A Clinician’s Guide to HCV Treatment in the Primary Care Setting by Integritas Communications

All rights reserved. No part of this eHealth Source may be used or reproduced in any manner whatsoever without written permission except in the case of brief quotations embedded in articles or reviews.

Integritas Communications 95 River Street, Suite 5B Hoboken, NJ 07030 www.integritasgrp.com www.exchangecme.com

FACULTY Sherilyn C. Brinkley, MSN, CRNP Nurse Practitioner/Program Manager Clinical Services and Research, Viral Hepatitis Center Johns Hopkins University School of Medicine Baltimore, Maryland Ms. Sherilyn Brinkley is Nurse Practitioner Manager and Program Manager of Clinical Services and Research at the Viral Hepatitis Center at the Johns Hopkins University (JHU) School of Medicine. She has clinical expertise in the care of persons with hepatitis B, hepatitis C, and human immunode ciency virus (HIV) coinfections. Having served as a Clinical Nurse for an HIV/acquired immune de ciency syndrome (AIDS)-dedicated unit at Johns Hopkins Hospital in the 1990s and as a Community Health Nurse for the AmeriCorps Service Program at the university’s School of Nursing, she has over 20 years of direct patient care and research experience working to eradicate hepatitis C and deliver curative therapies to the Baltimore community. She developed a multidisciplinary viral hepatitis clinical care team that included a walk-in outpatient program to improve hepatitis C screening and linkage to care.

Ms. Brinkley is the author or coauthor of abstracts and publications on viral hepatitis and has presented on the management and delivery of viral hepatitis clinical care at national medical meetings. She was the recipient of the 1st Annual Miller Coulson Nurse Practitioner Clinical Excellence Award in 2015 and the 2012 Hepatitis Hero Award, presented by the Maryland

Hepatitis Coalition. She earned her bachelor’s and master’s of science degrees from the JHU School of Nursing and is a member of the Sigma Theta Tau Nursing Honor Society (Nu Beta chapter), the American Association of Nurse Practitioners, and the American Association for the Study of Liver Diseases (AASLD).

Graham Foster, FRCP, PhD Professor of Hepatology Queen Mary University of London Consultant Hepatologist Barts Health NHS Trust London, United Kingdom

Dr. Graham Foster is a Professor of Hepatology at Queen Mary University of London and a consultant at Barts Health in East London. He trained in Medicine at Oxford and London Universities in the 1980s and completed a PhD in Molecular Biology in 1992. Professor Foster has a long-standing interest in the management of chronic viral hepatitis and runs a clinical research program studying the natural history of viral hepatitis, its impact on patients and their communities, and novel therapies for this disease. He leads an international study investigating community screening for viral hepatitis and supervises a laboratory research program investigating novel replication models for hepatitis C. Editor of the Journal of Viral Hepatitis, he has published widely in the eld of viral liver disease. He is a past President of the British Association for the Study of the Liver (BASL), past chairman of the National Health Service England (NHSE) Hepatobiliary Clinical Reference Group, and Clinical Lead for the NHSE Hepatitis C Programme.

PREAMBLE Target Audience The educational design of this activity addresses the needs of family medicine, internal medicine, and general practice clinicians involved in the treatment of patients with hepatitis C virus.

Program Overview The ability to treat and cure hepatitis C virus (HCV) infection is one of the greatest achievements of modern medicine. The simpli ed guidelines and the availability of highly effective and manageable direct-acting antiviral agents (DAA) regimens make it increasingly feasible to treat uncomplicated HCV in the primary care setting. This HCV eHealth Source™ activity was developed to empower primary care clinicians, who are ideally positioned to lead frontline efforts to achieve the worldwide goal of eliminating HCV. Practices such as universal screening for HCV, the implementation of treatment regimens, and strategies for supporting, as well as monitoring, patients postcure will be provided.

Educational Objectives After completing this activity, the participant should be better able to: • Implement primary care–based universal HCV screening and risk-based periodic HCV testing

• Discuss use of the simpli ed HCV treatment guidelines for comprehensive management of treatment-naïve patients

• Explain the patient-speci c needs, competing priorities, and comorbidities that are frequently associated with substance use disorders • Discuss best practices for longitudinal risk-strati ed support and surveillance following HCV cure

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurse Practitioner Continuing Education

This activity has been planned and implemented in accordance with the Accreditation Standards of the American Association of Nurse Practitioners (AANP) through the joint providership of Global Education Group and Integritas Communications. Global Education Group is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner

continuing education. Provider number: 110121. This activity is approved for 1.0 contact hour (which includes 0.1 hour of pharmacology).

Instructions to Receive Credit In order to receive credit for this activity, the participant must review the activity as well as successfully complete the posttest, by achieving a score of 70% or higher, and evaluation form.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosures of Con icts of Interest

Global Education Group (Global) adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scienti cally rigorous. All persons in a position to control the content of an accredited continuing education program provided by Global are required to

disclose all nancial relationships with any ineligible company within the past 24 months to Global. All nancial relationships reported are identi ed as relevant and mitigated by Global in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Global to assure objectivity and that the activity is free of commercial bias. All relevant nancial relationships have been mitigated. The faculty have the following relevant nancial relationships with ineligible companies: Sherilyn C. Brinkley, MSN, CRNP Consulting Fees: AbbVie Inc.; Speakers Bureau: AbbVie Inc., Gilead Sciences, Inc. Graham Foster, FRCP, PhD Consulting Fees, Honoraria, and Speakers Bureau: AbbVie Inc., BioMarin Pharmaceutical Inc., Gilead Sciences, Inc., GlaxoSmithKline, MSD (Merck & Co, Inc.), uniQure N.V. The planners and managers have the following relevant nancial relationships with ineligible companies:

Liddy Knight

Nothing to disclose

Ashley Cann

Nothing to disclose

Celeste Collazo, MD

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Ron Schaumburg (Medical Writer)

Nothing to disclose

Andrea Funk

Nothing to disclose

Lindsay Borvansky

Nothing to disclose

Kristin Delisi, NP

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/ or investigational uses of agents that are not indicated by the US Food and Drug Administration. Global Education Group (Global) and Integritas Communications do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the of cial prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

INTRODUCTION

VIDEO 1: Meet the Experts

The ability to treat and cure hepatitis C virus (HCV) infection is one of the greatest achievements of modern medicine. Since the discovery of the virus in 1989, treatment has rapidly evolved from interferon (IFN)- and ribavirin (RBV)-based therapies—with limited ef cacy and serious adverse effects—to direct-acting antiviral agents (DAAs)—targeted therapies with improved ef cacy and tolerability.1 By disrupting speci c steps within the HCV life cycle, these agents inhibit viral replication and infection. There are four classes of DAAs, with the latest generation demonstrating effectiveness regardless of virus genotype. Thus, in over 95% of HCV cases, completion of treatment with an oral pangenotypic DAA reduces the detectable level of viral RNA to zero, resulting in sustained virologic response (SVR) and cure with a low incidence of side effects.2

Because HCV infection is largely asymptomatic during its early stages, most cases are only diagnosed through vigilant screening and testing. Given the availability of effective, easily administered drug therapy, in 2016 the World Health Organization (WHO) established ambitious targets for increasing screening, testing, diagnosis, and treatment with the goal of eliminating the disease by 2030.3 Subsequently, in 2019 the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) issued Simpli ed Guidelines for managing treatment-naïve patients with HCV.2,4 Many countries have embraced the goals of the WHO and have implemented innovative public health policies to achieve them. Unfortunately, efforts are falling short as successful achievement requires expanding the pool of clinicians who are prepared to screen for and treat HCV.5

Primary care practitioners (PCPs) are ideally positioned to lead in the effort to eliminate HCV.6-9 The simpli ed guidelines and the availability of highly effective and simple DAA regimens make treatment of uncomplicated HCV in the primary care setting increasingly feasible. Underscoring the utility of PCP management of HCV are results from the real-world ASCEND study. Results revealed consistent SVR—cure rates—following HCV treatment by PCPs and nurse practitioners (NP) when compared with specialists (Figure 1).10 More notable is that the study population included patients with complex comorbidities, such as HIV coinfection, as well as patients with cirrhosis. However, despite evidence supporting the successful management of HCV in the primary care setting, nearly 6 out of 10 PCPs still refer all of their patients with HCV to a specialist.11 Additionally, due to the COVID-19 pandemic, adoption of the simpli ed guidelines has lagged.8

This educational activity was developed to empower PCPs, who are ideally positioned to lead frontline efforts, in helping to achieve the worldwide goal of eliminating HCV. Practices such as universal screening for HCV, the implementation of treatment regimens, and strategies for supporting, as well as monitoring, patients postcure will be provided.12

CHAPTER 1. THE WHY AND HOW OF HCV CURE: FROM EPIDEMIOLOGY TO ELIMINATION High-Risk Populations and Disproportionate Effects Approximately 400,000 deaths each year are attributed to HCV.13 Its worldwide prevalence is 1%, equivalent to about 70 million people.14 Left untreated, infection may progress to liver brosis, cirrhosis, and hepatocellular carcinoma (HCC). Consequently, HCV is the second leading cause of cancer-related deaths worldwide.15

