Viral Hepatitis Series Hepatitis C_STUDENT VERSION_Jan 2024.pptx

Viral Hepatitis Series: Hepatitis C Ana Muscarella, PharmD, BCACP Clinical Pharmacy Specialist, Infectious Disease Vanderbilt Specialty Pharmacy [email protected] Disclosures and Acknowledgements • Cody Chastain, MD, FIDP • Autumn Zuckerman, PharmD, BCPS, AAHIVP, CSP • Alicia Carver, PharmD, BCPS, CSP • Kristen Whelchel, PharmD, CSP Dr. Muscarella has no disclosures. About me  -Graduated from University of Health Sciences and Pharmacy (‘18) -Completed 2 years of post-graduate residency training (PGY-1 Community Residency/PGY-2 Ambulatory Care Residency) -Currently working within the Infectious Diseases Clinic at VUMC -Work primarily with patients with viral hepatitis, HIV, those on HIV PrEP, and those with other complex infections Objectives • Identify populations at highest risk for Hepatitis C virus (HCV) and important trends in HCV epidemiology • Review indications for HCV treatment • Discuss the current landscape of HCV treatment and ongoing barriers to cure • Describe treatment strategies for patients with HCV infection • Recognize common drug interactions with direct-acting antivirals (DAA) Resources to aid your studying and your future career!  • Hepatitis C Treatment Guidelines: https://www.hcvguidelines.org/ • University of Liverpool Drug Interaction Database: https://www.hep-druginteractions.org/checker • Includes HBV medications • Compare potential regimens side by side against current medication regimen • Does not have all U.S. medications, so recommend double-checking with another source (i.e. LexiComp, MicroMedex) • University of Washington Website: https://www.hepatitisc.uw.edu/ • APRI/FIB4/CTP/MELD calculators • Helpful course modules and overviews of all hepatitis C medications General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) General Information • Single-stranded, enveloped RNA virus • High degree of genetic heterogeneity (6 genotypes) • Transmission occurs through infected blood and bodily fluids • Predominantly infects liver cells • Progression of acute hepatitis C to chronic  75-85% of patients • Spontaneous clearance  ~30% of patients • Leading cause of hepatocellular carcinoma (HCC) • Prior infection does not protect against subsequent infections • Can be cured! HCV Epidemiology & Natural History • Epidemiology • 2.3-6 million Americans infected with HCV • Peak rates of decompensated cirrhosis, liver cancer, and mortality previously estimated as 2020 but now anticipated in 2034 • Natural history • Minority develop advanced liver disease • Cirrhosis usually takes years to develop in the absence of comorbidities • Timeline may be accelerated by comorbidities, including alcohol use, HBV, HIV, insulin resistance, and/or obesity CDC website, hepatitis C recommendations. Accessed at: www.cdc.gov/hepatitis/HCV Annual Number of Deaths in the U.S. KN et al. Clin Infect Dis 2016. Ly KN et al. Clin Infect Dis 2016 HCV Cases by County, 2022 Highest rates in non-urban areas  East, Northeast, and Upper Cumberland Regions of TN ee Viral Hepatitis Epidemiologic Profile, 2022. TN Department of Health. Published October 2023. Why Should We Treat? • 50% of infected persons unaware of diagnosis • “Generally, routine HCV testing is cost-effective because of increasing HCV incidence and prevalence among people who inject drugs (PWID) and the decreasing cost of DAA therapy. Many patients at greatest risk for HCV infection and transmission do not readily report their highly stigmatized risk activities.” • Reduces risk of all-cause mortality and HCC • Reduce transmission, viral clearance, and risk behaviors • A public health concern!! 2020 AASLD/IDSA Hepatitis C Treatment Guidelines. Accessed at Benefits of HCV Treatment an der Meer AJ et al. JAMA 2012. SVR=sustained virologic response Challenges to HCV Treatment (FYI) • Ongoing epidemic • Effective screening • Linkage to care and engagement in care • Access to treaters • Access to treatment FYI – Prescribing Restrictions Hepatitis C: The State of Medicaid Prescribing. August 2023 National Progress Report. National Viral Hepatitis Roundtable. Progression of HCV Fibrosis Factors affecting rate of progression: • Older age • Male sex • HIV or HBV coinfection • Alcohol use • Genotype 3 infection ESLD = end stage liver disease HCC = hepatocellular Lingala S, Ghany MG. Natural History of Hepatitis C. Gastroenterol Clin North Am. carcinoma General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) HCV Transmission Injection drug use • Greatest risk for HCV infection (60% of acute infections in the U.S.) • Sharing of contaminated paraphernalia (e.g. needles, cocaine straws) Healthcare exposures • • • • Receipt of blood products prior to 1992 Receipt of clotting factor concentrates prior to 1987 Receipt of blood or blood products in other countries Needlestick injuries Percutaneous or parenteral exposures in unregulated settings • Tattoos received outside licensed parlors Other • • • • Long-term hemodialysis Mother-to-infant transmission Incarceration Sexual transmission (highest risk in HIV-infected men who have sex with men) 2020 AASLD/IDSA Hepatitis C Treatment Guidelines. Accessed at https://www.hcvguidelines.org/evaluate/testing- HCV Screening Recommendations • One time testing recommended for all individuals >18 years old • Prenatal HCV testing as part of prenatal care with each pregnancy • Periodic repeat testing should be offered to all persons with activities, exposures, conditions or circumstances associated with an increased risk of HCV exposure (see next slide) • Annual testing for all persons who inject drugs, HIVinfected MSM, and MSM taking HIV PrEP MSM = men who have sex with men PrEP = pre-exposure prophylaxis 2020 AASLD/IDSA Hepatitis C Treatment Guidelines. Accessed at https://www.hcvguidelines.org/evaluate/testing-and- Hepatitis C Risk Activities, Exposures, and Conditions Risk activities • Injection drug use (current or ever) • Intranasal illicit drug use • Men who have sex with men (MSM) Risk exposures • Persons who were ever incarcerated • Persons with percutaneous/parenteral exposures in an unregulated setting (i.e. tattoos, procedures) • Persons on long-term hemodialysis (ever) • Healthcare workers after needlestick, sharps, or mucosal exposure to HCV-infected blood • Children born to HCV-infected mothers • Recipients of a prior transfusion or organ transplant, including persons who: • Were notified that they received blood from a donor who later tested positive for HCV • Received blood/blood components or underwent organ transplant before 1992 • Received clotting factor 2020 AASLD/IDSA Hepatitis C Treatment Guidelines. Accessedconcentrates at before 1987 Conditions/circumstances • HIV or HBV infection • Sexually active persons about to start HIV preexposure prophylaxis (PrEP) • Chronic liver disease and/or chronic hepatitis, including unexplained elevated ALT levels • Solid organ donors (living and deceased) and solid organ transplant recipients Interpreting HCV Test Results Collect hepatitis C antibody (HCV Ab) HCV Antibody -Tests for exposure -Near 100% sensitivity once >6 months after infection Positive HCV RNA -Tests for active infection -20% or more patients spontaneously clear HCV Negative Perform HCV RNA Positive Indicates current HCV infection No current HCV infection Negative No current HCV infection, indicates past exposure/treatm ent Concept check #1 • A 29-year-old male presents to your clinic for a primary care visit. He is here to establish care. Upon taking his history, you learn that he has no medical problems, but is sexually active with several partners (men and women). He is concerned about possible exposure to HIV, gonorrhea, and syphilis. You learn that he had a tattoo placed while he was incarcerated 2 years ago but denies use of any illicit drugs. He drinks 3-4 beers per day. Would you recommend this patient be screened for hepatitis C? Why or why not? Concept check #1 • The decision is made to test this patient for hepatitis C. His lab results came back showing a positive hepatitis C antibody with a negative hepatitis C RNA. How would you classify this patient’s status? Concept check #1 Should this patient be re-screened for hepatitis C at any point in time? Why or why not? General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) Clinical Manifestations of HCV • Acute HCV (~20%) • Fever • Fatigue and anorexia • Nausea and vomiting • Abdominal pain • Jaundice, dark urine, and clay-colored stools • Arthralgias • Chronic HCV • Often asymptomatic • May cause fatigue, chronic abdominal pain, arthralgias, insomnia, depression, and mental status changes • May cause extrahepatic manifestations including vasculitis and renal disease • Long-term outcomes include cirrhosis, liver failure, and hepatocellular carcinoma General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) Who Should be Treated? AASLD/IDSA Simplified Treatment Guidelines Treatment naïve, compensated cirrhosis Treatment naïve, noncirrhotic 2020 AASLD/IDSA Hepatitis C Simplified Treatment Information to Collect Prior to Treatment • Prior staging • Prior treatment history and outcome • Related other medical diseases, family history, alcohol use • Updated medication list (over-the-counter, prescription, herbals/supplements) • Social history • Pertinent physical exam findings Information to Collect Prior to Treatment (2) Laboratory parameters • Hepatitis C viral load (HCV RNA) • Hepatitis C genotype • Resistance testing (if applicable) • HIV antigen/antibody • Hepatitis B panel • Complete blood count (CBC) • Calculated eGFR/CrCl • Hepatic function panel • International normalized ratio (INR) if cirrhosis present Fibrosis status/disease severity (i.e. cirrhotic or non-cirrhotic) • Liver biopsy • Imaging (abdominal ultrasound with elastography, FibroScan™) • Indirect Markers of liver fibrosis (i.e. APRI score, FIB-4 score, Fibrosure™) • Child-Turcotte-Pugh (CTP) score, MELD score Drug-drug interactions Patient preference Treatment history • Treatment duration • Tablet size • Need to adjust based on possible drug-drug interactions • Child-bearing potential (for possible drug-drug interactions with contraceptive methods) • Treatment naïve vs treatment experienced • HBV or HIV co-infection • MUST test for HBV prior to initiation of HCV treatment! Indirect Markers of Liver Fibrosis APRI • • • • AST-To-Platelet Ratio Index [(AST/ ULN)/PLT] x 100 Sensitivity 76% and specificity 72% at cutoff of 1.0 for predicting cirrhosis Sensitivity 46% and specificity 91% at cutoff of 2.0 for predicting cirrhosis FIB-4 Index • Age x AST / [PLT x (ALT)1/2] • Negative predictive value 90% for advanced fibrosis if <1.45 • Positive predictive value 65% and specificity 97% for advanced fibrosis if >3.25 Fibrosure™ • Multiple known inputs and proprietary equation • Recognized by many payers ULN = upper limit of normal (usually 40) Disease Severity/Fibrosis Staging • Liver biopsy  historical gold standard • Invasive, expensive, has risks/complications • Ultrasound with elastography or Fibroscan™  more common • Anatomic ultrasound not adequate for staging • Provides fibrosis score called METAVIR score between F0-F4 • F0 = no cirrhosis  F4 = cirrhosis • CTP score: Class A – C (anything above 6 points considered to be decompensated) • Only calculate if patient has cirrhosis (see next slide) Child Turcotte Pugh Score • Developed for predicting operative mortality • Now used for assistance with predicting prognosis and liver dysfunction Image from www.hepatitis.va.gov COMPENSATED DECOMPENSAT DECOMPENSAT ED ED MELD Score • Used for organ allocation • Includes bilirubin, sodium, INR, serum creatinine, and dialysis status • Predicts 3-month mortality among: • Decompensated cirrhosis • Cirrhosis undergoing surgical procedures • Alcoholic hepatitis • Acute variceal hemorrhage • After transjugular intrahepatic portosystemic shunt (TIPS) Images from optn.transplant.hrsa.gov and mdcalc.com. Concept check #2 • A 58-year-old patient is being seen in your clinic as a referral for hepatitis C treatment. You begin your treatment work-up and need to determine his fibrosis status. An ultrasound with elastography is performed, and it is determined the patient has F4 fibrosis. Calculate his APRI, FIB4, CTP, and MELD scores. AST 152, ALT 205, Platelets 150, Tbili 2.5, albumin 3.7, INR 1.0, SCr 0.25, serum sodium 135. The patient has no other medical problems. All other labs and physical exam are considered normal. Concept check #3 • Which of the following options is NOT an accepted option for staging liver disease? A. Anatomic ultrasound B. AST to Platelet Ratio Index (APRI) C. Fibrosure™ D. Transient elastography (i.e., Fibroscan®) E. FIB-4 index What is Cirrhosis? • Severe scar tissue that forms from long-term liver injury to the liver • In the case of hepatitis C, the scar tissue that forms is due to the body attacking the liver cells • This can be compensated or DEcompensated, which refers to whether the liver can still properly carry out its functions • This can come in the form of lab abnormalities or physical exam findings • Patients can ALSO decompensate acutely due to infections, gastrointestinal bleeding, high alcohol intake / alcohol-related hepatitis or drug-induced liver injury • Patients with decompensated cirrhosis typically require a liver transplant Decompensated Cirrhosis • Symptomatic liver disease on a spectrum leading to overt liver failure and liver-associated mortality • Physical exam findings • Hepatic encephalopathy • Ascites • Lab abnormalities • Elevated bilirubin • Low albumin • Elevated prothrombin time/INR • Calculators to classify and predict outcomes should be ONLY be applied to patients with cirrhosis Interventions to reduce progression of liver disease • Immunizations • COVID-19 • Hepatitis A and B (if not chronically infected with HBV, MUST test prior to treatment initiation!) • Influenza • Pneumococcal • Alcohol abstinence • Appropriate acetaminophen use • Limited non-steroidal anti-inflammatory use, particularly in setting of advanced fibrosis Counseling to Reduce HCV Transmission • Keep wounds covered • Clean up blood or body fluid spills with alcohol and/or bleach • No shared personal devices such as razors, toothbrushes, or nail clippers • Barrier protection for intimate contact • Safer approaches to injection drug use Pre-Treatment Assessment (Simplified Guidelines) Fibrosis scoring • Calculate FIB4 • Calculate CTP (if cirrhotic) • Ultrasound of liver (if cirrhotic) Pre-treatment laboratory testing • Any time prior to start of treatment • Quantitative HCV RNA (HCV viral load) • HIV antigen/antibody test • Hepatitis B surface antigen • HCV genotype (if cirrhotic) • Before initiating antiviral therapy • Serum pregnancy testing and counseling about pregnancy risks of HCV medication should be offered to women of child-bearing age • Within 3-6 months of initiating treatment • Complete blood count • Hepatic function panel • Calculated eGFR or CrCl • INR (if cirrhotic) Medication reconciliation, drug interaction assessment, education General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) History of HCV Treatment • Early therapies had poor efficacy and tolerability • Development of direct acting antivirals (DAAs) with improved efficacy without additional adverse effects occurred ~2011 • Examples: Telaprevir, boceprevir, etc. • Newer DAAs (~2013-2014) have dramatically improved efficacy with few adverse effects • Examples: sofosbuvir, simeprevir, etc. Treatment Response in the DAA Era 100 80 60 SVR (%) 40 20 0 IFN = interferon PEG-IFN = pegylated interferon RBV = ribavirin P/R = peginterferon/ribavirin DAA = direct acting antiviral TPV = telaprevir BOC = boceprevir Goal of HCV Treatment • Sustained virologic response (SVR): Defined as an undetectable HCV RNA at least 12 weeks after treatment completion aka CURE! • Prevents fibrosis progression • Histologic fibrosis regression can occur in early stages of fibrosis and early cirrhosis • This ultimately reduces all-cause mortality and liverrelated complications including end-stage liver disease and hepatocellular carcinoma • HCV DAA’s are >95% effective with high chance of cure HCV Drug Targets FDA Approved HCV Therapies Non-specific antivirals NS3/4 Protease Inhibitors (“-previr”) NS5A inhibitors (“asvir”) NS5B inhibitors (“buvir”) • Interferon (IFN) • Ribavirin (RBV) • Pegylated interferon (PEG-IFN) • Telaprevir (TPV) • Boceprevir (BOC) • Simeprevir (SMV) • Paritaprevir (PTV) • Grazoprevir (GZP) • Voxilaprevir (VOX) • Glecaprevir (GLE) • Ledipasvir (LDV) • Ombitasvir (OBV) • Daclatasvir (DCV) • Elbasvir (EBR) • Velpatasvir (VEL) • Pibrentasvir (PIB) • Sofosbuvir (SOF) • Dasabuvir (DBV) HCV Treatment Selection • Select a medication with 1 direct acting antiviral (DAA) from at least 2 classes of drugs • NS3/4 Protease inhibitors  “-previr” • NS5A inhibitors  “-asvir” • NS5B inhibitors  “-buvir” • Treatment duration is usually 8-12 weeks • May extend to 16-24 weeks if decompensated cirrhosis (+/ribavirin), treatment failure, other patient-specific factors Primary Factors in HCV Treatment Selection • Genotype (GT) • Not required for treatment with simplified guidelines • Typically required for treatment approval, prognosis prediction, determine relapse vs infection, needed in setting of cirrhosis • GT 1-6 discussed in guidelines • Degree of fibrosis • Cirrhotic • Compensated • Decompensated • Non-cirrhotic • Treatment history • Treatment naïve • Treatment experienced • Recommendations will differ depending on what therapies were used previously (i.e. PEG-IFN or DAA therapy) Secondary Factors in HCV Treatment Selection • Side effect profile • Drug-drug interactions • Pharmacodynamics and metabolism • Access to treatment • Patient preference Commercially Available Formulations of DAAs Generic name Brand name glecaprevir/pibrentasvir (G/P)* Mavyret™ Ledipasvir/sofosbuvir (LED/SOF) Harvoni™ sofosbuvir/velpatasvir (SOF/VEL)* Epclusa™ sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) Vosevi™ sofosbuvir Sovaldi™ elbasvir/grazoprevir (EBR/GZR) Zepatier™ ribavirin Copegus™, Ribapak™ *G/P and SOF/VEL are pan-genotypic regimens (active against all genotypes) Administration requirements • Can be taken with or without food • ledipasvir/sofosbuvir (1 tablet once daily) • sofosbuvir/velpatasvir (1 tablet once daily) • elbasvir/grazoprevir (1 tablet once daily) • Must be taken with food • Glecaprevir/pibrentasvir (3 tablets once daily) • sofosbuvir/velpatasvir/voxilaprevir (1 tablet once daily) Side Effect Profile of DAAs • Mostly well tolerated • Typically, last ~1-2 weeks and then subsides (although may be present for duration of treatment) • Side effects are non-specific • • • • Fatigue (most common with SOF-based regimens) Headache GI upset (nausea, vomiting, diarrhea – most common with G/P) Insomnia • Management of side effects • OTC products for headache or diarrhea • Hydration • Non-pharmacologic recommendations Simplified Treatment Guidelines (No Cirrhosis) • Treatment naïve, non-cirrhotic 2020 AASLD/IDSA Hepatitis C Simplified Treatment Simplified Treatment Guidelines (Cirrhosis) • Treatment naïve, compensated cirrhosis 2020 AASLD/IDSA Hepatitis C Simplified Treatment Treatment Recommendations: Genotype 1a with and without cirrhosis Recommended regimens Duration glecaprevir/pibrentasvir 8 weeks ledipasvir/sofosbuvir 12 weeks sofosbuvir/velpatasvir 12 weeks Alternative regimens elbasvir/grazoprevir 12 weeks Notes Can use 8 weeks for HIVuninfected patients and whose HCV viral load is less than 6 million (noncirrhotic only) Treatment Recommendations: Genotype 1b with and without cirrhosis Recommended regimens Duration glecaprevir/pibrentasvir 8 weeks ledipasvir/sofosbuvir 12 weeks sofosbuvir/velpatasvir 12 weeks elbasvir/grazoprevir 12 weeks Notes Can use 8 weeks for HIVuninfected patients and whose HCV RNA is less than 6 million (non-cirrhotic or mild fibrosis only) For HIV/HCV co-infected patients, an 8-week treatment duration is recommended (noncirrhotic only) Treatment Recommendations: Genotype 2 with and without cirrhosis Recommended regimens Duration glecaprevir/pibrentasvir 8 weeks Sofosbuvir/velpatasvir 12 weeks Notes Treatment Recommendations: Genotype 3 with and without cirrhosis Recommended regimens Duration Notes glecaprevir/pibrentasvir 8 weeks sofosbuvir/velpatasvir 12 weeks For patients without baseline NS5A RAS Y93H mutation (cirrhotic only) Daily fixed-dose combination of sofosbuvir/velpatasvir with weight-based ribavirin for patients with baseline NS5A RAS Y93H mutation 12 weeks Cirrhotic only Daily fixed-dose combination of sofosbuvir/velpatasvir/voxila previr for patients with 12 weeks Cirrhotic only Alternatives (cirrhotic only) Treatment Recommendations: Genotype 4 without cirrhosis Recommended regimens Duration glecaprevir/pibrentasvir 8 weeks ledipasvir/sofosbuvir 12 weeks sofosbuvir/velpatasvir 12 weeks elbasvir/grazoprevir 12 weeks Notes Can use 8 weeks for patients without cirrhosis and who have an HCV RNA less than 6 million Treatment Recommendations: Genotype 4 with cirrhosis Recommended regimens Duration Notes glecaprevir/pibrentasvir 8 weeks A treatment duration of 12 weeks is recommended in HIV/HCV co-infected patients ledipasvir/sofosbuvir 12 weeks sofosbuvir/velpatasvir 12 weeks elbasvir/grazoprevir 12 weeks Treatment Recommendations Genotypes 5 and 6 (with and without cirrhosis) Recommended regimens Duration Notes glecaprevir/pibrentasvir 8 weeks Rating is 1B for compensated cirrhosis ledipasvir/sofosbuvir 12 weeks Not recommended for genotype 6e if subtype is known sofosbuvir/velpatasvir 12 weeks Resistance Testing • NS5A resistance lasts at least several years • NS3/4 resistance is short-lived (months) • NS5B resistance is rare • Available for GT 1 and GT 3 only • Indications • Treatment naive Medication Patient Type Resistance Test Zepatier™ (Elbasvir/Grazoprevir) GT1a NS5A Epclusa™ (velpatasvir/sofosbuvir) GT3 + cirrhosis NS5A (Y93) • After DAA failure to guide treatment decisions 2020 AASLD/IDSA Hepatitis C Treatment Treatment Experienced Patients • Often most complex patient population to treat • Resistance may or may not be helpful (depends on prior and anticipated regimen) • Two approved regimens for re-treatment • Sofosbuvir/velpatasvir/voxilaprevir (Vosevi™) • Glecaprevir/pibrentasvir (Mavyret™) • May include addition of sofosbuvir (Sovaldi™) or ribavirin • Usually requires extension of treatment duration to 1624 weeks 2020 AASLD/IDSA Hepatitis C Treatment Treatment-Experienced Patients (FYI) Sofosbuvir-based and elbasvir/grazoprevir treatment failures • With or without compensated cirrhosis • sofosbuvir/velpatasvir/voxilaprevir x 12 weeks • Alternative regimen includes glecaprevir/pibrentasvir x 16 weeks (not recommended in GT 3) Glecaprevir/pibrentasvir treatment failures • • • • With or without compensated cirrhosis glecaprevir/pibrentasvir + sofosbuvir + ribavirin sofosbuvir/velpatasvir/voxilaprevir x 12 weeks **If patients have compensated cirrhosis, recommended to add ribavirin** Multiple DAA treatment failures (all genotypes) • Includes sofosbuvir/velpatasvir/voxilaprevir or sofosbuvir + glecaprevir/pibrentasvir • glecaprevir/pibrentasvir + sofosbuvir + ribavirin x 16 weeks • sofosbuvir/velpatasvir/voxilaprevir + ribavirin x 24 weeks 2020 AASLD/IDSA Hepatitis C Treatment Guidelines. Accessed at https://www.hcvguidelines.org/treatment- Ribavirin • Not for monotherapy (only to be in combination with other DAAs) • Formulation is 200 mg tablets or capsules • Weight-based dosing (600 mg starting dose, can increase to 1200 mg in divided doses), dose reductions needed for renal dosing • Taken with food • DO NOT USE in pregnancy • Do not use in pregnancy and for 6 mo after treatment • Patients must have negative pregnancy test prior to therapy and use at least 2 forms of contraception • Must undergo monthly pregnancy tests • Frequent monitoring needed due to hemolytic anemia risk and gastrointestinal side effects (i.e. nausea, weight loss, reduced appetite) • Not well tolerated Treating Patients with Decompensated Cirrhosis • Protease inhibitors contraindicated • Patients that are ribavirin eligible • Genotypes 1-6 • Ledipasvir/sofosbuvir + ribavirin x 12 weeks OR sofosbuvir/velpatasvir + ribavirin x 12 weeks • Patients that are ribavirin ineligible • Genotypes 1-6 • Ledipasvir/sofosbuvir x 24 weeks OR sofosbuvir/velpatasvir x 24 weeks 2020 AASLD/IDSA Hepatitis C Treatment Guidelines. Accessed at HCV Treatment and Liver Failure (FYI) • HCV treatment reduces MELD score in patients with decompensated cirrhosis but mortality benefit uncertain • Liver transplant is the best treatment for HCV-related decompensated cirrhosis!! • The decision to treat HCV should be made in concert with expert clinicians at a liver transplant center in patients with decompensated cirrhosis (CTP Class B or C and/or MELD >10) Hepatitis C and Special Populations Chronic Kidney Disease • No dose adjustment needed with DAAs (ribavirin only if CKD stages 3-5) Pregnancy HIV co-infection • Treatment not recommended at this time • Recommended to screen prior to each pregnancy • Management of drugdrug interactions • May require extended durations of therapy Transplant patients (liver or kidney) • 12 weeks of treatment + ribavirin • Management of drugdrug interactions 2020 AASLD/IDSA Hepatitis C Treatment Children with HCV • Testing requirements after birth (>18 months) if born to HCV+ mother • Medications approved for age >3 if treatment required Hepatitis C and Incomplete Adherence Hepatitis C and Incomplete Adherence (2) Hepatitis C and Incomplete Adherence (3) Concept check #5 • Which of the following is an appropriate recommendation for a treatment naïve, non-cirrhotic, HIV/HCV co-infected, genotype 1b patient? A. glecaprevir/pibrentasvir x 12 weeks B. sofosbuvir/velpatasvir x 16 weeks C. ledipasvir/sofosbuvir x 8 weeks D. elbasvir/grazoprevir x 12 weeks Concept check #5 How would your answer change if the patient had decompensated cirrhosis? Concept check #5a Your patient was started on treatment and comes to the clinic for a 4 week check in appointment. Upon discussion about missed doses, the patient tells you they went out of town for 10 days and forgot their medication at home. They have now missed 14 doses since they weren’t sure whether to re-start after missing 10 days of doses. What is your recommendation for this patient? Importance of Drug-Drug Interactions “Prior to starting treatment, patients should be evaluated for potential drugdrug interactions with selected antiviral medications by consulting the prescribing information and using other resources.” 2020 AASLD/IDSA Hepatitis C Treatment Drug-Drug Interaction Terminology • Drug metabolizing enzymes and drug transporters • • • • Cytochrome P450 (CYP enzymes, i.e. CYP3A4, CYP2D6) P-glycoprotein (P-gp) Breast cancer resistance protein (BCRP) Organic anion transporting polypeptide (OATP) • Substrate – substance on which an enzyme acts • Inducer – “increases” enzyme activity (speeds up metabolism) • Inhibitor – “blocks” enzyme activity (slows down metabolism) Common Inhibitors and Inducers CYP3A4 inhibitors CYP3A4 inducers • Azole antifungals • Protease inhibitors • Calcium channel blockers • Ritonavir, cobicistat • • • • P-gp inhibitors P-gp inducers • Azole antifungals • Calcium channel blockers • Protease inhibitors • Amiodarone • Carbamazepine • Rifampin • Phenytoin Anticonvulsants NNRTIs Dexamethasone Rifamycins NNRTIs = Non-nucleoside reverse transcriptase inhibitors Drug-Drug Interaction Mechanisms Substrate Inhibitor Medication name CYP3A4 P-gp CYP3A4 P-gp glecaprevir/pibrentasvir X X X X sofosbuvir X ledipasvir Other X BCRP, OATP BCRP X X velpatasvir X X X BCRP, OATP voxilaprevir X X X BCRP, OATP elbasvir/grazoprevir X X OATP Drug-Drug Interaction Management Coadministration is safe Dose change required/recommended and/or additional monitoring needed Combination should be avoided Red Flag Medication Classes Antacids, H2RAs, PPIs ART regimens containing protease inhibitors, cobicistat, ritonavir, or efavirenz Amiodarone/ dronedarone Anticonvulsants [namely oxcarbazepine, phenytoin, carbamazepine), quetiapine (G/P only)] Statins Oral anticoagulants (namely rivaroxaban, warfarin) Hormone therapies (namely combined oral contraceptives containing estrogen, hormone replacement therapy) Herbal medications/supple ments PPI = proton pump inhibitor (i.e. omeprazole, pantoprazole) H2RA = histamine-2 receptor antagonists (i.e. famotidine) ART = antiretroviral therapy (for HIV) Green Flag Medication Classes Pain medications (oxycodone, hydrocodone, tramadol), benzodiazepines Diabetes medications SSRIs, SNRIs, mirtazapine MAT (buprenorphine, naloxone) Blood pressure medications Antibiotics used for STIs, uncomplicated URIs, or SSTIs SSRIs = selective serotonin reuptake inhibitors SNRIs= serotonin and norepinephrine reuptake inhibitors MAT = medication assisted treatment (for opioid use disorder) STIs = sexually transmitted infection (i.e. chlamydia, gonorrhea, syphilis) URI = upper respiratory tract infection DAAs and Acid-Reducing Agents ledipasvir/sofosbuvir sofosbuvir/velpatasvir glecaprevir/pibrentasvir PPI H2RA Antacids Doses equivalent to pantoprazole 40 mg daily administered simultaneously on an empty stomach Coadministration of famotidine (40 mg single dose) simultaneously with or 12 hours prior to DAA Separate administration by Not recommended; doses equivalent to omeprazole 20 mg daily administered 4 hours before DAA with food Coadministration of famotidine (40 mg BID) simultaneously with or 12 hours apart Separate administration by Doses equivalent to omeprazole 20 mg daily administered simultaneously with food Levels may decrease, no dose adjustment needed N/A Co-administration of famotidine (40 mg BID) simultaneously with or 12 hours apart Separate administration by sofosbuvir/velpatasvir/ voxilaprevir Doses equivalent to omeprazole 20 mg daily administered PPI = proton pump inhibitor (i.e. omeprazole, pantoprazole) simultaneously with food H2RA = histamine-2 receptor antagonists (i.e. famotidine) BID = twice daily DAA = direct acting antiviral 4 hours 4 hours 4 hours Contraindicated Products to Note • Certain statins and statin doses (next slides) • Certain HIV medications (next slides) • Certain oral anticoagulants (next slides) • Carbamazepine/oxcarbazepine contraindicated with all DAAs • Rifampin/rifabutin/rifamycin contraindicated with all DAAs • Ethinyl estradiol contraindicated with glecaprevir/pibrentasvir (Mavyret™) and sofosbuvir/velpatasvir/voxilaprevir (Vosevi™) due to ALT elevations, recommended to use alternative contraceptive method • Amiodarone contraindicated with any sofosbuvir-containing product due to life-threatening bradycardia DAAs and Statins Rosuvastat in Atorvastati n Pravastatin Lovastatin Simvastatin Pitavastati n Ledipasvir ↑ rosuvaNot rec. ↑ atorvaLowest dose, Monitor ↑ pravaLowest dose, Monitor ↑ lovaLowest dose, Monitor ↑ simvaLowest dose, Monitor ↑ pitavaLowest dose, Monitor Velpatasvir ↑ rosuvaMax 10mg ↑ atorvaLowest dose, Monitor OK ↑ lovaMonitor ↑ simvaLowest dose, Monitor ↑ pitavaLowest dose, Monitor Pibrentasvir / glecaprevir ↑ rosuvaMax 10mg ↑ atorvaNot rec. ↑ pravaMax 20mg Reduce 50% ↑ lovaNot rec. ↑ simvaNot rec. ↑ pitavaMonitor Elbasvir/ grazoprevir ↑ rosuvaMax 10mg ↑ atorvaMax 20mg OK ↑ lovaMax 20mg ↑ simvaMax 20mg OK Velpatasvir/ Voxilaprevir / Sofosbuvir ↑ rosuvaNot rec. ↑ atorvaLowest dose, Monitor ↑ pravaMax 40mg ↑ lovaLowest dose, Monitor ↑ simvaLowest dose, Monitor ↑ pitavaNot rec. DAAs and ART NRTIs Sofosbuvir/velpatasvir Monitor for TDFassociated ADEs Sofosbuvir/ledipasvir Sofosbuvir/velpatasvir/ voxilaprevir Glecaprevir/pibrentasvir √ Elbasvir/grazoprevir √ NNRTIs PIs INSTIs CCR5 antagonist Do not coadministe r with efavirenz, etravirine, or nevirapine √ √ √ √ Do not coadminister with c/EVG/TDF/FTC √ Do not coadminister √ √ √ √ Do not coadminister with c/EVG/TDF/FTC or c/EVG/TAF/FTC √ Monitor for renal toxicity when using SOF/VEL and TDF or LED/SOF and TDF ART = antiretroviral therapy NRTIs = nucleoside reverse transcriptase inhibitors NNRTIs = non-nucleoside reverse transcriptase inhibitors PIs = protease inhibitors INSTIs = integrase strand transfer inhibitors TDF = tenofovir disoproxil fumarate DAAs and Oral Anticoagulants Sofosbuvir Ledipasvir Velpatasvir Glecaprevir/pibrentasvir Sofosbuvir/velpatasvir/ voxilaprevir Warfarin Apixaban Rivaroxaba n Dabigatran Edoxaban **No effect on drug levels** ↑ apixaban concentratio ns, close monitoring recommend ed ↑ rivaroxaban concentratio ns, close monitoring for bleeding recommende d ↑ dabigatran concentrations, close monitoring for bleeding recommended ↑ edoxaban concentrations, close monitoring for side effects recommended Do not coadminister ↑ edoxaban concentrations, consider dose reduction of edoxaban if clinically appropriate Do not coadminister Do not coadminister Monitor INR while on treatment as improved liver function may affect levels. Frequent monitoring of INR values is recommende d during and after treatment Utilizing Pharmacists as Drug Experts! Concept check #6 You are planning to start a patient on ledipasvir/sofosbuvir. He is currently taking pantoprazole 40 mg daily, rosuvastatin 10 mg daily, warfarin 5 mg daily, metformin 1,000 mg BID, and buprenorphine 8 mg once daily. What drug interactions would you be concerned about? General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) Anticipated Treatment Course Recommended Monitoring During Antiviral Therapy Week 2 on treatme nt • CBC with diff if using ribavirin Week 4 on treatme nt • Hepatic functional panel if using elbasvir/graz oprevir • CBC with diff if using ribavirin • Consider hepatic function panel if symptomati c or baseline LFTs elevated • Consider HCV RNA PCR if concerns regarding 2020 AASLD/IDSA Hepatitis C Treatment Week 8 on treatme nt Week 12 on treatme nt • Hepatic functional panel if using elbasvir/ grazoprevir • CBC with diff if using ribavirin • Hepatic functional panel if using elbasvir/ grazoprevir (if receiving 16 weeks of treatment) End of treatme nt (EOT) • Consider HCV RNA to document viral suppression at EOT 12 weeks after treatme nt completi on • HCV RNA PCR to test for cure On-Treatment Monitoring (Simplified Guidelines) No cirrhosis Cirrhosis • No laboratory monitoring required • Tests to monitor for liver injury during treatment (if desired by provider) • Patients should see a specialist if they develop worsening liver function tests or physical symptoms of cirrhosis (ascites, jaundice, encephalopathy) SVR12 Achieved! What now? • “Undetectable or unquantifiable HCV RNA 12 weeks or longer after treatment completion is defined as sustained virologic response (SVR) which is consistent with cure of chronic HCV infection.” • Important counseling points • HCV Ab will be positive for rest of patient’s life • Re-infection is possible if re-exposed • Review recommendations for HCC screening if patient has cirrhosis • Screening recommend every 6 months, CT abdomen with triple phase contrast annually, or MRI abdomen with contrast annually • Usually requires hepatology referral for additional testing HCC = hepatocellular carcinoma 2020 AASLD/IDSA Hepatitis C Treatment Additional Guideline Recommendations 2020 AASLD/IDSA Hepatitis C Treatment Elevated LFTs on Therapy • Discontinue DAA therapy if: • ALT increases > 10-fold from baseline at any time during treatment • ALT increases <10-fold from baseline + signs/symptoms of liver inflammation • Weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or INR • Monitor ALT at 2-week intervals if: • There is an increase in ALT <10 without symptoms • If levels stay elevated, consider discontinuation of therapy 2020 AASLD/IDSA Hepatitis C Treatment What if Treatment is Not Working? • If HCV RNA present at week 4: • Almost all patients will be undetectable by week 4 • If not, consider discussion re: adherence and/or drug-drug interactions • Unclear guidance from guidelines regarding interpretation, further testing, or extending therapy • If patients do not achieve SVR12+: • • • • >90% SVR rate across all HCV genotypes Monitor for liver injury and/or liver failure/HCC Consider reasons for failure and options for re-treatment Unclear role for resistance testing prior to re-treatment 2020 AASLD/IDSA Hepatitis C Treatment General Outline • Hepatitis C epidemiology and natural history • HCV screening recommendations • HCV clinical manifestations • Pre-treatment evaluation/indications for treatment • Treatment selection and drug-drug interactions • Treatment monitoring and post-treatment surveillance • Access to therapy (FYI) Financial Support • All medications for hepatitis C require a prior authorization (PA) for coverage • Most medications as brand only, but some do have generics (LED/SOF, SOF/VEL, ELB/GRZ) • Cash price for HCV DAAs is >$20k • Co-pay cards available for all HCV DAAs for privately insured patients which will reduce co-pay to $5 if co-pay is high • Patient assistance programs available through all manufacturers for uninsured patients • Several foundation assistance grants available, especially through American Liver Foundation and Healthwell Viral Hepatitis Series: Hepatitis C Ana Muscarella, PharmD, BCACP Clinical Pharmacy Specialist, Infectious Disease Vanderbilt Specialty Pharmacy [email protected]

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