-outs [54,55]. Subsequent studies have demonstrated promising results with the use of all-oral DAA regimens in this population [56-59]. Treatment has also been shown to be effective in patients with liver cancer awaiting liver transplantation [58]. Of note, certain direct-acting antiviral regimens should not be used in patients with evidence of liver decompensation. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Decompensated' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Patients with decompensated cirrhosis'.)

Recurrence after liver transplantation — Recurrence of HCV occurs in more than 95 percent of patients after liver transplantation. Disease progression in this setting is more rapid, and complications are more frequent than in immunocompetent patients with HCV infection [27]. Disease progression correlates with HCV RNA levels at the time of transplantation, the age of the organ donor, and the degree of immunosuppression in the post-transplant period. Studies are demonstrating high SVR rates with DAA regimens in transplant populations [56,57]. All patients with post liver transplant recurrence of HCV should be considered for treatment with new DAA regimens. (See "Recurrence of hepatitis C virus infection following liver transplantation", section on 'Treatment of recurrence'.)

Extrahepatic manifestations of HCV infection — Successful eradication of the virus results in improvement in extrahepatic manifestations in most patients, thus those who have serious complications of HCV infection, such as essential mixed cryoglobulinemia and glomerulonephritis should be prioritized for treatment. However, among patients with severe vasculitic manifestations (eg, glomerulonephritis, cutaneous ulcers, and progressive neuropathy), immunosuppressive therapy may also be warranted and potential drug interactions should be evaluated. (See "Treatment of the mixed cryoglobulinemia syndrome", section on 'Initiation of HCV therapy' and "Treatment of chronic hepatitis C infection in adults with renal impairment", section on 'Timing of treatment'.)

In addition, some extrahepatic manifestations warrant additional management beyond antiviral therapy, such as management of iron overload in porphyria cutanea tarda. (See "Extrahepatic manifestations of hepatitis C virus infection" and "Treatment of the mixed cryoglobulinemia syndrome" and "Extrahepatic manifestations of hepatitis C virus infection", section on 'Porphyria cutanea tarda'.)

Kidney disease — Renal diseases commonly associated with HCV are mixed cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, nephrotic syndrome, and polyarteritis nodosa. Achieving SVR has a beneficial effect on the kidney disease in most, but not all, patients. Patient and regimen selection for antiviral therapy in the setting of renal impairment is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with renal impairment".)

HIV coinfection — Patients with HIV co-infection have an accelerated rate of progression of HCV and thus should be prioritized for treatment. Although studies with peginterferon and ribavirin therapy suggested that HIV/HCV co-infected patients had lower response rates compared with HCV monoinfected patients, SVR rates with regimens that contain a direct-acting antiviral appear to be comparable and result in high rates of cure in co-infected patients. The potential for drug interactions with antiretrovirals is a major consideration when selecting HCV antiviral regimens for co-infected patients. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'HIV-HCV coinfection' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'HIV and HCV coinfection'.)

HBV coinfection — Because reactivation of HBV infection, in some cases with fulminant hepatitis, has been reported in patients receiving DAA therapy [60,61], all patients should undergo testing for HBV coinfection prior to initiation of therapy. (See 'Evaluation for conditions that might affect therapy' above.)

In a systematic review of observational studies that evaluated patients with HBV infection undergoing HCV antiviral therapy, HBV reactivation (HBV DNA increase of ≥2 log or to >100 international units/mL if initially undetectable) was reported in 24 percent of 242 patients with chronic HBV infection (positive HBV surface antigen [HBsAg]), and 9 percent experienced HBV-related hepatitis   Among 1379 patients with resolved HBV infection (positive HBV core antibody [HBcAb] but negative HBsAg), reactivation occurred in 1.4 percent, and none had reactivation-associated hepatitis. In another study of 29 cases of HBV reactivation, two were fatal and one patient required liver transplant, reactivation occurred at an average of 53 days into DAA treatment, and it was not associated with a particular HCV genotype or DAA regimen [60,62].

Prior to initiating DAA therapy, antiviral therapy for HBV should be initiated for coinfected patients who meet criteria for HBV treatment. Otherwise, those who have evidence of HBV infection (ie, with positive HBcAb and negative HBV surface antibody [HBsAb]) should be monitored for HBV reactivation during HCV treatment. (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy' and "Overview of the management of chronic hepatitis C virus infection", section on 'Other monitoring'.)

The mechanism behind HBV reactivation with HCV treatment is unknown. One theory is that HCV infection results in a host innate immune response that impacts control of HBV replication and is interrupted with DAA therapy [63].

Active drug use — We agree with the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) guideline recommendation that treatment should not be withheld from those who currently use illicit drugs or those who are in an opioid agonist (eg, methadone or buprenorphine) treatment program, provided that they wish to be treated, are willing and able to maintain close monitoring, and practice contraception [2]. Barriers to HCV treatment among individuals who are actively using illicit drugs have included concerns about adherence, comorbid psychiatric conditions that might be exacerbated by an interferon-based regimen, and the risk of reinfection [64,65].

Nevertheless, successful treatment of patients with injection drug use (IDU) has been reported in several studies, even when they have not been abstinent from continued drug use or are receiving pharmacologic treatments for drug dependency (eg, methadone or buprenorphine) [66-68]. Studies that have evaluated for reinfection following successful treatment in patients with IDU are limited in size and duration of follow-up, but do not suggest a high rate of reinfection [67,69].

Furthermore, an additional benefit of achieving SVR in an individual with active IDU is a decreased risk of that individual transmitting HCV to others, which has the potential for positive public health consequences.