The primary route of HCV transmission is percutaneous exposure to infected blood.16 Less common routes of transmission include organ transplantation, hemodialysis, and perinatal (vertical) transmission.11 Within the past few decades, demographics of the HCV-infected population has substantially changed (Figures 2 & 3).17-19 Initially, most cases within the United States consisted of “baby boomers” (those born between 1945 and 1964) who received HCV-infected blood products—mainly transfusions—prior to universal screening of blood supply. Currently, however, the highest rate of HCV infection is found among younger persons (20 to 39 years of age), an incidence that has quadrupled since 2010.20 This increase has been largely attributed to the ongoing opioid epidemic and associated use of injected drugs. In fact, at least 75% of new cases of HCV infection in the United States are related to injection drug use.21 The parallel and overlapping rise in

opioid drug abuse and HCV infection—a synergistic epidemic or “syndemic”—is not only common in the United States but widespread across the globe.22 Worldwide, approximately 60% of the nearly 16 million people who inject drugs (PWID) have had HCV. Because PWID are disproportionately affected by HCV, a global effort to effectively screen, diagnose, and treat HCV in this population is vital to the elimination of the disease.23

HCV coinfection with other blood-borne viruses, notably human immunode ciency virus (HIV) and hepatitis B virus (HBV) is also common.24 Similar to HCV, HIV and HBV can be transmitted by shared needles, shared injection equipment, and unsafe sexual practices. Therefore, incidence of overlapping infections in an individual is high.24,25 One study found the risk of HCV infection to

be 6 times higher among people with HIV.16 A separate metaanalysis of international data found that in a subgroup of HIVpositive patients, men who have sex with men (MSM), the global prevalence of coinfection with HCV is 6.3%.26 In general, global rates of HCV/HIV coinfection have risen to over 2 million.16 In the European Union (EU), rates of HCV/HIV coinfection among PWID range from 15% to 95% in Sweden and Italy, respectively.27 While statistics on the rate of HCV/HBV coinfected are limited by the lack of large-scale population-based studies, it’s estimated that 10% to 15% of patients with chronic HBV are also infected with HCV. Ultimately, coinfection is more complex than single infection, necessitating assessment of the dominant virus—since viral codominance is uncommon—and a focus on treating a single infection rst while treating secondary issues.24 Nevertheless, management of patients with dual infection is not only safe but effective in signi cantly reducing risk of liver-related complications and achieving SVR. Further, rates of SVR and HCV cure are similar within this patient population compared with those with HCV monoinfection.24

Another high-risk population for HCV infection is individuals who are currently or have formerly been incarcerated.28,29 In the United States, more than 2 million people are incarcerated and approximately 33% of these inmates are infected with HCV.30 In the European Union, about half a million people were detained in correctional facilities in 2018.31 Prisons in Western Europe are estimated to have an HCV prevalence of 15% and those in Eastern Europe, prevalence is as high as 21%.32 Many incarcerated individuals are from disadvantaged and underserved communities with poor access to health care prior to imprisonment.31 Further, compared with the general population, incarcerated individuals have a higher prevalence of communicable diseases, including HCV, HIV, and HBV due, in part, to increased exposure as well as

high-risk behaviors. Therefore, preventive measures to control the spread of disease with screening, diagnosis, and treatment will reduce the HCV burden not only within these correctional facilities but also among the general population following their release.31 HCV is also highly prevalent among migrant populations and people experiencing homelessness due to poor quality health practices.33 Migration is driven by political, socioeconomic, and environmental factors such as con ict, poverty, and climate change.34 In 2019, more than 270 million people were living outside of their countries of birth.33 One current example of a major driver of migration is the Russo-Ukrainian war. An estimated 3.5% of the Ukrainian population is living with HCV and, as of May 2022, more than 6 million Ukrainians have been displaced to nearby countries; with approximately half seeking refuge in Poland.35 Among those experiencing homelessness, one systematic review of international literature found the prevalence of HCV to range from 3.9% to 36.2%.36 Challenges such as stigmatization, cultural or language barriers, and access to affordable health care impede proper HCV screening, diagnosis, and treatment for HCV within these populations.27

Screening Practices and Strategies for Linkage to Care

Increased HCV screening, diagnosis, and linkage to care practices are a critical to attain HCV elimination goals. However, worldwide, only 1 in 5 people with HCV is aware of their infection.21 Achieving the WHO targets for 2030―which include a 90% reduction in new cases of chronic HCV, a 65% reduction in HCV deaths, and diagnosis and subsequent treatment of 80% of eligible patients―will require a multiprong approach incorporating

aggressive screening at the primary care level, improved access to treatment, monitoring, behavioral interventions, and harmreduction strategies.37-39 Currently, HCV screening policies vary widely in different regions and countries of the world. Even within the EU, member states take different approaches.40 France offers universal HCV screening,41 but 76% of EU countries do not yet target high-risk groups, such as migrants or MSM for HCV testing.27 In the Middle East, Egypt, which has perhaps the highest prevalence of HCV in the world (about 10%), has pursued an aggressive strategy of testing 50 million people, coupled with access to DAA therapy at very low prices for identi ed cases.42 As a result, Egypt is poised to become the rst country in the world to eliminate HCV within its borders―well ahead of the WHO’s target date of 2030. In 2020, the US Centers for Disease Control and Prevention (CDC) took a major step toward promoting universal screening by expanding its recommendation to include one-time screening for all adults at least 18 years of age.11,43 Similarly, the US Preventive Services Task Force also recommends universal screening for adults 18 to 79 years old and encourages screening others with HCV risk exposures.44 The CDC speci es that pregnant persons should be screened for HCV once during each pregnancy.44 The WHO recommends offering screening (using HCV serology testing) to individuals who are part of a population with high HCV prevalence or who have a history of HCV risk exposure or behavior.45 AASLD-IDSA recommends one-time routine screening for those over 18, but with the proviso that patients can opt out if they choose.22

Universal HCV screening (and subsequent treatment of identi ed cases) is cost-effective. Analysis shows that early diagnosis of

HCV, followed by treatment with DAAs, reduces the risk of cirrhosis and HCC and thus imposes a much lower cost burden (measured in quality-adjusted life-years (QALY) than does a no-screening strategy or a strategy of screening only members of a birth cohort.46 On the global level, however, there is still wide variability in the way countries address HCV screening. The potential risk of one-time-only screening is that such a strategy might not identify HCV in people who engage in behaviors that increase the risk of HCV after screening has occurred.8 To address that concern, some experts also recommend periodic testing for individuals at increased risk for HCV and annual testing for all PWID and all MSM infected with HIV.44 Harm-reduction strategies should also be adopted as they are highly effective in preventing the acquisition and transmission of HCV as well as other blood-borne infections such as HIV.25

VIDEO 2: Strategies to Optimize Engagement in PWID Populations

One key barrier to wider HCV screening—and subsequent treatment—is the stigma attached to the disease. HCV is associated with high-risk drug use, unsafe sexual practices, and homelessness. One recent study found that more than 95% of people with HCV infection have experienced some degree of disease-related stigma.47 Optimal medical care may be inhibited by negative perceptions of PWID or other disadvantaged persons engaging in high-risk behaviors.34 Conversely, people with HCV may not seek medical care due to fear of having to disclose high risk behaviors or judgment for their actions.8 Wider adoption of universal screening would aid in reducing stigma by eliminating the need to identify at-risk individuals or stratify populations according to risks.

Another barrier to wider screening for HCV is the need for 2 tests to con rm chronic infection, HCV antibody (HCV Ab) testing as well as HCV ribonucleic acid (HCV RNA) testing via polymerase chain reaction [PCR]. However, re ex testing—in which the lab automatically performs HCV RNA testing on the same positive HCV antibody serum sample—removes the additional effort of manually ordering follow-up con rmatory testing and avoids another patient venipuncture (Figure 4).48,49 Studies have also demonstrated the effectiveness of re ex testing, when adopted as standard practice, in signi cantly decreasing the rate of missed PCR con rmation of HCV infection. Another strategy for effective HCV screening and diagnosis is the use of a dried blood spot (DBS) test.50 This test provides a simpler means of detecting HCV antibodies and antigens in lieu of RNA testing. Among other advantages, DBS is accurate, inexpensive, and easy to administer in a variety of care settings, with the potential to improve screening in hard-to-reach populations, such as PWID and people living in remote areas.

As noted, HCV screening and con rmatory testing are critical to identifying HCV but are only effective if they lead to treatment. Linkage to care and treatment is essential. Toward that end, many countries have developed innovative strategies to coordinate HCV care and provide low barrier access to DAA therapy. The growing use of telemedicine (“virtual health”), for example—fueled by COVID-19 restrictions limiting in-person clinic visits—has proven effective.51 Founded in New Mexico, Project ECHO (Extension for Community Healthcare Outcomes) uses videoconferencing to connect PCPs with multidisciplinary specialists to expand care to rural and underserved populations across the globe.52 In New York State, the TEAM-C (Telemedicine for Evaluation, Adherence, and Medication for Hepatitis C) study is underway to compare outcomes of HCV care for people in opioid treatment programs delivered through either telemedicine or offsite specialty referrals.51 Peer-support programs, in which people who themselves have personally dealt with issues such as substance use disorders and HCV provide education and counseling, have also been shown to facilitate linkage to care and adherence to treatment.9

With respect to current rates of diagnosis, very few countries have achieved the WHO’s 2020 target for diagnosing at least 50% of HCV cases. Figure 5 illustrates the proportion of diagnosed cases in the European Economic Area (EEA), which includes the 27 members of the EU plus Iceland, Liechtenstein, and Norway.27 And while the rate of diagnosis is just under 50% in the United States, collectively, the United States isn’t projected to meet HCV elimination targets until 2037 (Figure 6).53

In summary, prevention, screening, diagnosis, and testing are necessary for eliminating HCV, but they are not suf cient in themselves. Linkage to care is essential. Individuals diagnosed with HCV must be connected to health care providers who can initiate treatment, promote adherence and harm-reduction strategies, assess response, and monitor appropriate patients postcure for progressive liver disease and reinfection.9,50 Given the recent recommendations for universal screening, the publication of simpli ed treatment guidelines, and the widening availability of easily administered, highly effective drug therapy, PCPs are ideally positioned to serve as vital frontline providers of HCV care for many patients infected with HCV.

