5/24/16 Hepatitis C: The New Landscape Advances in Internal Medicine May 24, 2016 I have no disclosures Rena K. Fo, MD Professor of Clinical Medicine, UCSF Outline I. Current HCV outcomes in the US II. Screening and Initial Evaluation III. Direct Acting Antivirals HCV Disease Outcomes in the US IV. Whom to Treat, Pre-Treatment Workup V. On-Treatment Care VI. Post-Treatment Care 1
Projected Prevalence of Decompensated Cirrhosis and HCC Rises Through 2020 #1: HCV mortality higher than from top 60 other infections combined From 2003-2013, number of HCV deaths surpassed the major 60 other nationally notifiable infectious conditions combined Although the overall prevalence of HCV infection is decreasing, the prevalence of cirrhosis is increasing Decompensated cirrhosis more common after 1995 HCC rose steeply after 1990, predicted to peak in 2019 at 14,000/year Davis GL et al. Gastro. 2010; 138 (2): 513-521 Mortality from other conditions (eg TB, pneumococcal disease) is declining while HCV mortality rising HCV deaths mainly among ages 55-64 yo Ly K et al. Clin Infect Dis; 2016;62:1287-1288 #2: Deaths from liver cancer increased at the highest rate of all cancers HCC has second highest rise in incidence second only to thyroid cancer #3: Rising Number of New Infections Death rates from HCC highest of all cancer sites During same time, death rates decline from all cancers combined HCV associated liver cancer death rates highest among persons born 1945-65 Ryerson AB et al. Cancer 2016 May 1;122(9):1312-17 Estimated Actual New Cases of HCV 2011 2012 2013 16,500 24,700 29,700 http://www.cdc.gov/hepatitis/statistics/inde.htm 2
Screening Recommendations from the CDC and USPSTF Risk Based Screening: 1 or more Risk Factors IDU Screening and Initial Evaluation Transfusion before 1992 Clotting factors before 1987 HIV or HBV Chronic Hemodialysis Elevated ALT Birth Year Screening: Born 1945-1965 Smith BD, et al. MMWR Morb Mortal Wkly Rep. 2012;61(RR04);1-18. Primary Care Evaluation of HCV HCV RNA (viral load) HCV Genotype Baseline Every 6 mos *if cirrhosis* Annually CBC/Platelet PT/ INR BMP / LFTs HIV Ab HAV IgG HBsAg, HBsAb, HBcAb Fibrosis assessment Cryoglobulins Abdominal US Immunizations As needed Direct Acting Antivirals 3
60% US HCV Treatment During Interferon-Ribavirin Era Direct Acting Antivirals (DAAs) Against specific HCV targets 50% 40% 30% 20% 10% 0% 50% 32-38% 7-11% Diagnosed Referred to care Treated Successfully Treated 5-6% Holmberg SD, et al. New Eng J Med. 2013;368:1859-18 61. Sites: NS3 NS4a NS5A NS5B Regimen Drug Class Approved Year Regimen Drug Class Approved Year Sofosbuvir + Simeprevir NS5B inhibitor + Protease inhibitor 1, 4 2014 4
Regimen Drug Class Approved Year Regimen Drug Class Approved Year Sofosbuvir + Simeprevir NS5B inhibitor + Protease inhibitor 1, 4 2014 Sofosbuvir + Simeprevir NS5B inhibitor + Protease inhibitor 1, 4 2014 Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + 1, 4, 5, 6 2014 Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + 1, 4, 5, 6 2014 Paritaprevir/ RTV/ Ombitasvir + Dasabuvir Protease inhibitor + + NS5B Non-nucleotide inhibitor 1 2014 Regimen Drug Class Approved Year Regimen Drug Class Approved Year Sofosbuvir + Simeprevir NS5B inhibitor + Protease inhibitor 1, 4 2014 Sofosbuvir + Simeprevir NS5B inhibitor + Protease inhibitor 1, 4 2014 Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + 1, 4, 5, 6 2014 Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + 1, 4, 5, 6 2014 Paritaprevir/ RTV/ ombitasvir + dasabuvir Protease inhibitor + + NS5B Non-nucleotide inhibitor 1 2014 Paritaprevir/ RTV/ ombitasvir + dasabuvir Protease inhibitor + + NS5B Non-nucleotide inhibitor 1 2014 Sofosbuvir + Daclatasvir NS5B Nucleotide inhibitor + 3 2015 Sofosbuvir + Daclatasvir NS5B Nucleotide inhibitor + Grazoprevir/ Elbasvir Protease inhibitor + 3 2015 1, 4 2016 5
