Pretreatment Assessment in Adults With Chronic Hepatitis C Virus Infection

Purpose of This Guideline

Date of current publication: October 6, 2022 Lead author: Christine A. Kerr, MD Writing group: Joshua S. Aron, MD; David E. Bernstein, MD; Colleen Flanigan, RN, MS; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD Committee: Hepatitis C Virus (HCV) Guideline Committee Date of original publication: October 6, 2022

This guideline on pretreatment assessment of patients with chronic hepatitis C virus (HCV) was developed by the New York State Department of Health AIDS Institute (NYSDOH AI) to guide primary care providers and other practitioners in New York State in all aspects of treating and curing patients with chronic HCV. The guideline aims to achieve the following goals:

• Provide evidence-based treatment guidelines to New York State clinicians to increase the number of New York State residents with chronic HCV who are treated and cured.
• Provide guidance to clinicians on key pretreatment assessment criteria to ensure that HCV medications are prescribed safely and correctly and that all patients receive the highest quality of care.
• Provide evidence-based clinical recommendations to support the goals of the New York State Hepatitis C Elimination Plan (NY Cures HepC).

Medical History and Physical Examination

Table

Medical History and Physical Examination Clinicians should assess all patients with a confirmed diagnosis of chronic HCV infection, defined as a positive HCV surface antibody test result and detectable HCV RNA, for treatment. (A1)

With few exceptions, nonpregnant patients with confirmed HCV are candidates for treatment [EASL 2020; Ghany and Morgan 2020]. Treatment of HCV infection reduces all-cause mortality, regardless of disease stage [Simmons, et al. 2015]. Patients who are not candidates for treatment with DAAs are those with a life expectancy of fewer than 12 months or for whom treatment or liver transplantation would not improve symptoms or prognosis [AASLD/IDSA 2021]. For recommendations for pregnant patients with chronic HCV and those who become pregnant while taking antiviral therapy for chronic HCV, see the NYSDOH AI guideline Treatment of Chronic Hepatitis C Virus Infection in Adults > HCV Testing and Management in Pregnant Adults.

Screening for mental health and substance use disorders and providing treatment or referral as needed is essential but is not a reason to defer treatment. The approach to treating HCV infection in patients with mental health or substance use disorders is the same as for other patients with HCV. Patients with active substance use or mental health disorders can and should be successfully treated, although additional support for adherence, follow-up, and harm reduction may be necessary [Granozzi, et al. 2021; Hajarizadeh, et al. 2020; Torrens, et al. 2020; Gountas, et al. 2018; Sackey, et al. 2018; Tsui, et al. 2016].

Key elements of medical history and physical examination: Table 1, below, lists components of the patient history and physical examination that apply specifically to pretreatment assessment of patients with chronic HCV.

Table

HCV treatment may be deferred during pregnancy [a]. Clinician could discuss the possibility of clinical trial participation and refer patient as appropriate (see Clinical Trials.gov).

Mental Health, Substance Use, and Adherence

Mental health: Mental health disorders are not contraindications to treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs). Strategies to overcome mental health-related barriers to successful HCV treatment include counseling, education, and referral to psychiatry and behavioral health services. Patients with mental health disorders may need increased attention to management of adverse effects and coordination of care during HCV treatment. An integrated care model in which mental health care providers provide HCV treatment and risk-reduction counseling has been effective [Sackey, et al. 2018; Groessl, et al. 2013]. Few data are currently available regarding the effect of an existing psychiatric diagnosis on patient adherence to any oral HCV treatment regimen.

With interferon-free regimens, depression is no longer a common adverse effect of HCV treatment. However, antidepressant and antipsychotic drug-drug interactions have been reported with DAAs, so monitoring is necessary; see Table 1: Key Elements of Patient History and Physical Examination for resources for identifying drug-drug interactions. Similarly, it is important to be aware of patient use of nonprescription medication. St. John’s wort (Hypericum perforatum), an herbal self-remedy for depression, may decrease the effectiveness of DAA therapy [FDA 2019; FDA 2017; FDA 2016].

Substance use: A history of or active use of alcohol, tobacco, marijuana, and other substances is not a contraindication to HCV treatment unless the drug or alcohol use significantly interferes with adherence to medications or appointments. Studies have demonstrated that individuals who are receiving substance use treatment can be effectively treated for chronic HCV infection [Coffin, et al. 2019; Grebely, et al. 2018; Tsui, et al. 2016].