References 1.

González Grande R, Santaella Leiva I, et al. Present and future management of viral hepatitis. World J Gastroenterol. 2021;27(47):8081-8102.

2. Ghany MG, Morgan TR, Panel A-IHCG. 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. 3. Blake A, Smith JE. Modeling hepatitis C elimination among people who inject drugs in New Hampshire. JAMA Netw Open. 2021;4(8):e2119092. 4. Dieterich DT. A simpli ed algorithm for the management of hepatitis C infection. Gastroenterol Hepatol (N Y). 2019;15(5 suppl 3):1-12. 5. Tran TT. Hepatitis C: Who should treat hepatitis C virus? The role of the primary care provider. Clin Liver Dis (Hoboken). 2018;11(3):66-68. 6. Andrews RR. Family physicians can manage adults with hepatitis C. Am Fam Physician. 2018;98(7):413-416. 7. Bagchi AD. A structural competency curriculum for primary care providers to address the opioid use disorder, HIV, and hepatitis C syndemic. Front Public Health. 2020;8:210. 8. Schneider MS. Improving HCV treatment and screening in primary care. ACP Internist. https://acpinternist.org/archives/2022/01/improving-hcv-treatment-and-screeningin-primary-care.htm. 2022. 9. Schwarz T, Horváth I, Fenz L, et al. Interventions to increase linkage to care and adherence to treatment for hepatitis C among people who inject drugs: A systematic review and practical considerations from an expert panel consultation. Int J Drug Policy. 2022;102:103588. 10. Kattakuzhy S, Gross C, Emmanuel B, et al. Expansion of treatment for hepatitis C virus infection by task shifting to community-based nonspecialist providers: a nonrandomized clinical trial. Ann Intern Med. 2017;167(5):311-318. 11. Castaneda D, Gonzalez AJ, Alomari M, et al. From hepatitis A to E: a critical review of viral hepatitis. World J Gastroenterol. 2021;27(16):1691-1715. 12. Jose R, Kahal D, Testa K, Goldstein ND. A qualitative study of implementing universal hepatitis C screening among adults at an urban community-based health provider in Delaware. Dela J Public Health. 2021;7(3):16-23. 13. Roblero JP, Arab JP, Mezzano G, et al. Hepatitis C virus infection: what are we currently doing in Latin America about WHO's proposals for 2030? Clin Liver Dis (Hoboken). 2021;18(2):72-75. 14. Centers for Disease Control and Prevention (CDC). Viral hepatitis Statistics and Surveillance. https://www.cdc.gov/hepatitis/statistics/index.htm 2021. 15. Russo FP, Zanetto A, Pinto E, et al. Hepatocellular carcinoma in chronic viral hepatitis: where do we stand? Int J Mol Sci. 2022;23(1):500. 16. Gobran ST, Ancuta P, Shoukry NH. A tale of two viruses: immunological insights into HCV/HIV coinfection. Front Immunol. 2021;12:726419.

17. Ryerson AB, Schillie S, Barker LK, et al. Vital signs: newly reported acute and chronic hepatitis C cases—United States, 2009-2018. MMWR Morb Mortal Wkly Rep. 2020;69(14):399-404.

18. Zibbell JE, Iqbal K, Patel RC, et al. Increases in hepatitis c virus infection related to injection drug use among persons aged ≤30 years—Kentucky, Tennessee, Virginia, and West Virginia, 2006–2012. MMWR Morb Mortal Wkly Rep. 2015;64(17):453-458. 19. Suryaprasad AG, White JZ, Xu F, et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012. Clin Infect Dis. 2014;59(10):1411-1419. 20. Maness DL, Riley E, Studebaker G. Hepatitis C: diagnosis and management. Am Fam Physician. 2021;104(6):626-635. 21. Feld JJ, Ward JW. Key elements on the pathway to HCV elimination: lessons learned from the AASLD HCV Special Interest Group 2020. Hepatol Commun. 2021;5(6):911-922. 22. AASLD-IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org/. Last updated October 2021. 23. Eckhardt B, Mateu-Gelabert P, Aponte-Melendez Y, et al. Accessible hepatitis C care for people who inject drugs: a randomized clinical trial. JAMA Intern Med. 2022;182(5):494-502. 24. Shahriar S, Araf Y, Ahmad R, et al. Insights into the coinfections of human immunode ciency virus-hepatitis B virus, human immunode ciency virus-hepatitis C virus, and hepatitis B virus-hepatitis C virus: prevalence, risk factors, pathogenesis, diagnosis, and treatment. Front Microbiol. 2021;12:780887. 25. European Monitoring Center for Drugs and Drug Addiction (EMCDDA). Hepatitis C. emcdda.europa.eu/topics/hepatitis_en. 2021. 26. Jin F, Dore GJ, Matthews G, et al. Prevalence and incidence of hepatitis C virus infection in men who have sex with men: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(1):39-56. 27. European Centre for Disease Prevention and Control (ECDC). Hepatitis B and C testing in the EU/EEA: progress in reaching the elimination targets. https:// www.ecdc.europa.eu/en/publications-data/hepatitis-b-and-c-testing-eueeaprogress-reaching-elimination-targets. March 2021. 28. Kamis KF, Wyles DL, Minturn MS, et al. Hepatitis C testing and linkage to care among adults on probation in a large US city. Open Forum Infect Dis. 2022;9(2):ofab636. 29. Taweh N, Schlossberg E, Frank C, et al. Linking criminal justice-involved individuals to HIV, hepatitis C, and opioid use disorder prevention and treatment services upon release to the community: progress, gaps, and future directions. Int J Drug Policy. 2021;96:103283. 30. World Population Review. Incarceration rates by country 2022. https:// worldpopulationreview.com/country-rankings/incarceration-rates-by-country.

31. Fiore V, De Vito A, Pontali E, et al. Chronic viral hepatitis in the Italian prison setting: prevalence, outcomes, literature needs and perspectives. Healthcare (Basel). 2021;9(9):1186.

32. Bielen R, Stumo SR, Halford R, et al. Harm reduction and viral hepatitis C in European prisons: a cross-sectional survey of 25 countries. Harm Reduct J. 2018;15(1):25. 33. Place V, Nabb B, Viksten Assel K, et al. Interventions to increase migrants' careseeking behaviour for stigmatised conditions: a scoping review. Soc Psychiatry Psychiatr Epidemiol. 2021;56(6):913-930. 34. Harris M, Guy D, Picchio CA, et al. Conceptualising hepatitis C stigma: a thematic synthesis of qualitative research. Int J Drug Policy. 2021;96:103320. 35. Devi S. Ukrainian health authorities adopt hepatitis C project. Lancet. 2020;396(10246):228. 36. Paisi M, Crombag N, Burns L, et al. Barriers and facilitators to hepatitis C screening and treatment for people with lived experience of homelessness: a mixed-methods systematic review. Health Expect. 2022;25(1):48-60. 37. Cardoso AC, Figueiredo-Mendes C, Villela-Nogueira CA, et al. Staging brosis in chronic viral hepatitis. Viruses. 2022;14(4):660. 38. Di Marco L, La Mantia C, Di Marco V. Hepatitis C: Standard of treatment and what to do for global elimination. Viruses. 2022;14(3):505. 39. Martin NK, Boerekamps A, Hill AM, et al. Is hepatitis C virus elimination possible among people living with HIV and what will it take to achieve it? J Int AIDS Soc. 2018;21(suppl 2):e25062. 40. Bechini A, Levi M, Falla A, et al. The role of the general practitioner in the screening and clinical management of chronic viral hepatitis in six EU countries. J Prev Med Hyg. 2016;57(2):E51-E60. 41. Pol S, Fouad F, Lemaitre M, et al. Impact of extending direct antiviral agents (DAA) availability in France: an observational cohort study (2015-2019) of data from French administrative healthcare databases (SNDS). Lancet Reg Health Eur. 2022;13:100281. 42. Waked I, Esmat G, Elsharkawy A, et al. Screening and treatment program to eliminate hepatitis C in Egypt. N Engl J Med. 2020;382(12):1166-1174. 43. Schillie S, Wester C, Osborne M, et al. CDC Recommendations for hepatitis C screening among adults—United States, 2020. MMWR Recomm Rep. 2020;69(2):1-17. 44. Owens DK, Davidson KW, Krist AH, et al. Screening for hepatitis C virus infection in adolescents and adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(10):970-975. 45. World Health Organization (WHO). Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection, Updated version, April 2016. https:// apps.who.int/iris/handle/10665/205035.

