Hepatitis C New Medications, New Hope and New Opportunities for Primary Care Disclosures: Grant for quality improvement Gilead In this talk, 10 drugs will be discussed, 4 of which are manufactured by Gilead. Learning Objectives 1. Review the evidence based and guideline recommended screening for hepatitis C virus (HCV) infection for primary care 2. Understand how new HCV antivirals work and review the current treatment options and success rates HCV Disease Outcomes in the US 3. Recognize which patients can be treated in primary care and which patients should be referred. 4. Understand the need for adherence on HCV treatment 5. Recognize the need for cirrhosis and HCC monitoring after patients achieve HCV cure 1
Decompensated Cirrhosis and HCC Projected Prevalence Rises Through 2020 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 Deaths from liver cancer increased at the highest rate of all cancers HCC has second highest rise in incidence second only to thyroid cancer 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 2014 16,500 24,700 29,700 30,500 http://www.cdc.gov/hepatitis/statistics/inde.htm 2
Screening Recommendations from the CDC and USPSTF Birth Year Screening: Born 1945-1965 Screening and Initial Evaluation Risk Based Screening: 1 or more Risk Factors IDU Transfusion before 1992 Clotting factors before 1987 HIV or HBV Chronic Hemodialysis Elevated ALT Smith BD, et al. MMWR Morb Mortal Wkly Rep. 2012;61(RR04);1-18. HCV RNA (viral load) HCV Genotype Primary Care Evaluation of HCV 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 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 3
Calculators for Fibrosis APRI FIB-4 HCV Treatment Chou R, et al. Ann Intern Med. 2013;158:807-20. http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp 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 (%) 25 20 15 10 5 0 5-Yr Risk of All-Cause Death by SVR SVR No SVR 4.5 10.5 3.6 11.3 General Cirrhotic Pts HIV- Coinfected Pts Hill AM, et al. AASLD 2014. Abstract 44. 1.3 10.0 Pts With HCC After 5 Yrs (%) 25 20 15 10 5 0 2.9 9.3 General 5-Yr Risk of HCC by SVR SVR No SVR 5.3 13.9 0.9 10.0 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;368:1859-1861. 4
Direct Acting Antivirals (DAAs) Against specific HCV targets Sites: NS3 NS4a NS5A NS5B DAA Regimens and Abbreviations Sofosbuvir SOF Sofosbuvir + Simeprevir+ Ledipasvir++/Sofosbuvir SOF + SIM LDV/SOF Paritaprevir+/ritonavir/Ombitasvir++ + Dasabuvir PrOD Paritaprevir+/ritonavir/Ombitasvir++ Elbasvir++/Grazoprevir+ Daclatasvir++ + Sofosbuvir Sofosbuvir/Velpatasvir++ Sofosbuvir/Velpatasvir++/Voeliprevir+ * Glecaprevir+/Pibrentasvir++ ** * FDA approved July 2017; ** FDA approved August 2017; + NS3/4A protease inhibitor; ++ NS5A Inhibitor PrO EBR/GZR DCV + SOF SOF/VEL SOF/VEL/VOX GLE/PIB Sofosbuvir DAA Regimens and Trade Names Sofosbuvir + Simeprevir+ Ledipasvir++/Sofosbuvir Sovaldi Sovaldi + Olysio Harvoni Paritaprevir+/ritonavir/Ombitasvir++ + Dasabuvir Viekira Pak Paritaprevir+/ritonavir/Ombitasvir++ Elbasvir++/Grazoprevir+ Daclatasvir++ + Sofosbuvir Sofosbuvir/Velpatasvir++ Sofosbuvir/Velpatasvir++/Voeliprevir+ * Glecaprevir+/Pibrentasvir++ ** * FDA approved July 2017; ** FDA approved August 2017; + NS3/4A protease inhibitor drug; ++ NS5A Inhibitor drug Technivie Zepatier Daklinza +Sovaldi Epclusa Vosevi Mavyret 3 Major Factors in Choosing HCV Treatment Regimen Cirrhosis Genotype/subtype Treatment history 5