Once a patient’s alcohol consumption habits have been assessed, counseling may help the patient reduce or eliminate alcohol use. It is important for patients with HCV who use alcohol to be made aware of the effects of alcohol on the course of HCV disease. Alcohol use has been associated with increased rates of liver disease progression and hepatocellular carcinoma (HCC) in people with chronic HCV. Moderate alcohol intake is associated with an increased risk of fibrosis progression [Westin, et al. 2002], and light-to-moderate alcohol intake is associated with an increased risk of HCC in patients with compensated cirrhosis [Vandenbulcke, et al. 2016]. There is no consensus on a safe level of alcohol ingestion for people with chronic HCV.

Barriers to adherence: The purpose of the adherence assessment is to optimize support, not to deny access to treatment. After the pretreatment assessment and before treatment initiation, a plan can be developed with the patient to address potential barriers and put support resources in place [Al-Khazraji, et al. 2020]. Support groups and peer programs can promote increased patient engagement.

Table

The purpose of the adherence assessment is to optimize support, not to deny access to treatment. Though HCV treatment regimens are relatively short, assessing a patient’s readiness for treatment and ability to adhere to a medication regimen and (more...)

Baseline Laboratory Testing

Hepatitis C virus (HCV) genotype may influence the choice of direct-acting antiviral regimen and treatment duration in patients with chronic HCV; however, given the availability of pangenotypic regimens, genotyping is not required to initiate treatment in treatment-naive patients. Baseline genotyping may also help in understanding treatment options if a sustained viral response is not attained because it may help distinguish reinfection from virologic relapse.

There are 6 common HCV genotypes [Chevaliez and Pawlotsky 2007]. Based on data from 8,140 participants (≥18 years old) in the U.S.-based Chronic Hepatitis Cohort Study, genotype 1 was most common (75.4%), followed by genotypes 2 (12.6%) and 3 (10.2%); genotypes 4 (1.5%) and 6 (0.3%) were less prevalent [Gordon, et al. 2019]. The single participant with genotype 5 was excluded from the study. Distribution varied significantly by geography and demographics; birth decade, race, and study site were independently associated with genotype distribution (P < 0.01).

Additional baseline laboratory testing essential to pre-HCV treatment is listed in Table 2, below.

Table

Low platelet count (<140,000 platelets/µL) suggests cirrhosis and portal hypertension [Ebell 2003; Kaul and Munoz 2000]. Anemia may necessitate choice of a regimen that does not contain ribavirin.

Fibrosis Assessment

Table

Fibrosis Assessment Clinicians should assess the degree of fibrosis in patients with chronic HCV infection to aid in determining the need for pretreatment varices and HCC screening, the duration of antiviral treatment, whether the regimen should include (more...)

Fibrosis stage predicts HCV treatment response [Ogawa, et al. 2015]. An assessment of the degree of fibrosis should be performed regardless of alanine aminotransferase (ALT) patterns because significant fibrosis may be present in patients with repeatedly normal ALT [EASL 2020]. In 1 study, approximately 50% of people with HCV born between 1945 and 1965 had severe fibrosis or cirrhosis as measured by Fibrosis-4 (FIB-4) index scoring [Klevens, et al. 2016]. It is particularly important to identify patients with bridging fibrosis or cirrhosis; these findings may influence treatment selection and duration and may dictate post-treatment follow-up, such as the need for ongoing assessment for esophageal varices, hepatic function, and surveillance monitoring for HCC [AASLD/IDSA 2021; Bruix and Sherman 2011; Garcia-Tsao, et al. 2007]. Patients known to have cirrhosis do not require repeat determination of the degree of fibrosis before treatment.

Fibrosis stage can be assessed using noninvasive modalities, such as transient elastography, aspartate aminotransferase (AST)-to-platelet ratio index (APRI), FIB-4 index, and assays of direct markers of liver fibrosis (see Table 3, below). Noninvasive modalities are well suited for rapid pretreatment assessment of chronic HCV infection in the primary care setting. Indirect serum markers use mathematical algorithms with different variables to predict fibrosis and are easily accessible in the primary care setting. Tests such as the APRI and FIB-4 index (age, AST, ALT, platelet count) appear efficacious in patients with little or no fibrosis and those with cirrhosis. However, these tests have limited ability to discriminate between intermediate stages of fibrosis [Castera, et al. 2014; Patel and Shackel 2014; Schiavon Lde, et al. 2014]. Several studies have found the FIB-4 index to predict fibrosis more accurately than the APRI [Amorim, et al. 2012; Shaikh, et al. 2009].