46. Eckman MH, Ward JW, Sherman KE. Cost Effectiveness of universal screening for hepatitis C virus infection in the era of direct-acting, pangenotypic treatment regimens. Clin Gastroenterol Hepatol. 2019;17(5):930-939.e939.

47. Saine ME, Szymczak JE, Moore TM, et al. The impact of disease-related knowledge on perceptions of stigma among patients with hepatitis C virus (HCV) infection. PLoS One. 2021;16(10):e0258143. 48. Hung CK, Demabildo M, Bernstein DE, et al. The effectiveness of inpatient re ex hepatitis C PCR testing in tertiary medical centers. Am J Gastroenterol. 2018;113:933. https://journals.lww.com/ajg/Fulltext/2018/10001/ The_Effectiveness_of_Inpatient_Re ex_Hepatitis_C.933.aspx. 49. CDC. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62(18):362-365. 50. Biondi MJ, van Tilborg M, Smookler D, et al. Hepatitis C core-antigen testing from dried blood spots. Viruses. 2019;11(9):830. 51. Talal AH, Markatou M, So kitou EM, et al. Patient-centered HCV care via telemedicine for individuals on medication for opioid use disorder: Telemedicine for Evaluation, Adherence and Medication for Hepatitis C (TEAM-C). Contemp Clin Trials. 2022;112:106632. 52. Sherbuk JE, Knick TK, Canan C, et al. Development of an interdisciplinary telehealth model of provider training and comprehensive care for hepatitis C and opioid use disorder in a high-burden region. J Infect Dis. 2020;222(suppl 5):S354-S364.

53. Sulkowski M, Cheng W-H, Marx S, et al. Estimating the year each state in the United States will achieve the World Health Organization’s elimination targets for hepatitis C. Adv Ther. 2021;38(1):423-440.

CHAPTER 2. CURRENT HCV DIRECT-ACTING ANTIVIRAL REGIMENS: WE’VE COME A VERY LONG WAY Within the past few years, the treatment of HCV infection has been streamlined—all patients with active HCV infection (except those with life expectancy less than 1 year) are candidates for curative treatment with oral direct-acting antiviral drugs (DAAs).1,2 The documented safety, ef cacy, and ease of administration of DAAs lends itself to a simpli ed and curative management strategy that can be practically implemented within the primary care setting. Task-shifting responsibility for HCV management to primary care increases treatment capacity by reducing the need for gastroenterology or hepatology specialty care— elds currently experiencing provider shortages.3,4

There are 4 classes of DAAs, each de ned by its mechanism of action and therapeutic target. Broadly, DAAs inhibit nonstructural (NS) proteins—NS3/4A protease, NS5A protein, NS5B nonnucleoside polymerase, and NS5B nucleoside polymerase— involved in HCV replication.5-7 The suf x “-asvir” is indicative of NS5A protein inhibitors (daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir, and pibrentasvir. The suf x “-buvir” is indicative of the NS5B nucleoside polymerase inhibitor (sofosbuvir) or nonnucleoside inhibitor (dasabuvir). The suf x “-previr” is indicative of NS3/4A protease inhibitors (boceprevir, telaprevir,

simeprevir, paritaprevir, grazoprevir, glecaprevir, and voxilaprevir).5 Currently, the cornerstone for the treatment of HCV infection is a combination of 2 or more DAAs.7

Timeline of DAA Development The rst-generation DAAs, telaprevir and boceprevir, were approved in the United States in 2011 for use in combination with pegylated interferon (PegIFN) and ribavirin (RBV) (Figure 7).8 These agents were soon withdrawn from the US market in 2014 and 2015, respectively, due to their broad range of adverse events, cumbersome administration schedule, and the overwhelming superiority of newer DAAs.

The second-generation DAAs—consisting of different combinations of sofosbuvir, simeprevir, ledipasvir, daclatasvir with or without RBV, and ombitasvir/paritaprevir/ritonavir with dasabuvir and/or RBV—were better tolerated, more convenient, and offered greater ef cacy with or without the need for RBV or PegIFN. However, the effect of these oral agents varied across virus genotype (HCV is classi ed into 6 major genotypes [GT] and

subdivided into various subtypes with GT1 accounting for over half of worldwide infection)5 and, therefore, HCV RNA genotyping was required, before selecting multitarget, multidrug combinations.9 In 2014, the rst single-pill regimen, xed-dose combination ledipasvir and sofosbuvir, was available for HCV,10 drastically improving convenience of administration and eliminating the need for RBV. Recognized by the American Chemical Society with a Heroes of Chemistry Award in 2015, this major scienti c achievement delivered a cure for GT1 with up to 99% ef cacy in just 1 pill, taken daily for 12 weeks.

VIDEO 3: Pangenotypic vs Non-Pangenotypic DAAs

The next year, 2016, marked yet another new era in the evolution of HCV therapy. This time, the rst oral, single-tablet, pangenotypic regimen for GT 1-6 was approved—sofosbuvir/velpatasvir (SOF/ VEL)—eliminating the need for HCV genotyping and signi cantly simplifying treatment for all patients.1,11 Shortly thereafter, 2 additional pangenotypic combination products for HCV treatment

were approved and available: glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir/voxilaprevir) (SOF/VEL/VOX).

Ef cacy Across High-Risk Populations

Activity of HCV infection is determined through quantitative HCV RNA testing, which is assessed prior to initiation and during treatment. A viral load <800,000 IU/mL is considered low and >800,000 IU/mL is high. Current therapies are effective for both high and low viral loads. Sustained virologic response (SVR) is de ned as achieving a viral load of <15 IU/mL (undetectable) following the 12-week posttreatment time point (SVR12) and is considered a marker for cure.12 All available pangenotypic HCV agents demonstrate comparable ef cacy and cure in up to 95% of cases, across all genotypes.13-17 Real-world ef cacy data for DAAs recommended for use within the simpli ed treatment guidelines can be seen in Figures 8-9.18,19 The safety and tolerability pro les of the DAAs are also excellent.2,19 The most common adverse effects, occurring in 10% or more cases, are headache and fatigue. Serious adverse events from HCV therapy affect less than 0.1% of patients, and no serious hepatoxicity has been reported.20

The availability of HCV drugs and their indications varies from country to country. In England, for example, clinicians must prescribe therapies proportionally according to a negotiated agreement with drug manufacturers.13

While coinfection with human immunode ciency virus (HIV) may seem to pose a challenge, HIV drug treatment has become better standardized, and management has increasingly fallen within the

purview of PCPs. Thus, many people living with diagnosed HIV are already engaged in primary care, ideally facilitating HCV testing and treatment. Patients coinfected with HCV and HIV should be managed according to the same basic HCV protocols as those without HIV infection. Pangenotypic DAA therapies recommended for use within the simpli ed treatment guidelines—SOL/VEL and GLE/PIB—offer equivalent ef cacy, safety, and tolerability outcomes irrespective of coinfection (Figure 10).21-24 Of note, before initiating HCV treatment in coinfected individuals, concomitant medications must be carefully reviewed to avoid potential drugdrug interactions. Studies have shown that using a “microelimination” approach that aims at screening and treating HCV within the speci c HIV-positive men who have sex with men (MSM) population can reduce acute HCV infection by 50% (at least in high-income countries), as demonstrated by programs undertaken in Australia, the Netherlands, and Scotland.25,26

Lastly, people who inject drugs (PWID) are among the high-risk populations disproportionately affected by HCV who would greatly bene t from HCV management within primary care. Although concerted efforts are needed to overcome multiple barriers to achieve optimal outcomes, pangenotypic DAA therapy

recommended for use within the simpli ed treatment guidelines— SOL/VEL and GLE/PIB—have proven ef cacious in this population regardless of whether they are receiving opioid substitution therapy (Figure 11).27,28 Additionally, 1 Italian study demonstrated that collocating DAA treatment within clinics that serve injection drug users can result in SVR rates of approximately 95%, similar to those seen in other settings.29 Another study that took place in China reported an SVR of 92% in PWID, compared with 99% among those who did not use drugs.30 A US-based study found that removing sobriety barriers, such as those requiring abstinence from drug use or participation in a drug treatment plan before HCV treatment begins, led to higher rates of cure.25 Consequently, imposing barriers on access to therapy substantially reduces the societal bene ts of treatment. Therefore, most treating physicians now adopt a “treat on contact” policy.

Summary

Pangenotypic DAA therapy is the rst line of defense against HCV. DAAs are safe and effective in all genotypes and a wide variety of patient types including high-risk populations of PWID and individuals coinfected with HIV. Further, because HCV can be

treated and cured with daily oral medications for 8 or 12 weeks offering minimal adverse effects, management can successfully take place within the primary care setting.

References 1.

AASLD-IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org/. Last updated October 5, 2021.

