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

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.

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.

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.

Fibrosis Assessment

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].

Cirrhosis Evaluation

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.

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].

Renal, HAV/HBV, Metabolic, and Cardiovascular Status

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.

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

References

• AASLD/IDSA. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. 2021. https://www​.hcvguidelines.org/ [accessed 2022 Aug 29] [PubMed: 26111063]
• Agbim U., Asrani S. K. Non-invasive assessment of liver fibrosis and prognosis: an update on serum and elastography markers. Expert Rev Gastroenterol Hepatol. 2019;13(4):361–374. [PubMed: 30791772]
• Al-Khazraji A., Patel I., Saleh M., et al. Identifying barriers to the treatment of chronic hepatitis C infection. Dig Dis. 2020;38(1):46–52. [PubMed: 31422405]
• Amorim T. G., Staub G. J., Lazzarotto C., et al. Validation and comparison of simple noninvasive models for the prediction of liver fibrosis in chronic hepatitis C. Ann Hepatol. 2012;11(6):855–861. [PubMed: 23109448]
• Andres J., Barros M., Arutunian M., et al. Treatment of hepatitis C virus and long-term effect on glycemic control. J Manag Care Spec Pharm. 2020;26(6):775–781. [PMC free article: PMC10390901] [PubMed: 32463777]
• Arase Y., Suzuki F., Suzuki Y., et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49(3):739–744. [PubMed: 19127513]
• Belperio P. S., Shahoumian T. A., Mole L. A., et al. Evaluation of hepatitis B reactivation among 62,920 veterans treated with oral hepatitis C antivirals. Hepatology. 2017;66(1):27–36. [PubMed: 28240789]
• Bohte A. E., de Niet A., Jansen L., et al. Non-invasive evaluation of liver fibrosis: a comparison of ultrasound-based transient elastography and MR elastography in patients with viral hepatitis B and C. Eur Radiol. 2014;24(3):638–648. [PubMed: 24158528]
• Bressler B. L., Guindi M., Tomlinson G., et al. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology. 2003;38(3):639–644. [PubMed: 12939590]
• Bruix J., Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–1022. [PMC free article: PMC3084991] [PubMed: 21374666]
• Butt A. A., Yan P., Shaikh O. S., et al. Hepatitis B reactivation and outcomes in persons treated with directly acting antiviral agents against hepatitis C virus: results from ERCHIVES. Aliment Pharmacol Ther. 2018;47(3):412–420. [PubMed: 29181838]
• Castera L., Winnock M., Pambrun E., et al. Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these non-invasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC Collaboration. HIV Med. 2014;15(1):30–39. [PubMed: 24007567]
• Charlton M. R., Pockros P. J., Harrison S. A. Impact of obesity on treatment of chronic hepatitis C. Hepatology. 2006;43(6):1177–1186. [PubMed: 16729327]
• Chevaliez S., Pawlotsky J. M. Hepatitis C virus: virology, diagnosis and management of antiviral therapy. World J Gastroenterol. 2007;13(17):2461–2466. [PMC free article: PMC4146765] [PubMed: 17552030]
• Coffin P. O., Santos G. M., Behar E., et al. Randomized feasibility trial of directly observed versus unobserved hepatitis C treatment with ledipasvir-sofosbuvir among people who inject drugs. PLoS One. 2019;14(6):e0217471. [PMC free article: PMC6546233] [PubMed: 31158245]
• Collins J. M., Raphael K. L., Terry C., et al. Hepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir. Clin Infect Dis. 2015;61(8):1304–1306. [PubMed: 26082511]
• De Monte A., Courjon J., Anty R., et al. Direct-acting antiviral treatment in adults infected with hepatitis C virus: reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol. 2016;78:27–30. [PubMed: 26967675]
• Donadon V., Balbi M., Zanette G. Hyperinsulinemia and risk for hepatocellular carcinoma in patients with chronic liver diseases and type 2 diabetes mellitus. Expert Rev Gastroenterol Hepatol. 2009;3(5):465–467. [PubMed: 19817667]
