Fundamentals of HCV Treatment

Author: Philip Bolduc, MD. New England AETC
This lesson will focus on the fundamentals of treating HCV infection. Understanding the treatment of HCV mono-infection is critical to mastering care of HIV/HCV co-infection.

1. July 2017 Updated: December 2018 Lesson 1: Fundamentals of Hepatitis C Virus Treatment Core Competency 4: HCV Treatment

2. Lesson Objectives At the end of this lesson, participants will be able to: Understand the goal of treatment Choose appropriate treatment settings Describe systems for successful treatment Identify patients to treat Evaluate patients before treatment Select the correct treatment regimen Monitor during and after treatment Reassess if treatment fails Build further knowledge 2

3. Goal of Treatment “The goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by a sustained virologic response. 1 AASLD-IDSA https://www.hcvguidelines.org/ 3

4. Current All-Oral Therapies 2 Highly effective, simple, well-tolerated Cure Rates Sustained HCV Virologic Response (%) IFN 6 Mos PegIFN/RBV 12 Mos IFN 12 Mos IFN/RBV 12 Mos PegIFN 12 Mos 2001 1998 2011 Standard Interferon (IFN) Ribavirin (RBV) Peginterferon ( pegIFN ) 1991 PegIFN/ RBV + DAA IFN/RBV 6 Mos 6 16 34 42 39 55 70+ 20 40 60 80 100 DAA + RBV ± PegIFN 90+ 2013 All–Oral DAA± RBV Current 95+ All-Oral Therapy Direct-Acting Antivirals (DAAs) Box T, Clinical Care Options. 2017

5. Then (pre-2013) and Now Cure rates are much higher today, in some populations close to 100% There is far less medication toxicity Length of treatment is shorter While HCV medications are expensive, the cost has come down considerably and they have been shown to be highly cost-effective in the long run Treatment depends on genotype, degree of liver damage and prior treatment history Pan-genotypic medications have simplified treatment considerably 5

6. HCV Treatment Workforce “All persons with current active HCV infection should be linked to a practitioner who is prepared to provide comprehensive management.” 3 New potent and well-tolerated hepatitis C treatments present an opportunity to expand the number of advanced practice practitioners and primary care physicians trained in the management and treatment of HCV infection. 6

7. HCV Provider by Stage of Liver Disease 1 7 Child- Turcotte -Pugh Class A (score 5-6) GI and HCV-informed ID and primary care providers Child-Turcotte-Pugh Class B (score 7-9) Hepatologists GI and HCV-informed ID and primary care providers in close communication with a supporting hepatologist Child- Turcotte -Pugh Class C (score ≥10) Hepatologists For an online calculator of the Child-Pugh- Turcotte score, see: http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp

8. Help Patients Succeed Use pharmacist, nurse or medical assistant-based medical case management to: Schedule patient intakes Submit and track prior authorizations Resolve pharmacy and medication delivery issues Make reminder calls for patient visits and labs Field patient questions 8

9. Appropriate Patients for Treatment 1 See Lesson 3.2 to review who and when to treat Goal should be to treat whenever possible to reduce HCV transmission and HCV-related morbidity and mortality Treatment may not be of sufficient benefit to justify the cost if life expectancy is <12 months 9

10. Preparing for Treatment Approval for treatment varies by insurer. Factors may include: Fibrosis stage Sobriety requirements Prescriber type: Hepatology, GI, ID, primary care Some states (for example, Maryland) provide and require a certification process to prescribe HCV medications A good place to start is to investigate your state’s Medicaid HCV prior authorization process as many have adopted a standardized form used across various insurers 10

11. Preparing Patients for Treatment Achieve medical stability before HCV treatment HCV treatment usually is not urgent; most experts prefer to control HIV infection, cardiac disease, asthma, etc. prior to HCV treatment Waiting until the patient has no acute or unstable chronic conditions avoids confounding comorbid symptoms with treatment side effects Patient must be able to understand and adhere to care plan HCV medications are expensive – use resources wisely by working aggressively to resolve barriers to success before treating 11

12. Pretreatment Evaluation – History and Exam: Evaluate symptoms and medical comorbidities Ask about alcohol and drug use that may impact treatment Elicit information about housing or food insecurity that may impact treatment Reconcile medication list Look for stigmata of liver disease (see Module 3) 12

