Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection

INTRODUCTION — Direct-acting antiviral (DAA) regimens to treat chronic hepatitis C (HCV) infection result in extremely high cure rates with minimal side effects. With their widespread availability, the vast majority of patients with chronic HCV infection can be cured with treatment. In light of this potential and the substantial morbidity of chronic HCV infection, the World Health Organization (WHO) global hepatitis strategy includes a goal of reducing new infections by 90 percent and deaths by 65 percent by 2030 [1].

This topic will review the benefits of antiviral therapy and the evaluation of patients prior to antiviral therapy. 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 "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults".)

●(See "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

BENEFITS OF 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].

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 an SVR remain free of detectable virus during long-term follow-up [3].

Safety and virologic efficacy of treatment — In locations where combination direct-acting antiviral (DAA) regimens are available, these highly effective, well-tolerated, interferon-free regimens can result in sustained virologic response (SVR) in over 90 percent of patients with HCV [4]. 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 "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

Reduction in mortality and liver-related morbidity — 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 (HCC) rates, and liver-related complications [5-12]. As an example, in a systematic review that included over 30,000 patients with HCV infection, achievement of SVR was independently associated with a decreased mortality after a median follow-up of 5.4 years (adjusted hazard ratio [HR] 0.50, 95% CI 0.37-0.67) [5]. For individuals without cirrhosis who have achieved SVR, the risk of HCC is likely negligible in the absence of other risk factors [13].

Even after advanced fibrosis (bridging fibrosis or cirrhosis) has already developed, achieving SVR through successful antiviral treatment can dramatically reduce HCV-related morbidity and mortality, including the risk of HCC [5,14-18]. 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 [16]. 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). Similarly, in a large observational study that included over 15,000 patients with HCV infection and advanced fibrosis, SVR was independently associated with reduced mortality (HR 0.26, 95% CI 0.22-0.31) [17].

Nevertheless, some data suggest that mortality rates among individuals who have been cured of HCV infection remain higher than among the general population, even after adjustment for extent of chronic liver disease; this difference may be related to associated comorbidities, including substance and alcohol use disorder [19].

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 [20]. 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 cardiovascular disease, diabetes mellitus, and insulin resistance, and successful treatment of HCV is associated with a reduced risk of these conditions [21,22]. As an example, in a retrospective study of United States veterans with HCV infections, the incidence of cardiovascular events was lower among patients who had received DAA treatment compared with no treatment (16.3 versus 30.4 events per 1000 patient-years) [22]. (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 an SVR following antiviral therapy [23-32].

As an example, a multicenter observational cohort study of 1601 patients treated with DAAs reported small but clinically meaningful improvements in fatigue, sleep, abdominal pain, and functional well-being, which were sustained at 12 months after therapy [32]. Patients with cirrhosis and Model for End-Stage Liver Disease (MELD) score ≥12 achieved the greatest benefit in functional well-being.

Decreased transmission risk — Increasing evidence suggests that expanding HCV antiviral treatment among specific populations can reduce the burden of ongoing transmission and make progress toward elimination of HCV infection in those populations.

As an example, in a trial of over 3500 men who have sex with men (MSM) who were enrolled in the Swiss HIV cohort, all participants were tested for HCV RNA at the outset, all HCV RNA-positive participants were offered treatment over an eight-month period, and all participants were tested again for HCV RNA over the next eight months [33,34]. Of the 177 participants who were HCV RNA positive on initial screening, 85 percent underwent treatment and achieved SVR. Two years after the intervention, the incidence of HCV among the cohort had decreased by 77 percent, from 0.53 to 0.12 infections per 100 person-years.

Studies performed in prisons have also reported decreased incidence of HCV infection following scale up of antiviral treatment programs in those settings [35].

Other data highlight decreases in HCV infection prevalence following augmented screening and treatment efforts that are not fully explained by the proportion of individuals treated. In the country of Georgia, which had initiated an HCV-elimination program in 2015 that resulted in the treatment of approximately 51 percent of the population with chronic HCV infection by 2021, the prevalence of HCV viremia had decreased over that time by 67 percent, from 5.4 to 1.8 percent [36].

Similarly, in cohort studies of individuals who use injection drugs, expanded access to HCV antiviral therapy has been associated with decreasing population rates of HCV viremia [37-39].

EVALUATION — All patients should be considered for antiviral therapy. Evaluation of patients with chronic HCV infection focuses on assessing factors that inform antiviral selection and identifying complications and common comorbidities that may impact prognosis and other non-antiviral management decisions.

