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Hepatitis C: Updates in Therapeutics Presented by Whitney Jandreau, PharmD PGY1 Pharmacy Practice Resident VA Maine Healthcare System April 2, 2016 The author of this presentation has the following to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation. Whitney Jandreau: Nothing to disclose Objectives 1. Examine recent trends in the diagnosis and management of hepatitis C virus (HCV) infection. 2. Identify risk factor-based screening strategies to improves rates of detection and treatment of HCV infection. 3. Construct an individualized management plan for both treatment-naïve and treatment-experienced patients with HCV infection. 4. Develop a monitoring and assessment plan for patients with HCV infection who are initiated on various pharmacotherapies. 5. Describe strategies for optimized care of HCV patients who VETERANSare ADMINISTRATION PATIENT CARE SERVICESHIV/HCV coinfected, or cirrhotic. post-liver transplant, 2 Introduction OVERVIEW OF HEPATITIS C VIRUS (HCV) VETERANS ADMINISTRATION PATIENT CARE SERVICES Introduction to HCV • Hepatitis C is a viral liver infection and the most common blood-borne infection in the United States • The virus lacks a proofreading polymerase – the resulting mutations allow the virus to evade the immune system VETERANS ADMINISTRATION PATIENT CARE SERVICES Viral Genotypes VETERANS ADMINISTRATION PATIENT CARE SERVICES Negro, F. & Alberti, A. Liver Transpl. 31 (Suppl. 2), 1–3 (2011) and Center for Disease Analysis Pathophysiology ISG: interferon-stimulated genes VETERANS ADMINISTRATION PATIENT CARE SERVICES IFN: interferon HCV: hepatitis C virus CHC: chronic hepatitis C 6 Assessment of Fibrosis/Cirrhosis METAVIR Score FIB-4 Index *Histologic* APRI Child-Turcotte-Pugh Score *Non-invasive* *Non-invasive* *Non-invasive* (age x AST)/(plt x [sqr ALT]) (AST to platelet ratio index) Points assigned for clinical parameters: ascites, T bili, alb, PT/INR, hepatic encephalopathy. F0: no fibrosis F1: portal fibrosis without septa F2: portal fibrosis with septa F3: portal fibrosis with numerous septa without cirrhosis HCV: <1.45 = METAVIR F0-F1 >3.25 = METAVIR F3-F4 NASH: <1.30 = METAVIR F0-F1 >2.67 = METAVIR F3-F4 F4: cirrhosis Intensity of necroinflammatory lesions is graded A0 (no activity) to A3 (severe). ≤0.3: unlikely cirrhosis or significant fibrosis >0.3 and ≤0.5: unlikely cirrhosis, significant fibrosis possible >0.5 and ≤1.5: significant fibrosis or cirrhosis possible 7 to 9: B (significant functional compromise; 60% 2-yr survival) 10 to 15: C (decompensated; 35% 2-yr survival) >1.5 and ≤2: likely significant fibrosis, cirrhosis possible >2: likely cirrhosis VETERANS ADMINISTRATION PATIENT CARE SERVICES Prepared by Whitney Jandreau, PharmD 5 to 6: A (well-compensated; 85% 2-yr survival) 7 Viral Transmission • Primarily through large or repeated percutaneous exposure to infectious blood – Injection drug use – Receipt of blood, blood products, or organs – Needlestick injuries – Birth to an HCV-infected mother • Infrequently through – Sexual contact – Sharing personal items (e.g. razors) – Other invasive healthcare procedures VETERANS ADMINISTRATION PATIENT CARE SERVICES 8 Burden of Disease • Chronic HCV carries significant morbidity and mortality as the primary reason for: – Liver transplant and the leading cause of: – End-stage liver disease – Liver-related death – Hepatocellular carcinoma (HCC) VETERANS ADMINISTRATION PATIENT CARE SERVICES Infographic: CDC Examine recent trends in the diagnosis and management of hepatitis C virus (HCV) infection. OBJECTIVE 1 VETERANS ADMINISTRATION PATIENT CARE SERVICES Diagnosis HCV Antibody Nonreactive Reactive HCV RNA STOP Follow-up testing for those with continued risk factors. HCV RNA testing may be considered for immunocompromised patients. Not Detected Detected No current HCV infection* Current HCV infection AdaptedVETERANS from CentersADMINISTRATION for Disease Control andPATIENT Prevention, 2013SERVICES CARE *Additional testing as appropriate. Repeat RNA testing if the person is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease. Link to Care Barriers to Treatment Less than 20% of HCV-infected receive treatment. About 50% of HCV-infected personspersons are unaware they are infected. Lack of Appropriate Screening Patient-related Barriers • • • • • Lack of knowledge of risk factors Asymptomatic; physical exam and routine labs not remarkable VETERANS ADMINISTRATION PATIENT CARE SERVICES Contraindications to treatment Lack of acceptance of treatment Lack of access to treatment Overcoming Barriers • Education − Healthcare providers − Patients • A multidisciplinary approach to care increases the proportion of patients with psychiatric or substance abuse comorbidities who begin treatment. This approach ensures that the most appropriate course is chosen. VETERANS ADMINISTRATION PATIENT CARE SERVICES Patient-related Barriers to Treatment Initiation ● Contraindications to treatment Medical or psychiatric comorbidities ● Lack of acceptance of treatment Asymptomatic nature of disease Competing priorities Perceived low treatment efficacy Perceived long treatment duration Adverse effects ● Lack of access to treatment Cost Distance to specialist Overcoming Barriers • Current pharmacologic therapies provide better side effect profiles, shorter durations, and very high cure rates. These make healthcare providers more capable than ever of maximizing the individuals screened, treated, and cured. • Telemedicine and knowledge networks have successfully overcome geographic barriers to treatment centers as well as to specialists. VETERANS ADMINISTRATION PATIENT CARE SERVICES Patient-related Barriers to Treatment Initiation ● Contraindications to treatment Medical or psychiatric comorbidities ● Lack of acceptance of treatment Asymptomatic nature of disease Competing priorities Perceived low treatment efficacy Perceived long treatment duration Adverse effects ● Lack of access to treatment Cost Distance to specialist AASLD/IDSA Guidance on Hepatitis C COMPREHENSIVE & DYNAMIC GUIDELINE Supported by membership-based societies and not by pharmaceutical companies or other commercial interests. VETERANS ADMINISTRATION PATIENT CARE SERVICES 15 Identify risk factor-based screening strategies to improves rates of detection and treatment of HCV infection. OBJECTIVE 2 VETERANS ADMINISTRATION PATIENT CARE SERVICES Recommendations for One-time HCV Testing AASLD/IDSA HCV Guidance • One-time HCV testing is recommended for all persons born between 1945 and 1965, without prior ascertainment of risk. – 51 to 71 years old in 2016 • Risk behaviors – Injection-drug use (current or ever, including those who injected once) – Intranasal illicit drug use VETERANS ADMINISTRATION PATIENT CARE SERVICES Infographic: Axium Healthcare Pharmacy Recommendations for One-time HCV Testing AASLD/IDSA HCV Guidance • Risk exposures – Long-term hemodialysis (ever) – Getting a tattoo in an unregulated setting – Healthcare, emergency medical, and public safety workers after needlesticks, sharps, or mucosal exposures to HCV-infected blood – Children born to HCV-infected women – Prior recipients of transfusions or organ transplants, including persons who: • Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992 • Received clotting factor concentrates produced before 1987 – Persons who were ever incarcerated • Other – HIV infection – Unexplained chronic liver disease and/or chronic hepatitis including elevated alanine aminotransferase levels – Solid organ donors (deceased and living) VETERANS ADMINISTRATION PATIENT CARE SERVICES Recommendations for HCV Testing those with Ongoing Risk Factors AASLD/IDSA HCV Guidance • Annual HCV testing is recommended for persons who inject drugs and for HIV-seropositive men who have unprotected sex with men. • Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV. VETERANS ADMINISTRATION PATIENT CARE SERVICES Construct an individualized management plan for both treatment-naïve and treatmentexperienced patients with HCV infection. OBJECTIVE 3 Develop a monitoring and assessment plan for patients with HCV infection who are initiated on various pharmacotherapies. OBJECTIVE 4 VETERANS ADMINISTRATION PATIENT CARE SERVICES When and in Whom To Initiate Treatment AASLD/IDSA All patients with chronic HCV infection should be treated when (s)he is ready and the necessary resources are available. Exception: those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. VETERANS ADMINISTRATION PATIENT CARE SERVICES 21 Goal of Treatment AASLD/IDSA Reduce all-cause mortality and liver-related health adverse consequences by achievement of virologic cure as evidenced by a sustained virologic response (SVR). VETERANS ADMINISTRATION PATIENT CARE SERVICES 22 Pre-treatment Assessments Renal & Hepatic Function HCV Genotype & Viral Load CBC & INR (& TSH if IFN therapy) VETERANS IFN: interferonADMINISTRATION PATIENT CARE SERVICES 23 HCV Pharmacotherapy Timeline Daclatasvir (Daklinza™) Boceprevir (Victrelis®) Telaprevir (Incivek®) Interferon (IFN) Pegylated IFN + RBV taken with Pegylated IFN + RBV 50 – 75% Ombitasvir/ paritaprevir/ ritonavir/ (Technivie™) Sofosbuvir (Sovaldi®) Simeprevir (Olysio®) taken in combination or with RBV Pegylated IFN 85 – 93% 40 – 50% 6 – 26% Ledipasvir/ sofosbuvir (Harvoni®) Elbasvir/ grazoprevir (Zepatier™) Ombitasvir/ paritaprevir/ ritonavir/ dasabuvir (Viekira Pak™) Sofosbuvir/ velpatasvir (under FDA review) 94 – 100% 90 – 100% 1991 2002 2011 VETERANS ADMINISTRATION PATIENT CARE SERVICES 2013 2014 2015 2016 24 HCV Pharmacotherapy Timeline Daclatasvir (Daklinza™) NS3/4A PI NS5B polymerase inhibitor Ombitasvir/ paritaprevir/ ritonavir/ (Technivie™) NS5A replication inhibitor Non-specific agent Non-Nuc NS5B inhibitor Pharmacokinetic enhancer Boceprevir (Victrelis®) Telaprevir (Incivek®) Interferon (IFN) Pegylated IFN + RBV taken with Pegylated IFN + RBV 50 – 75% Sofosbuvir (Sovaldi®) Simeprevir (Olysio®) taken in combination or with RBV Pegylated IFN 85 – 93% 40 – 50% 6 – 26% Ledipasvir/ sofosbuvir (Harvoni®) Elbasvir/ grazoprevir (Zepatier™) Ombitasvir/ paritaprevir/ ritonavir/ dasabuvir (Viekira Pak™) Sofosbuvir/ velpatasvir (under FDA review) 94 – 100% 90 – 100% 1991 2002 2011 VETERANS ADMINISTRATION PATIENT CARE SERVICES 2013 2014 2015 2016 25 Targeted Drug Therapies VETERANS ADMINISTRATION PATIENT CARE SERVICES 26 Monitoring Virologic Response Sustained Virologic Response (SVR) • The continued absence of detectable HCV RNA at least 12 weeks after therapy completion • Virologic CURE Assessment of HCV Viral Load Baseline Treatment Week 4 End of Treatment (EOT) EOT + 12 weeks VETERANS ADMINISTRATION PATIENT CARE SERVICES 27 Summary of Recommendations for Patients Who are Initiating Therapy for HCV Infection TREATMENT-NAÏVE VETERANS ADMINISTRATION PATIENT CARE SERVICES Recommendations for Initial Treatment AASLD/IDSA Zepatier™ [elbasvir 50 mg/grazoprevir 100 mg] x 12 weeks if no baseline high foldchange NS5A resistance-associated variants for elbasvir are detected (no cirrhosis or compensated cirrhosis). Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (no cirrhosis or compensated cirrhosis). Genotype 1a Viekira Pak™ [paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg daily + dasabuvir 250 mg BID] + RBV (weight based) BID x 12 weeks (no cirrhosis). Sovaldi™ [SOF 400 mg] + Olysio™ [SMV 150 mg] daily RBV (weight-based) BID x 12 weeks (no cirrhosis). Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis). VETERANS ADMINISTRATION PATIENT CARE SERVICES LDV: ledipasvir RBV: ribavirin BID: twice daily SOF: sofosbuvir SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 29 Recommendations for Initial Treatment AASLD/IDSA Zepatier™ [elbasvir 50 mg/grazoprevir 100 mg] x 12 weeks (no cirrhosis or compensated cirrhosis). Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (no cirrhosis or compensated cirrhosis). Genotype 1b Viekira Pak™ [paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg daily + dasabuvir 250 mg BID] + RBV (weight based) BID x 12 weeks (no cirrhosis or compensated cirrhosis). Sovaldi™ [SOF 400 mg] + Olysio™ [SMV 150 mg] daily RBV (weight-based) BID x 12 weeks (no cirrhosis). Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis). VETERANS ADMINISTRATION PATIENT CARE SERVICES LDV: ledipasvir RBV: ribavirin BID: twice daily SOF: sofosbuvir SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 30 Recommendations for Initial Treatment AASLD/IDSA Sovaldi™ [SOF 400 mg] + RBV (weight-based) BID x 12 weeks (no cirrhosis) OR x 16-24 weeks (compensated cirrhosis). Genotype 2 Genotype 3 Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis) OR x 16-24 weeks (compensated cirrhosis). Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis) OR Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] RBV (weight-based) BID x 24 weeks (compensated cirrhosis). Sovaldi™ [SOF 400 mg] + PegIFN SC weekly + RBV (weight-based) BID x 12 weeks (no cirrhosis or compensated cirrhosis). VETERANS ADMINISTRATION PATIENT CARE SERVICES RBV: ribavirin BID: twice daily PegIFN: pegylated interferon SC: subcutaneously SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 31 Recommendations for Initial Treatment AASLD/IDSA Zepatier™ [elbasvir 50 mg/grazoprevir 100 mg] x 12 weeks (no cirrhosis or compensated cirrhosis). Genotype 4 Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (no cirrhosis or compensated cirrhosis). Technivie™ [paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg daily] + RBV (weight based) BID x 12 weeks (no cirrhosis or compensated cirrhosis). Genotypes 5/6 Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (regardless of cirrhosis status). VETERANS ADMINISTRATION PATIENT CARE SERVICES LDV: ledipasvir RBV: ribavirin BID: twice daily SOF: sofosbuvir SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 32 Summary of Recommendations for Patients in Whom Previous Treatment Has Failed TREATMENT-EXPERIENCED VETERANS ADMINISTRATION PATIENT CARE SERVICES Considerations for Treatment-Experienced Patients with HCV Infection • The retreatment regimen selection for persons in whom prior therapy has failed is dependent on: – Failed agents – Genotype – Cirrhosis status • General approach – Different agents (mechanisms of action) – May add ribavirin – May extend treatment duration Included in this presentation are recommendations for pegylated interferon (PegIFN) and ribavirin (RBV) treatment failures ONLY VETERANS ADMINISTRATION PATIENT CARE SERVICES 34 Recommendations for Retreatment after PegIFN/RBV Treatment Failure AASLD/IDSA Zepatier™ [elbasvir 50 mg/grazoprevir 100 mg] x 12 weeks if no baseline high foldchange NS5A resistance-associated variants for elbasvir are detected (no cirrhosis or compensated cirrhosis). Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (no cirrhosis). Harvoni® [LDV 90 mg/SOF 400 mg] daily x 24 weeks OR x Harvoni® [LDV 90 mg/SOF 400 mg] daily 12 weeks + RBV (weight based) BID (compensated cirrhosis). Genotype 1a Viekira Pak™ [paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg daily + dasabuvir 250 mg BID] + RBV (weight based) BID x 12 weeks (no cirrhosis). Sovaldi™ [SOF 400 mg] + Olysio™ [SMV 150 mg] daily x 12 weeks (no cirrhosis). Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis). VETERANS ADMINISTRATION PATIENT CARE SERVICES LDV: ledipasvir RBV: ribavirin BID: twice daily PegIFN: pegylated interferon SOF: sofosbuvir SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 35 Recommendations for Retreatment after PegIFN/RBV Treatment Failure AASLD/IDSA Zepatier™ [elbasvir 50 mg/grazoprevir 100 mg] x 12 weeks (no cirrhosis or compensated cirrhosis). Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (no cirrhosis). Harvoni® [LDV 90 mg/SOF 400 mg] daily x 24 weeks OR x Harvoni® [LDV 90 mg/SOF 400 mg] daily 12 weeks + RBV (weight based) BID (compensated cirrhosis). Genotype 1b Viekira Pak™ [paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg daily + dasabuvir 250 mg BID] + RBV (weight based) BID x 12 weeks (no cirrhosis or compensated cirrhosis). Sovaldi™ [SOF 400 mg] + Olysio™ [SMV 150 mg] daily x 12 weeks (no cirrhosis). Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis). VETERANS ADMINISTRATION PATIENT CARE SERVICES LDV: ledipasvir RBV: ribavirin BID: twice daily PegIFN: pegylated interferon SOF: sofosbuvir SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 36 Recommendations for Retreatment after PegIFN/RBV Treatment Failure AASLD/IDSA Sovaldi™ [SOF 400 mg] + RBV (weight-based) BID x 12 weeks (no cirrhosis) OR x 16-24 weeks (compensated cirrhosis). Genotype 2 Genotype 3 Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis) OR x 16-24 weeks (compensated cirrhosis). Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] x 12 weeks (no cirrhosis) OR Daklinza® [daclatasvir 60mg*] daily + Sovaldi™ [SOF 400 mg] + RBV (weight-based) BID x 24 weeks (compensated cirrhosis). Sovaldi™ [SOF 400 mg] + PegIFN SC weekly + RBV (weight-based) BID x 12 weeks (no cirrhosis or compensated cirrhosis). VETERANS ADMINISTRATION PATIENT CARE SERVICES LDV: ledipasvir RBV: ribavirin BID: twice daily PegIFN: pegylated interferon SOF: sofosbuvir SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 37 Recommendations for Retreatment after PegIFN/RBV Treatment Failure AASLD/IDSA Technivie™ [paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg daily] + RBV (weight based) BID x 12 weeks (no cirrhosis or compensated cirrhosis). Genotype 4 Zepatier™ [elbasvir 50 mg/grazoprevir 100 mg] RBV (weight-based) BID x 12-16 weeks (no cirrhosis or compensated cirrhosis). Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (no cirrhosis) or 24 weeks (compensated cirrhosis) OR Harvoni® [LDV 90 mg/SOF 400 mg] daily + RBV (weight-based) BID x 12 weeks (compensated cirrhosis). Genotypes 5/6 Harvoni® [LDV 90 mg/SOF 400 mg] daily x 12 weeks (regardless of cirrhosis status). VETERANS ADMINISTRATION PATIENT CARE SERVICES LDV: ledipasvir RBV: ribavirin BID: twice daily PegIFN: pegylated interferon SOF: sofosbuvir SMV: simeprevir *Dose adjusted when used concomitantly with CYP 450 3A4 inducers/inhibitors. 38 Direct Acting Antivirals for HCV Infection APPROVED IN 2014 TO 2016 VETERANS ADMINISTRATION PATIENT CARE SERVICES 39 • Place in Therapy – Genotypes 1 & 4 • Mechanism of Action – Elbasvir – Grazoprevir NS5A replication inhibitor NS3/4A PI • Significant DDIs – CYP3A Inducers, OATP1B1/3 Inhibitors • Warning – ALT elevations • Monitoring – Hepatic labs prior to therapy, at treatment week 8, and as clinically indicated; CBC periodically VETERANS ADMINISTRATION PATIENT CARE SERVICES 40 • Directions for Use – One tablet once daily • Common Side Effects – Fatigue, headache, nausea, anemia • Additional Testing – NS5A resistance testing in HCV genotype 1a prior to therapy • Resistance associated variants (RAVs) found in 10% to 15% of genotype 1-infected patients without prior exposure to NS5A inhibitors • If baseline RAVs are present, treatment extension to 16 weeks with the addition of weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) is recommended VETERANS ADMINISTRATION PATIENT CARE SERVICES 41 • Place in Therapy – Genotypes 1, 2, 3 • Mechanism of Action – Daclatasvir NS5A replication inhibitor • Significant DDIs – Strong CYP3A Inhibitors • Dose adjustment: 30 mg once daily – Moderate CYP3A Inducers • Dose adjustment: 90 mg once daily – Strong CYP3A Inducers: concomitant use is contraindicated VETERANS ADMINISTRATION PATIENT CARE SERVICES 42 • Warnings – Bradycardia (in combination with sofosbuvir and amiodarone) – Do not use as monotherapy • Monitoring – Liver enzymes and serum creatinine at baseline and when clinically indicated • Directions for Use – 60 mg once daily with concomitant sofosbuvir • Common Side Effects (STUDIED IN COMBINATION WITH SOFOSBUVIR) – Fatigue, headache, nausea, diarrhea VETERANS ADMINISTRATION PATIENT CARE SERVICES 43 technivie™ ombitasvir, paritaprevir and ritonavir tablets 12.5mg/75mg/50mg • Place in Therapy – Genotype 4 • Mechanism of Action – Ombitasvir – Paritaprevir – Ritonavir NS5A replication inhibitor NS3/4A PI Pharmacokinetic enhancer • Significant DDIs – CYP3A Inducers – Ethinyl estradiol-containing products contraindicated • Warnings – Hepatic failure or liver decompensation in patients with underlying cirrhosis, VETERANS hypersensitivity ADMINISTRATION PATIENT CARE(including SERVICES angioedema) reaction 44 technivie™ ombitasvir, paritaprevir and ritonavir tablets 12.5mg/75mg/50mg • Directions for Use – Two tablets once daily with a meal – In combination with RBV • Common Side Effects – Weakness, fatigue, insomnia, nausea, increased serum ALT, anemia • Serious Side Effects – Jaundice, dark urine, loss of appetite, vomiting • Monitoring – Hepatic function; consider discontinuation of therapy if ALT persists >10x ULN or if ALT is elevated with additional s/sx of hepatic inflammation • Contraception Counseling – RBV may cause birth defects and/or fetal death; two forms of appropriate birth control required during treatment and for 6 months after VETERANS ADMINISTRATION PATIENT CARE SERVICES completion. 45 • Place in Therapy – Genotype 1 • Mechanism of Action – – – – Ombitasvir Paritaprevir Ritonavir Dasabuvir NS5A replication inhibitor NS3/4A PI Pharmacokinetic enhancer Non-Nuc NS5B inhibitor • Significant DDIs – CYP3A Inducers – Ethinyl estradiol-containing products contraindicated • Warning/Monitoring – Hepatic failure (underlying cirrhosis)/hepatic function VETERANS ADMINISTRATION PATIENT CARE SERVICES 46 • Directions for Use – Daily dose packs – Take with food • Common Side Effects – Fatigue, nausea, pruritis, insomnia • Serious Side Effects – Jaundice, dark urine, loss of appetite, vomiting • Missed Dose Instructions – Ombitasvir/paritaprevir/ritonavir: if it has been more than 12 hours since the missed dose, skip the missed dose and resume normal dosing schedule – Dasabuvir: if it has been more than 6 hours since your missed dose, skip the missed dose and resume normal dosing schedule VETERANS ADMINISTRATION CARE – Do not double PATIENT the dose of SERVICES either tablet 47 • Place in Therapy – Genotypes 1, 4, 5, 6 • Mechanism of Action – Ledipasvir – Sofosbuvir NS5A replication inhibitor NS5B polymerase inhibitor • Significant DDIs – Antacids (acid-dependent absorption) • Warning – Administration with amiodarone is not recommended due to risk of serious (possibly fatal) bradycardia • Monitoring – Bilirubin, liver enzymes, SCr at baseline VETERANS ADMINISTRATION PATIENT CARE SERVICES periodically when clinically indicated and 48 • Directions for Use – One tablet, once a day • Common Side Effects – Fatigue, headache • Use of Antacids & Reflux Medications – Antacids (Tums, Rolaids, Maalox, Mylanta, Alka-Seltzer) • TAKE ANTACID 4 HOURS BEFORE OR 4 HOURS AFTER HARVONI® – H2 Receptor Antagonists • TAKE AT THE SAME TIME AS HARVONI® OR 12 HOURS APART • Dose not to exceed famotidine 40 mg BID = cimetidine 800 mg BID = ranitidine 150 mg BID – Proton Pump Inhibitors • TAKE AT THE SAME TIME AS HARVONI® ON AN EMPTY STOMACH • Dose not to exceed omeprazole 20 mg = lansoprazole 30 mg = esomeprazole 20 mg to 40 mg = pantoprazole 40 mg = dexlansoprazole 60 mg VETERANS ADMINISTRATION PATIENT CARE SERVICES 49 Other Pharmacotherapies for HCV INCLUDED FOR REFERENCE VETERANS ADMINISTRATION PATIENT CARE SERVICES 50 Ribasphere® ribavirin MECHANISM OF ACTION WARNINGS & MONITORING PATIENT COUNSELING HIGHLIGHTS Inhibits replication of RNA and DNA viruses; inhibits influenza virus RNA polymerase activity and inhibits the initiation and elongation of RNA fragments resulting in inhibition of viral protein synthesis. US Boxed Warnings, Associated Monitoring Appropriate use (oral): Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus. • Weight-based dosing given in two divided doses daily. • Ribavirin may cause birth defects and/or death of the exposed fetus. Use 2 forms of contraception to avoid pregnancy (in female patients and female partners of male patients) during and for 6 months after therapy. • This drug can cause hemolytic anemia which can cause significant fatigue, make heart disease worse, and lead to heart attacks. Tell your doctor if you have ever had heart problems. Do not take this drug if you have ever had very bad heart disease or heart problems that are not being treated. Call your doctor right away if you have chest pain while taking this drug. • This drug is typically dosed twice daily. • Take a missed dose as soon as you think about it. If it is close to the time for your next dose, skip the missed dose and resume your regular dosing schedule. Do not double doses. Used to treat HCV genotypes 1-4. Hemolytic anemia (oral): The primary clinical toxicity of ribavirin is hemolytic anemia, which may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Anemia usually occurs within 1 to 2 weeks of therapy initiation Pregnancy (oral): Significant teratogenic and/or embryocidal effects. Ribavirin has a multiple-dose half-life of 12 days, and may persist in nonplasma compartments for as long as 6 months. Therefore, ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. At least 2 reliable forms of effective contraception must be used during treatment and for 6 months posttreatment. VETERANS ADMINISTRATION PATIENT CARE SERVICES Contraindicated if CrCl < 50 mL/min. 51 Sovaldi® sofosbuvir MECHANISM OF ACTION After being metabolized to its active form, sofosbuvir inhibits HCV NS5B RNAdependent RNA polymerase, essential for viral replication, and acts as a chain terminator. Used to treat HCV genotypes 1-4. WARNINGS & MONITORING Warnings Administration with amiodarone in combination with another direct-acting antiviral (e.g. simeprevir) is not recommended due to risk of serious, even life-threatening, symptomatic bradycardia. Do not use as monotherapy; use only in combination with ribavirin (with or without PEG-IFN depending upon the clinical indication). Monitoring Bilirubin, liver enzymes, and serum creatinine at baseline and periodically when indicated. If used in combination with amiodarone and another direct acting antihepaciviral (or in patients who discontinued amiodarone just prior to initiating sofosbuvir in combination with a direct acting antihepaciviral), inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient or selfof heart rate daily through at VETERANS ADMINISTRATION monitoring PATIENT CARE SERVICES least the first 2 weeks of treatment. PATIENT COUNSELING HIGHLIGHTS • May be taken with or without food. • There are multiple significant drug-drug interactions for this drug. Consult a healthcare professional prior to new drug use (including over-the-counter and herbal drugs). • RBV counseling points (if used in combination with RBV). • Side effects may include itching, headache, insomnia, or feeling tired or weak. • Take a missed dose as soon as possible on the same day or resume regular dosing schedule on the next day. 52 Olysio® simeprevir MECHANISM OF ACTION Inhibits HCV NS3/4A protease, a protease that is essential for viral replication. It is considered a direct-acting antiviral treatment for HCV, also called a specifically targeted antiviral therapy for HCV (STAT-C). Used to treat HCV genotype 1. WARNINGS & MONITORING Warnings Serious symptomatic bradycardia when co‐administered with sofosbuvir and amiodarone. Hepatic decompensation and failure have been reported, most cases in patients with advanced and/or decompensated cirrhosis. Sulfa allergy: Contains a sulfonamide moiety. In patients with a history of sulfa allergy, the risk of reaction cannot be excluded. Photosensitivity, rash. Women of reproductive potential should use effective contraception during therapy. Child-Pugh class B or C: Use is not recommended. Use with peginterferon and ribavirin is contraindicated. Monitoring Bilirubin, liver enzymes, and uric acid at baseline and periodically when clinically VETERANS ADMINISTRATION indicated. PATIENT CARE SERVICES PATIENT COUNSELING HIGHLIGHTS • Take capsule (150 mg once daily) with food to increase the amount of drug absorbed. Swallow the capsule whole. • This drug will make you more sensitive to the sun. Avoid excessive exposure to sunlight or sunlamps. Use sunscreen and wear protective clothing. • Side effects may include itching, headache, nausea, or feeling tired or weak. • If you experience rash, report this to your provider immediately. • There are multiple significant drug-drug interactions for this drug. Consult a healthcare professional prior to new drug use (including over-the-counter and herbal drugs). • Take a missed dose as soon as possible, but if next dose is in less than 12 hours, skip the missed dose. • RBV counseling points (if used in combination with RBV). 53 Pegasys® peginterferon alfa-2 MECHANISM OF ACTION WARNINGS & MONITORING PATIENT COUNSELING HIGHLIGHTS Interferons interact with cells through high affinity cell surface receptors. Interferons inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages, and augment cytotoxicity of lymphocytes for target cells. US Boxed Warning Peginterferon alfa-2a may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. • Weekly subcutaneous injection that can be given in the abdomen or thighs. • Suicidal or homicidal ideation, depression, hallucinations, psychoses, and relapse of drug addiction have happened during treatment and within 6 months after the last dose. • Hypotension, tachycardia, chest pain or pressure, trouble breathing, and heart attacks have happened while taking alpha interferons. • RBV counseling points (if used in combination with RBV). • If a dose is missed or up to 2 days late, patient should take dose as soon as possible. If the missed dose is more than 2 days late, patient should contact healthcare professional. Used to treat HCV genotypes 1-4. Monitoring Periodic CBC (including hemoglobin, WBC, and platelets) and chemistries (including liver function tests and uric acid); TSH measured every 12 weeks. In combination with RBV, pregnancy tests should continue monthly up to 6 months after discontinuation of therapy. Evaluate for depression and other psychiatric symptoms; baseline eye exams and periodically in patients with baseline disorders; baseline echocardiogram in patients with cardiac disease. Child-Pugh Classes B & C. VETERANS ADMINISTRATION Contraindicated PATIENT CARE inSERVICES 54 Describe strategies for optimized care of HCV patients who are post-liver transplant, HIV/HCV coinfected, or cirrhotic. OBJECTIVE 5 VETERANS ADMINISTRATION PATIENT CARE SERVICES Post-Liver Transplantation • HCV infection occurs universally in those with viremia at the time of transplantation – Histologic features present within 6 months for most • Consider DDIs with transplantation medications VETERANS ADMINISTRATION PATIENT CARE SERVICES 56 HIV/HCV Coinfection • HIV/HCV-coinfection increases risk of – Liver-related morbidity and mortality – Non-hepatic organ dysfunction – Overall mortality • Treatment requires continued awareness of complex drug interactions between HCV and HIV medications VETERANS ADMINISTRATION PATIENT CARE SERVICES 57 Decompensated Cirrhosis • Achievement of SVR significantly decreases hepatic decompensation events, HCC, and liver-related mortality • Referral to experienced specialist is recommended VETERANS ADMINISTRATION PATIENT CARE SERVICES 58 In Summary • Increased awareness of risk factors and implementation of risk-factor based screening can improve rates of detection of hepatitis C virus • The treatment options and recommendations for HCV infection are rapidly evolving • New agents and progressive practice models have overcome several barriers to HCV treatment… … But barriers remain Hepatitis VETERANS ADMINISTRATION PATIENT CARE SERVICES 59 Questions? VETERANS ADMINISTRATION PATIENT CARE SERVICES References • • • • • • • • • • • Searson G , Engelson E, Carriero D, et al. Treatment of chronic hepatitis C virus infection in the United States: some remaining obstacles. Liver Int. 2014;34:668-671. Lemoine M, Thursz M. Hepatitis C, a global issue: access to care and new therapeutic and preventive approaches in resource-contained areas. Semin Liver Dis. 2014;34:89-97. Saifu H, Asch S, Bidwell M et al. Evaluation of HIV and hepatitis C telemedicine clinics. Am J Manag Care. 2012;18(4):207-212. Groessl E, Sklar M, Cheung R, et al. Increasing antiviral treatment through integrated hepatitis C care: a randomized multicenter trial. Contemp Clin Trials. 2013;35:97-107. Chopra S. Epidemiology and transmission of hepatitis C virus infection. UpToDate. March 1, 2015. Chopra S & Pockros P. Overview of the management of chronic hepatitis C virus infection. UpToDate. March 30, 2015. American Association for the Study of Liver Diseases. Hepatology 2004; 39:1147. Chronic Hepatitis C Virus (HCV) Infection: Treatment Considerations. Department of Veterans Affairs National Hepatitis C Resource Center Program and the Office of Public Health, March 2014; revised February 17, 2015. Recommendations for Testing, Managing, and Treating Hepatitis C. Joint panel from the American Association of the Study of Liver Diseases and the Infectious Diseases Society of America. December 2014. Viral Hepatitis – Hepatitis C Information. Centers for Disease Control and Prevention. www.cdc.gov/hepatitis/HCV. Accessed September 17, 2015. Martin M, McNicholl I. Advances in hepatitis C therapy. In: Murphy JE, Lee MW, eds. Pharmacotherapy Self-Assessment Program, 2015 Book 1. Infectious Diseases. Lenexa, KS: American College of Clinical Pharmacy, 2015:167-191. VETERANS ADMINISTRATION PATIENT CARE SERVICES Post-Questions for Pharmacy Technicians VETERANS ADMINISTRATION PATIENT CARE SERVICES Post-Questions for Pharmacy Technicians 1. Which of the following is a TRUE statement about hepatitis C virus (HCV) diagnosis and treatment? a. About 75 percent of persons infected with HCV receive treatment. b. Chronic HCV infection can be diagnosed based on routine physical examination and labs. c. All cases of acute HCV infection progress to chronic disease. Answer: D Targeted Objective: Examine recent trends in the diagnosis and management of hepatitis C virus (HCV). Option A: less than 20% of HCV-infected persons receive treatment. Option B: Diagnosis of HCV requires an antibody blood test and confirmatory RNA testing. Option C: Up to 30% of people acutely infected with HCV will clear the virus on their own. d. Diagnosis of HCV infection relies upon appropriate identification of risk factors. VETERANS ADMINISTRATION PATIENT CARE SERVICES 63 Post-Questions for Pharmacy Technicians 2. Which one of the following U.S. patients is MOST at risk for the transmission of hepatitis C virus (HCV)? a. An infant born at 38 weeks gestation to a 25 year-old mother infected with HCV. b. A 19-year-old woman who uses intravenous heroin. c. A 32-year-old man who has sex with men. d. A 50-year-old woman who received a kidney transplant in 2001. VETERANS ADMINISTRATION PATIENT CARE SERVICES Answer: B Targeted Objective: Identify risk factor-based screening strategies to improves rates of detection and treatment of HCV. According to AASLD/IDSA 2016, the most important risk for HCV infection is injection drug use, accounting for at least 60% of acute HCV infections in the United States. Considerations for other options: Option A: represents a risk exposure that is less likely to transmit HCV compared to IV drug use. Option C: sexual transmission of HCV is inefficient except among HIV-infected men who have unprotected sex with men. Option D: routine screening of donated blood and organs began in 1992. 64 Post-Questions for Pharmacy Technicians 3. Annual hepatitis C virus (HCV) testing is recommended for which of the following selections? a. Injection drug users. b. Persons born between 1945 and 1965. c. Answer: A Targeted Objective: Identify risk factor-based screening strategies to improves rates of detection and treatment of HCV. Per AASLD/IDSA 2016, annual HCV testing is recommended for persons who inject drugs and for HIVseropositive men who have unprotected sex with men. Persons who are HIV-positive. d. Healthcare workers. VETERANS ADMINISTRATION PATIENT CARE SERVICES 65 Post-Questions for Pharmacists VETERANS ADMINISTRATION PATIENT CARE SERVICES Post-Questions for Pharmacists 1. Which one of the following U.S. patients is MOST at risk for the transmission of hepatitis C virus (HCV)? a. An infant born at 38 weeks gestation to a 25 year-old mother infected with HCV. b. A 19-year-old woman who uses intravenous heroin. c. A 32-year-old man who has sex with men. d. A 50-year-old woman who received a kidney transplant in 2001. VETERANS ADMINISTRATION PATIENT CARE SERVICES Answer: B Targeted Objective: Identify risk factor-based screening strategies to improves rates of detection and treatment of HCV. According to AASLD/IDSA 2016, the most important risk for HCV infection is injection drug use, accounting for at least 60% of acute HCV infections in the United States. Considerations for other options: Option A: represents a risk exposure that is less likely to transmit HCV compared to IV drug use. Option C: sexual transmission of HCV is inefficient except among HIV-infected men who have unprotected sex with men. Option D: routine screening of donated blood and organs began in 1992. 67 Post-Questions for Pharmacists 2. A 62-year-old treatment-naïve non-cirrhotic man with HCV genotype 1a presents for initial evaluation of HCV. His HCV viral load is 12.4 million. The patient’s medication list includes amlodipine 5 mg daily, sildenafil 100 mg as needed for erectile dysfunction, atorvastatin 40 mg daily, and omeprazole 20 mg daily before breakfast. Which of the following regimens would be best to recommend for this patient? a. b. c. Daily fixed-dose combination of ledipasvir 90 mg/sofosbuvir 400 mg for 12 weeks. Daily fixed-dose combination of paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg plus weightbased ribavirin for 12 weeks. Daily combination of sofosbuvir 400 mg with weight-based ribavirin for 24 weeks. Three-times-daily boceprevir 800 mg with weightbased ribavirin for 12 weeks. VETERANS ADMINISTRATION PATIENT CARE SERVICES Answer: A Targeted Objective: Construct an individualized management plan for both treatment-naïve and treatment-experienced patients with HCV infection. Option B is not correct because the use of Viekira Pak™ is contraindicated with sildenafil. Sildenafil therapy would need to be held during HCV treatment. Option C is not correct because sofosbuvir with RBV is a regimen that is not recommended for GT1 treatmentnaïve patients due to relatively low efficacy compared to newer agents. Option D is not correct because boceprevir-based regimens are no longer recommended for treatment of HCV due to relatively low efficacy compared to newer agents. Boceprevir is no longer manufactured. d. 68 Post-Questions for Pharmacists 3. A 40-year-old treatment-experienced woman with HCV genotype 4 has compensated cirrhosis and is 3 months post-liver transplantation. Which of the following regimens would be best to recommend for this patient? a. b. c. d. Twice-daily telaprevir 1125 mg with weightbased ribavirin and pegylated interferon for 24 weeks. Daily fixed-dose combination of ledipasvir 90 mg/sofosbuvir 400 mg for 24 weeks. Daily daclatasvir 60mg plus sofosbuvir 400 mg with low initial dose of ribavirin (600 mg, titrated as tolerated) for 12 weeks. Daily fixed-dose combination of elbasvir 50mg/grazoprevir 100 mg for 12 weeks. VETERANS ADMINISTRATION PATIENT CARE SERVICES Answer: C Targeted Objective: Describe strategies for optimized care of HCV patients who are post-transplant, HIV co-infected, or cirrhotic. Option A is not correct because telaprevir-based regimens are no longer recommended for treatment of HCV due to relatively low efficacy compared to newer agents. Telaprevir is no longer manufactured. Option B is not correct because Harvoni® monotherapy is not recommended in this patient population; it would be correct if it were in combination with weight-based RBV. Option D is not correct because the use of Zepatier™ has not been studied in liver transplant recipients. The impact of Zepatier™ on the efficacy of immunosuppressive therapy is unknown. 