Lesson 1: Fundamentals of Hepatitis C Virus Treatment Core Competency 4: HCV Treatment Lesson 1: Fundamentals of Hepatitis C Virus Treatment July 2017

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

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 Unlike HIV and HBV, HCV can be cured. Multiple studies, referenced in the AASLD-IDSA website, demonstrate the significant morbidity and mortality benefits of successfully treating chronic HCV infection. Sustained Virologic Response (SVR) is defined as an undetectable HCV viral load 12 weeks after treatment is completed. People who achieve an SVR are considered cured.

Current All-Oral Therapies2 Highly effective, simple, well-tolerated Cure Rates Direct-Acting Antivirals (DAAs) All-Oral Therapy 2013 Current 100 95+ Peginterferon (pegIFN) 2011 90+ 80 Ribavirin (RBV) 2001 Standard Interferon (IFN) 70+ 1998 60 55 Sustained HCV Virologic Response (%) 1991 42 39 40 34 DAA = direct-acting antiviral HCV = hepatitis C virus IFN = interferon pegIFN = peginterferon RBV = ribavirin Treatments have become increasingly efficacious as can be seen in the SVR rates of various regimens over the last 25 years. This slide shows you the progress we have made in the last quarter of a century with regards treating chronic hepatitis C. First of all, it wasn’t until the 1980s that we knew that hepatitis C was an infectious disease associated with contaminated blood products. Once that was identified, it took some time to really study the virus and develop a treatment approach. And that first treatment approach was interferon, which first became available in 1991, and as you can see, by itself, given every other day was woefully inadequate with a 6% cure rate or a sustained virologic response rate.   As we learned that the more interferon for longer periods of time the better, our cure rate got better, but it still was stuck at an unacceptably low level until we added an adjunct called ribavirin, which also upregulates the immune system, as does interferon. In 2011, our first direct-acting antiviral, which was not just a way to stimulate the immune system but a way to directly attack the virus, became available. These were difficult to use toxic drugs, but at least it pushed the cure rate to 70+%. Two years later, we added better direct-acting antivirals plus or minus interferon with a 90% SVR rate. And finally today, we are now above 95% cure with all-oral no interferon-based direct-acting antivirals. Slide References: Manns MP, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347:975-982. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. Ferenci P, et al. N Engl J Med. 2014;370:1983-1992. Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Kwo P, et al. EASL 2015. Abstract LB14. Zeuzem S, et al. Ann Intern Med. 2015;163:1-13. Feld JJ, et al. N Engl J Med. 2015;373:2599-2607. Foster GR, et al. N Engl J Med. 2015;373:2608-2617. 20 16 6 IFN 6 Mos IFN 12 Mos IFN/RBV 6 Mos IFN/RBV 12 Mos PegIFN 12 Mos PegIFN/RBV 12 Mos PegIFN/ RBV + DAA DAA + RBV ± PegIFN All–Oral DAA± RBV Box T, Clinical Care Options. 2017

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 Treatment is much more expensive Treatments are now more complex and depend on genotype, degree of liver damage, and history of previous treatment failure The new direct-acting HCV antiviral agents (DAAs) have revolutionized HCV treatment with vast improvements in potency, tolerability, shorter courses, and higher price, although negotiated pricing with pharmacies reportedly has reduced the cost significantly.

Appropriate HCV Providers “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. HCV-educated primary care providers and ID specialists are well-suited to treating HCV, a position supported by AASLD-IDSA. In order to decrease HCV-related morbidity and mortality and decrease new transmissions, the HCV-treating workforce must be expanded.

Appropriate Provider by Stage of Liver Disease1 Child-Turcotte-Pugh Class A (score 5-6) ID and HCV-informed primary care providers Child-Turcotte-Pugh Class B (score 7-9) Hepatologists ID and HCV-informed primary care providers in close communication with a supporting hepatologist Child-Turcotte-Pugh Class C (score ≥10) ID = Infectious Disease For an online calculator, see Hepatitis C Online: http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp Child-Turcotte-Pugh Class A and B patients are generally stable enough for treatment in these settings, although with Class B patients, it is best to work in close communication with a supporting hepatologist. Owing to a higher risk of hepatic decompensation, Class C patients should be treated by a hepatologist and are often evaluated and listed for transplant simultaneously while undergoing treatment. Some centers will leave patients untreated so they may received a transplant from an HCV-infected donor, and then are treated for HCV post-transplant.

Help Patients Succeed Use 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 Regardless of the care setting: optimize patients’ ability to adhere to the care plan before starting treatment. We advise creating a case management system to help book patient intakes, submit PAs, resolve pharmacy and medication delivery issues, call patients to remind them of visits and labs, and field questions from patients.

Appropriate Patients for Treatment1 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 Treating as many people as we can is key to reducing HCV transmission and eliminating chronic HCV infection, although from a cost-effectiveness standpoint treatment may not be beneficial if life expectancy is less than 12 months.

Preparing for Treatment Approval for treatment varies by insurer. Factors may include: Fibrosis stage Sobriety requirements Prescriber type: Hepatology, ID, primary care Some states provide and require a certification process to prescribe HCV medications Some insurers will only approve Prior Authorizations (PAs) for Metavir fibrosis stage 3 or higher, or if patients have been sober for 6 or more months. Others will only approve a PA if the requesting provider is a hepatologist or Infectious Disease specialist (ID). These requirements are beginning to loosen across the country as health care systems realize that the current lack of availability of prescribers is limiting the feared flood of new prescriptions that would overwhelm insurance budgets.

Preparing Patients for Treatment Achieve medical stability before HCV treatment HCV treatment usually not urgent 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 As HCV treatment is usually not urgent, one should first stabilize cardiac, pulmonary, renal/metabolic, or psychiatric diseases. This will help patients adhere to treatment and avoid confounding comorbid disease symptoms with HCV treatment side effects, although the new HCV direct-acting antivirals (DAAs) are generally very well tolerated. Insurers may vary in their ability to cover treatment more than once for a given patient, so use health system resources wisely and work aggressively to resolve barriers to success before treating patients.

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) A comprehensive history is needed to detect symptoms of decompensated liver disease or other medical comorbidities that may affect HCV treatment, including ongoing alcohol and drug use or housing or food insecurity (although these are not a contraindication to treatment per se, they should be managed to the extent necessary to allow the patient to succeed with HCV treatment). Medications should be reconciled in preparation to check for interactions with HCV agents. Stigmata of liver disease should be noted as part of liver disease staging along with labs and tests.

Pre-treatment Tests1 Fibrosis staging: (see Module 3 for more details) AASLD-IDSA recommends combining a serum biomarker assay (such as 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 Individuals with clinically evident cirrhosis do not require additional staging (biopsy or noninvasive assessment) Liver ultrasound AASLD-IDSA recommend an assessment of the degree of fibrosis with a combination of serum biomarkers and vibration-controlled transient liver elastography, reserving liver biopsy for when discordant test results will impact treatment decisions. AASLD also recommends a liver ultrasound, which can demonstrate ascites and/or echotextures consistent with advanced fibrosis or cirrhosis, portal fibrosis, and hepatic masses.

Pre-treatment Labs4 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 – 4th-generation test preferred (if not already known to be HIV infected) HAV Ab and HBV cAb, sAb, sAg (vaccinate if not immune) LFTs, INR – needed to calculate Child-Turcotte-Pugh score CBC (for platelets) and BMP creatinine/eGFR TSH if IFN to be used Pre-treatment evaluation recommended by AASLD also includes a CBC, BMP, LFTs and TSH if the patient is to be on interferon. The platelet count can indicate cirrhosis if <130, LFTs and INR are needed to calculate the Child-Turcotte-Pugh score, and an eGFR is needed when choosing HCV medications. Chronic HCV patients, whether treated or not, should also be screened for HIV, HAV and HBV, and vaccinated against HAV and HBV if not immune.

Influences on HCV Regimen Selection5 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 AASLD-IDSA organizes its treatment recommendations based around a cascade of characteristics: prior treatment history, HCV genotype, presence or absence of cirrhosis, if cirrhotic – compensated vs. decompensated, renal impairment, and other comorbid conditions and medication interactions.

HCV Treatment in Pregnancy4 No DAAs are approved for use during pregnancy 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 pregnant women Bottom line: do not treat HCV during pregnancy No DAAs are approved for use in pregnant women. Ribavirin, still used in selected patients, is highly teratogenic; patients taking it should not be pregnant or in close contact with pregnant women during treatment and for 6mo thereafter.

