Arming the Frontlines of Hepatitis C Care: Treatment in the Family Medicine Clinic

Transcription

1 Arming the Frontlines of Hepatitis C Care: Treatment in the Family Medicine Clinic

2 Sponsorship and Support This activity is supported by an educational grant from Gilead Sciences, Inc. This educational activity is jointly provided by the North Carolina Academy of Family Physicians (NCAFP) and Med IQ. Copyright 2018 Med IQ, Inc.

3 Statement of Evidence Based Content Educational activities that assist physicians in carrying out their professional responsibilities more effectively and efficiently are consistent with the ACCME definition of CME. As an ACCME accredited provider of CME, it is the policy of Med IQ to review and ensure that all the content and any recommendations, treatments, and manners of practicing medicine in CME activities are scientifically based, valid, and relevant to the practice of medicine. Med IQ is responsible for validating the content of the CME activities it provides. Specifically, (1) all recommendations addressing the medical care of patients must be based on evidence that is scientifically sound and recognized as such within the profession; (2) all scientific research referred to, reported, or used in CME in support or justification of a patient care recommendation must conform to generally accepted standards of experimental design, data collection, and analysis. Med IQ is not liable for any decision made or action taken in reliance upon the information provided through this activity.

4 Faculty Lesley Miller, MD (Co Chair and Presenter) Associate Professor of Medicine Division of General Medicine and Geriatrics Emory University School of Medicine Medical Director, Grady Liver Clinic Atlanta, GA Fred Poordad, MD (Presenter) Professor of Medicine UT Health, San Antonio Vice President, Academic and Clinical Affairs The Texas Liver Institute San Antonio, TX Andrew Muir, MD (Co Chair and Presenter) Professor of Medicine Chief, Division of Gastroenterology in the Department of Medicine Director, GI/Hepatology Program, DCRI Duke University School of Medicine Durham, NC

5 Activity Planners Christie Avraamides, PhD Clinical Content Manager Med IQ Baltimore, MD Marietta Saunders CME Specialist NC Academy of Family Physicians Raleigh, NC

6 Contact Information For questions or comments about this activity, please contact Marietta Saunders. Call (toll free) (919) Please visit us online at IQ.com for additional activities provided by Med IQ. Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors.

7 Learning Objectives Initiate timely and appropriate HCV treatment based on available evidence and patient specific characteristics Describe current knowledge of effectiveness and adherence to treatment among patients with HCV and related comorbidities such as substance use disorder, HIV, and/or cirrhosis Describe recommendations for monitoring and follow up care for patients with HCV who are receiving or who have completed DAA therapy

8 HCV Epidemiology

9 HCV Infection in the US 2.7 to 5.0 million living with chronic HCV in the US Underestimated in NHANES? Homeless Incarcerated Veterans Active military Populations of special interest Baby boomers HIV co infected Persons with SUD Cirrhotic patients Number of Cases, millions Total Estimated HCV Cases Conservative estimate Upper limit estimate 3.8 Not included in NHANES 3.2 NHANES Denniston M, et al. Ann Int Med. 2014;160: ; Chak E, et al. Liver Int. 2011;31: ; Zalesak M, et al. PLoS ONE. 2013;8:e63959.

10 Cirrhosis to Peak in 2030 Estimated Number of New Cases 350, , , , , ,000 50,000 Incidence of HCV by Year, US, Year 2009 Estimated Peak Incidence: years ago 5% 1989 Historical and Projected % Prevalence of Cirrhosis Among HCV Patients 10% % % % % 2030 CDC. Davis GL, et al. Gastroenterology. 2010;138:513 21; Armstrong GL, et al. Hepatology. 2000;31:

11 HCV and Baby Boomers 2012 CDC recommendation: screen for HCV in all Americans born between 1945 and 1965 Smith BD, et al. MMWR Recomm Rep. 2012;61(RR 4):1 32.

12 HCV and Baby Boomers 2012 CDC recommendation: screen for HCV in all Americans born between 1945 and 1965 Prevalence, % Year of Birth Smith BD, et al. MMWR Recomm Rep. 2012;61(RR 4):1 32.