13. Pre-treatment Tests 1 Fibrosis staging: (see Module 3 for more details) AASLD-IDSA recommends combining a non-invasive serum biomarker assay (such as FIB-4, FibroSURE , FIBROSpect II) and elastography (vibration-controlled transient liver elastography , MR elastography , acoustic radiation force impulse) Liver biopsy is reserved for situations in which discordance between serum and elastography tests will impact clinical decisions May also use the biomarker assay alone and reserve elastography or biopsy for intermediate results (i.e. F2-F3) Individuals with clinically evident cirrhosis do not require additional staging (biopsy or noninvasive assessment) Liver ultrasound for most patients; consider CT scan if cirrhosis present 13 FIB-4 Calculator: https://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4

14. Pre-treatment Labs 4 Any time prior to treatment: HCV genotype and VL (but insurers often require a VL within 6 months of treatment) Labs <12 weeks prior to treatment: HIV – 4 th -generation test preferred (if not HIV infected) HAV Ab and HBV cAb , sAb , sAg (vaccinate if not immune) If HBV cAb +/ sAg -, consider checking HBV DNA, especially if patient is immunosuppressed, due to HBV reactivation risk with HCV treatment LFTs, INR – needed to calculate Child- Turcotte -Pugh score CBC (for platelets) and BMP creatinine/ eGFR TSH if IFN to be used Consider AFP if HCC risk higher (cirrhotic or HBV or HDV co-infected) 14

15. Influences on HCV Regimen Selection 5 Prior treatment history, whether with IFN or DAAs HCV genotype Presence or absence of cirrhosis If cirrhotic: compensated vs. decompensated Renal impairment Other comorbid conditions and medication interactions 15

16. HCV Treatment in Pregnancy and Breastfeeding 4 No DAAs are approved for use during pregnancy or breastfeeding Ribavirin is highly teratogenic Women of childbearing age need dependable contraception when taking ribavirin and for 6 months thereafter Men taking ribavirin should avoid close contact with pregnant women during treatment and for 6 months thereafter See Lesson 5.1 for full review of HCV management in pregnancy Bottom line: do not treat HCV during pregnancy Best to treat before pregnancy until we have data from ongoing trials in pregnancy Providers can however prepare patients for treatment after completion of pregnancy and breastfeeding 16

17. HCV Medication Classes 4 Used in combinations of usually two but sometimes three medications: Protease inhibitors: “ previr ” e.g., glecaprevir , grazoprevir NS5A inhibitors: “ asvir ” e.g., ledipasvir , pibretasvir NS5B nucleotide polymerase inhibitors: “ buvir ” e.g., sofosbuvir , dasabuvir Ribavirin 17

18. Resistance 4 There is no cross-resistance between classes AASLD/IDSA HCV medication recommendations tell you when to screen for resistance prior to treatment These guidelines should be consulted each time a treatment regimen is selected For example: treatment-naïve, non-cirrhotic genotype 1a patients require NS5A resistance testing prior to treatment with elbasvir / grazoprevir For a full review of HCV resistance, please see https://www.hcvguidelines.org/evaluate/resistance 18

19. Laboratory Monitoring during Treatment 4 4-week HCV VL, eGFR , LFTs for all regimens Plus other labs for some specific regimens – see guidelines HCV VL check is recommended by AASLD-IDSA and required by some insurers, but treatment should not be stopped if the HCV VL is not done Consult guidelines for stopping treatment based on side effects or lab abnormalities If 4-week HCV VL undetectable, continue treatment and consider rechecking at end of treatment (recommendations are not firm) If 4-week HCV VL detectable, recheck at 6 weeks Consider stopping treatment if 6-week HCV VL has increased, particularly if 10-fold increase from 4-week level Consultation with an HCV expert or clinical resource such as the National Clinician’s Consultation Center (see http://nccc.ucsf.edu/ ) is recommended 19

20. Monitoring after Treatment 4 12-week post-treatment HCV VL: if undetectable = SVR = 99% chance of durable cure 24-week post-treatment HCV VL is optional; order if risk is higher, such as: Viremia present on 4-week HCV VL check Adherence problems identified Patients who have received a liver transplant If viremia reappears at 12 or 24 weeks, consider rechecking HCV genotype to see if patient may have been dually infected with a different minority genotype 20