For individuals who have not been previously treated for HCV infection, the evaluation to inform antiviral selection can be limited and should not be a barrier to treatment access. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Limited pretreatment evaluation'.)

History of prior treatment — Clinicians should ask patients 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 the current HCV infection are considered treatment-naïve. Individuals who were successfully treated for HCV infection in the past (eg, had documented SVR) but had subsequent HCV reinfection can be treated with a regimen used for initial therapy in treatment-naïve individuals. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults".)

For patients with relapsed infection following antiviral therapy (ie, treatment-experienced patients), it is important to clarify what the regimen was, as the approach to regimen selection is different for relapse following peginterferon and ribavirin alone compared with relapse after a direct-acting antiviral (DAA) regimen. (See "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

Assessment of fibrosis stage — The presence of advanced fibrosis (bridging fibrosis or cirrhosis) helps inform antiviral regimen selection in some cases; it also informs general prognosis and need for ongoing evaluation after antiviral therapy. 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).

History, examination, and basic laboratory tests — The history should include questions regarding nonspecific symptoms (eg, anorexia, weight loss, weakness) or specific complications (eg, a history of jaundice, ascites, hematemesis, and mental status changes) that could suggest underlying cirrhosis. History should also evaluate factors associated with accelerated disease progression, including alcohol use, metabolic complications associated with fatty liver, and menopausal status (in females). (See "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Factors associated with disease progression'.)

A directed physical examination should assess for signs consistent with cirrhosis (eg, spider angiomata, palmar erythema, gynecomastia, firm liver on palpation, and splenomegaly). However, clinicians should be aware that absence of any of these findings does not rule out the possibility of underlying cirrhosis. (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'.)

Noninvasive tests for fibrosis — 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 [40]. A detailed discussion on noninvasive tests to assess hepatic fibrosis is found elsewhere. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

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 (HCC), 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 "Surveillance for hepatocellular carcinoma in adults" and "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

Minimal role of liver biopsy — We do not routinely perform liver biopsy in patients with chronic HCV infection. Liver biopsy 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 widely available, and as treatment for HCV is less toxic and more effective than before, there is less need to precisely stage the patient’s liver disease through biopsy. We perform liver biopsy only in selected 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 of liver disease is in doubt.

Limitations of liver biopsy include [41,42]:

●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.

HCV genotype in selected cases — Commonly used regimens are pangenotypic (eg, they are effective and used for the same duration regardless of HCV genotype), and so knowledge of the HCV genotype has become less crucial in making treatment decisions. We do not routinely check genotype in patients who undergoing initial treatment for HCV infection and have no known cirrhosis, although some insurers may require it before covering the medications. We continue to check genotype in other patient populations (eg, those with known cirrhosis or relapse after antiviral treatment), among whom genotype is still relevant for treatment decisions with certain regimens. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

The HCV family of viruses is extremely heterogeneous, and at least six genotypes and numerous subtypes have been identified [43]. A variety of methods are available to identify genotypes, and some methods also identify the subtype. Currently, only genotype (not subtype) is used in making clinical decisions regarding treatment. (See "Characteristics of the hepatitis C virus", section on 'Genotypes'.)

In certain situations, testing for pre-existing resistance-associated substitutions (RASs) can be helpful to guide antiviral selection. As an example, patients with genotype 3 infection who have cirrhosis or prior treatment failure should be tested for NS5A RASs if sofosbuvir-velpatasvir is being considered. The presence of RASs impacts the regimen duration and/or whether ribavirin should be added. This is discussed in detail elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Antiviral regimen selection' and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults", section on 'Limited role for resistance testing'.)

Evaluation for comorbidities or conditions that might affect therapy — Prior to initiating antiviral therapy, an 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, with blood urea nitrogen (BUN), creatinine, and urinalysis

●Complete blood count and differential

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

●Extrahepatic manifestations of HCV infection (see 'Kidney disease and other 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) (see 'HBV coinfection' below)

●Presence of severe comorbidity (eg, cardiac disease)

●Potential for drug interactions (see 'Precautions with anti-HCV agents' below)

●Pregnancy test (for females of childbearing potential)

If ribavirin is used in patients who have potential to conceive a child (female or male), a contraceptive plan should be assessed. (See 'Ribavirin' below.)