In general, management decisions for patients with active IDU are similar to those for the general HCV-infected population. Additionally, an important adjunct to antiviral treatment is continued support from drug abuse and psychiatric counseling services. (See "Pharmacotherapy for opioid use disorder" and "Clinical assessment of substance use disorders".)

Ongoing alcohol use — Alcohol is an important cofactor in HCV disease progression, and the amount of alcohol that is safe during treatment is unknown. While a history of alcohol abuse is not an absolute contraindication to treatment, continued alcohol use decreases the response to interferon-based therapy, accelerates disease progression, and increases the risk of HCC [70,71]. Patients should be encouraged to abstain from alcohol. There are limited data on the effectiveness of direct-acting antiviral-based regimens in patients who continue to drink.

In patients who continue to drink alcohol, efforts to treat the alcohol abuse should accompany antiviral treatment. (See "Hepatitis C and alcohol" and "Psychosocial treatment of alcohol use disorder".)

Older adults — We follow the same general principles in deciding which older patients with HCV to treat and when as we do for the general population. (See 'Deciding when to treat' above.)

Prior studies of peginterferon and ribavirin for HCV had revealed lower SVR rates in older patients [72]. Older patients often have comorbid illnesses and may be less tolerant of the side effects of interferon and ribavirin-based treatment, such as anemia. However, the all-oral treatments have not shown any evidence of decline in efficacy with increasing age.

Children — The management of children with hepatitis C virus infection is discussed elsewhere. No data on the use of the major direct-acting antiviral regimens in children are available. (See "Hepatitis C virus infection in children", section on 'Management of chronic HCV'.)

PROPORTION OF PATIENTS WHO RECEIVE TREATMENT — With the introduction of potent, well-tolerated direct-acting antivirals that obviate the need for interferon in many patients, the hope is that more HCV-infected patients will be offered, accept, and tolerate treatment in locations with ready access to these agents. This is in contrast to the suboptimal treatment uptake of peginterferon and ribavirin.

In the era of peginterferon and ribavirin combination therapy, the proportion of patients with chronic HCV infection who were treated was not accurately determined, but the reported rate ranged from 12 to 28 percent [1,73,74].

Of 327 patients referred to a liver clinic in a metropolitan area, 83 (28 percent) were ultimately treated [73]. The most common reasons for a lack of treatment were failure to adhere to evaluation procedures (37 percent), medical or psychiatric contraindications (34 percent), patient preferences (11 percent), absence of HCV RNA (10 percent), and normal liver enzymes (5 percent).

Among 134,934 HCV-infected United States veterans, only 12 percent were treated with peginterferon and ribavirin [74]. Furthermore, of those on treatment who were followed for more than one year, only 23 percent completed a full 48-week course of treatment. Noncompletion was significantly associated with baseline anemia and depression.

Other risk factors for nontreatment include relatively inexperienced providers, older age, single patients, hepatic dysfunction, genotype 1, African American race with genotype 1, and anemia [1].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

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 topic (see "Patient education: Hepatitis C (The Basics)")

Beyond the Basics topic (see "Patient education: Hepatitis C (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Patients who achieve a sustained virologic response (SVR) following antiviral therapy (negative HCV RNA 12 weeks later) are considered cured, as studies show that 99 percent of such patients remain free of detectable virus during long term follow up. Curing HCV prior to the development of decompensated cirrhosis results in decreased all-cause mortality, liver-related death, need for liver transplantation, hepatocellular carcinoma rates, and liver-related complications. A cure of HCV also prevents the development of extrahepatic manifestations, which can be life threatening. (See 'Rationale for treatment' above.)

All patients should be considered for treatment. The urgency with which to treat chronic HCV infection and which regimen to use is based upon several factors, including the infecting genotype (and for some regimens, pre-existing viral mutations), natural history and stage of the disease, availability of all oral antiviral therapies, expected efficacy of therapy, prior treatment history, and potential side effects of the appropriate treatment regimen. Evaluation prior to management decisions should focus on these factors. (See 'Evaluation to guide management decisions' above.)

A focused clinical exam, routine laboratory tests, and noninvasive markers of fibrosis (such as the FibroSure test or ultrasound-based transient elastography) can be used to assess the severity of liver disease. We generally limit liver biopsy to select HCV-infected patients, including those with a liver transplant or other causes of liver disease (such as autoimmune or drug induced liver disease). (See 'Assessment of fibrosis stage' above and "Noninvasive assessment of hepatic fibrosis: Overview of serologic and radiographic tests".)

With the availability of direct-acting antivirals, treatment regimens that achieve very high SVR rates, have more favorable adverse effect profiles and greater ease of administration than earlier regimens, and have relatively short treatment durations are possible for many patients. Candidacy for treatment is limited mainly by the presence of contraindications to the available regimens. (See 'Deciding when to treat' above and 'Contraindications/precautions with anti-HCV agents' above.)

In resource-constrained settings, it may be reasonable to prioritize treatment for patients who are expected to benefit the most in the short term. These include those with advanced fibrosis or cirrhosis, transplant consideration, severe extrahepatic manifestations, high risk for fibrosis progression, symptomatic disease, and high potential for transmission. (See 'Deciding when to treat' above and 'Bridging fibrosis and compensated cirrhosis' above and 'Extrahepatic manifestations of HCV infection' above and 'HIV coinfection' above.)

Active substance abuse is not a contraindication to antiviral treatment for patients who are willing to undergo treatment and monitoring. Ongoing support from drug/alcohol abuse and psychiatric counseling services is an important adjunct to antiviral therapy. (See 'Active drug use' above and 'Ongoing alcohol use' above.)

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