13 HCV and the Opioid Epidemic HCV cases states: > 200% compared with cases reported during Most new HCV cases are among PWID Who? Young persons, nonurban counties, particularly in Appalachian states CDC.

14 HCV and HIV HCV positive in HIV positive patients in the US 30% HIV HCV risk if injection drug use risk if MSM risk vertical transmission (OR 1.9) Accelerated liver disease progression 70% HCV infection in HIVpositive patients HIV positive patients with no HCV infection Staples CT, et al. Clin Inf Dis. 1999;29:150 4; Polis CB, et al. Clin Infect Dis. 2007;44: ; Thein HH, et al. AIDS. 2008;22: ; Thein HH, et al. Hepatology. 2008;48:

15 WHO and National HCV Elimination Goals WHO goals: Incidence new cases of chronic HCV infections: between 6 and 10 million infections are reduced to 0.9 million infections by 2030 (80% decline in HCV infections) Mortality HCV deaths: 1.4 million deaths reduced to less than 500,000 by 2030 (65% reduction) National goals: Goal 1 Prevent new viral hepatitis infections Indicator or progress: decrease the number of new HCV infections by at least 60% Goal 2 Reduce deaths and improve the health of people living with viral hepatitis Indicator of progress:» Increase the percent of persons aware of their HCV infection to 66%» Reduce the number of HCV related deaths by 25% DHHS. plan/national viral hepatitis action plan overview/index.html;

16 Evaluation of the Patient With HCV Infection

17 Case Study Jerry, a 60 year old man sees you for an annual exam Medical history includes GERD, hyperlipidemia, and hypertension Drinks 1 beer daily with dinner No past or present drug use You note that he has never been screened for HCV Do you recommend HCV screening? What do the guidelines say?

18 HCV Screening Recommendations AASLD/IDSA guidelines: One time HCV testing is recommended for persons born 1945 through 1965 without prior ascertainment of risk Other persons should be screened for HCV infection risk factors; one time testing should be performed for all persons with behaviors, exposures, and conditions or circumstances associated with an increased risk of HCV infection AASLD/IDSA. report view.

19 HCV Screening Recommendations AASLD/IDSA Guidelines: Risk behaviors Injection drug use (current or ever, including those who injected only once) Intranasal illicit drug use Risk exposures Persons on long term hemodialysis (ever) Persons with percutaneous/parenteral exposures in an unregulated setting Healthcare, emergency medical, and public safety workers after needle stick, sharps, or mucosal exposures to HCV infected blood Children born to HCV infected women Persons who have been incarcerated AASLD/IDSA. report view.

20 HCV Screening Recommendations AASLD/IDSA guidelines: Risk exposures Prior recipients of transfusions or organ transplants, including persons who: Were notified that they received blood from a donor who later tested positive for HCV Received a transfusion of blood or blood components or underwent an organ transplant before July 1992 Received clotting factor concentrates produced before 1987 Other conditions and circumstances HIV infection Sexually active persons about to start PrEP for HIV Unexplained chronic liver disease and/or chronic hepatitis, including elevated ALT levels Solid organ donors (deceased and living) AASLD/IDSA. report view.

21 HCV Screening Recommendations AASLD/IDSA guidelines: Annual HCV testing is recommended for PWID and for HIV infected men who have unprotected sex with men Periodic testing should be offered to other persons with ongoing risk factors for HCV exposure AASLD/IDSA.

22 HCV Diagnostic Process HCV Ab + Nonreactive Reactive Not detected HCV RNA + Detected No HCV Ab detected No current HCV infection Current HCV infection STOP Additional testing* Link to care *Discussion of risk factors and repeat HCV RNA testing if recent exposure or ongoing risk behaviors CDC. MMWR. 2013;62:362 5.

23 Case Study You decide to screen Jerry for HCV based on birth cohort risk Results: HCV Ab: positive HCV RNA: 500,000 IU/mL Is Jerry a candidate for treatment? What initial counseling and work up is recommended to prepare Jerry for treatment?