DECIDING WHEN TO TREAT — Contemporary antiviral therapy is well tolerated and highly effective, and a cure of HCV infection results in improved survival, reduced morbidity, and higher quality of life in the vast majority of patients (see 'Benefits of treatment' above). Thus, 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 exception is patients with limited life expectancy (<12 months) due to non-related conditions, in whom the absolute benefits of curing HCV are limited. Potential drug interactions or decompensated liver disease may limit antiviral options but are not contraindications to therapy. (See 'Precautions with anti-HCV agents' below.)

Active drug use is not a contraindication to antiviral therapy, which can be successfully completed in that setting. (See 'Active drug use' 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 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.

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

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.

Direct-acting antivirals — There are generally few contraindications or precautions with the use of direct-acting antiviral (DAA) agents.

●Drug interactions – The main precaution with DAAs are drug interactions; these are more significant for regimens that contain HCV protease inhibitors (eg, simeprevir, paritaprevir, grazoprevir) but affect use of all DAA agents. Potential drug interactions with specific regimens are discussed in detail elsewhere and can be evaluated through the drug interactions program included with UpToDate. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

●Decompensated cirrhosis and protease inhibitor-containing regimens – Additionally, for patients with decompensated cirrhosis (Child-Pugh classes B and C), pibrentasvir-glecaprevir, sofosbuvir-velpatasvir-voxilaprevir, elbasvir-grazoprevir, simeprevir, and ombitasvir-paritaprevir-ritonavir-based regimens should be avoided. The US Food and Drug Administration has reiterated this caution and highlighted cases of worsening liver function or liver failure in patients with advanced liver disease who were treated with one of these agents; in some cases, the severity of the underlying liver disease was not initially recognized [44].

Some of these patients were not initially known to have decompensated cirrhosis. Thus, some experts, including some UpToDate contributors, perform endoscopy in patients with cirrhosis if they have platelet count <150,000/microL or a transient elastography score >20 kPa prior to antiviral treatment and avoid protease inhibitor-containing regimens in those with evidence of any esophageal varices. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Protease inhibitors and hepatic decompensation'.)

Ribavirin — Ribavirin is usually not used for HCV infection but may occasionally be part of an antiviral regimen in selected patients.

●Risk of hemolysis – The main adverse effect is hemolysis. This effect is generally only clinically relevant among patients with pre-existing anemia (eg, hemoglobin <12 g/dL for males and <11 g/dL for females), 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].

Ribavirin should also be only used with caution, dose reduction, and frequent monitoring in patients with hemoglobinopathies.

●Dose adjustment for kidney impairment – Ribavirin is excreted renally and may accumulate to toxic levels in patients with impaired kidney function or on hemodialysis. Extreme caution, significant dose reductions and careful monitoring are warranted when ribavirin is used in such patients. (See 'Kidney disease and other extrahepatic manifestations of HCV infection' below.)

●Adverse fetal affects – Ribavirin is contraindicated in pregnant females because of significant teratogenic and embryocidal effects. It also should not be used in individuals who have the potential to conceive a child (male or female) and cannot or will not use contraception during treatment and for six (for males) or nine (for females) months afterwards.

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

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".)

Active drug use — We recommend antiviral therapy for chronic HCV infection regardless of active drug use, as long as patients are amenable to treatment [2]. Barriers to HCV treatment among individuals who are actively using drugs have included concerns about adherence, comorbid psychiatric conditions or unstable social situations, and the risk of reinfection [46,47].

Nevertheless, successful treatment of patients with injection drug use (IDU) has been reported in multiple studies, even in the setting of recent or active drug use and opioid substitution therapy (eg, methadone or buprenorphine) [48-55]. As an example, in a systematic review, the pooled sustained virologic response (SVR) rates were 90 percent among 1700 patients on opioid substitution therapy and 88 percent among 540 patients who were actively using injection drugs [53].

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 [49,56,57].

Furthermore, an additional benefit of achieving SVR in an individual with active IDU is a decreased risk HCV transmission, which has the potential for positive public health consequences. (See 'Decreased transmission risk' above.)

Antiviral treatment for chronic HCV infection among patients with active drug use is the same as in the general population. Additionally, an important adjunct to antiviral treatment is continued support from substance use disorder and psychiatric counseling services. (See "Opioid use disorder: Pharmacologic management" and "Substance use disorders: Clinical assessment".)

