Hepatitis C ew Medications, New Hope and New. V. Opportunities for Primary Care. Outline. HCV Disease Outcomes in the US 9/21/2016

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1 Hepatitis C ew Medications, New Hope and New Opportunities for Primary Care Primary Care Principles and Practice October 14, 2016 Disclosures: Grant support Gilead Sciences, Inc Quality improvement Systematized HCV and HIV screening in Primary care 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 IV. Pre Treatment Workup V. Opportunities for Primary Care HCV Disease Outcomes in the US 1

2 Projected Prevalence of Decompensated Cirrhosis and HCC Rises Through 2020 #1: HCV mortality higher than from top 60 other infections combined From , number of HCV deaths surpassed the major 60 other nationally notifiable infectious conditions combined Mortality from other conditions (eg TB, pneumococcal disease) is declining while HCV mortality rising 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): HCV deaths mainly among ages yo Ly K et al. Clin Infect Dis; 2016;62: #2: Deaths from liver cancer increased at the highest rate of all cancers #3: Rising Number of New Infections HCC has second highest rise in incidence second only to thyroid cancer 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 Ryerson AB et al. Cancer 2016 May 1;122(9): Estimated Actual New Cases of HCV ,500 24,700 29,

3 Screening Recommendations from the CDC and USPSTF Risk Based Screening: 1 or more Risk Factors Screening and Initial Evaluation IDU Transfusion before 1992 Clotting factors before 1987 HIV or HBV Chronic Hemodialysis Elevated ALT Birth Year Screening: Born Smith BD, et al. MMWR Morb Mortal Wkly Rep. 2012;61(RR04);1-18. Primary Care Evaluation of HCV Baseline Every 6 mos *if cirrhosis* Annually HCV RNA (viral load) HCV Genotype 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

4 Viral Cure (SVR) Associated With Reduced Risk of Death,Transplant and HCC 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 60% 50% US HCV Treatment During Interferon Ribavirin Era 50% Pts Dead After 5 Yrs (%) Yr Risk of All-Cause Death by SVR SVR No SVR General Cirrhotic Pts HIV- Coinfected Pts Hill AM, et al. AASLD Abstract Pts With HCC After 5 Yrs (%) General 5-Yr Risk of HCC by SVR SVR No SVR Cirrhotic Pts HIV- Coinfected Pts 40% 30% 20% 10% 0% 32 38% 7 11% 5 6% Diagnosed Referred to care Treated Successfully Treated Holmberg SD, et al. New Eng J Med. 2013;368: Direct Acting Antivirals (DAAs) Against specific HCV targets 2016: All Oral Regimens for HCV Regimen Drug Class Approved Genotypes Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + Year 1, 4, 5, Sites: NS3 NS4a NS5A NS5B 4

5 2016: All Oral Regimens for HCV Regimen Drug Class Approved Genotypes Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + Year 1, 4, 5, : All Oral Regimens for HCV Regimen Drug Class Approved Genotypes Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + Year 1, 4, 5, Paritaprevir/ RTV/ Ombitasvir + Dasabuvir Protease inhibitor + + NS5B Non-nucleotide inhibitor Paritaprevir/ RTV/ ombitasvir + dasabuvir Protease inhibitor + + NS5B Non-nucleotide inhibitor Sofosbuvir + Daclatasvir NS5B Nucleotide inhibitor : All Oral Regimens for HCV Regimen Drug Class Approved Genotypes Sofosbuvir/ Ledipasvir NS5B Nucleotide inhibitor + Paritaprevir/ RTV/ ombitasvir + dasabuvir Protease inhibitor + + NS5B Non-nucleotide inhibitor Sofosbuvir + Daclatasvir NS5B Nucleotide inhibitor + Grazoprevir/ Elbasvir Protease inhibitor + Year 1, 4, 5, , : All Oral Regimens for HCV Regimen Drug Class Approved Genotypes Sofosbuvir/ Ledipasvir Paritaprevir/ RTV/ ombitasvir + dasabuvir Sofosbuvir + Daclatasvir Grazoprevir/ Elbasvir Sofosbuvir/ Velpatasvir NS5B Nucleotide inhibitor + Protease inhibitor + + NS5B Non-nucleotide inhibitor NS5B Nucleotide inhibitor + Protease inhibitor + NS5B Nucleotide inhibitor + Year 1, 4, 5, , ,2,3,4,5, In order of time of FDA approval 5

6 3 Major Factors in Choosing HCV Treatment Regimen Sofosbuvir/Ledipasvir (Harvoni ) ION 1 Trial Genotype 1 Genotype/subtype Patients with SVR 12 (%) LDV-SOF LDV-SOF +RBV LDV-SOF LDV-SOF + RBV 12-Week Regimen 24-Week Regimen Presence of cirrhosis Treatment History LDV-SOF= ledipasvir-sofosbuvir RBV = ribavirin Afdhal N, et al. NEJM. 2014;370: Patients with SVR12 (%) Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir (Viekira ) PEARL III and PEARL IV Trials GT / / / / D + RBV 3D 3D + RBV 3D Genotype 1a Genotype 1b 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 3D = Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir RBV = Ribavirin Ferenci P, et al. NEJM. 2014;370:

7 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) SVR12 (%) Sofosbuvir/Velpatasvir ASTRAL 1: GTs 1, 2, 4, 5, 6 for 12 wks 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: / / / / /201 Total Non Cirrhotic Cirrhotic Treatment Naive Treatment Eperienced Feld J, et al. NEJM. 2015;373: Sof/Vel 12 wks vs Sof + Riba 24 wks ASTRAL 3 Trial Genotype 3 Case: Genotype 1b SVR12 (%) Total, N=277 SOF/VEL SOF + RBV 160/163 40/43 31/34 33/37 141/156 33/45 22/31 22/38 Treatment Naïve, Non cirrhotic Treatment Naïve, Cirrhotic 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 Foster GR, et al. New Engl J Med yo man with chronic HCV diagnosed in 1995 Liver biopsy in 1997 stage 2 fibrosis, Updated Fibrosure = F4 Current HCV RNA 2.5 million Regimen choices (in alphabetical order): Elbasvir/grazoprevir 12 weeks Paritaprevir/ RTV/ ombitasvir + dasabuvir 12 weeks Sofosbuvir/ledipasvir 12 weeks 7

8 Case Eample: Genotype 3 60 yo woman, Genotype 3, Treatment Naïve Cirrhosis (F4) based on ultrasound showing shrunken small nodular liver and splenomegaly Options: Sofosbuvir/Velpatsvir (if no NS5A mutation) Sofosbuvir/Velpatasvir + Ribavirin (if NS5A mutation) Pre Treatment Considerations NS5A mutation testing sent > Positive Presence of Y93H mutation Optimal regimen = Sof/Vel + Ribavirin 12 weeks Whom to treat 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 Factors Influencing HCV Treatment Decisions Viral 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, etc) Renal function Drug drug interactions Insurance approval 8

9 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 Calculators for Fibrosis APRI FIB 4 Chou R, et al. Ann Intern Med. 2013;158: 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/ DCV GZR/EBV OBV + DSV Acid-reducing agents* X X Amiodarone X X X X X X Anticonvulsants X X X X X X Digoin X X X X Ethinyl estradiol containing X 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 X X X X X Slide credit: clinicaloptions.com 9

10 Considerations for Referral HCV/HIV coinfection Decompensated cirrhosis Renal disease Drug drug interactions Retreatment after a DAA regimen failure Comorbidities Whole Sale Costs Regimen Cost per pill Total Elbasvir/Grazoprevir 12 wks $650 $54,600 Ledipasvir/Sofosbuvir 8 wks $1125 $63,000 Sofosbuvir/Velpatasvir 12 wks $890 $74,760 Ombitasvir/Paritaprevir/Ritonavir + $991 $83,319 Dasabuvir 12 wks Ledipasvir/Sofosbuvir 12 wks $1125 $94,500 Daclatasvir + Sofosbuvir 12 wks $750 + $1000 $147,000 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 Treatment IS Cost Effective 1. Real world SVR rates comparable to clinical trials 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 McAdam-Mar C, et al. J Manag Care Pharm. 2011;17(7): Chahal M et al. JAMA Intern Med Nov 23:1 9 10

11 Price of sofosbuvir in selected countries Managing Medication Authorization Denial Don t give up after first prior authorization denied Carefully read reason for denial Mild fibrosis Not the preferred drug Missing data Payor creates eligibility criteria and drug preference Appeal or peer to peer available Access pt assistance programs Hill et al. Journal of Virus Eradication 2016; 2: Monitoring on HCV Treatment Adverse Events Genotype Baseline 4 wks 12 wks after finishing X Notes Discuss most common adverse events and management strategies in pre education session 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 Headaches, Fatigue, Nausea, Insomnia less than 10% Anemia still a concern with Ribavirin GFR X X Every 2 weeks if abnl or drug interactions INR X Source: hcvguidelines.org 11

12 Primary Care can provide most of the spectrum of HCV care Opportunities for Primary Care Such as: Screening and diagnosis Performing initial evaluation after diagnosis Caring for patient with chronic liver disease Performing pre treatment assessment Prescribing and managing DAA treatment of uncomplicated cases Managing compensated cirrhosis Linkage to Care Any patient with HCV RNA should be referred to a medical provider who can further evaluate and manage the patient s HCV infection, such as: 1) A primary care clinician (physician, nurse practitioner, or physician assistant) with interest and eperience evaluating and treating HCV patients Why Gaps Occur in Linkage of Care Provider failure to offer follow up appointment Patient failure to follow up on the referral Lack of medical insurance Substance abuse problems that interfere with making or keeping the appointment 2) An infectious diseases specialist with HCV evaluation and treatment competence 3) A hepatology or gastroenterology specialist 12

13 Untreated HCV From The Interferon Era Many patients diagnosed in the interferon era were ineligible or were counseled not to undergo treatment Many patients in the interferon era failed or didn t tolerate treatment These patients should be re evaluated for DAA treatment now Recommended for Referral Decompensated cirrhosis Etrahepatic manifestations HIV HCV coinfection DAA treatment failure Renal insufficiency Drug Drug interactions Conclusions Compelling evidence for use of DAAs etremely high cure rates, short duration, few side effects Ease of regimen many regimens are one pill per day and ribavirinfree regimens now eist Resistance testing is required for some genotypes with some regimens, and some retreatment situations Major barriers are access to an HCV prescriber and insurance coverage yet coverage is very dynamic Goal of eliminating HCV needs participation from specialists and generalists Systems need to be in place to make HCV screening and linkage to care more reliable 13