SVR 100 90 80 70 60 50 40 30 20 10 0 Efficacy of GLE/PIB 12 Weeks in GT 1-6 Patients with Cirrhosis Treatment Naïve and Peg/SOF treatment eperienced 99 100 100 100 100 100 98 96 N= 47/48 39/39 34/34 16/16 1/1 7/7 39/40. 45/47 GT1A GT1B GT2 GT4 GT5 GT6 GT3 TN 12 wks EXPEDITION-1 12 weeks GT3 TE 16 wks SURVEYOR 2 Forns X, Lancet Infect Dis 2017; Wyles D. Hepatology 2017 Summary of Glecaprevir/Pibrentasvir Label For Treatment Naïve and Retreatment Without Cirrhosis With Compensated Cirrhosis HCV Genotype Prior Treatment Eperience Duration 1, 2, 3, 4, 5, 6 Naïve 8 Weeks 12 Weeks 1, 2, 4, 5, 6 PRS 8 Weeks 12 Weeks 3 PRS 16 Weeks 16 Weeks NS5A inhibitor (NS3/4A PI naive) 16 Weeks 16 Weeks Dosage 1 and durations NS3/4A PI are (NS5A applicable inhibitor naive) to patients * 12 with: Weeks 12 Weeks HCV mono-infection and HCV/HIV-1 co-infection Any stage of renal impairment, including patients receiving dialysis GLE/PIB not recommended with moderate hepatic impairment (CPT-B) GLE/PIB is contraindicated with severe hepatic impairment (CPT-C) PRS: regimens containing interferon, pegylated interferon, ribavirin and/or sofosbuvir (but no eperience with NS3/4A PI or NS5A inhibitors); CP: Child-Pugh classification MAVYRET US Prescribing Information; Accessed August 222017. SOF/VEL/VOX FDA Approved for Retreatment Genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an NS5A inhibitor Eamples of regimens containing NS5A inhibitors: 1. Ledipasvir/Sofosbuvir 2. Elbasvir/Grazoprevir 3. Sofosbuvir + Daclatasvir 4. Paritaprevir/ritonovir/ Ombitasvir + Dasabuvir SOF/VEL/VOX FDA Approved for Retreatment, cont d Genotype 1a or 3 previously treated with Sofosbuvir, without an NS5A inhibitor Eamples of regimens containing SOF without NS5A inhibitor 1. Sofosbuvir + Ribavirin 2. Peginterferon + Ribavirin + Sofosbuvir 3. Sofosbuvir + Simeprevir 6
Genotype 1a Treatment Naive LDV/SOF 8 weeks SVR 93%-97% Only if HCV RNA < 6 mill AND F0-F2 AND HIV neg GLE/PIB 8 or 12 weeks SVR 99% 12 weeks if cirrhosis SOF/VEL 12 weeks SVR 98-100% LDV/SOF 12 weeks SVR 94-96% if HCV RNA > 6 mill OR F3-4 OR HIV pos PrOD + Ribavirin 12 weeks SVR 96% 24 weeks if cirrhosis EBR/GZR 12 weeks SVR 95-99% if no baseline NS5A RAV EBR/GZR + Ribavirin 16 weeks SVR 97% if baseline NS5A RAV Genotype 1b Treatment Naive LDV/SOF 8 weeks SVR 93%-97% if HCV RNA < 6 mill AND F0-F2 AND HIV neg GLE/PIB 8 or 12 weeks SVR 99% 12 weeks if cirrhosis SOF/VEL 12 weeks SVR 97-100% LDV/SOF 12 weeks SVR 94-96% if HCV RNA > 6 mill OR F3-4 OR HIV pos PrOD 12 weeks SVR 99% EBR/GZR 12 weeks SVR 95-98% Genotype 2 Treatment Naive Genotype 3 Treatment Naive GLE/PIB 8 or 12 weeks SVR 98-100% 12 weeks if cirrhosis SOF/VEL 12 weeks SVR 99-100% DAC + SOF 12 weeks SVR 100% GLE/PIB 8 or 12 weeks SVR 95-98% 12 weeks if cirrhosis SOF/VEL 12 weeks SVR 93-99% If cirrhosis and baseline RAV, add ribavirin DAC + SOF 12 weeks SVR 97% Add ribavirin if cirrhosis 7
Genotype 4 - Treatment Naive GLE/PIB 8 or 12 weeks SVR 93-100% 12 weeks if cirrhosis EBR/GZR 12 weeks SVR 97% SOF/VEL 12 weeks SVR 98-100% LDV/SOF 12 weeks SVR 93% Add ribavirin PrO 12 weeks SVR 95% Genotype 5,6 - Treatment Naive GLE/PIB 8 or 12 weeks SVR 100% 12 weeks if cirrhosis SOF/VEL 12 weeks SVR 97-100% LDV/SOF 12 weeks SVR 93-96%% Resistance Associated Variants (RAVs) Drug resistance mutations in HCV, usually to specific - NS3/4 Protease inhibitor drugs - NS5A inhibitor drugs Genotype 3 patients with RAVs, especially if have cirrhosis, have much lower SVR rates Genotype 1a patients with RAVs also have lower SVR rates. Patients Who Failed DAA Need RAV Testing Before Retreatment Test for NS3/4A RAV if treated previously with: 1. SOF + SIM 2. PrOD 3. EBR/GZR Test for NS5A RAV if treated previously with: 1. LDV/SOF 2. PrOD 3. EBR/GZR 4. DCV + SOF 5. SOF/VEL Pre-Treatment Considerations 8
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 Barriers to Optimizing Treatment Patient Factors Not offered linkage to care with an HCV treater Alcohol/drug use Missed appointments Fear of side effects due to previous information about interferon Contraindications to treatment (eg, medical or psychiatric comorbidity) 1 Provider Factors Under-diagnosis of HCV Knowledge gaps about new HCV treatments and recommendations Hesitation to treat past substance abusers Lack of access to specialist help Cultural inertia Time constraints AASLD = American Association of for the Study of Liver Diseases; IDSA = Infectious Diseases Society of America. Other Lack of awareness of infection Access to care/loss of insurance Payer restrictions Cost concerns 1. AASLD/IDSA. http://www.hcvguidelines.org/. Sept 16, 2016;. Accessed February 9, 2017. 