Decompensated cirrhosis — Antiviral therapy in patients with decompensated cirrhosis (eg, Child-Pugh class B or C (table 1), with ascites, with hepatic encephalopathy, or with gastroesophageal variceal hemorrhage) should only be undertaken by or in close consultation with an expert in the management of such patients. Antiviral therapy in such patients needs to take into consideration candidacy for transplant, timing of therapy related to potential transplant, and need for close monitoring. Furthermore, certain antiviral agents are contraindicated in the setting of decompensated cirrhosis because of increased drug levels or concern for worsened hepatic decompensation. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Decompensated cirrhosis (Child-Pugh class B or C)' and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults", section on 'Patients with decompensated cirrhosis'.)

As in the general population, successful treatment of HCV in patients with decompensated cirrhosis is associated with decreases in all-cause mortality, liver-related mortality, transplantation, and hepatocellular carcinoma (HCC) [58]. However, not all patients with decompensated cirrhosis benefit substantially from treatment. Although most achieve SVR with antiviral therapy, SVR rates are somewhat lower than in patients without cirrhosis, particularly among those with the most advanced liver disease (ie, Child-Pugh class C).

Furthermore, SVR does not necessarily reverse the complications of liver disease at that stage, so substantial liver-related morbidity persists despite SVR [59,60]. As an example, in a study of 667 patients with advanced cirrhosis (MELD score >10; 60 percent with Child-Pugh class B or C) who were treated with contemporary direct-acting antiviral (DAA) regimens, the overall SVR rate was 91 percent; ascites, low albumin level, and Child-Pugh class B or C were among the factors associated with failure to achieve SVR [59]. Of 158 patients with long-term follow-up, only 29 percent achieved ≥3-point decrease in the MELD score and only 25 percent had a MELD score reduction to <10.

Hepatocellular carcinoma — For patients with chronic HCV and hepatocellular carcinoma (HCC), the approach to and timing of antiviral treatment depend on transplant candidacy.

●For those who are candidates for liver transplantation, this is discussed elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Deciding to treat before or after transplant'.)

●For patients with HCC who are not candidates for liver transplantation, the approach to antiviral therapy depends on the planned treatment for HCC. Generally, we administer antiviral therapy soon after completion of treatment with modalities such as radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE). Most oncologists prefer to complete antiviral therapy prior to administering systemic chemotherapy, such as sorafenib or other chemotherapeutic agents. In patients with far-advanced HCC or advanced decompensated cirrhosis, palliative care is often the only option. In these circumstances, when no HCC treatment is planned, antiviral therapy is unlikely to benefit the patient and should not be administered.

Antiviral selection is the same as that in the general population and is discussed in detail elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)

As in other populations, successful treatment of HCV can result in reduced morbidity and mortality in patients with HCC [61,62]. In a meta-analysis of observational studies of patients who underwent resection or loco-regional therapy for HCV-associated HCC, SVR following interferon-based therapy was associated with improved overall survival and progression-free survival [61]. Successful DAA-based therapy was similarly associated with survival in a retrospective study of 800 patients (hazard ratio 0.54, 95% CI 0.33-0.90) [63]. Since clinical trials of HCV therapy have largely excluded patients with HCC, most data on efficacy of DAA-based therapy in this population are from retrospective studies, which generally suggest a lower SVR rate than in the general population [64-67], although the mechanism for this is not well understood. In a systematic review of 49 studies, the pooled SVR rate was 89.6 percent among 3300 patients with HCC compared with 93.3 percent among 35,700 patients without HCC [67]. SVR rates were especially low among patients who had active or residual HCC (73 percent compared with 93 percent among those with inactive or ablated HCC).

Although some observational studies have suggested an unexpectedly high risk of HCC recurrence following DAA therapy [68-71], other large studies have not [72-75]. In a meta-analysis of 17 studies evaluating HCC recurrence following HCV treatment, the rate of recurrence was not different with DAA-based regimens compared with interferon-based regimens [76]. Given that there is no clear, consistent evidence supporting an increased rate of HCC recurrence following DAA therapy, this should not be a reason to withhold antiviral therapy in patients with HCC.

Recurrence after liver transplantation — In individuals with chronic HCV infection who do not undergo successful antiviral treatment prior to liver transplant, HCV recurs in almost all patients. The management of HCV infection in liver transplant recipients is discussed in detail elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Post-transplant antiviral therapy'.)