21. Additional Monitoring Post-treatment HCC screening with every 6-month liver ultrasound if F3-F4 fibrosis or cirrhosis Also includes: Counseling to prevent reinfection Screening for reinfection Behavior modifications See Lesson 2.4 (preventing reinfection) for additional information 21

22. Chronic HBV/HCV Co-infected Patients Require Extra Monitoring 4 HCV can suppress HBV in vivo, so HBV may flare when HCV is treated More common in HBV sAg + patients, but also can occur in isolated HBV cAb + patients from latent cccDNA Risk is much lower in HIV co-infected patients who are on tenofovir, lamivudine, or emtricitabine Stage chronic HBV patients with eAg / eAb /ALT/VL before treatment for HCV (along with the fibrosis assessment), then check ALT and HBV VL during and immediately after HCV treatment Treat if HBV treatment criteria are met (see Resources) 22

23. If Treatment Is Deferred 1 Annual assessment of fibrosis progression – labs and vibration-controlled transient elastography or equivalent testing HCC screening with liver ultrasound every 6 months in patients with advanced fibrosis (METAVIR F3 or F4) Work to resolve barriers to treatment 23

24. When Treatment Fails DAA resistance and re-treatment strategies are areas of ongoing research; consult AASLD-IDSA guidelines 7 General approach – do two of the following 8:   Switch regimen Add ribavirin Lengthen treatment Consider NS5A resistance testing With all patients, assess adherence and work to resolve adherence barriers May also wait for new therapies if re-treatment is not urgent 24

25. Key Points Non-hepatologists can and should provide HCV treatment to confront the HCV epidemic The AASLD-IDSA HCV Guideline website is the definitive source for treatment recommendations Other websites provide helpful clinical tools and opportunity to practice and reinforce knowledge The main challenge in HIV/HCV co-infection treatment is managing drug interactions 25

26. References AASLD-IDSA. When and in whom to initiate HCV therapy. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy . Accessed December 31, 2018. Box TD. Hepatitis C Update for Primary Care. Clinical Care Options. February 21, 2017. Accessed July 7, 2017 at http://review.clinicaloptions.com/Hepatitis/Treatment%20Updates/Primary%20Care.aspx AASLD-IDSA. HCV testing and linkage to care. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care . Accessed December 31, 2018. AASLD-IDSA. Monitoring patients who are starting hepatitis C treatment, are on treatment, or have completed therapy. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report/monitoring-patients-who-are-starting-hepatitis-c-treatment-are-treatment-or-have . Accessed December 31, 2018. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org . Accessed December 31, 2018. AASLD-IDSA. Retreatment of Persons in whom prior therapy has failed. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed. Accessed December 31, 2018. Feld JJ. How I manage patients with HCV after DAA treatment failure. Clinical Care Options Hepatitis. http://review.clinicaloptions.com/Hepatitis/Treatment%20Updates/HCV%20Resistance%20Alert/Clinical%20Thoughts/CT2.aspx. Posted 11/19/2016. Accessed April 17, 2017. 26

27. Resources Hepatitis C Online: Module 5: Treatment of Chronic Hepatitis C Infection. Slide presentations http://www.hepatitisc.uw.edu/browse/all/lectures Case studies http://www.hepatitisc.uw.edu/go/treatment-infection It is essential to practice what you have learned right away, so take the time to complete these cases before moving on. Hepatitis C Online: Child- Turcotte -Pugh Calculator http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp Hepatitis B Web Study. https://www.hepwebstudy.org Live expert support: National Clinicians Consultation Center http://nccc.ucsf.edu/ or call (844) HEP‐INFO or [phone] Monday – Friday, 9 a.m. – 8 p.m. ET 27

28. Authors and Funders This presentation was prepared by Philip J. Bolduc, MD (New England AETC) for the AETC National Coordinating Resource Center in July 2017 and updated December 2018. This presentation is part of a curriculum developed by the AETC Program for the project: Jurisdictional Approach to Curing Hepatitis C among HIV/HCV Co-infected People of Color (HRSA 16-189), funded by the Secretary's Minority AIDS Initiative through the Health Resources and Services Administration HIV/AIDS Bureau. 28

29. Disclaimer and Permissions Users are cautioned that because of the rapidly changing medical field, information could become out of date quickly. You may use or present this slide set and other material in its entirely or incorporate into another presentation if you credit the author and/or source of the materials. The complete HIV/HCV Co-infection: An AETC National Curriculum is available at: https://aidsetc.org/hivhcv 29