2. McGowan CE, et al. Hepatol. 2013:57:1325-1332; 3. Rein DB, et al. Ann Intern Med. 2015;156:263-270; 4. Spach DH. HCV Incidence and Prevalence. In: Hepatitis C Online. Updated Sep 5, 2016. http://www.hepatitisc.uw.edu/go/screening-diagnosis/epidemiology-us/coreconcept/all#hcv-incidence-prevalence; 5. Morrill JA, et al. J Gen Intern Med. 2005;20:754-758; 6. Fo R. Dig Dis Sci. 2016 September 12. [Epub ahead of print]; 7. Thomson M, et al. Dig Dis Sci. 2016;61:3460-3468; 8. Kattakuzhy S, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abstract LBP524. 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, etc) Renal function Drug-drug interactions Insurance approval Adherence is crucial Patient adherence Note the factors that may complicate adherence: active substance use, depression, neurocognitive disorders, and lack of social support Address issues of adherence before initiating medications. Incorporate strategies for measuring and supporting adherence within your clinics. 9
Whole Sale Costs Regimen Total Ledipasvir/Sofosbuvir 8 wks-12 wks $63,000 - $94,500 Elbasvir/Grazoprevir 12 wks $54,600 Daclatasvir + Sofosbuvir 12 wks $147,000 Sofosbuvir/Velpatasvir 12 wks $74,760 Sof/Vel/Vo 12 weeks $74,760 Glecaprevir/Pibrentasvir 8wks-12 wks $26,400 - $39,600 Whole Sale Costs 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 http://hepatitisc.hcvadvocate.org/2017/08/fair-pricing-coalition-welcomes-fda-approvalabbvies-new-pangenotypic-hcv-combinationmavyret.htmlhttp://www.hepatitisc.uw.edu/page/treatment/drugs McAdam-Mar C, et al. J Manag Care Pharm. 2011;17(7):531-546. Treatment is Cost-Effective Price of sofosbuvir in selected countries 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 Chahal M 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 ü Don t give up after first prior authorization denied ü Carefully read reason for denial q Mild fibrosis q Not the preferred drug q Missing data ü Payor creates eligibility criteria and drug preference ü Appeal or peer to peer available ü Access pt assistance programs ü Often the pharmaceutical will cover the pt s copay Genotype Monitoring on HCV Treatment Pre-Treat X 4 wks On T 12 wks After T = SVR 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 Source: hcvguidelines.org After SVR: Long-term Monitoring Patients with advanced fibrosis should be screened for liver cancer every 6 months Patients who are active IV drug users should be screened for reinfection and receive counseling 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 11
HBV Reactivation During HCV Treatment FDA Drug Safety Communication 24 cases of HBV reactivation (including 3 cases of acute liver failure) over a 31 month period, Boed Warning requirement issued All patients should be tested before treatment for HBsAg, HBsAb, HBcAb If HBsAg positive, refer for HBV treatment while on HCV treatment Opportunities for Primary Care FDA. FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. Oct 4, 2016. http://www.fda.gov/drugs/drugsafety/ucm522932.htm. Accessed Feb 2, 2016; 2. ISMP. QuarterWatch. Jan 25, 2017. http://www.ismp.org/quarterwatch/pdfs/2016q2.pdf. Accessed Feb 2, 2017; 3. Grady D. Are New Drugs for Hepatitis C Safe? A Report Raises Concerns. The New York Times. Jan 24, 2017. https://www.nytimes.com/2017/01/24/health/hepatitis-c-antiviral-drugstudy.html?smprod=nytcore-ipad&smid=nytcore-ipad-share. Accessed Feb 2, 2017. Primary Care can provide most of the spectrum of HCV 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 2) An infectious diseases specialist with HCV evaluation and treatment competence 3) A hepatology or gastroenterology specialist 12
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 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 (Child Pugh B or C) 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 ribavirin-free 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