Liver biopsies are not routinely required but are useful for patients with highly discordant results on noninvasive testing and in patients suspected of having a second etiology for liver disease in addition to HCV infection. Liver biopsy is an important instrument for diagnosing concurrent diseases, such as metabolic nonalcoholic steatohepatitis, hemochromatosis, autoimmune primary biliary cholangitis, and autoimmune hepatitis. Although liver biopsy is safe and has a very low risk of complications, invasive procedures may be difficult to obtain in a timely fashion or unacceptably costly for uninsured patients [Seeff, et al. 2010].

An APRI calculator, FIB-4 index calculator, and other online clinical tools are available at Hepatitis C Online. Assays of direct markers of liver fibrosis measure various combinations of liver matrix components in combination with standard biochemical markers. These assays (FibroSure, FibroTest, FibroMeter, FIBROSpect II, and HepaScore) appear efficacious in patients with little or no fibrosis and those with cirrhosis, but, like the FIB-4 index and APRI, these assays have limited ability to discriminate between intermediate stages of fibrosis [Castera, et al. 2014; Patel and Shackel 2014; Schiavon Lde, et al. 2014]. These tests will provide an indication of disease progression over time and can be helpful in counseling patients who are considering treatment [Poynard, et al. 2014].

Vibration-controlled transient elastography (VCTE) measures shear wave velocity (expressed in kilopascals) and assesses a larger volume of liver parenchyma than liver biopsy. VCTE is most efficacious in F0 to F1 and F4 fibrosis but may be difficult to interpret in F2 and F3 disease [Loomba, et al. 2023; Tapper, et al. 2015; Castera, et al. 2014; Schiavon Lde, et al. 2014; Verveer, et al. 2012]. Although VCTE is approved by the U.S. Food and Drug Administration, it is not yet available in all settings and, although highly accurate, is not as cost-effective as laboratory liver fibrosis determinations [Schmid, et al. 2015]. There may also be limitations for patients with obesity [Lai and Afdhal 2019]. Other technologies, such as acoustic radiation force imaging, portal venous transit time, and magnetic resonance imaging elastography or a combination of modalities, show promise for possible future use; these procedures are not recommended at this time because of their lack of sensitivity and specificity in early fibrosis, high cost, and limited availability [EASL 2020; Agbim and Asrani 2019; Bohte, et al. 2014].

Table

Noninvasive Inexpensive

Cirrhosis Evaluation

Table

Cirrhosis Evaluation Clinicians should determine the severity of cirrhosis (A1) and refer patients with a history of decompensation or decompensated cirrhosis (CTP class B or C) to a liver disease specialist. (A3)

The Model for End-Stage Liver Disease (MELD) score (MELD calculator) or the CTP score (see Table 4, below) may be used to classify the severity of cirrhosis.

Table

Notes:

Assessment for decompensation in patients with cirrhosis can be accomplished through medical history-taking and initial laboratory testing (see Table 5, below). Decompensation is defined as a MELD score of >15 or the presence of ascites, hepatic encephalopathy, portal hypertensive bleeding, HCC, intractable pruritus, hepatopulmonary syndrome, coagulopathy, or portopulmonary hypertension [Fox and Brown 2012]. Because of the clinical complexity of the condition, patients with a history or presence of decompensated cirrhosis should be referred to a liver disease specialist.

All patients with cirrhosis should undergo an upper endoscopy to screen for the presence of esophageal varices. Patients with HCV-related bridging fibrosis or cirrhosis are at increased risk of developing primary HCC and should undergo surveillance with an ultrasound every 6 months [Shoreibah, et al. 2014; Bruix and Sherman 2011]. Alpha-fetoprotein (AFP) testing lacks adequate sensitivity and specificity for effective use in surveillance and diagnosis of HCC. Elevated AFP levels may be seen in HCV infection in the absence of HCC [EASL 2018; El-Serag and Mason 1999].

For additional risk stratification and diagnosis information, see the American Association of the Study for Liver Diseases practice guidance on portal hypertensive bleeding in cirrhosis [Garcia-Tsao, et al. 2017].

Table

CTP class B or C MELD score of >15

Renal, HAV/HBV, Metabolic, and Cardiovascular Status

Table

Renal Status Clinicians should assess CrCl in all patients with HCV. (A1)

Renal status: A patient’s renal status will influence the choice of direct-acting antiviral (DAA) regimen. Evaluation for renal disease includes assessing HCV-related causes of kidney disease, such as membranoproliferative glomerulonephritis and membranous glomerulonephritis, even if patients have other comorbidities also associated with kidney disease, such as diabetes and hypertension.