HCV Medication Classes4 Protease inhibitors: “previr” e.g., simeprevir, paritaprevir NS5A inhibitors: “asvir” e.g., elbasvir, ombitasvir NS5B nucleotide polymerase inhibitors: “buvir” e.g., sofosbuvir, dasabuvir Ribavirin Most regimens comprise an NS5B inhibitor with either a protease inhibitor or an NS5A inhibitor. Patients with cirrhosis and/or prior treatment failure will sometimes also need to take ribavirin, whose mechanism of action is not clearly understood, and is know to cause hemolytic anemia, insomnia and anxiety. Resistance testing varies widely between DAA medications, so the guidelines must be consulted when ordering pre-treatment labs.

Resistance4 There is no cross-resistance between classes Recommendations include discussion of how to screen for resistance if necessary before treatment Most regimens comprise an NS5B inhibitor with either a protease inhibitor or an NS5A inhibitor. Patients with cirrhosis and/or prior treatment failure will sometimes also need to take ribavirin, whose mechanism of action is not clearly understood, and is know to cause hemolytic anemia, insomnia and anxiety. Resistance testing varies widely between DAA medications, so the guidelines must be consulted when ordering pre-treatment labs.

Laboratory Monitoring during Treatment4 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 Stop treatment if 6-week HCV VL has increased 10-fold from 4-week level Some experts recommend stopping treatment if 6-week HCV VL is higher than 4-week HCV VL, even if not 10-fold higher Ribavirin requires more frequent CBCs, interferon (rarely used) requires TSH and other labs more frequently. Futility rules in DAA era are only clear on stopping treatment if there is a 1-log (tenfold) increase in a second VL at 6 or more weeks.

Monitoring after Treatment4 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 Further checking of the HCV VL at 24wks post-treatment is optional and usually reserved for patients in whom the stakes are high (transplant patients) or in those with a higher risk of viral rebound (poor adherence, detectable VL during treatment); beyond that no VL checking is needed unless the patient re-exposes themselves to HCV. HCC screening is not cost-effective in the setting of current or prior HCV infection if there is no advanced fibrosis (i.e. F3 or higher). AFP testing is no longer recommended for hepatocellular carcinoma screening in chronic HCV.

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

Chronic HBV/HCV Co-infected Patients Require Extra Monitoring4 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) Through unknown mechanisms HCV is thought to suppress HBV replication, as cases of HBV flares have been reported following DAA treatment of HCV. Therefore, chronic HBV patients must be monitored with ALT and HBV DNA levels during and immediately after HCV treatment.

If Treatment Is Deferred1 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 From AASLD-IDSA: “Although an ideal interval for assessment has not been established, annual evaluation is appropriate to discuss modifiable risk factors and to update testing for hepatic function and markers for disease progression. For all individuals with advanced fibrosis, liver cancer screening dictates a minimum of evaluation every 6 months.”

When Treatment Fails DAA resistance and re-treatment strategies are areas of ongoing research; consult AASLD-IDSA guidelines7 General approach – do two of the following if cirrhosis is not present8:  Switch regimen Add ribavirin Lengthen treatment With all patients, assess adherence and work to resolve adherence barriers May also wait for new therapies if re-treatment is not urgent Prior IFN failures are readily treated by new DAA combination regimens. Combination DAA failures are (thankfully) quite uncommon and there are no firm data on best practices. Nevertheless the guidelines do include recommendations. When “treatment fails” consider also the possibility of reinfection, mixed infection, or superinfection (see lesson 2.4).

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 AASLD/IDSA supports primary care providers developing skills and treating HCV. Their website is a user-friendly and practical as a point-of care reference. The crux of treating HCV in HIV infected patients is looking up drug interactions and choosing compatible regimens.

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 April 17, 2017. 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 April 17, 2017. 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 April 17, 2017. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. July 7, 2017. 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 April 17, 2017. 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. The definitive guideline for testing, evaluation, and treatment of Hepatitis C in the US is published on-line by the American Association for the Study of Liver Diseases and the Infectious Disease Society of America (AASLD/IDSA)

Online 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

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. 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.

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