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
The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) initiated the hepatitis C virus (HCV) guidance project (hereafter HCV guidance) in 2013. The AASLD-IDSA HCV guidance website (www.HCVGuidelines.org) disseminates up-to-date, peer-reviewed, unbiased, evidence-based recommendations to aid clinicians making decisions regarding the testing, management, and treatment of HCV infection. Using a web-based system enables timely and nimble distribution of the HCV guidance, which is periodically updated in near real time as necessitated by emerging research data, recommendations from public health agencies, the availability of therapeutic agents, or other significant developments affecting the rapidly evolving hepatitis C arena. The value and utility of the online HCV guidance to the community of hepatitis C care providers throughout the world is evidence by the nearly 10 million pageviews by 1.5 million users originating from 228 countries and territories since the January 2014 launch of the website. A major update of the HCV guidance was released electronically in November 2019. This HCV guidance update summarizes and highlights key new or amended recommendations since the previous October 2018 print publication.1 The advent of safe, well-tolerated, and highly efficacious (>95% cure rate)2 direct-acting antiviral (DAA) therapy for HCV infection has ushered in an era in which elimination of hepatitis C is conceivable. In 2016, the World Health Organization (WHO) proposed a global health sector strategy to eliminate hepatitis C as a public health threat by 2030 and developed an action plan to facilitate this goal.3 In response to the WHO action plan, the National Academies of Science, Engineering, and Medicine (NASEM) developed a US strategy for the elimination of hepatitis C.4 Key elements of the elimination plan include improved detection of undiagnosed cases, increased linkage and access to care for newly diagnosed persons, and expanded treatment access. Many of the recommendations included in the latest update to the HCV guidance and highlighted herein align with and support the goals of the NASEM and WHO strategies to move from control to eventual elimination of hepatitis C. Topics addressed include universal and risk-based hepatitis C screening, simplified treatment algorithms for treatment-naive adults without cirrhosis or with compensated cirrhosis, hepatitis C management in the pediatric population, acute hepatitis C testing and management, and transplantation of organs from HCV-viremic donors into HCV-negative recipients. For detailed evidence reviews related to these topics and information addressing other aspects of HCV testing and management, see the online HCV guidance (www.HCVGuidelines.org). The HCV guidance was developed and is updated by a volunteer panel (representing the AASLD and the IDSA) of hepatology and infectious diseases clinicians with hepatitis C expertise using an evidence-based review of available data, including information presented at scientific conferences and published in peer-reviewed journals. Based on scientific evidence and expert opinion, recommendations are rated by the level of evidence (I, II, or III) and the strength of the recommendation (A, B, or C) using a system adapted from the American College of Cardiology and the American Heart Association.5, 6 See the original AASLD–IDSA hepatitis C guidance publication7 or the HCV guidance website for additional details about the processes and methods employed. All recommendations are reviewed and approved by the governing boards of the AASLD and the IDSA. The HCV guidance panel classifies therapeutic regimens as recommended, alternative, or not recommended based on patient factors (i.e., treatment-naive versus experienced, cirrhosis status, and comorbidities) and viral characteristics (i.e., genotype, subtype, resistance-associated substitutions). Recommended regimens are considered equivalent; alternative regimens are effective but, compared to recommended regimens, have potential disadvantages, limitations for use in certain patient populations, or less supporting data. The identification of risk factors associated with contracting HCV infection served as the basis for the risk-based hepatitis C screening recommendations issued by the US Centers for Disease Control and Prevention (CDC) in 1998.8 Although sensitive for the identification of persons with chronic HCV infection, risk-based screening failed to identify the majority of individuals with HCV infection due to both clinician and patient barriers.9-12 Analysis of the 2003-2010 National Health and Nutrition Examination Survey prevalence data demonstrated that approximately three fourths of individuals with chronic hepatitis C in the United States belonged to the 1945-1965 birth cohort.13 Based on these data, both the CDC and the US Preventive Services Task Force (USPSTF) recommended one-time hepatitis C screening of all individuals in this birth cohort (1945-1965) regardless of risk factors.14, 15 Since these recommendations were established in 2012, HCV epidemiology in the United States has changed. Hepatitis C