Kidney disease and other extrahepatic manifestations of HCV infection — Kidney diseases commonly associated with HCV are mixed cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, nephrotic syndrome, and polyarteritis nodosa. Successful eradication of the HCV results in improvement in extrahepatic manifestations, including kidney disease in most patients.

The selection of HCV antiviral regimens for patients with kidney disease is largely the same as that among patients without it. Antiviral treatment in such patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)

Among patients with severe vasculitic manifestations (eg, glomerulonephritis, cutaneous ulcers, and progressive neuropathy), immunosuppressive therapy may be warranted in addition to antiviral therapy, and potential drug interactions should be evaluated. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment", section on 'Timing of treatment' and "Mixed cryoglobulinemia syndrome: Treatment and prognosis", section on 'Hepatitis C infection'.)

Some extrahepatic manifestations warrant other management beyond antiviral therapy, such as management of iron overload in porphyria cutanea tarda. (See "Extrahepatic manifestations of hepatitis C virus infection" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".)

HIV coinfection — Patients with HIV coinfection have an accelerated rate of progression of HCV. SVR rates with regimens that contain a DAA result in high rates of HCV cure in patients with coinfection, similar to those in patients with HCV monoinfection. The potential for drug interactions with antiretrovirals is a major consideration when selecting HCV antiviral regimens for such patients. (See "Treatment of chronic hepatitis C virus infection in the patient with HIV", section on 'Potential drug interactions with ART'.)

HBV coinfection — Because reactivation of HBV infection, in some cases with fulminant hepatitis, has been reported in patients receiving DAA therapy [77-79], all patients should undergo testing for HBV coinfection prior to initiation of therapy. (See 'Evaluation for comorbidities or conditions that might affect therapy' above.)

Patients with evidence of prior or current HBV infection (ie, those with positive HBV core antibody [HBcAb] with or without a positive HBV surface antigen [HBsAg]) who are not on HBV antiviral therapy warrant specific monitoring, and in some cases treatment, because of the risk of HBV reactivation during HCV treatment. This is discussed in detail elsewhere. (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 'Additional monitoring for HBV coinfection'.)

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 [77,80].

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 [81].

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 use disorder is not an absolute contraindication to treatment, continued alcohol use accelerates disease progression and increases the risk of HCC [82,83]. Patients with chronic HCV infection should be encouraged to abstain from alcohol. There are limited data on the effectiveness of DAA-based regimens in patients who drink alcohol.

In patients who continue to drink alcohol, efforts to treat alcohol use disorder should accompany antiviral treatment. (See "Alcohol use disorder: Treatment overview".)

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.)

Several retrospective studies have suggested that combination DAA regimens are highly effective in older adults, as in the general population [84-88]. However, older adults (eg, those >65 years old) were more likely to have significant drug interactions with DAA regimens and, in some studies, had a higher likelihood of adverse effects.

This is in contrast to prior studies of peginterferon and ribavirin for HCV infection, which had revealed lower SVR rates in older patients [89].

Children — The management of children with HCV infection is discussed elsewhere. (See "Hepatitis C virus infection in children", section on 'Management of chronic hepatitis C virus'.)

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" and "Society guideline links: Hepatitis C infection in solid organ transplant candidates and recipients".)

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 5^th to 6^th 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 10^th to 12^th 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

●Benefits of therapy – Patients who achieve a sustained virologic response (SVR) following antiviral therapy (negative hepatitis C virus [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 'Benefits of treatment' above.)

●Considerations prior to treatment – We recommend direct-acting antiviral (DAA) therapy for all patients with chronic HCV infection (Grade 1A). Evaluation of patients with chronic HCV infection focuses on assessing factors that inform antiviral selection and identifying complications and common comorbidities that may impact prognosis and other non-antiviral management decisions. (See 'Evaluation' above.)

•Assessment of liver disease – 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 patients with HCV infection, 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 tests and imaging examinations".)

•Limited genotype testing – With pangenotypic regimens, HCV genotype determination is less crucial to treatment decisions. We check genotype in patients with known cirrhosis or relapse after prior antiviral therapy but do not routinely check it in patients undergoing initial antiviral therapy unless required by payers. (See 'HCV genotype in selected cases' above.)

•Other evaluation – Assessing for renal function, substance use, extrahepatic manifestations, HIV or HBV coinfection, pregnancy, and potential for drug interactions can help identify other patient factors that may impact treatment decisions. (See 'Evaluation for comorbidities or conditions that might affect therapy' above and 'Special situations' above.)

●Priority populations for treatment – 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.)

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