24 For All HCV Patients Liver Wellness HAV and HBV testing/vaccination DAAs have a risk of reactivating HBV Screen all patients for evidence of current or prior HBV infection before starting treatment Minimal to zero alcohol Avoid fatty liver Normal weight Control diabetes if present Coffee beneficial AASLD/IDSA. Freedman ND, et al. Hepatology. 2009;50:

25 Work up for HCV Treatment 1. HCV genotype 2. HBV, HAV, HIV testing 3. HCV treatment history Interferon regimen? DAA? 4. Fibrosis stage? If cirrhosis, is it decompensated? Ascites, varices, encephalopathy 5. Comorbidity assessment (CKD, medications) Transplant evaluation? AASLD/IDSA.

26 HCV Natural History Decompensated cirrhosis 3% 6% per year Acute infection Chronic hepatitis 75% 85% Compensated cirrhosis 20% 30% HCC 1% 5% per year NIH Consens State Sci Statements. 2002;19:1 46; Di Bisceglie AM. Hepatology. 2000;31:1014 8; Bialek SR, et al. Clin Liver Dis. 2006;10:

27 Fibrosis Stages METAVIR Scale (fibrosis) Score F0 F1 F2 F3 F4 Fibrosis (scarring) No damage Mild Portal fibrosis without septa Moderate Portal fibrosis with rare septa Advanced Numerous septa, not cirrhosis Severe Cirrhosis Goodman ZD. J Hepatol. 2007;47:

28 Fibrosis Evaluation History and physical exam Laboratory studies Imaging Liver biopsy Elastography (Fibroscan) Alpanis Z, et al. Ann Gastroenterol. 2016;29:

29 History and Physical Is history compatible with advanced fibrosis or cirrhosis? 23 year old with drug use starting at age 20 Risk for cirrhosis? No 63 year old with new diagnosis of HCV Risk for cirrhosis? Yes Pradat P, et al. Liver Int. 2007;27:335 9.

30 History and Physical Are there signs or symptoms of cirrhosis or portal hypertension? Physical examination Spider angioma Palmar erythema Gynecomastia Caput medusae Ascites Lower extremity edema Splenomegaly Muscle wasting hypertension in adults.

31 Laboratory Studies Are there signs of cirrhosis or portal hypertension? serum bilirubin alkaline phosphatase PT INR albumin Thrombocytopenia AST/ALT ratio Normal 0.8 Teaching > 1 = cirrhosis Brau N. Clin Infect Dis. 2013;56:

32 Fibrosis Evaluation Features of portal hypertension? No diagnostic tests needed No features of portal hypertension Fibrosis assessments Fibroscan Serum markers APRI, FIB 4 Liver biopsy rarely Procopet B, et al. Gastroenterol Rep (Oxf). 2017;5:79 89; Expert opinion.

33 FIB 4 Score

34 Imaging U/S CT MRI Helpful if advanced and obvious signs of portal hypertension Nodular liver not a reliable finding Patient education needed about role of imaging in HCC surveillance Alpanis Z, et al. Ann Gastroenterol. 2016;29:445 53; Expert opinion.

35 Case Study Jerry undergoes initial work up which reveals: HCV genotype 1a AST 84, ALT 42, PLT 150,000, albumin 3.8 Fibrosis assessment: Fib 4: 5.2 (> 3.25 = cirrhosis) Fibroscan: 15 kpa (> 12.5 = cirrhosis) RUQ U/S: nodular liver contour, no lesions Is treatment recommended for this patient? What agent should we use? Does he need referral to a specialist?

36 When Referral Is Critical Cirrhosis, especially decompensated Co infection with HIV and/or HBV Hepatocellular carcinoma AASLD/IDSA. and linkage; Expert opinion.

37 HCV Therapy

38 When to Initiate Treatment and Who Should Receive It Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert. Rating: Class I, Level A AASLD/IDSA.

39 HCV Therapy Targets Release of (+)RNA Viral entry Nucleus Release of virus from cell Viral packaging Translation, polyprotein processing E1 E2 C P7 NS2 NS4B NS5B Viral replication NS3 NS4A NS5A Protease inhibitors NS5A inhibitors NS5B polymerase inhibitors Drug names end in previr Drug names end in asvir Drug names end in buvir Image courtesy of Dr. Andrew Muir; Holmes JA, et al. Hepat Med. 2015;7:51 70.