Regimen Drug Class Approved Year 3 Major Factors in Choosing HCV Treatment Regimen Genotype/subtype Sofosbuvir + Simeprevir NS5B inhibitor + Protease inhibitor 1, 4 2014 Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + 1, 4, 5, 6 2014 Paritaprevir/ RTV/ ombitasvir + dasabuvir Protease inhibitor + + NS5B Non-nucleotide inhibitor 1 2014 Sofosbuvir + Daclatasvir NS5B Nucleotide inhibitor + 3 2015 Grazoprevir/ Elbasvir Protease inhibitor + Sofosbuvir/ Velpatasvir NS5B Nucleotide inhibitor + 1, 4 2016 Under review Under review Presence of cirrhosis Treatment History Patients with SVR 12 (%) Sofosbuvir/Ledipasvir (Harvoni ) ION-1 Trial Genotype 1 100 99 97 98 99 80 60 40 20 0 LDV-SOF LDV-SOF +RBV LDV-SOF LDV-SOF + RBV 12-Week Regimen 24-Week Regimen Patients with SVR12 (%) Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira ) PEARL-III and PEARL-IV Trials - GT 1 100 97.0 99.5 99.0 80 90.2 60 40 20 97/100 185/205 209/210 207/209 0 3D + RBV 3D 3D + RBV 3D Genotype 1a Genotype 1b LDV-SOF= ledipasvir-sofosbuvir RBV = ribavirin AfdhalN, et al. NEJM. 2014;370:1889-98. 3D = Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir RBV = Ribavirin FerenciP, et al. NEJM. 2014;370:1983-92 6
Resistance Associated Variants (RAVs) Amino acid substitutions within HCV proteins that create drug resistance, usually affecting - NS3/4 Protease inhibitor drugs - drugs Genotype 1a, Genotype 3 patients affected Testing can be done before choosing regimen More information at: www.hcvguidelines.org www.hepatitis.va.gov Grazoprevir/Elbasvir (Zepatier ) GT1, 4, or 6 and Resistance Associated Variants: NS5A Genotype 1a RAV Status in Patients with Baseline Sequence % (n/m) SVR12 All Patients % (N/n) Baseline NS5A RAVS 12% (19/154) 58% (11/19) No baseline NS5A RAVs 88% (135/154) 99% (133/135) Genotype 1b Baseline NS5A RAVS 14% (18/130) 94% (17/18) No baseline NS5A RAVs 86% (112/130) 100% (112/112) Zeuzem S, et al. Ann Intern Med. 2015;163:1-13 SVR12 (%) Sofosbuvir/Velpatasvir ASTRAL-1: GTs 1, 2, 4, 5, 6 for 12 wks 100 80 60 40 20 0 Total 99 99 99 99 99 618/624 496/501 120/121 418/423 200/201 Non- Cirrhotic Cirrhotic Treatment Naive Treatment Eperienced Feld J, et al. NEJM. 2015;373:2599-2607. SVR12 ( %) Sof/Vel 12 wks vs Sof + Riba 24 wks ASTRAL-3 Trial - Genotype 3 100 80 60 40 20 0 Total, N=277 SOF/VEL 98 93 4391 90 89 73 71 163 SOF + RBV 33/37 160/163 141/156 40/43 Treatment Naïve, Non-cirrhotic 33/45 31/34 22/31 Treatment Naïve, Cirrhotic 22/38 Treatment Eperienced, Non-cirrhotic Treatment Eperienced, Cirrhotic TN Non-Cirrhotic TN Cirrhotic TE Non-Cirrhotic TE Cirrhotic Sof=Sofosbuvir; Vel=Velpatasvir TN=Treatment Naïve; TE=Treatment Eperienced 37 34 58 Foster GR, et al. New Engl J Med. 2015 7