69 Slides for Reference VETERANS ADMINISTRATION PATIENT CARE SERVICES Expanding Access to Hepatitis C Care for Rural Maine Veterans Using Pharmacist-Driven Education Whitney Jandreau, PharmD Rachel Mayer, PharmD Sarah Smith, PharmD, BCACP Gina Puglisi, PharmD Tomasz Jodlowski, PharmD, BCPS (AQ-ID), AAHIVP VA Maine Healthcare System, Augusta, Maine Background • HCV infection is the most common blood borne infection in the United States, with a prevalence estimated above 3 million • Current pharmacologic options against HCV are safe and highly efficacious • 75% of HCV-infected persons are unaware of the infection and less than 20% receive treatment • In a primarily rural location, geographical barriers prevent access to care, including disease screening Objectives • Increase HCV screening and utilization of CVT to link rural Veterans t to treatment Data Collection • Number of rural patients screened for HCV prior to, then after, intervention • Number of rural patients with HCV connected to gastroenterology team of specialists for medical care Abbreviations: HCV, hepatitis C virus; CVT, clinical video telehealth; CBOC, Community Based Outpatient Clinic; VAMEHCS, Veterans Affairs Maine Healthcare System Recommendations for Medical Management and Monitoring in Acute HCV Infection AASLD/IDSA VETERANS ADMINISTRATION PATIENT CARE SERVICES 72 Recommended Treatment for Patients with Acute HCV Infection AASLD/IDSA VETERANS ADMINISTRATION PATIENT CARE SERVICES 73 Recommendations for Follow-up of Initial Testing AASLD/IDSA HCV Guidance • An anti-HCV test is recommended for HCV testing, and if the result is positive, current infection should be confirmed by a sensitive HCV RNA test. • Among persons at risk of reinfection after previous spontaneous or treatment-related viral clearance, initial HCV-RNA testing is recommended because an anti-HCV test is expected to be positive. • Quantitative HCV-RNA testing is recommended prior to the initiation of antiviral therapy to document the baseline level of viremia (i.e., baseline viral load). • Testing for HCV genotype is recommended to guide selection of the most appropriate antiviral VETERANS ADMINISTRATION PATIENT CARE SERVICES regimen. FDA: 2016 Updates • 02/12/2016 – On February 12, 2016, the FDA approved changes to the Harvoni (ledipasvir and sofosbuvir) fixed-dose combination label to expand the patient population to include those with chronic hepatitis C virus genotype 1, infection who are liver transplant recipients, genotype 4 infection who are liver transplant recipients without cirrhosis, or with compensated cirrhosis, and genotype 1 infection with decompensated cirrhosis. The major changes to the label are the following. • 03/01/2016 – The OLYSIO (simeprevir) label was updated to include pharmacokinetic, safety and efficacy data in treatment-naïve adult patients of East Asian ancestry with chronic hepatitis C virus genotype 1 infection. Patients of East Asian ancestry exhibit higher simeprevir plasma exposures but no dosage adjustment is required based on race. VETERANS ADMINISTRATION PATIENT CARE SERVICES FDA 75 FDA: 2015 Updates • 03/24/2015 – FDA Drug Safety Communication: Harvoni and Sovaldi • The U.S. Food and Drug Administration (FDA) is warning that serious slowing of the heart rate can occur when the antiarrhythmic drug amiodarone is taken together with either the hepatitis C drug Harvoni (ledipasvir/sofosbuvir) or with Sovaldi (sofosbuvir) taken in combination with another direct acting antiviral for the treatment of hepatitis C infection. We are adding information about serious slowing of the heart rate, known as symptomatic bradycardia, to the Harvoni and Sovaldi labels. We are recommending that health care professionals should not prescribe either Harvoni or Sovaldi combined with another direct acting antiviral, such as the investigational drug daclatasvir or Olysio (simeprevir), with amiodarone. Patients should not stop taking any of their medicines without first talking to their health care professionals. • 04/15/2015 – FDA approved changes to Olysio package insert VETERANS ADMINISTRATION PATIENT CARE SERVICES FDA 76 FDA: 2015 Updates • 10/22/2015 – FDA Drug Safety Communication: Viekira Pak and Technivie • The U.S. Food and Drug Administration (FDA) is warning that hepatitis C treatments Viekira Pak and Technivie can cause serious liver injury mostly in patients with underlying advanced liver disease. As a result, new information about this safety risk was added to the Viekira Pak and Technivie labels. • 11/13/2015 – Harvoni label updated • The HARVONI (ledipasvir/sofosbuvir) labeling was updated to: (1) expand the indication to the treatment of chronic hepatitis C virus (HCV) genotype 4, 5 and 6 infection, (2) include dosage recommendations for HCV/HIV-1 co-infection and (3) state HARVONI + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin. Additionally the label was updated with drug-drug interaction information. VETERANS ADMINISTRATION PATIENT CARE SERVICES FDA 77 CTP VETERANS ADMINISTRATION PATIENT CARE SERVICES 78 ALT AST BOC CBC CTP DAA ESRD FDA GFR HBsAg HBV HCC IDU INR MELD MSM NAT NIH OATP P-gp PrOD RAV RBC RBV RGT RVR sAg SMV alanine aminotransferase aspartate aminotransferase boceprevir complete blood cell (eg, complete blood cell count) Child Turcotte Pugh direct-acting antiviral end-stage renal disease Food and Drug Administration glomerular filtration rate hepatitis B virus surface antigen hepatitis B virus hepatocellular carcinoma injection drug use or user international normalized ratio model for end-stage liver disease men who have sex with men nucleic acid testing National Institutes of Health organic anion-transporting polypeptide p-glycoprotein paritaprevir/ritonavir/ombitasvir plus dasabuvir resistance-associated variant red blood cell (eg, red blood cell count) ribavirin response-guided therapy rapid virologic response surface antigen simeprevir; used for the treatment of those with genotype 1 of hepatitis C virus (HCV) who have compensated liver disease, including cirrhosis SOF sofosbuvir; a nucleoside analogue used in combination with other drugs for the treatment of HCV infection SVR12 (or sustained virologic response at 12 weeks (or at 24 weeks, or at 48 weeks, etc) 24 or 48, etc) Select Abbreviations