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Updates, Authorship, and Related Guidelines | |
Developer and funding source |
New York State Department of Health AIDS Institute (NYSDOH AI) |
Intended users |
Clinicians in New York State who treat adults with chronic HCV |
Development |
See Supplement: Guideline Development and Recommendation Ratings |
Updates | |
October 06, 2022 |
|
Author and writing group conflict of interest disclosures |
See Conflict of Interest statement* |
Related NYSDOH AI guidelines |
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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
RECOMMENDATIONS |
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Medical History and Physical Examination
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Abbreviations: CrCl, creatinine clearance; DAA, direct-acting antiviral; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus.
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 1: Key Elements of Patient History and Physical Examination | |
Elements of Patient History | Rationale |
Previous treatment for HCV infection | Previous regimen and treatment outcome will guide choice and duration of therapy. |
History of hepatic decompensation | Warrants referral to a liver disease specialist. |
History of renal disease | Findings may influence choice of regimen. |
Medication history and current medications, including over-the-counter and herbal products | Carefully consider potential drug-drug interactions with DAAs. See American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) or University of Liverpool HEP Drug Interactions. |
Pregnancy status and plans |
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HIV infection |
|
History of infection/vaccination status |
|
Elements of Pretreatment Physical Examination | Clinical Details |
Presence or absence of ankle edema, abdominal veins, jaundice, palmar erythema, gynecomastia, spider telangiectasia, ascites, encephalopathy, and asterixis | Presence may suggest cirrhosis or decompensated cirrhosis and may require additional evaluation and management or treatment. |
Presence or absence of physical signs related to extrahepatic manifestations of HCV, such as porphyria cutanea tarda, vasculitis, or lichen planus | Presence may increase urgency of HCV treatment and may require additional evaluation and treatment needs [e]. |
Liver size by palpation or auscultation for hepatomegaly or splenomegaly, as well as tenderness or hepatic bruits | Size and tenderness may suggest the severity of liver disease and may require additional evaluation. |
Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; ART, antiretroviral therapy; DAA, direct-acting antiviral; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IgG, immunoglobulin G.
Notes:
- a
- b
See NYSDOH AI guideline Rapid ART Initiation.
- c
As indicated in the Centers for Disease Control and Prevention Adult Immunization Schedule (recommendations for ages 19 years or older).
- d
See U.S. Food and Drug Administration Influenza Virus Vaccine Safety & Availability.
- e
See, for instance, Medscape Cutaneous Manifestations of Hepatitis C Clinical Presentation.
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.
Key Points |
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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 2: Pretreatment Laboratory Testing | |
Test | Clinical Note |
Quantitative HCV RNA | Confirms active HCV infection and determines HCV viral load. |
Genotype/subtype | Genotype and subtype guide choice of regimen. |
Complete blood count |
|
Serum electrolytes with creatinine |
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Hepatic function panel |
|
INR | Elevated INR suggests decompensated cirrhosis. |
Pregnancy test for all individuals of childbearing potential | If patient is pregnant, suggest treatment deferral [a]. |
HAV antibodies | Obtain HAV antibody test (IgG or total) and administer the full HAV vaccine series in patients not immune to HAV. |
HBV antibodies |
|
HIV test if status is unknown | If HIV infection is confirmed, offer the patient antiretroviral therapy [b]. |
Urinalysis | Protein may suggest extrahepatic manifestation of HCV. |
Fibrosis serum markers | If not previously evaluated by biopsy or FibroScan. |
Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; ART, antiretroviral therapy; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IgG, immunoglobulin G; INR, international normalized ratio.
Notes:
- a
- b
See NYSDOH AI guideline Rapid ART Initiation.
Fibrosis Assessment
RECOMMENDATIONS |
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Fibrosis Assessment
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Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; RBV, ribavirin.
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 3: Methods for Staging Fibrosis | |||
Method | Procedure | Advantages | Disadvantages |
Indirect serum markers | APRI, FIB-4 [a] |
| Limited ability to differentiate intermediate stages of fibrosis |
Direct markers | FibroSure, FibroTest, FibroMeter, FIBROSpect II, and HepaScore |
| Limited ability to differentiate intermediate stages of fibrosis |
VCTE | Shear wave velocity |
|
|
Liver biopsy | Pathologic examination |
|
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Abbreviations: APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, Fibrosis-4; VCTE, vibration-controlled transient elastography.
Note:
- a
See Hepatitis C Online for APRI and FIB-4 index calculators.
Cirrhosis Evaluation
RECOMMENDATIONS |
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Cirrhosis Evaluation
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Abbreviations: CTP, Child-Turcotte-Pugh; CT, computerized axial tomography; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MRI, magnetic resonance imaging.
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 4: Calculating the Child-Turcotte-Pugh (CTP) Score for Severity of Cirrhosis [a] | |||
1 point [b] | 2 points [b] | 3 points [b] | |
Encephalopathy | None | Stage 1 to 2 (or precipitant-induced) | Stage 3 to 4 (or chronic) |
Ascites | None | Mild/moderate (diuretic-responsive) | Severe (diuretic-refractory) |
Bilirubin (mg/dL) | <2.0 | 2.0 to 3.0 | >3.0 |
Albumin (g/dL) | >3.5 | 2.8 to 3.5 | <2.8 |
Prothrombin time (sec prolonged) or international normalized ratio (INR) | <4.0 | 4.0 to 6.0 | >6.0 |
<1.7 | 1.7 to 2.3 | >2.3 |
Notes:
- a
Adapted from U.S. Department of Veterans Affairs Viral Hepatitis and Liver Disease: Child-Turcotte-Pugh Calculator.
- b
CTP score is obtained by adding the score for each parameter. CTP class:
A = 5 to 6 points (compensated, least severe liver disease)
B = 7 to 9 points (decompensated, moderately severe liver disease)
C = 10 to 15 points (decompensated, most severe liver disease)
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 5: Baseline Evaluation and Follow-Up Screening for Patients With Cirrhosis | |
Type of Evaluation | Rationale |
Assess for decompensation; refer to a liver disease specialist if history of or current decompensation | Decompensation is defined as the presence (or history) of 1 of the following:
|
Abdominal ultrasound to screen for HCC | Ongoing HCC surveillance should be performed for patients with bridging fibrosis or cirrhosis every 6 to 12 months. |
Upper endoscopy | Refer to a liver disease specialist to screen for varices. |
Abbreviations: CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; MELD, Model of End-Stage Liver Disease.
Renal, HAV/HBV, Metabolic, and Cardiovascular Status
RECOMMENDATIONS |
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Renal Status
HAV and HBV Immunity Status
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Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; CrCl, creatinine clearance; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IgG, immunoglobulin G.
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.
Key Point |
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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
RECOMMENDATIONS |
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Medical History and Physical Examination
Fibrosis Assessment
Cirrhosis Evaluation
Renal Status
HAV and HBV Immunity Status
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Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; CTP, Child-Turcotte-Pugh; CrCl, creatinine clearance; CT, computerized axial tomography; DAA, direct-acting antiviral; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IgG, immunoglobulin G; MRI, magnetic resonance imaging.
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Supplementary Material
Supplement: Guideline Development and Recommendation Ratings
Footnotes
Conflict of Interest: There are no author or writing group conflict of interest disclosures.
Created: October 2022; Last Update: October 2022.
- Pretreatment Assessment in Adults With Chronic Hepatitis C Virus InfectionPretreatment Assessment in Adults With Chronic Hepatitis C Virus Infection
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