2. Falade-Nwulia O, Sulkowski MS. Hepatitis C virus treatment: simplifying the simple and optimizing the dif cult. J Infect Dis. 2020;222(suppl 9):S745-S757. 3. Andrews RR. Family physicians can manage adults with hepatitis C. Am Fam Physician. 2018:98(7):413-416. 4. Capraru C, Feld JJ. Remaining challenges in HCV elimination. J Hepatol. 2021;74(4):964-965. 5. Castaneda D, Gonzalez AJ, Alomari M, Tandon K, Zervos XB. From hepatitis A to E: a critical review of viral hepatitis. World J Gastroenterol. 2021;27(16):1691-1715. 6. Fabrizi F, Cerutti R, Messa P. An updated view on the antiviral therapy of hepatitis C in chronic kidney disease. Pathogens. 2021;10(11):1381. 7. Geddawy A, Ibrahim YF, Elbahie NM, et al. Direct acting anti-hepatitis C virus drugs: clinical pharmacology and future direction. J Transl Int Med. 2017;5(1):8-17. 8. González Grande R, Santaella Leiva I, López Ortega S, et al. Present and future management of viral hepatitis. World J Gastroenterol. 2021;27(47):8081-8102. 9. Basyte-Bacevice V, Kupcinskas J. Evolution and revolution of hepatitis C management: from non-A, non-B hepatitis toward global elimination. Dig Dis. 2020:1-6. 10. Yang T, Oliyai R, Kent KM. The making of the one pill—developing single tablet regimens for HIV and for HCV. Antivir Ther. 2022;27(2):13596535211067606. 11. Cornberg M, Manns MP. The curing regimens of HCV: a SWOT analysis. Antivir Ther. 2022;27(2):13596535211072672. 12. Pecoraro V, Banzi R, Cariani E, et al. New direct-acting antivirals for the treatment of patients with hepatitis C virus infection: a systematic review of randomized controlled trials. J Clin Exp Hepatol. 2019;9(4):522-538. 13. Brown RS, Buti M, Rodrigues L, et al. Glecaprevir/pibrentasvir for 8 weeks in treatmentnaïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: the EXPEDITION-8 trial. J Hepatol. 2020;72(3):441-449. 14. Dieterich DT. A simpli ed algorithm for the management of hepatitis C infection. Gastroenterol Hepatol (N Y). 2019;15(5 suppl 3):1-12.

15. Mei X, Lu H. Prevalence, diagnosis, and treatment of hepatitis C in mainland China. Glob Health Med. 2021;3(5):270-275.

16. Ridruejo E, Pereson MJ, Flichman DM, et al. Hepatitis C virus treatment failure: clinical utility for testing resistance-associated substitutions. World J Hepatol. 2021;13(9):1069-1078. 17. Saracco GM, Marzano A, Rizzetto M. Therapy of chronic viral hepatitis: the light at the end of the tunnel? Biomedicines. 2022;10(3):534. 18. Buggisch P, Wursthorn K, Stoehr A, et al. Real-world effectiveness and safety of sofosbuvir/velpatasvir and ledipasvir/sofosbuvir hepatitis C treatment in a single centre in Germany. PLOS ONE. 2019;14(4):e0214795. 19. Berg T, Naumann U, Stoehr A, et al. Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C infection: data from the German hepatitis C registry. Aliment Pharmacol Ther. 2019;49(8):1052-1059. 20. Forns X, Feld JJ, Dylla DE, et al. Safety of patients with hepatitis C virus treated with glecaprevir/pibrentasvir from clinical trials and real-world cohorts. Adv Ther. 2021;38(6):3409-3426. 21. Wyles D, Bräu N, Kottilil S, et al. Sofosbuvir and velpatasvir for the treatment of hepatitis C virus in patients coinfected with human immunode ciency virus type 1: an open-label, phase 3 study. Clin Infect Dis. 2017;65(1):6-12. 22. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599-2607. 23. Rockstroh JK, Lacombe K, Viani RM, et al. Ef cacy and safety of glecaprevir/ pibrentasvir in patients coinfected with hepatitis C virus and human immunode ciency virus type 1: the EXPEDITION-2 study. Clin Infect Dis. 2018;67(7):1010-1017. 24. Asselah T, Kowdley KV, Zadeikis N, et al. Ef cacy of glecaprevir/pibrentasvir for 8 or 12 weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol. 2018;16(3):417-426. 25. Feld JJ, Ward JW. Key elements on the pathway to HCV elimination: lessons learned from the AASLD HCV special interest group 2020. Hepatol Commun. 2021;5(6):911-922. 26. Martin NK, Boerekamps A, Hill AM, et al. Is hepatitis C virus elimination possible among people living with HIV and what will it take to achieve it? J Int AIDS Soc. 2018;21(suppl 2):e25062. 27. Grebely J, Dore GJ, Zeuzem S, et al. ef cacy and safety of sofosbuvir/velpatasvir in patients with chronic hepatitis C virus infection receiving opioid substitution therapy: analysis of phase 3 ASTRAL trials. Clin Infect Dis. 2016;63(11):1479-1481. 28. Puoti M, Foster GR, Wang S, et al. High SVR12 with 8-week and 12-week glecaprevir/ pibrentasvir therapy: an integrated analysis of HCV genotype 1-6 patients without cirrhosis. J Hepatol. 2018;69(2):293-300.

29. Foschi FG, Borghi A, Grassi A, et al. Model of care for microelimination of hepatitis C virus infection among people who inject drugs. J Clin Med. 2021;10(17).

30. Hsu JT, Hsu PI, Shie CB, et al. Comparison of the ef cacies of direct-acting antiviral treatment for HCV infection in people who inject drugs and non-drug users. Medicina (Kaunas). 2022;58(3).

CHAPTER 3. APPLYING THE SIMPLIFIED HCV TREATMENT GUIDELINES IN PRIMARY CARE PRACTICE The availability of safe, effective, pangenotypic direct-acting antivirals (DAAs) that avoid the need for ribavirin or interferon and minimize the pretreatment evaluation and on-treatment monitoring has greatly streamlined the treatment of HCV. In the past few years, leading professional societies including the World Health Organization (WHO), European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLDIDSA) have all embraced simpli ed guidelines for managing HCV. PCPs are ideally positioned to apply these guidelines to patients in their practice and to advance the global effort to eliminate HCV. Further, HCV treatment by PCPs avoids a delay in access to care posed by specialty referral or the potential for incomplete linkage to care to an outside provider.

In this section, we discuss the simpli ed guidelines developed by AASLD-IDSA for use in the United States. Clinicians who practice in other countries and regions should consult their local health regulatory agencies, since speci c policies (including access to speci c drugs, use of various assessment modalities, and followup protocols) can vary widely.

HCV Screening and Pretreatment Evaluation Laboratory Testing Universal screening for HCV with antibody testing is now a standard recommendation.1 In individuals who test positive, quantitative HCV-ribonucleic acid (RNA) testing should be done to document baseline viral load (viremia).2,3 Other pretreatment labs include: • HIV antigen/antibody • Hepatitis B surface antigen (HBsAg) • Complete blood count (CBC) • Liver function tests (ie, albumin, total and direct bilirubin, alanine aminotransferase [ALT], and aspartate aminotransferase [AST]) • Estimated glomerular ltration rate (eGFR) • Serum pregnancy testing for women of childbearing age (counseling on potential pregnancy risks of DAA therapy)

Liver Fibrosis Assessment

Liver brosis assessment is recommended to evaluate the presence, and the extent, of potential liver damage. The hepatitis C virus induces the immune response and triggers in ammation, which promotes brogenesis (liver stiffness), which in turn is a precursor of cirrhosis.4 Thus brosis is one of the key factors that predicts liver morbidity, including progression to hepatocellular carcinoma (HCC). Fibrosis can also be used to assess response to treatment with DAAs, which has been shown to reverse brosis in some patients.5 Until recently, liver biopsy was the gold standard for assessing brosis. However, other noninvasive tests are

VIDEO 4: Noninvasive Liver Fibrosis Assessment • The Fibrosis Index Based on Four Factors (FIB-4) score can be calculated by mathematical formula, also available as an online calculator (Figure 12), https://www.hepatitisc.uw.edu/page/ clinical-calculators/ b-4. A FIB-4 score <1.45 rules out advanced brosis, whereas a score of >3.25 indicates cirrhosis and accurately predicts high risk for HCC and mortality.6

available that can be used for pretreatment assessment of brosis.

• AST to platelet ratio index (APRI) is a laboratory test that is readily available and can be quickly completed in real time. APRI values of ≤0.3 and ≤0.5 rule out signi cant brosis and cirrhosis, respectively, and a value of ≥1.5 rules in signi cant brosis.7 • Proprietary serum-based brosis marker tests FibroTest, FibroSURE, FibroMeter, and Enhanced Liver Fibrosis Test provide information about the degree of liver in ammation and brosis.8 • Vibration-controlled transient elastography (FibroScan)5,9 uses ultrasound technology to assess liver stiffness in an ef cient, noninvasvie manner. A liver stiffness score >12.5 kPa indicates cirrhosis.3 FibroScan units can be used in various settings, including primary care practices and community clinics. They can be operated by trained staff and are portable enough to be deployed on mobile health units to deliver care to hard-to-reach patients with HCV, including people who inject drugs (PWID), those living in remote areas, or people experiencing homelessness.10 • Other clinical evidence of liver brosis or signs of cirrhosis, such as liver nodularity and/or splenomegaly on imaging, platelet count <150,000/mm3 etc, can also be used to determine the extent of liver disease.3

Based on results from the liver brosis assessment, the AASLDIDSA guidance provides 2 distinct simpli ed treatment algorithms for treatment-naïve adult patients infected with HCV. One provides guidance for management of HCV WITHOUT cirrhosis and the other provides guidance for HCV WITH COMPENSATED cirrhosis. Severity of cirrhosis—compensated vs uncompensated—is de ned according to the Child-Turcotte-Pugh (CTP) system, which provides a score based on the presence of complications of reduced liver function: ascites, jaundice (total bilirubin >2.0 mg/dL), hepatic encephalopathy, albumin ≥3.5 g/dL, and international normalized

ratio (INR) ≥1.7.2 An online calculator can be found here: https:// www.hepatitis.va.gov/cirrhosis/background/child-pughcalculator.asp. CTP class A (CTP score of <7) indicates compensated cirrhosis, wherein cirrhosis is present but asymptomatic and the liver can maintain most of its basic functions. Class B and C (CTP score ≥7) indicate decompensated cirrhosis. Patients infected with HCV who have been found to have decompensated cirrhosis (CTP class B or C) are not eligible for HCV management using the simpli ed HCV treatment guidance and should be referred to specialty care.1,11 Management of HCV without cirrhosis in treatment-naïve adult patients will be described rst.