• Dyal H. K., Aguilar M., Bhuket T., et al. Concurrent obesity, diabetes, and steatosis increase risk of advanced fibrosis among HCV patients: a systematic review. Dig Dis Sci. 2015;60(9):2813–2824. [PubMed: 26138651]
• EASL EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. [PubMed: 29628281]
• EASL EASL recommendations on treatment of hepatitis C: final update of the series. J Hepatol. 2020;73(5):1170–1218. [PubMed: 32956768]
• Ebell M. H. Probability of cirrhosis in patients with hepatitis C. Am Fam Physician. 2003;68(9):1831–1833. [PubMed: 14620604]
• El-Serag H. B., Mason A. C. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340(10):745–750. [PubMed: 10072408]
• Ende A. R., Kim N. H., Yeh M. M., et al. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep. 2015;9:164. [PMC free article: PMC4535371] [PubMed: 26215390]
• FDA. Epclusa (sofosbuvir and velpatasvir) tablets, for oral use. 2016. https://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2016/208341s000lbl.pdf [accessed 2022 Feb 1]
• FDA. Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) tablets, for oral use. 2017. https://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2017/209195s000lbl.pdf [accessed 2022 Feb 1]
• FDA. Harvoni (ledipasvir and sofosbuvir) tablets, for oral use. 2019. https://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2019/212477s000lbl.pdf [accessed 2022 Feb 1]
• Fox A. N., Brown R. S. Is the patient a candidate for liver transplantation?. Clin Liver Dis. 2012;16(2):435–448. [PubMed: 22541708]
• Garcia-Tsao G., Abraldes J. G., Berzigotti A., et al. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, an management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2017;65(1):310–335. [PubMed: 27786365]
• Garcia-Tsao G., Sanyal A. J., Grace N. D., et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922–938. [PubMed: 17879356]
• Ghany M. G., Morgan T. R. Hepatitis C guidance 2019 update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology. 2020;71(2):686–721. [PMC free article: PMC9710295] [PubMed: 31816111]
• Goossens N., Negro F. The impact of obesity and metabolic syndrome on chronic hepatitis C. Clin Liver Dis. 2014;18(1):147–156. [PubMed: 24274870]
• Gordon S. C., Lamerato L. E., Rupp L. B., et al. Prevalence of cirrhosis in hepatitis C patients in the Chronic Hepatitis Cohort Study (CHeCS): a retrospective and prospective observational study. Am J Gastroenterol. 2015;110(8):1169–77; quiz 1178. [PMC free article: PMC5731242] [PubMed: 26215529]
• Gordon S. C., Trudeau S., Li J., et al. Race, age, and geography impact hepatitis C genotype distribution in the United States. J Clin Gastroenterol. 2019;53(1):40–50. [PMC free article: PMC5776051] [PubMed: 28737649]
• Gountas I., Sypsa V., Blach S., et al. HCV elimination among people who inject drugs. Modelling pre- and post-WHO elimination era. PLoS One. 2018;13(8):e0202109. [PMC free article: PMC6095544] [PubMed: 30114207]
• Granozzi B., Guardigni V., Badia L., et al. Out-of-hospital treatment of hepatitis C increases retention in care among people who inject drugs and homeless persons: an observational study. J Clin Med. 2021;10(21):4955. [PMC free article: PMC8584608] [PubMed: 34768474]
• Grebely J., Dalgard O., Conway B., et al. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial. Lancet Gastroenterol Hepatol. 2018;3(3):153–161. [PubMed: 29310928]
• Groessl E. J., Sklar M., Cheung R. C., et al. Increasing antiviral treatment through integrated hepatitis C care: a randomized multicenter trial. Contemp Clin Trials. 2013;35(2):97–107. [PubMed: 23669414]
• Hajarizadeh B., Cunningham E. B., Valerio H., et al. Hepatitis C reinfection after successful antiviral treatment among people who inject drugs: a meta-analysis. J Hepatol. 2020;72(4):643–657. [PubMed: 31785345]
• Hayashi K., Ishigami M., Ishizu Y., et al. A case of acute hepatitis B in a chronic hepatitis C patient after daclatasvir and asunaprevir combination therapy: hepatitis B virus reactivation or acute self-limited hepatitis?. Clin J Gastroenterol. 2016;9(4):252–256. [PubMed: 27329484]