Whom to treat Whom to Treatment and Pre-Treatment Considerations Everyone should be considered for treatment Most urgent for patients at increased risk of: Decompensation and death Morbidity, symptoms Transmitting virus to others Rapid progression Viral Factors Influencing HCV Treatment Decisions Genotype Subtype Viral load Treatment History Naïve or eperienced Ribavirin eligibility Resistance mutations Prior treatments Fibrosis stage Comorbidities Payor requirements Financial Fibrosis stage (F0-F4) If cirrhosis, Childs score A, B or C Pre- or Post-Transplant HIV coinfection Etrahepatic manifestations (cryoglobulinemia, Renal function Drug-drug interactions Insurance approval etc) Staging and Assessment of Fibrosis Why test for fibrosis? Determine treatment urgency Assess need for additional care Cirrhosis requires additional management How to test for fibrosis? Gold standard: liver biopsy Serum markers Fibrosure, APRI, Fib-4 Elastography (FibroScan, MRE) Imaging may detect cirrhotic features 8
Calculators for Fibrosis APRI FIB-4 Chou R, et al. Ann Intern Med. 2013;158:807-20. http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp Patient adherence Adherence is crucial Factors that may complicate adherence, such as active substance use, depression, neurocognitive disorders, and lack of social support, should be noted Address issues of adherence before initiating medications. Providers should incorporate strategies for measuring and supporting adherence within their clinics. Selected Potential Drug Drug Interactions Concomitant Medication SOF SIM LDV PTV/RTV/ OBV + DSV Acid-reducing agents* X X DCV GZR/EBV Amiodarone X X X X X X Anticonvulsants X X X X X X Digoin X X X X Ethinyl estradiol containing products Glucocorticoids X X X X PDE5 inhibitors X X X Rifamycin antimicrobials X X X X X X Sedatives X X X St John s wort X X X X X X Statins AASLD/IDSA Guidelines. February 2016. X X X X X Slide credit: clinicaloptions.com X Considerations for Referral HCV/HIV coinfection Decompensated cirrhosis Renal disease Drug drug interactions Retreatment after a DAA regimen failure Comorbidities 9
Estimated Medication Cost Regimen Cost Sofosbuvir + Ribavirin 12 weeks $84,000 Ledipasvir/Sofosbuvir 8 weeks $63,000 Ledipasvir/Sofosbuvir 12 weeks $94,500 Ledipasvir/Sofosbuvir 24 weeks $189,000 Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir +/- Ribavirin 12 weeks Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir +/- Ribavirin 24 weeks $84,000 $168,000 Incremental Costs of HCV Patients with HCV $9681 per patient per year HCV with decompensated cirrhosis $27,845 per patient per year HCV with hepatocellular carcinoma $43,671 per patient per year HCV with liver transplant $93,609 per patient per year McAdam-Mar C, et al. J Manag Care Pharm. 2011;17(7):531-546. Treatment IS Cost-Effective 1. Real world SVR rates comparable to clinical trials Price of sofosbuvir in selected countries 2. HCV treatment for genotype 1 patients at all fibrosis stages, Ledipasvir/Sofosbuvir was cost effective. 3. Cost-effective yes, but affordable no. 4. Advanced fibrosis no longer always required by payors ChahalM et al. JAMA Intern Med. 2015 Nov 23:1-9 Hill et al. Journal of Virus Eradication 2016; 2: 28 31 10