Treatment-Naïve Adult Patients WITHOUT Cirrhosis Eligibility Criteria Treatment-naïve adult patients without cirrhosis are not eligible for simpli ed treatment if one of the following characteristics is present3: • Prior treatment for HCV • Cirrhosis (a separate algorithm is available for those with compensated cirrhosis) • Current or prior episode of decompensated cirrhosis • HIV or hepatitis B virus infection • Current pregnancy • Known or suspected HCC

• Prior liver transplantation

The initial therapeutic regimen for treatment-naive patients without cirrhosis who meet eligibility criteria include the following pangenotypic DAA options: • Glecaprevir/pibrentasvir (GLE/PIB) – 300/120 mg once daily (QD) for 8 weeks (with food) 3 - FDA label – indicated for patients aged ≥3 years; dispensed as xed-dose 100/40 mg tablets or 50/20 mg pellets12 OR • Sofosbuvir/velpatasvir (SOF/VEL) – 400/100 mg QD for 12 weeks (with or without food)3 - FDA label – indicated for patients aged ≥3 years; dispensed as xed-dose 400/100 mg tablets, 200/50 mg tablets, 200/50 mg pellets, or 150/37.5 mg pellets (pediatric dosing varies by body weight)13 There is no need to conduct a baseline assessment of resistanceassociated substitutions (RAS) in treatment-naïve patients without cirrhosis before initiating treatment.14 However, prior to initiation, the patient’s medication history and current medication list should be carefully reviewed to avoid potential drug interactions.15 A table of potential drug interactions is available at https:// www.hcvguidelines.org/node/647/print-full#monitoring-table-ddi. A free and frequently updated HCV drug interaction tool is also available at www.hep-druginteractions.org. Once treatment begins, no laboratory monitoring is required. This strategy of minimal monitoring (MINMON) has been shown to be effective and cost-ef cient.16 A recent study followed nearly 400 patients in 38 sites in Brazil, South Africa, Thailand, Uganda, and the United States who were treated with a pangenotypic regimen

Recommended DAA Regimens

(SOF/VEL) for 12 weeks. Minimal monitoring involved 4 components: no pretreatment genotyping, dispensing of all 84 tablets (1 pill per day x 12 weeks) at treatment initiation, no scheduled follow-up visits or laboratory monitoring, and 2 remote contacts (1 at week 4 to assess adherence and 1 at week 22 to schedule the outcome assessment). Sustained virologic response (SVR) was achieved in 95% of the study participants and the incidence of serious adverse effects was low (4%). As the investigators noted, the MINMON approach with SOF/VEL treatment was safe and effective, with cure rates comparable to those seen with standard monitoring. Thus, streamlining HCV treatment by minimizing monitoring requirements not only enhances the likelihood of successful HCV management within primary care but also signi cantly increases the potential for global HCV elimination.16

Patient Education and Risk Reduction Patients should receive education on proper administration of medication and counseling on adherence.15 Skipping doses or taking pills at inconsistent times of the day can reduce the ef cacy of DAAs and increase risk of resistance. The treatment plan should include practical advice for patients, including carrying their medications with them if they travel, or if they are subject to incarceration. Counseling should also include prevention strategies to avoid reinfection or causes of injury to the liver (ie. excess alcohol use, engaging in unprotected sex, high-risk injection practices, drug-induced liver toxicity, etc). Lastly, patients should be knowledgeable of SVR12 as a goal for treatment as well as an indication of cure.

Posttreatment Follow-up

AASLD-IDSA recommends quantitative HCV RNA and liver function tests 12 weeks or later following completion of therapy to con rm

SVR12 or virologic cure, as well as normalization of liver enzymes. Patients with ongoing risk for HCV infection, including PWID and men who have sex with men (MSM) engaging in high-risk sexual practices, should continue to receive risk reduction support and annual HCV RNA screening. If after 12 weeks the HCV treatment fails to achieve SVR or if liver enzymes remain persistently elevated, the patient should be referred to specialty care.

Treatment-Naïve Adult Patients WITH COMPENSATED Cirrhosis Eligibility Criteria Treatment-naïve adult patients with compensated cirrhosis are not eligible for the simpli ed approach if any of the following characteristics are present2: • Current or prior episode of decompensated cirrhosis • Prior HCV treatment • End-stage renal disease (eGFR <30 mL/min/m2) • HIV or HBsAg positive • Current pregnancy • Known or suspected HCC • Prior liver transplantation

Patients with compensated cirrhosis should have a liver ultrasound within the prior 6 months of treatment to rule out HCC and subclinical ascites. Further, lifelong cirrhosis management is indicated including HCC screening with liver ultrasound and liver function tests every 6 months.

Recommended DAA Regimens Initial pangenotypic DAA options for treatment-naive patients with compensated cirrhosis who meet eligibility criteria are similar to those of patients without cirrhosis, with the exception of pretreatment HCV genotype testing if SOF/VEL is the regimen of choice. See below for recommendations: • GLE/PIB – 300/120 mg QD for 8 weeks (with food)2 OR • SOF/VEL – 400/100 mg QD for 12 weeks for genotype (GT) 1, 2, 4, 5, or 6 (with or without food)2 - Pretreatment genotype testing required; if genotype 3 is present, patients should undergo RAS testing and be evaluated for the presence of a speci c polymorphism (Y93H) associated with the NS5A protein - Patients without Y93H can be treated with the above SOF/VEL regimen - If the Y93H RAS is present, alternative regimens are recommended per HCV Guidance Monitoring for patients with compensated cirrhosis may include, at the discretion of the provider, blood tests to assess for the rare occurrence of hepatic decompensation while on treatment. If signs of worsening liver function are found, patients should be referred to a specialist.2

Patient Education and Risk Prevention

Like patients without cirrhosis, patients with compensated cirrhosis should receive education on proper administration of medication, potential side effects, and the importance of treatment adherence. Harm-reduction strategies (alcohol abstinence, safe sexual and injection use practices) should also be incorporated

into patient encounters before, during and after treatment to prevent progressive liver disease and reinfection.

Posttreatment Follow-up SVR should be assessed at 12 weeks posttreatment or later. If cure is achieved, patients with compensated cirrhosis should undergo lab assessment of liver function and abdominal ultrasound every 6 months to screen for HCC. Endoscopic surveillance to assess for portal hypertension and the presence of esophageal varices is also recommended every 2 to 3 years, as these are common complications of HCV-related cirrhosis.2,3 Patients with ongoing risk for HCV infection, including PWID and MSM, should continue to receive risk-reduction support and annual HCV RNA screening. If HCV treatment fails to result in cure, the patient should be referred to specialty care.

Special Circumstances and Rescue Therapy Patients who are receiving diabetes medication should be monitored for hypoglycemia during HCV treatment. It is also recommended that patients receiving warfarin be monitored for any changes to their anticoagulation status with international normalized ratio (INR).2,3

Treatment failure with DAAs is rare but it does occur. Retreatment by a specialist is recommended by the AASLD-IDSA. The main option for retreatment, or rescue therapy, is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX; xed-dose combination 400/100/100 mg tablets, QD).17,18,19 Severe cirrhosis, HCC, HCV GT3a or a rare subtype, GT1a, have been associated with failure of SOF/VEL/VOX.17 Following SOF/VEL/VOX, the next-line

therapeutic option includes a combination of SOF + GLE/PIB + ribavirin.14 A small case series found that 12 of 12 patients taking this 4-drug combination achieved SVR with no safety concerns.20

Summary Treatment-naïve patients with HCV infection, without cirrhosis or with compensated cirrhosis, are appropriate candidates for HCV management within the primary care setting. PCPs play a major role in HCV screening, evaluating liver function and liver brosis, assessing risk for potential complications, and managing the holistic care of patients over the long term. In uncomplicated cases, HCV treatment outcomes in primary care are comparable to those seen in specialty care.11 Simpli ed guidelines have recently been promulgated globally to guide the management of HCV.2,3 The availability of pangenotypic DAA regimens has changed the treatment paradigm, offering safe, highly effective therapies with short treatment durations that lead to cure rates of >95% in the majority of those infected. As a result, tools to eliminate HCV are readily available. However, the challenge of providing access to DAA therapies irrespective of patient characteristics and demographics persists. Thus, the continued adoption of HCV screening and treatment practices into primary care is a fundamental support to low-barrier access to HCV treatment and cure.