HAV and HBV immunity status: Completion of HAV and HBV vaccination is not a pretreatment mandate and is appropriate during or after treatment for chronic HCV infection. Coinfection with HCV and either HAV or HBV may result in additional liver inflammation and pathology; vaccination against HAV and HBV is important for patients with HCV to prevent acute decompensation and the sequelae of chronic superinfection by HBV [Lau and Hewlett 2005]. Approximately 40% to 50% of patients with HCV have no documented immunity against HAV or HBV [Henkle, et al. 2015].

If a patient is susceptible to both HAV and HBV infection, the combined vaccine series should be initiated.

The laboratory assessment and vaccination (as appropriate) for HAV and HBV should be performed as soon as possible, but completion of the vaccine series is not necessary before initiation of HCV treatment.

Vaccination of patients with positive anti-HBc and negative HBsAg and anti-HBs (i.e., isolated anti-HBc) test results is controversial because results are subject to several interpretations. In patients from regions where HBV infection is highly endemic or in patients with risk factors for acquiring HBV, a positive anti-HBc result may represent acute or chronic active HBV or serologic clearance of anti-HBs after a prior infection. In patients who have no risk factors or are from regions where HBV infection rates are low, a positive anti-HBc result may represent a false-positive result. In patients with isolated anti-HBc, HBV DNA testing to assess for active HBV infection is recommended, with subsequent vaccination if results are negative.

HBV reactivation and HBV-related hepatic flares, sometimes fulminant, have been reported both during and after DAA therapy in patients who were not receiving concurrent HBV treatment [Butt, et al. 2018; Belperio, et al. 2017; Wang, et al. 2017; De Monte, et al. 2016; Hayashi, et al. 2016; Sulkowski, et al. 2016; Takayama, et al. 2016; Collins, et al. 2015; Ende, et al. 2015]. Studies have demonstrated that HCV has a suppressive effect on HBV replication. For more information about the risk of HBV reactivation, see the U.S. Food and Drug Administration Drug Safety Communication.

Table

For patients with active HBV infection, treatment of both HBV and HCV should be provided in consultation with a clinician experienced in managing both HCV and HBV.

Metabolic status: Obesity does not affect the treatment of HCV with DAAs. Among individuals with HCV, both obesity and hepatic steatosis have been associated with progression of fibrosis, increased risk of advanced liver disease, and hepatocellular carcinoma (HCC) [Minami, et al. 2021; Dyal, et al. 2015; Goossens and Negro 2014; Charlton, et al. 2006; Bressler, et al. 2003].

Chronic HCV infection appears to be associated with an increased risk of developing type 2 diabetes mellitus (DM2) in predisposed individuals [Lecube, et al. 2004; Mehta, et al. 2003; Mehta, et al. 2000]. Insulin resistance (IR) and diabetes are associated with increased liver fibrosis [Patel, et al. 2011; Moucari, et al. 2008; Petta, et al. 2008], cirrhosis [Gordon, et al. 2015], and HCC [Hung, et al. 2011; Donadon, et al. 2009; Veldt, et al. 2008; Tazawa, et al. 2002] in patients with HCV. Successful treatment of chronic HCV infection may be associated with improved IR, reduced incidence of DM2, and potentially decreased DM2-associated renovascular complications [Hsu, et al. 2014; Thompson, et al. 2012; Arase, et al. 2009]. No serious drug-drug interactions have been reported with DAA agents and insulin-sensitizing or diabetic medications. However, because of the potential for improved glycemic control, diabetic patients have a higher risk for hypoglycemia during or after treatment with DAAs [Zhou, et al. 2022; Andres, et al. 2020; Yuan, et al. 2020; Li(b), et al. 2019; Li(a), et al. 2019] and should be counseled to monitor blood sugars during and after treatment.

Cardiovascular status: Although cardiovascular disease and congestive heart failure may be worsened by possible anemia associated with the use of ribavirin (RBV)-containing regimens, no such concern is noted with DAA regimens that do not contain RBV. However, drug-drug interactions between DAA medications and cardiovascular medications have been reported and may require adjustments or changes before initiation of therapy.

All Recommendations

Table

Medical History and Physical Examination Clinicians should assess all patients with a confirmed diagnosis of chronic HCV infection, defined as a positive HCV surface antibody test result and detectable HCV RNA, for treatment. (A1)

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Supplementary Material

Supplement: Guideline Development and Recommendation Ratings