Managing Medication Authorization Denial q Don t give up after first prior authorization denied q Carefully read reason for denial q Mild fibrosis q Not the preferred drug q Missing data q Payor creates eligibility criteria and drug preference q Appeal or peer to peer available q Access pt assistance programs On-Treatment Care Monitoring on HCV Treatment Genotype Baseline 4 wks 12 wks after finishing X Notes HCV RNA X X X Or every 2 weeks until undetectable. Stop treatment if not undetectable by 6 wks CBCD X X Every 2 weeks if on RBV LFTs X X Stop if AST/ALT 10 GFR X X Every 2 weeks if abnl or drug interactions INR X Adverse Events Discuss most common adverse events and management strategies in pre-education session Headaches, Fatigue, Nausea, Insomnia less than 10% Anemia still a concern with Ribavirin Source: hcvguidelines.org 11
Viral Cure (SVR) Associated With Reduced Risk of Death,Transplant and HCC Post-Treatment Care Pts Dead After 5 Yrs (%) Meta-analysis of over 23,000 patients from 129 studies Achieving SVR vs. no SVR was associated with substantial benefits 62% to 84% reduction in all-cause mortality, 90% reduction in liver transplantation, 68% to 79% reduction in HCC 25 20 15 10 5 0 5-Yr Risk of All-Cause Death by SVR 4.5 10.5 3.6 SVR No SVR 11.3 1.3 10.0 General Cirrhotic Pts HIV- Coinfected Pts Pts With HCC After 5 Yrs (%) 25 20 15 10 5 0 2.9 9.3 5-Yr Risk of HCC by SVR SVR No SVR 5.3 13.9 0.9 10.0 General Cirrhotic Pts HIV- Coinfected Pts Hill AM, et al. AASLD 2014. Abstract 44. Monitoring in Cured Patients With Early Fibrosis Stage Annual LFTs and CBC Repeat HCV RNA if LFTs normal and become abnormal If pt has another liver disease diagnosis (eg, fatty liver, HBV), may have persistently abnormal results after cure Should routinely follow-up for progression of liver disease Liver cancer surveillance: not indicated Variceal surveillance: not indicated AASLD/IDSA Guidelines. February 2016. Brui J, et al. Hepatology. 2011;53:1020-1022. Monitoring in Cured Patients With Advanced Fibrosis Routine clinic appointments 1-2 times per year Consider alternating with hepatologist Obtain history and eamine for signs of portal HTN Obtain comprehensive metabolic profile, INR, CBC Repeat HCV RNA if abnormal LFTs To tal bi l i rubi n, cre atini ne, PT-INR for MELD score Contact hepatologist if rising Eamine for portal HTN if low platelet count HCC surveillance and screening for esophageal varices van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 3. Aleman S, et al. Clin Infect Dis. 2013;57:230-236 12
No alcohol or NSAIDS Immunizations Cirrhosis Management in Primary Care Screen for HCC with US every 6 mos Calculate MELD every 6 mo if compensated; every 3-4 mo if decompensated Screen for varices with EGD every 2 years Refer for decompensation asci tes, vari ces, portal HTN Refer for Transplant evaluation if MELD 10-15 Reducing Risk of Reinfection Has been demonstrated among MSM, IDU Variable risk- may be associated with increased rate of spontaneous clearance Counsel and educate on risk reduction Seual transmission Partner testing Safer se practices Pts using injection drugs should be Referred for treatment Counseled on strategies to avoid HCV transmission Conclusions Compelling evidence for use of DAA Etremely high cure rates, short duration, few mild side effects Ease of regimen many regimens are one pill per day Ribavirin-free regimens are on the horizon Regimen selection remains comple Resistance testing is required for some regimens and some retreatment situations Major barriers are access to an HCV prescriber and insurance coverage but insurance coverage is very dynamic 13