References 1.

AASLD-IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. https://www.hcvguidelines.org/. Last updated October 2021.

2. AASLD-IDSA. Simpli ed HCV treatment algorithm for treatment-naive adults with compensated cirrhosis. https://www.hcvguidelines.org/sites/default/ les/fullguidance-pdf/AASLD-IDSA_HCV-Guidance_TxN-Simpli ed-Tx-Comp-Cirr_e.pdf. August 2020.

3. AASLD-IDSA. Simpli ed HCV treatment algorithm for treatment-naive adults without cirrhosis. https://www.hcvguidelines.org/treatment-naive/simpli ed-treatment. September 2021. 4. Cardoso AC, Figueiredo-Mendes C, Villela-Nogueira CA, et al. Staging brosis in chronic viral hepatitis. Viruses. 2022;14(4):660. 5. Luna-Cuadros MA, Chen HW, Hanif H, et al. Risk of hepatocellular carcinoma after hepatitis C virus cure. World J Gastroenterol. 2022;28(1):96-107. 6. Xu XL, Jiang LS, Wu CS, et al. The role of brosis index FIB-4 in predicting liver brosis stage and clinical prognosis: a diagnostic or screening tool? J Formos Med Assoc. 2022;121(2):454-466. 7. Loaeza-del-Castillo A, Paz-Pineda F, Oviedo-Cárdenas E, et al. AST to platelet ratio index (APRI) for the noninvasive evaluation of liver brosis. Ann Hepatol. 2008;7(4):350-357. 8. Dieterich DT. A simpli ed algorithm for the management of hepatitis C infection. Gastroenterol Hepatol (N Y). 2019;15(5 suppl 3):1-12. 9. Harrison SA. Utilization of FibroScan testing in hepatitis C virus management. Gastroenterol Hepatol (N Y). 2015;11(3):187-189. 10. Sherbuk JE, Knick TK, Canan C, et al. Development of an interdisciplinary telehealth model of provider training and comprehensive care for hepatitis C and opioid use disorder in a high-burden region. J Infect Dis. 2020;222(suppl 5):S354-S364. 11. Andrews RR. Family physicians can manage adults with hepatitis C. Am Fam Physician. 2018:98(7):413-416. 12. MAVYRET [prescribing information]. North Chicago, IL: AbbVie Inc; 2021. 13. EPCLUSA [prescribing information]. Foster City, CA: Gilead Sciences, Inc; 2022. 14. Ridruejo E, Pereson MJ, Flichman DM, et al. Hepatitis C virus treatment failure: clinical utility for testing resistance-associated substitutions. World J Hepatol. 2021;13(9):1069-1078. 15. Molino S, Cottreau J. Treatment of hepatitis C virus: an update on medications and patient education. Orthop Nurs. 2019;38(4):273-277. 16. Solomon SS, Wagner-Cardoso S, Smeaton L, et al. A minimal monitoring approach for the treatment of hepatitis C virus infection (ACTG A5360 [MINMON]): a phase 4, openlabel, single-arm trial. Lancet Gastroenterol Hepatol. 2022;7(4):307-317. 17. Dietz J, Di Maio VC, de Salazar A, et al. Failure on voxilaprevir, velpatasvir, sofosbuvir and ef cacy of rescue therapy. J Hepatol. 2021;74(4):801-810. 18. Schmitt A, Günther R, Mauss S, et al. Treatment-failure to direct antiviral HCV regimens in real world: frequency, patient characteristics and rescue therapy—data from the German hepatitis C registry (DHC-R). Z Gastroenterol. 2020;58(4):341-351.

19. VOSEVI [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2019.

20. Saxena V, McKinney J, Chamberland SL, et al. Excellent ef cacy and safety of sofosbuvir, glecaprevir, pibrentasvir and ribavirin for retreatment of chronic hepatitis C after sofosbuvir, velpatasvir and voxilaprevir failure. Presented at: AASLD, The Liver Meeting; November 12-15, 2021; Parallel session 14: Hepatitis C Oral Session.

CHAPTER 4. TAKING THE LONG VIEW: POSTCURE PATIENT SUPPORT AND DISEASE SURVEILLANCE Postcure Reinfection and Patient Support Despite being cured of HCV infection, patients who engage in highrisk behavior are at increased risk of reinfection.1 The overall 5year risk of reinfection is about 11% among vulnerable populations such as current or former PWID, incarcerated persons, and MSM with high-risk sexual practices; the risk is even greater, about 15%, among those coinfected with HIV.2 Transient populations— which include migrants and people experiencing homelessness— are also at increased risk for reinfection. In many cases, however, treatment may serve as prevention within these populations, decreasing transmission and improving long-term clinical outcomes for the individual as well as the community (Figure 13).3-5

Risk-based screening and retesting for HCV is effective and costef cient.2 Reinfection with HCV is identi ed through HCV RNA testing, not through the presence of HCV antibodies.6 HCV antibodies will remain positive lifelong but do not protect against reinfection. The presence of HCV RNA, on the other hand, indicates active HCV disease. To determine the presence of active HCV disease, HCV RNA is indicated. In addition to retesting, patients vulnerable to HCV reinfection should be provided additional support and counseling regarding prevention strategies and techniques for mitigating risks to avoid reinfection and transmission of infection to others.6 For PWID, this not only includes addiction treatment but training in, or greater linkage to, harm-reduction strategies such as needle exchange programs, access to supervised injection sites, and use of directly observed opioid substitution therapy as warranted (Table 1).7-12

Therapeutic nihilism is frequent among clinicians with respect to treating or retreating HCV in PWID. However, treatment should not be withheld from patients because of possible risk of reinfection. AASLD-IDSA HCV Guidance states, “Active or recent drug use or a concern for reinfection is not a contraindication to HCV treatment.”2 Retreatment for HCV with DAA is not only possible, it is uncomplicated—mirroring that of treatment-naïve patients—and results in high rates of (re-)cure.13

Long-term Surveillance of Hepatic and Extrahepatic Complications

The development of HCC is a major concern in patients with cirrhosis who have been treated for HCV as the onset of disease may occur as late as 10 years after cure.14 While the risk is signi cantly reduced following successful DAA treatment—the annual incidence of HCC is <1% among those achieving SVR compared with 3.5% in those not achieving SVR13—the annual risk is 1.4% to 4.9%.6,15 Higher rates of HCC also occur among patients with additional risk factors such as obesity, nonalcoholic fatty liver

Whether to conduct surveillance among patients with advanced brosis is a subject of ongoing debate.14 One study in postcure HCV patients that used a combination of factors–changes from baseline in liver stiffness, FIB-4 score, and serum albumin–found that patients with compensated advanced brosis had a very low risk of developing HCC.6 While guidelines from the European Association for the Study of the Liver (EASL) recommend ultrasound surveillance in patients with advanced brosis, METAVIR stage F3, based on the presence of individual risk factors, surveillance for this population is not recommended in US guidelines.14

VIDEO 5: Long-term Monitoring for HCC

disease, type 2 diabetes, or alcohol abuse.16 Thus, continued surveillance using ultrasound, with or without α-fetoprotein (AFP), every 6 months for patients with cirrhosis who were treated for HCV is recommended by the AASLD-IDSA.6,17

While the long-term surveillance of posttreatment HCV patients traditionally lies within the purview of specialty care, cases involving patients with moderate brosis who achieved SVR can be managed in the primary care setting.16 The same is true with respect to extrahepatic manifestations of disease. A number of extrahepatic complications can arise from liver disease, including autoimmune disorders, lymphoma, cardiovascular disease, and psychological disorders (Figure 14).6,18,19 Even after cure, many patients may experience long-term consequences of HCV infection and primary care providers are often the rst point of contact for the assessment and management of extrahepatic consequences of HCV.20

Liver Transplant in the Era of DAA Therapy Since the advent of DAA therapy, the need for transplantation due to HCV has declined dramatically.15 In the United States, the rate of HCV-associated liver transplantation fell from 45% in 2010 to just 19% in 2019.21 DAA therapy can be administered prophylactically to patients with HCV who are awaiting transplant to reduce the risk of HCV recurrence, or it can be given after transplant if the patient tests positive for HCV.15 In fact, SVR rates among transplant patients treated with 12 weeks of DAA therapy approach 100% with no apparent impact on graft survival. The availability of DAAs has also meant that livers infected with HCV can be used for transplant in patients with or without HCV. This has resulted in a greater number of livers available for life-saving transplantation as well as shorter wait-list times.15

Summary

DAA therapy for HCV is highly effective, but even after cure, the risk of reinfection or future complications of disease, such as HCC or liver decompensation, are possible. Therefore, it is imperative that providers as well as patients are educated on strategies to prevent reinfection—including harm-reduction techniques and long-term HCC screening and liver function monitoring for patients with advanced brosis and cirrhosis. This holistic approach to HCV management and postcure monitoring not only supports efforts to eliminate HCV but mitigates its long-term consequences while optimizing liver health outcomes.6,22

References 1.

Andrews RR. Family physicians can manage adults with hepatitis C. Am Fam Physician. 2018;98(7):413-416.

2. AASLD-IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org/. Last updated October 5, 2021. 3. Smith-Palmer J, Cerri K, Valentine W. Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life bene ts. BMC Infect Dis. 2015;15:19. 4. Negro F, Forton D, Craxì A, et al. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology. 2015;149(6):1345-1360. 5. George SL, Bacon BR, Brunt EM, et al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology (Baltimore, Md). 2009;49(3):729-738. 6. Dunn R, Wetten A, McPherson S, et al. Viral hepatitis in 2021: the challenges remaining and how we should tackle them. World J Gastroenterol. 2022;28(1):76-95. 7. Breve F, Batastini L, LeQuang JAK, et al. Mobile narcotic treatment programs: on the road again? Cureus. 2022;14(3):e23221. 8. Capraru C, Feld JJ. Remaining challenges in HCV elimination. J Hepatol. 2021;74(4):964-965. 9. Biondi MJ, van Tilborg M, Smookler D, et al. Hepatitis C core-antigen testing from dried blood spots. Viruses. 2019;11(9):830. 10. Feld JJ, Ward JW. Key Elements on the pathway to HCV elimination: lessons learned from the AASLD HCV Special Interest Group 2020. Hepatol Commun. 2021;5(6):911-922. 11. Taweh N, Schlossberg E, Frank C, et al. Linking criminal justice-involved individuals to HIV, Hepatitis C, and opioid use disorder prevention and treatment services upon release to the community: progress, gaps, and future directions. Int J Drug Policy. 2021;96:103283. 12. Trooskin SB, Dore G, Kostman J. We must do better: addressing HCV treatment barriers in persons who inject drugs in the United States. J Infect Dis. 2020;222(suppl 9):S773-S781. 13. Falade-Nwulia O, Sulkowski MS. Hepatitis C virus treatment: simplifying the simple and optimizing the dif cult. J Infect Dis. 2020;222(suppl 9):S745-S757. 14. Russo FP, Zanetto A, Pinto E, et al. Hepatocellular carcinoma in chronic viral hepatitis: where do we stand? Int J Mol Sci. 2022;23(1):500. 15. Castaneda D, Gonzalez AJ, Alomari M, et al.. From hepatitis A to E: A critical review of viral hepatitis. World J Gastroenterol. 2021;27(16):1691-1715.

16. Luna-Cuadros MA, Chen HW, Hanif H, et al. Risk of hepatocellular carcinoma after hepatitis C virus cure. World J Gastroenterol. 2022;28(1):96-107.

17. Isfordink CJ, Maan R, de Man RA, et al. Should we continue surveillance for hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection? Eur J Intern Med. 2021;94:6-14. 18. Mazzaro C, Quartuccio L, Adinol LE, et al. A review on extrahepatic manifestations of chronic hepatitis C virus infection and the impact of direct-acting antiviral therapy. Viruses. 2021;13(11):2249. 19. Nevola R, Rinaldi L, Zeni L, et al. Changes in clinical scenarios, management, and perspectives of patients with chronic hepatitis C after viral clearance by direct-acting antivirals. Expert Rev Gastroenterol Hepatol. 2021;15(6):643-656. 20. He N, Feng G, Hao S, et al. The impact of direct-acting antivirals on quality of life in patients with hepatitis C virus infection: A meta-analysis. Ann Hepatol. 2022;27(4):100705. 21. Wang S, Toy M, Hang Pham TT, So S. Causes and trends in liver disease and hepatocellular carcinoma among men and women who received liver transplants in the U.S., 2010-2019. PLoS One. 2020;15(9):e0239393.

22. Amoako A, Ortiz-Paredes D, Engler K, Lebouché B, Klein MB. Patient and provider perceived barriers and facilitators to direct acting antiviral hepatitis C treatment among priority populations in high income countries: a knowledge synthesis. Int J Drug Policy. 2021;96:103247.

CLINICAL RESOURCE CENTER™ Clinical Practice Guidelines CDC Recommendations for Hepatitis C Screening Among Adults in the United States. Centers for Disease Control and Prevention (CDC). Last reviewed July 2020. https://www.cdc.gov/hepatitis/hcv/guidelinesc.htm

HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for the Study of Liver Diseases (AASLD)/ Infectious Diseases Society of America (IDSA), Last updated March 2021. https://www.hcvguidelines.org/

Simpli ed HCV Treatment Algorithm for Treatment-Naive Adults Without Cirrhosis. American Association for the Study of Liver Diseases (AASLD)/ Infectious Diseases Society of America (IDSA). Last updated August 2020.

https://www.hcvguidelines.org/sites/default/ les/full-guidance-pdf/AASLDIDSA_HCV-Guidance_TxN-Simpli ed-Tx-No-Cirr_e.pdf

Clinical Resources Recommended Testing Sequence for Identifying Current HCV Infection Center for Disease Control and Prevention; Morbidity and Mortality Weekly Report (MMWR) https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_ ow.pdf

Hepatitis C Online Tools and Calculators: APRI Hepatitis C Online: University of Washington https://www.hepatitisc.uw.edu/page/clinical-calculators/apri.

Hepatitis C Online Tools and Calculators: FIB-4 Hepatitis C Online: University of Washington https://www.hepatitisc.uw.edu/page/clinical-calculators/ b-4

HEP Drug Interactions University of Liverpool. https://www.hep-druginteractions.org/

Action and Advocacy: National HCV Resources Center for Health Law and Policy Innovation (CHLPI) CHLPI advocates for legal, regulatory, and policy reforms to improve the health of underserved populations. It has played a pivotal role in removing Medicaid restrictions on HCV treatment.

https://www.chlpi.org/

Hepatitis Education Project (HEP) HEP provides support, education, advocacy, and direct services for people affected by hepatitis, and works to raise hepatitis awareness among patients, medical providers, and the general public. http://hepeducation.org/

National Viral Hepatitis Roundtable National Viral Hepatitis Roundtable (NVHR) is a coalition working together to eliminate hepatitis B and C in the United States It offers practical online resources for practice management. https://nvhr.org/

Substance Abuse and Mental Health Services Administration (SAMHSA): Locator Map SAMHSA provides an interactive national map that facilitates identi cation of local resources and services for substance use and mental health disorders. https:// ndtreatment.samhsa.gov/

National Harm Reduction Coalition The National Harm Reduction Coalition builds evidence-based strategies with and for people who use drugs. http://harmreduction.org/

Patient Resources Hepatitis C Information Center

American Liver Foundation. The American Liver Foundation’s Hepatitis C Information Center website is a dedicated online

information and resource center created in support of individuals impacted by HCV infection. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/ hepatitis-c/

Hepatitis C Questions and Answers for the Public Centers for Disease Control and Prevention (CDC). Last reviewed July 2020. The CDC is a division within the US Department of Health and Human Services (DHHS), the principal agency for protecting the health of all Americans. This patient-directed website addresses basics across the HCV clinical continuum. https://www.cdc.gov/hepatitis/hcv/cfaq.htm

Suggested Reading Expansion of treatment for hepatitis C virus infection by task shifting to community-based nonspecialist providers: a nonrandomized clinical trial. Kattakuzhy S, et al. Ann Intern Med. 2017;167(5):311-318. https://pubmed.ncbi.nlm.nih.gov/28785771/

Patient centeredness in hepatitis C direct-acting antiviral treatment delivery to people who inject drugs: a scoping review. Abdelwadoud M, et al. Patient. 2021;14(5):471-484. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357769/pdf/ 40271_2020_Article_489.pdf

Association between opioid agonist therapy and testing, treatment uptake, and treatment outcomes for hepatitis C infection among people who inject drugs: a systematic review and meta-analysis. Grebely J, et al. Clin Infect Dis. 2021;73(1):e107-e118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246796/pdf/ciaa612.pdf

Minimal monitoring of treatment for hepatitis C virus infection. Sulkowski MS. Gastroenterol Hepatol. 2021;17(5):230-232. https://www.gastroenterologyandhepatology.net/ les/2021/05/ gh0521Sulkowski-1.pdf

The curing regimens of HCV: a SWOT analysis. Cornberg M, Manns MP. Antivir Ther. 2022;27(2):13596535211072672. https://pubmed.ncbi.nlm.nih.gov/35491553/

Therapy of chronic viral hepatitis: the light at the end of the tunnel? Saracco GM, et al. Biomedicines. 2022;10(3):534. https://pubmed.ncbi.nlm.nih.gov/35327336/

Real-world effectiveness and safety of sofosbuvir/ velpatasvir and ledipasvir/sofosbuvir hepatitis C treatment in a single centre in Germany. Buggisch P, et al. PLOS ONE. 2019;14(4):e0214795.

https://pubmed.ncbi.nlm.nih.gov/30946776/ #:~:text=Conclusion%3A%20Overall%2C%20SOF%2FVEL,global%20effort s%20to%20eradicate%20HCV.

Real-world effectiveness and safety of glecaprevir/ pibrentasvir for the treatment of chronic hepatitis C infection: data from the German hepatitis C registry. Berg T, et al. Aliment Pharmacol Ther. 2019;49(8):1052-1059. https://pubmed.ncbi.nlm.nih.gov/30874328/

Key elements on the pathway to HCV elimination: lessons learned from the AASLD HCV special interest group 2020. Feld JJ, Ward JW. Hepatol Commun. 2021;5(6):911-922. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1731