• Henkle E., Lu M., Rupp L. B., et al. Hepatitis A and B immunity and vaccination in chronic hepatitis B and C patients in a large United States cohort. Clin Infect Dis. 2015;60(4):514–522. [PubMed: 25371489]
• Hsu Y. C., Wu C. Y., Lane H. Y., et al. Determinants of hepatocellular carcinoma in cirrhotic patients treated with nucleos(t)ide analogues for chronic hepatitis B. J Antimicrob Chemother. 2014;69(7):1920–1927. [PubMed: 24576950]
• Hung C. H., Lee C. M., Wang J. H., et al. Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon-based antiviral therapy. Int J Cancer. 2011;128(10):2344–2352. [PubMed: 20669224]
• Jalan R., Fernandez J., Wiest R., et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol. 2014;60(6):1310–1324. [PubMed: 24530646]
• Kaul V. V., Munoz S. J. Coagulopathy of liver disease. Curr Treat Options Gastroenterol. 2000;3(6):433–438. [PubMed: 11096602]
• Klevens R. M., Canary L., Huang X., et al. The burden of hepatitis C infection-related liver fibrosis in the United States. Clin Infect Dis. 2016;63(8):1049–1055. [PubMed: 27506688]
• Lai M., Afdhal N. H. Liver fibrosis determination. Gastroenterol Clin North Am. 2019;48(2):281–289. [PubMed: 31046975]
• Lau D. T., Hewlett A. T. Screening for hepatitis A and B antibodies in patients with chronic liver disease. Am J Med. 2005;118 Suppl 10A:28s–33s. [PubMed: 16271538]
• Lecube A., Hernandez C., Genesca J., et al. High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury. Diabetes Care. 2004;27(5):1171–1175. [PubMed: 15111540]
• Li(a) J., Gordon S. C., Rupp L. B., et al. Sustained virological response does not improve long-term glycaemic control in patients with type 2 diabetes and chronic hepatitis C. Liver Int. 2019;39(6):1027–1032. [PMC free article: PMC6628708] [PubMed: 30570808]
• Li(b) J., Gordon S. C., Rupp L. B., et al. Sustained virological response to hepatitis C treatment decreases the incidence of complications associated with type 2 diabetes. Aliment Pharmacol Ther. 2019;49(5):599–608. [PMC free article: PMC6599612] [PubMed: 30650468]
• Loomba R., Huang D. Q., Sanyal A. J., et al. Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis. Gut. 2023;72(3):581–589. [PMC free article: PMC9905707] [PubMed: 36750244]
• Mehta S. H., Brancati F. L., Strathdee S. A., et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38(1):50–56. [PubMed: 12829986]
• Mehta S. H., Brancati F. L., Sulkowski M. S., et al. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133(8):592–599. [PubMed: 11033586]
• Minami T., Tateishi R., Fujiwara N., et al. Impact of obesity and heavy alcohol consumption on hepatocellular carcinoma development after HCV eradication with antivirals. Liver Cancer. 2021;10(4):309–319. [PMC free article: PMC8339497] [PubMed: 34414119]
• Moucari R., Asselah T., Cazals-Hatem D., et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134(2):416–423. [PubMed: 18164296]
• Ogawa E., Furusyo N., Shimizu M., et al. Non-invasive fibrosis assessment predicts sustained virological response to telaprevir with pegylated interferon and ribavirin for chronic hepatitis C. Antivir Ther. 2015;20(2):185–192. [PubMed: 24941012]
• Patel K., Shackel N. A. Current status of fibrosis markers. Curr Opin Gastroenterol. 2014;30(3):253–259. [PubMed: 24671009]
• Patel K., Thompson A. J., Chuang W. L., et al. Insulin resistance is independently associated with significant hepatic fibrosis in Asian chronic hepatitis C genotype 2 or 3 patients. J Gastroenterol Hepatol. 2011;26(7):1182–1188. [PubMed: 21410752]
• Petta S., Camma C., Di Marco V., et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol. 2008;103(5):1136–1144. [PubMed: 18477344]
• Poynard T., Vergniol J., Ngo Y., et al. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest) and transient elastography (FibroScan(R)). J Hepatol. 2014;60(4):706–714. [PubMed: 24291240]
• Sackey B., Shults J. G., Moore T. A., et al. Evaluating psychiatric outcomes associated with direct-acting antiviral treatment in veterans with hepatitis C infection. Ment Health Clin. 2018;8(3):116–121. [PMC free article: PMC6007636] [PubMed: 29955556]