40 HCV Direct Acting Antiviral Agents Brand Name Drugs FDA Approval FDA Indications Harvoni Ledipasvir + sofosbuvir 2014 Genotypes 1, 4, 5, 6 Zepatier Grazoprevir + elbasvir 2016 Genotypes 1, 4 Epclusa Sofosbuvir + velpatasvir 2016 Genotypes 1 6 Mavyret Glecaprevir + pibrentasvir 2017 Genotypes 1 6 Vosevi Sofosbuvir + velpatasvir + voxilaprevir 2017 DAA treatment failures Genotype 1 6 Data derived from prescribing information of individual agents.

41 Navigating the HCV Guidelines AASLD/IDSA. naive/gt1a/no cirrhosis.

42 Sofosbuvir + Lepidasvir SOFOSBUVIR polymerase inhibitor LEPIDASVIR NS5A inhibitor Indications Genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis Genotype 1 infection with decompensated cirrhosis with ribavirin Genotype 1 or 4 infection in liver transplant recipients without cirrhosis or with compensated cirrhosis in combination with ribavirin Duration: 12 weeks Trial programs: ION 3, ION 1, study 1119, ELECTRON 2 SVR12 with or without cirrhosis: GT1 99%, GT4 93%, GT5 93%, GT6 96% Precautions: bradycardia with amiodarone co administration Adverse events: fatigue, headache, asthenia Afdal N, et al. N Engl J Med. 2014;370: ; Gane EJ, et al. Gastroenterology. 2015;149: ; prescribing information.

43 Grazoprevir + Elbasvir GRAZOPREVIR NS3/4A protease inhibitor ELBASVIR NS5A inhibitor Indications Genotype 1 or 4 Treatment naïve and experienced With or without cirrhosis Duration: 12 weeks (16 weeks treatment naïve or PegIFN/RBV experienced with baseline NS5A polymorphisms) Contraindications: moderate or severe hepatic impairment (Child Pugh B or C) Can be used with PPIs; can be used in patients with CKD Trial programs: C SCAPE, C EDGE TN, C EDGE COINFECTION SVR12 with or without cirrhosis: GT1 95% (non cirrhotic 94%, cirrhotic 97%), GT4 97% Adverse events: fatigue, headache, nausea Zeuzem S, et al. Ann Intern Med. 2015;163:1 13; prescribing information.

44 Sofosbuvir + Velpatasvir SOFOSBUVIR polymerase inhibitor VELPATASVIR NS5A inhibitor Indications GT 1 6 Treatment naïve and experienced No cirrhosis, compensated cirrhosis, decompensated cirrhosis Duration: 12 weeks Precautions: renal elimination Trials: ASTRAL 1, ASTRAL 2, ASTRAL 3, ASTRAL 4 (decompensated), ASTRAL 5 (HIV/HCV) SVR12 without cirrhosis or with compensated cirrhosis: GT1 98%, GT2 100%, GT3 95%, GT4 100%, GT5 97%, GT6 100% Adverse events: fatigue, headache Feld JJ, et al. N Engl J Med. 2015;373: ; Foster GR, et al. N Engl J Med. 2015;373: ; prescribing information.

45 Glecaprevir + Pibrentasvir GLECAPREVIR protease inhibitor PIBRENTASVIR NS5A inhibitor Indications Genotype 1 6 No cirrhosis or compensated cirrhosis Prior failure of regimens with NS5A or NS3/4A but not both Minimal renal elimination Durations No cirrhosis: 8 weeks Cirrhosis: 12 weeks DAA failure: weeks Trials: ENDURANCE 1, EXPEDITION 2; ENDURANCE 3, EXPEDITION 1 SVR8 no cirrhosis: GT1 99%, GT2 98%, GT3 95%, GT4 93%, GT5 100%, GT6 100% SVR12 cirrhosis: GT1,2,4,5,6 99% Adverse events: fatigue, headache Precautions Not for decompensated cirrhosis Zeuzem S, et al. N Engl J Med. 2018;378:354 69; Rockstroh J. J Hepatol. 2017;66:Suppl S102 3; Foster GR. J Hepatol. 2017;66:S33; Forns X, et al. Lancet Inf Dis :1062 8; prescribing information.