infection incidence nearly quadrupled from 2010 to 2017, primarily driven by increased injection drug use related to the opioid epidemic.16-19 CDC viral hepatitis surveillance data indicate progressively increasing acute HCV infection incidence each year from 2009 through 2017. Most of these new HCV infections occurred in persons born after 1965, with those aged 20-39 years accounting for the majority of cases. This ongoing trend has spurred interest in expanding HCV screening among the general US population. Several modeling studies suggest the cost-effectiveness of such an approach.20-23 Accordingly, the AASLD–IDSA guidance HCV screening and follow-up recommendations have been updated and include recommended universal HCV screening for all adults aged 18 years or older followed by periodic testing for persons with ongoing risk behaviors and/or exposures. In light of the inadequacy of targeted HCV case finding using risk-based and birth cohort HCV screening,24, 25 investigators have modeled the cost-effectiveness of one-time universal HCV screening for adults aged ≥ 18 years. Independent studies using different modeling techniques demonstrate that one-time universal screening for adults aged ≥ 18 years is cost-effective (<$30,000/quality-adjusted life-years) compared with birth-cohort screening.20, 26 Additionally, the cost-effectiveness of nontargeted HCV screening has proven robust in a variety of venues including correctional,27 prenatal,28, 29 and primary care30 settings as well as substance use treatment centers.31, 32 Given the current epidemiology of HCV disease in the United States, the cost-effectiveness of universal HCV screening, the high efficacy of DAA therapy, and the myriad liver-related and other health benefits of virologic cure,33-38 the HCV guidance panel recommends universal, one-time, opt-out HCV screening of adults aged ≥ 18 years. Although neither the CDC nor the USPSTF currently recommend universal HCV screening in adults, the CDC initiated a peer review process to consider such a recommendation in July 2019. Similarly, in August 2019, the USPSTF published a draft recommendation for universal HCV screening among adults aged 18-79 years. The USPSTF draft universal hepatitis C screening recommendation differs from that of the AASLD–IDSA HCV guidance by setting an upper age limit of 79 years. The HCV guidance panel does not recommend an age limit for universal adult HCV screening due to the excellent quality of life of many octogenarians and the association between advanced age and more rapid HCV disease progression. The HCV guidance panel's new universal screening recommendation is intended to enhance HCV case finding among adults not included in the 1945-1965 birth cohort and aligns with the WHO and NASEM goals of eliminating HCV as a public health threat by 2030. This is particularly important for men and women aged 20-39 years due to the disproportionate overlapping impact of the opioid epidemic and associated injection drug use and the rising rate of incident HCV infections in this age group. Universal HCV screening also bypasses the inherent barriers in ascertaining an accurate risk factor assessment. One-time, risk-based HCV screening is recommended for persons younger than 18 years old with current or past behaviors, exposures, or conditions or circumstances associated with an increased risk of HCV infection (see Table 1). There is currently insufficient evidence to support universal HCV screening in the pediatric population. People with an ongoing risk factor(s) for HCV infection remain vulnerable for as long as the behavior, exposure, condition, or circumstance persists, thereby warranting periodic repeat HCV testing. There is a paucity of data addressing the optimal frequency of repeat testing, thereby leaving the periodicity to the clinician's discretion on a case-by-case basis with consideration of an individual's risk for HCV infection or reinfection. People who inject drugs (PWID) and men with HIV infection who have unprotected sex with men are exceptions to this guidance. Because of the high incidence and prevalence of HCV infection in these populations,39-47 at least annual HCV testing is recommended. Given that many PWID lack access to or eschew traditional health care–delivery systems, integration of HCV testing services into substance use treatment programs, needle/syringe service programs, and acute detoxification programs expands the opportunities to accomplish periodic HCV testing in this key population.48-50 HCV-antibody testing using a US Food and Drug Administration (FDA)–approved assay (laboratory-based or point-of-care) is recommended for initial HCV screening.51, 52 The sensitivity and specificity of the lone FDA-approved point-of-care test (OraQuick HCV Rapid Antibody Test; OraSure Technologies Inc., Bethlehem, PA) are similar to laboratory-based assays.53, 54 A positive HCV-antibody test indicates current (active) HCV infection (acute or chronic), a past resolved infection, or rarely a false-positive result.55 A test to detect HCV viremia is necessary to confirm active HCV infection (see Fig. 1). Ideally, a positive HCV-antibody test automatically reflexes