• Schiavon Lde L., Narciso-Schiavon J. L., de Carvalho-Filho R. J. Non-invasive diagnosis of liver fibrosis in chronic hepatitis C. World J Gastroenterol. 2014;20(11):2854–2866. [PMC free article: PMC3961992] [PubMed: 24659877]
• Schmid P., Bregenzer A., Huber M., et al. Progression of liver fibrosis in HIV/HCV co-infection: a comparison between non-invasive assessment methods and liver biopsy. PLoS One. 2015;10(9):e0138838. [PMC free article: PMC4587859] [PubMed: 26418061]
• Seeff L. B., Everson G. T., Morgan T. R., et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(10):877–883. [PMC free article: PMC3771318] [PubMed: 20362695]
• Shaikh S., Memon M. S., Ghani H., et al. Validation of three non-invasive markers in assessing the severity of liver fibrosis in chronic hepatitis C. J Coll Physicians Surg Pak. 2009;19(8):478–482. [PubMed: 19651008]
• Shoreibah M. G., Bloomer J. R., McGuire B. M., et al. Surveillance for hepatocellular carcinoma: evidence, guidelines and utilization. Am J Med Sci. 2014;347(5):415–419. [PubMed: 24759379]
• Simmons B., Saleem J., Heath K., et al. Long-term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a sustained virological response. Clin Infect Dis. 2015;61(5):730–740. [PMC free article: PMC4530725] [PubMed: 25987643]
• Sulkowski M. S., Chuang W. L., Kao J. H., et al. No evidence of reactivation of hepatitis B virus among patients treated with ledipasvir-sofosbuvir for hepatitis C virus infection. Clin Infect Dis. 2016;63(9):1202–1204. [PMC free article: PMC6276897] [PubMed: 27486112]
• Takayama H., Sato T., Ikeda F., et al. Reactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co-infection. Hepatol Res. 2016;46(5):489–491. [PubMed: 26297529]
• Tapper E. B., Castera L., Afdhal N. H. FibroScan (vibration-controlled transient elastography): where does it stand in the United States practice. Clin Gastroenterol Hepatol. 2015;13(1):27–36. [PubMed: 24909907]
• Tazawa J., Maeda M., Nakagawa M., et al. Diabetes mellitus may be associated with hepatocarcinogenesis in patients with chronic hepatitis C. Dig Dis Sci. 2002;47(4):710–715. [PubMed: 11991597]
• Thompson A. J., Patel K., Chuang W. L., et al. Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3. Gut. 2012;61(1):128–134. [PMC free article: PMC3766841] [PubMed: 21873466]
• Torrens M., Soyemi T., Bowman D., et al. Beyond clinical outcomes: the social and healthcare system implications of hepatitis C treatment. BMC Infect Dis. 2020;20(1):702. [PMC free article: PMC7517680] [PubMed: 32972393]
• Tsui J. I., Williams E. C., Green P. K., et al. Alcohol use and hepatitis C virus treatment outcomes among patients receiving direct antiviral agents. Drug Alcohol Depend. 2016;169:101–109. [PMC free article: PMC6534140] [PubMed: 27810652]
• Vandenbulcke H., Moreno C., Colle I., et al. Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: a prospective study. J Hepatol. 2016;65(3):543–551. [PubMed: 27180899]
• Veldt B. J., Chen W., Heathcote E. J., et al. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology. 2008;47(6):1856–1862. [PubMed: 18506898]
• Verveer C., Zondervan P. E., ten Kate F. J., et al. Evaluation of transient elastography for fibrosis assessment compared with large biopsies in chronic hepatitis B and C. Liver Int. 2012;32(4):622–628. [PubMed: 22098684]
• Wang C., Ji D., Chen J., et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2017;15(1):132–136. [PubMed: 27392759]
• Westin J., Lagging L. M., Spak F., et al. Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection. J Viral Hepat. 2002;9(3):235–241. [PubMed: 12010513]
• Yuan M., Zhou J., Du L., et al. Hepatitis C virus clearance with glucose improvement and factors affecting the glucose control in chronic hepatitis C patients. Sci Rep. 2020;10(1):1976. [PMC free article: PMC7005176] [PubMed: 32029793]
• Zhou Y., Xie W., Zheng C., et al. Hypoglycemia associated with direct-acting anti-hepatitis C virus drugs: an epidemiologic surveillance study of the FDA adverse event reporting system (FAERS). Clin Endocrinol (Oxf). 2022;96(5):690–697. [PubMed: 34913180]

Supplementary Material

Supplement: Guideline Development and Recommendation Ratings