46 Sofosbuvir + Velpatasvir + Voxilaprevir SOFOSBUVIR polymerase inhibitor VELPATASVIR NS5A inhibitor VOXILAPREVIR protease inhibitor Indications Genotype 1 6 DAA failures No cirrhosis or compensated cirrhosis Renal elimination Duration: 12 weeks Precaution: not for decompensated cirrhosis Trials: POLARIS 2 (GT 1 6, naïve, with or without cirrhosis; except GT3 patients with cirrhosis); POLARIS 3 (GT 3 cirrhosis, DAAnaïve); POLARIS 1 (GT1 6, NS5Aexperienced); POLARIS 4 (GT1 4, non NS5A experienced) SVR12: POLARIS 2 98%, POLARIS 3 96%, POLARIS 1 96%, POLARIS 4 97% Adverse events: headache, fatigue, nausea, diarrhea Bourlière M, et al. N Engl J Med. 2017;376: ; prescribing information.

47 Case Study Jerry is genotype 1a, treatment naïve with F4 fibrosis (cirrhosis) HBV sab positive HIV negative Creatinine 0.9 MELD 6, CTP A (compensated cirrhosis) He is on a PPI and a statin What are our medication choices?

48 Amiodarone Rivaroxaban Phenytoin, phenobarb, carbamazepine oxcarbamazepine Rifampin, rifabutin, rifapentine St. John s Wort Digoxin H2 blockers PPIs DAA Drug Drug Interactions Ledipasvir + sofosbuvir Grazoprevir + elbasvir Sofosbuvir + velpatasvir Glecaprevir+ pibrentasvir Sofosbuvir + velpatasvir + voxilaprevir Omeprazole can be administered; other PPIs not been studied Comments Causes symptomatic bradycardia Therapeutic monitoring of digoxin recommended Must be administered simultaneously or 12 hours apart from DAA and should not exceed equivalent of 40 mg famotidine twice daily Must be administered simultaneously with ledipasvir/sofosbuvir and dose may not exceed equivalent of 20 mg esomeprazole daily Magnesium and/or aluminum antacids Separate by 4 hours from DAA administration Atorvastatin Rosuvastatin Simvastatin Not Studied Monitor for adverse effects (rhabdo) if use not contraindicated Max dose 20 mg w/ grazoprevir/elbasvir Monitor for adverse effects (rhabdo) if use not contraindicated Max dose 10 mg w/grazoprevir/elbasvir Contraindicated Not recommended Monitor closely No significant interactions Data derived from prescribing information of individual agents; druginteractions.org/checker.

49 Case Study: Medication Choices Recommended and alternative regiments listed by evidence level and alphabetically for: Treatment Naïve Genotype 1a Patients With Compensated Cirrhosis a Recommended Duration Rating PPI Daily fixed dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks I, A patients without baseline NS5A RASs b for elbasvir Daily fixed dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) c 12 weeks I, A Daily fixed dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) 12 weeks I, A Daily fixed dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) 12 weeks I, A Alternative Duration Rating PPI Daily fixed dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight based ribavirin for patients with baseline NS5A RASs b for elbasvir 16 weeks IIa, B a For decompensated cirrhosis, please refer to the appropriate section. b Includes genotype 1a resistance associated substitutions at amino acid positions 28, 30, 31, or 93 known to confer antiviral resistance. c This is a 3 tablet coformulation. Refer to prescribing information. AASLD/IDSA.

50 Sample of a 12 Week Treatment Timeline Treatment Start Week 4 Week 8 Week Weeks After Treatment Lab visit Lab visit Lab visit Phone visit Phone reminder Office visit Office visit Office visit Treatment ends Lab visit Medication given Medication given Medication given Phone call with results Slide courtesy of Dr. Lesley Miller.