to HCV-RNA testing. This approach requires a single blood collection and avoids a return visit for confirmatory testing, a major barrier in the continuum of care.56 Collection of dried blood spots is an option for sequential HCV-antibody and reflex HCV-RNA testing. Dried blood spot collection can be accomplished with a fingerstick rather than venepuncture, and transport does not require an intact cold chain, making this an advantageous testing option in rural areas and among people for whom phlebotomy is a testing barrier.57 An FDA-approved quantitative or qualitative HCV-RNA assay with a detection level of ≤25 IU/mL should be used. HCV-RNA testing is required to detect reinfection after previous spontaneous or treatment-related viral clearance because HCV-antibody positivity is expected (see Fig. 1). Immunocompromised persons and those with possible HCV exposure in the prior 6 months may be HCV antibody–negative due to delayed or failed seroconversion58 or being in the seroconversion window period,52 respectively. HCV-RNA testing is a consideration for these individuals, particularly for those with a known risk factor(s). Persons who have a reactive HCV-antibody test and a negative (not detected) HCV-RNA test should be informed that they do not have evidence of current HCV infection. Although additional testing is typically unnecessary, HCV-RNA testing can be repeated for persons with ongoing HCV infection risk or if there is a high index of suspicion for recent infection. If either the clinician or the patient wishes to determine whether a positive HCV-antibody test in the absence of HCV viremia represents a resolved HCV infection or a biologic false positive, repeat testing with a different HCV-antibody assay can be undertaken. A false positive typically does not occur with two different assays.51, 59 Quantitative HCV-RNA testing is recommended prior to initiating antiviral therapy to determine baseline viremia (viral load), which may affect treatment duration with ledipasvir/sofosbuvir therapy. With the advent of pangenotypic DAA regimens, HCV genotyping is no longer universally required prior to treatment initiation. Pretreatment genotyping is recommended for persons with a prior HCV treatment failure because DAA regimen selection and duration may differ by genotype. Pretreatment genotyping is not required for treatment-naive patients without cirrhosis if a pangenotypic regimen is used. Upon diagnosis of active HCV infection, patients require counseling and certain clinical interventions prior to initiation of antiviral therapy. Prevention of further liver damage is crucial. To that end, counseling patients to abstain from alcohol takes priority because of associations between excess alcohol use and incident or progressive fibrosis and the development of HCC.60-69 There is no known safe level of alcohol use for patients with chronic hepatitis C. All patients with chronic hepatitis C, especially those with advanced fibrosis or cirrhosis, should be advised to abstain from alcohol use.70-72 Persons suffering from alcohol use disorder require treatment for this condition; consider referring these individuals to an addiction specialist. Ongoing alcohol use, however, is not a contraindication to antiviral therapy. Data indicate that ongoing alcohol use does not affect therapeutic outcomes with DAA regimens among treatment-adherent patients.73 From a public health perspective, educating persons with HCV infection about how to avoid transmitting the virus to others (Table 2) serves as an essential primary prevention measure to curb and eventually eliminate the hepatitis C epidemic. Exposure to infected blood is the primary mode of HCV transmission. Epidemics of acute HCV due to sexual transmission in men with HIV infection who have sex with men have also been described.74-77 Persons should be counseled to stop using illicit drugs and enter substance abuse treatment. Those who continue to inject drugs should be counseled to: Assessing liver disease severity is an essential component of the workup for all persons with newly diagnosed chronic hepatitis C as this factor influences initial and follow-up evaluation. This assessment (i.e., presence or absence of cirrhosis) can usually be accomplished with noninvasive tests (Table 3). Liver biopsy is rarely required but is a consideration if other causes of liver disease are suspected. Persons with known or suspected cirrhosis are at increased risk for complications of advanced liver disease and require frequent follow-up. They should also avoid hepatotoxic drugs, such as excessive acetaminophen (>2 g/day) and certain herbal supplements. Nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) should also be avoided. Ongoing imaging surveillance for HCC and gastroesophageal varices is recommended for patients with cirrhosis.78-80 Cirrhosis with portal hypertension portends a greater likelihood of developing future hepatic complications in untreated patients.81, 82 Transient elastography provides point-of-care information regarding liver stiffness and can reliably distinguish patients with a high versus low likelihood of cirrhosis.83-85 Screening for HBV with an FDA-approved hepatitis B surface antigen (HBsAg) assay and HIV with an FDA-approved HIV-antigen/antibody test is recommended because these coinfections are associated with a poorer HCV prognosis.86-90 Persons who test positive for HBsAg require additional monitoring during HCV treatment due to HBV reactivation risk.91 Anti-HBV therapy is another consideration for these patients. For persons who test negative for HBsAg but positive for hepatitis B core antibodies (with or without hepatitis B surface antibodies) have resolved HBV infection, and no further workup or additional monitoring is needed.92 Primary prevention measures for persons without coinfection include counseling about how to avoid contracting HIV and HBV and immunization against HBV and hepatitis A virus (HAV) as needed. The CDC also recommends pneumococcal vaccination for all persons with chronic liver disease.93 Chronic HCV infection is an important infectious cause of death in the United States and a major contributor to morbidity and mortality from viral hepatitis globally. The availability of safe, effective, well-tolerated therapy substantially facilitates the goal of expanding HCV treatment as recommended in the HCV elimination strategies of the WHO3 and the NASEM.4 Overall, DAA regimens successfully cure HCV infection in > 95% of treated persons.2 Moreover, the development of coformulated, pangenotypic regimens that require relatively short treatment durations has greatly simplified HCV antiviral therapy administration. Despite these remarkable therapeutic improvements, in 2015, only 7.4% of persons with diagnosed HCV had begun antiviral treatment.94 Although more recent limited data indicate increased DAA access and uptake, this has been uneven geographically and across different patient populations.95-97 Thus, only a minority of persons with HCV infection obtain the many health benefits of successful treatment. From a public health perspective, successful HCV treatment also supports primary prevention by decreasing the population of persons capable of transmitting the virus, thereby reducing the incidence of HCV infection. Eradicating hepatitis C infection results in numerous health benefits, including reduced rates of all-cause mortality, cirrhosis, hepatic decompensation, and HCC.33, 37, 98-110 Successful treatment also confers improvement in extrahepatic manifestations of HCV disease, including cryoglobulinemic vasculitis111-116 and HCV-related non-Hodgkin lymphoma and other lymphoproliferative disorders,117-125 as well as improved productivity and quality of life.34, 35, 126-131 Given these and other benefits associated with virologic cure, the HCV guidance panel strongly recommends antiviral treatment for all adults with acute or chronic HCV infection (except those with a short life expectancy that cannot be remediated). Importantly, this recommendation includes persons with ongoing substance use (alcohol or drugs). Several studies demonstrate that treatment-committed individuals in this disproportionately affected population achieve sustained virologic response (SVR) rates with DAA therapy comparable to those without known, current substance use.73, 132-139 The universal treatment recommendation represents a principal tenet of the HCV guidance along with newly recommended universal hepatitis C screening of adults. The HCV guidance panel urges health care providers caring for adults to encourage hepatitis C screening and treatment (if positive) because DAA therapy is safe and cures HCV infection in most people.2 One approach to improving access to curative HCV treatment is expanding the number of health care providers administering antiviral therapy. Data demonstrate that HCV treatment can be effectively provided by a broad range of health care professionals with differing expertise—including specialists, primary care physicians, nurse practitioners, clinical pharmacy specialists, physician assistants, and registered nurses—without compromising treatment efficacy or safety.95, 140 Consequently, the HCV guidance panel developed simplified HCV treatment algorithms for treatment-naive adults (without cirrhosis or with compensated cirrhosis), which align with the NASEM plan to eliminate HCV as a US public health burden by 2030. These simplified treatment algorithms are designed to be used by any health care provider knowledgeable about HCV disease and treatment, including those without extensive experience who have timely access to a specialist. The simplified treatment algorithms provide concise, clear guidance on pretreatment assessment, on-treatment monitoring, assessment of response, and posttreatment management (see Figs. 2 and 3). The simplified HCV treatment algorithm for adults without cirrhosis (see Fig. 2) applies to persons aged ≥ 18 years who have not been previously treated for their infection and do not have evidence of cirrhosis as defined by the noninvasive parameters specified in the HCV guidance. Evidence of cirrhosis includes a FIB-4 score > 3.25 or any of the from a previously elastography cirrhosis (e.g., stiffness > noninvasive tests that (e.g., Liver clinical evidence of cirrhosis (e.g., liver and/or on and/or prior liver biopsy This simplified treatment algorithm is not recommended for persons with HIV and/or HBV infection, prior liver disease (i.e., rate and/or current because they require more See the online HCV guidance for management and treatment recommendations for these patients. The pretreatment should include an assessment for cirrhosis, and patient regarding treatment and the of and transmission Recommended pretreatment testing is to confirm chronic HCV infection and liver disease, HBV and/or HIV disease, and prior to treatment initiation. of HCV infection with DAA therapy can hepatic and thereby affect the and efficacy of data indicate an association between DAA therapy and reduced particularly among people with should be informed of the potential for during and after DAA therapy. monitoring during and after DAA treatment is of may be needed. data also indicate an association between DAA therapy and a significant in should be informed of the potential for a in their monitoring for is recommended during and after DAA may be needed. For on-treatment monitoring is not required a patient treatment-related or there are Several robust clinical have demonstrated the and high curative efficacy of and among treatment-naive persons without cirrhosis regardless of HCV genotype. These have been in cohort studies for both and Based on these data, of or of is recommended for adults for the simplified treatment To treatment response, HCV-RNA and hepatic testing is recommended or more after DAA treatment. HCV represents and virologic In the absence of cirrhosis, persons who require no follow-up. For those with ongoing HCV risk counseling is recommended as well as HCV-RNA testing or an in hepatic HCV viremia after of represents either reinfection or a (i.e., of the HCV With treatment are to those for initial treatment. If is suspected or cannot be such patients should be by clinicians with expertise in HCV treatment Persons who but have hepatic require for other causes of liver for whom treatment can be successfully see the online HCV guidance for management and antiviral regimen recommendations for If is delayed or not assessment for liver disease months is recommended, as specified in Fig. all regardless of to avoid excess alcohol to liver The simplified HCV treatment algorithm for adults with compensated cirrhosis (see Fig. applies to persons aged ≥ 18 years who have not been previously treated for their infection and have evidence of compensated cirrhosis (i.e., but not cirrhosis (i.e., B or evidence of cirrhosis the parameters specified in the previous and are in Fig. of the score is recommended to compensated versus A score ≥ or any of these patients for the simplified treatment Recommended pretreatment assessment also includes clinical for and hepatic and imaging of the liver the prior 6 months to for HCC and any of these clinical or imaging are to use of the simplified treatment See the online HCV guidance for treatment and management of persons with circumstances and conditions that a patient for use of the simplified treatment algorithm those in the previous and are in Fig. Similarly, assessment for potential and pretreatment and counseling are the as for treatment-naive patients without cirrhosis (see Fig. 3). Pretreatment assessment of patients with compensated cirrhosis for use of the simplified treatment algorithm includes blood a hepatic and months of initiating antiviral therapy. Quantitative and HBsAg tests are recommended any time prior to initiating DAA therapy. pretreatment testing is recommended if therapy is because of the for baseline testing in persons with cirrhosis and infection. Because hepatic rarely during HCV DAA treatment, clinicians may for on-treatment blood tests to detect liver who experience hepatic parameters and/or or other new liver-related or should see a liver specialist. monitoring of blood and are recommended for persons on or with as (see previous for a more detailed clinical have demonstrated the and high curative efficacy of and among treatment-naive adults with compensated cirrhosis, regardless of HCV genotype. These have been in cohort studies for both and Based on these data, recommended regimens for adults for the simplified treatment algorithm are of for patients with or of for those with or Pretreatment testing is recommended for persons with because only those without a baseline are for a of with and a baseline should be treated with or an alternative regimen (see the online HCV HCV-RNA and testing are recommended or more after of DAA therapy to treatment HCV represents and virologic surveillance for HCC (with or without 6 months after treatment is recommended for patients with cirrhosis, regardless of surveillance for varices is recommended, with AASLD guidance on portal in all patients to abstain from alcohol use to the risk of liver disease progression. counseling is recommended for persons with ongoing HCV risk HCV-RNA testing or an in hepatic is also recommended for these HCV viremia after of represents either reinfection or a With the treatment are to those for initial treatment. If is suspected or cannot be such patients should be by clinicians with expertise in HCV