51 What Does Cure Mean? Long term follow up study 5 centers Europe and Canada 530 chronic HCV patients HCV treatment Advanced fibrosis or cirrhosis Follow up median 8.4 years (IQR ) Main outcome measures All cause mortality Secondary outcomes: liver failure, HCC, liver related mortality, transplantation Percent P <.001 P < All cause mortality Liver related mortality or transplant SVR No SVR P < Year Cumulative Incidence HCC van der Meer AJ, et al. JAMA. 2012;308:

52 Ongoing Care for Patients Who Have Been Cured For patients who do not have advanced fibrosis (F0 F2), recommended follow up is the same as if they were never infected with HCV Assessment for HCV recurrence or reinfection Patients with ongoing risk of HCV infection Otherwise unexplained hepatic dysfunction Need HCV RNA test (not HCV antibody) to check for HCV recurrence or reinfection Surveillance for HCC with twice yearly U/S examination is recommended for patients with advanced fibrosis (i.e., Metavir stage F3 or F4) who achieve SVR AASLD/IDSA.

53 What Do These Medicines Offer to Mental illness Substance abuse Heart failure and lung disease African Americans HIV HCV Decompensated cirrhosis Liver transplant Kidney disease

54 HCV Treatment Considerations Among PWID Treatment is recommended for PWID with chronic HCV infection History of injection drug use and recent drug use at treatment initiation are not associated with reduced SVR The decision to initiate therapy should be based on the availability of agents and disease characteristics DAA therapy does not require specific methadone and buprenorphine dose adjustment; monitor for signs of opioid toxicity or withdrawal PWID with ongoing social issues, history of psychiatric disease, and more frequent drug use during therapy are at risk of lower adherence; counsel on the importance of adherence Clinical management should include harm reduction programs, social work, and social support services Grebely J, et al. Int J Drug Policy. 2015;26:

55 HCV Treatment in Persons With HIV HIV/HCV coinfected patients suffer from more: Liver related morbidity and mortality and overall mortality Nonhepatic organ dysfunction Treatment outcomes/adverse effects the same as in persons without HIV DAA regimens are the same Checking for drug drug interactions is paramount! Resources: Liverpool HEP Drug Interactions ( druginteractions.org) Hcvguidelines.org AASLD/IDSA.

56 HCV Treatment in Persons With Decompensated Cirrhosis Not a contraindication to treatment Most patients experience improvement in clinical and biochemical indicators of liver disease Always consult hepatology Timing of treatment relative to transplant Ideally treatment by or in conjunction with experienced provider in a transplant setting Choose DAA regimen carefully Avoid protease inhibitors in decompensated cirrhosis Patients may need closer on treatment monitoring CBC and comprehensive metabolic panel every 2 4 weeks AASLD/IDSA.

57 Practicalities of HCV Treatment in the Family Medicine Clinic

58 Navigating Insurance Restrictions Based on Provider Type Many state Medicaid programs have limited access to HCV treatment due to cost concerns; restrictions include: Only allowing certain specialists (who are not readily available) to prescribe treatment Solutions Telemedicine HCV certificate 2017 Medicaid FFS Prescriber Restrictions for HCV Treatment No restrictions By or in consultation with a specialist Specialist must prescribe Restrictions unknown

59 Navigating Other Insurance Issues Other restrictions include: Liver disease progression: requires that patients reach a certain stage of fibrosis Solution: variety of fibrosis assessment tools Solution: appeal decision (shared materials, staff to do this is helpful) Substance/sobriety requirements: barring patients with a history of substance or alcohol abuse Solution: advocacy, appeal, apply evidence Resource: National Viral Hepatitis Roundtable (nvhr.org) Expert opinion.

60 Navigating Prior Authorization Medicaid/Medicare Private insurance Uninsured Pharmaceutical company patient assistance programs Needymeds.org Partnership for prescription assistance ( Patient access network foundation ( Patient advocate foundation co pay relief ( Clinical trials Expert opinion.

61 Summary HCV can be a silent disease and requires effective screening to identify patients All patients with HCV need an evaluation of the stage of liver fibrosis and counseling on liver health HCV antiviral therapy is highly effective and well tolerated and has few contraindications HCV cure significantly lowers the risk of complications of cirrhosis and liver cancer A combination of increased screening, linkage to care, and treatment is necessary to meet HCV elimination goals

62 Contact Information Fred Poordad, MD M: O: F: E: