HCV Screening, Management and Guidelines

Transcription

1 HCV ECHO WESTERN STATES HCV Screening, Management and Guidelines Paulina Deming, PharmD, PhC Associate Professor of Pharmacy-College of Pharmacy Project ECHO University of New Mexico Health Sciences Center Brad Moran, PharmD Chief of Pharmacy Fort Peck Service Unit IHS January 30, 2017 Original presentation by: Date prepared:

2 OBJECTIVES 1. Recognize and stage a patient s level of liver disease using common laboratory tests and imaging 2. Describe new therapeutic options for the treatment of chronic HCV 3. Recognize and assess the clinical significance of common drug-drug interactions with oral-hcv therapies 4. Use national algorithms and guidelines to guide treatment strategies for patients with HCV infection

3 HCV ECHO WESTERN STATES Conflict of Interest Disclosure Statement

4 Hepatitis Spread via blood-to-blood contact usually asymptomatic Leading cause for liver transplantation in the US ~75-80% of acute infections become chronic chronic infection- detection of virus 6 months post-exposure No vaccine available Prevalence is 1.6% of US population

5 Hepatitis C is a Global Health Problem Estimated 170 million persons with HCV infection worldwide > 10% 2.5%-10% 1%-2.50% Prevalence of infection NA World Health Organization 2008 (

6 Risk Factors for HCV Infection Persons born between Received blood transfusion or organ donation prior to 1992 Current or former injection drug users Chronic hemodialysis patients Any known blood exposure to HCV-positive blood Persons with HIV Children born to HCV-infected mother

7 CDC Testing Algorithm for Chronic HCV

8 Hepatitis C Genotypes 15% Prevalence in US population 7% 4% Genotype 1 6 major genotypes (1-6), most with subtypes Genotype 1 - GT 1b different than GT 1a 74% Genotype 2 Genotype 3 Genotypes 4-6 GT 2 easier to treat than GT 3 GT 3 associated with higher mortality, steatohepatitis Alter MJ et al. N Engl J Med 1999; 341:556-62

9 Hepatitis C Epidemiology-Fort Peck Reservation HCV AB TESTS PERFORMED

10 FPSU HCV Epidemiology HCV Ab+ Chronic HCV Spontaneous clearance number of living patients

11 Age Group HCV Ab+ by age group and younger # patients

12 Natural history following initial infection with HCV Time years years

13 HCV is Not Just a Liver Disease Common Symptoms of HCV in Absence of Cirrhosis Fatigue Impaired cognitive function (brain fog) Migratory arthralgia or myalgia Depression Extrahepatic Manifestations of Chronic HCV Renal Disease Lymphomas Neuropathy Dermatologic Manifestations Diabetes Neurological Impairments

14 Overview: Routine Evaluation and Follow Up of Persons with Chronic HCV Baseline studies Screening for other causes of liver disease Vaccinations Staging of Liver Disease Special considerations for cirrhotic patients: Monitoring for hepatocellular carcinoma Evaluation for cirrhosis related complications Referral for liver transplantation Assessment and management of alcohol and substance abuse

15 Overview: Part 2- HCV Therapy HCV Therapies Special populations Choosing a regimen Common side effects and laboratory abnormalities Drug-drug interactions Monitoring of patients on HCV therapy Monitoring of patients after HCV therapy

16 Baseline Studies in Persons with Chronic HCV Complete blood count with differential Comprehensive metabolic panel including serum creatinine Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, serum albumin International normalized ratio (INR) HCV genotype and subtype Quantitative HCV RNA HIV antibody Hepatitis A serology (IgG or total) Hepatitis B serology (HBsAg, anti- HBs, anti-hbc) Alpha-fetal protein (AFP) Abdominal ultrasound with measurement of spleen size

17 Baseline Studies in Persons with Chronic HCV Complete blood count with differential Comprehensive metabolic panel including serum creatinine Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, serum albumin Identify changes consistent with cirrhosis; identify anemia especially if requiring ribavirin therapy Evaluate renal function for choosing appropriate HCV therapy Recognize level of inflammation and liver injury International normalized ratio (INR) Assess hepatic synthetic function

18 Why is the CBC Important for Understand Liver Disease Severity? Thrombocytopenia (<150 thousand) Due to portal hypertension caused by cirrhosis Portal hypertension causes: Platelets to become stuck in spleen More platelets damaged/destroyed Neutropenia Cirrhosis can cause bone marrow suppression

19 Abnormalities in Hepatic Panel Elevations in AST or ALT useful for measuring liver cell injury What is normal AST or ALT? 40 IU/mL Studies suggest this is too high and normal should be lower and different for men vs. women Healthy ALT is <30 IU/mL for men and <19 IU/mL for women Elevations in conjugated bilirubin suggest liver disease Loss of liver s ability to synthesize (lack of synthetic function) can be seen with: Low serum albumin Prolonged prothrombin time (elevated INR) Important to look at trends in labs over time

20 Baseline Studies in Persons with Chronic HCV HCV genotype and subtype Quantitative HCV RNA Determine appropriate HCV therapy and treatment duration; demonstrate chronic HCV HIV antibody Hepatitis A serology (IgG or total) Hepatitis B serology (HBsAg, anti- HBs, anti-hbc) Share similar routes of transmission; determine need for HAV and/or HBV vaccination; determine risk for HBV reactivation Alpha-fetal protein (AFP) Abdominal ultrasound with measurement of spleen size Evaluate for cirrhosis; screen for hepatocellular carcinoma

21 Other Viral Hepatitis Hepatitis A Check HAV antibody (total or IgG) Hepatitis B Check hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-hbs; total or IgG), and hepatitis B core antibody (anti-hbc) Labs needed irrespective of vaccination

22 Hepatitis B Serologies Test Result Interpretation HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc Anti-HBs Negative Negative Negative Negative Positive Positive or Negative Susceptible to HBV Previous exposure to HBV.These patients are not immune or protected and frequently have subclinical infection and are at risk for reactivation with immunosuppression. There is no role to vaccinate (or boost) these patients. HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc IgM anti-hbc Anti-HBs HBsAg Anti-HBc IgM anti-hbc Anti-HBs Negative Negative Positive Positive Positive Positive Negative Positive Positive Negative Negative Immune to HBV due to HBV vaccine Acute HBV infection Chronic HBV infection

23 HBV Reactivation Risk in HCV FDA warning issued 2016 following 24 reported cases of HBV reactivation in patients treated with HCV DAAs 2 deaths 1 liver transplant Mechanism of reactivation unclear HCV DAAs do not have immunosuppressive effects Current recommendations are to evaluate patients for potential coinfection of HCV and HBV

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25 Vaccinations HAV HBV Pneumococcal vaccine for all patients with chronic liver disease, including on-going alcoholism Annual flu

26 Disease States Potentiating Fibrosis NASH NAFLD Alcohol Fibrosis Viral Hepatitis HIV Autoimmune Practice guidelines:

27 Natural history following initial infection with HCV Time years years

28 Findings Suggestive of Advanced Fibrosis/ Cirrhosis Presence or history of ascites or esophageal varices Low platelet count (<150,000 mm 3 ) APRI > 1.0 FIB-4 > 3.25 Fibrosure > 0.72 Imaging with evidence of cirrhosis (nodular contour of liver or evidence of portal hypertension) Liver biopsy with F3 or F4 fibrosis Transient elastography consistent with advanced fibrosis/cirrhosis

29 Use an upper limit of normal of 40

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31 Child-Pugh Classification of Cirrhosis for Drug Dosing 1 Point 2 Points 3 Points Encephalopathy None Moderate Severe Ascites Absent Mild- Moderate Severe/ Refractory Bilirubin (mg/dl) < > 3 Albumin (g/dl) > < 2.8 INR (PT Prolongation sec over control) <1.7 (0-4) >2.3 (>6)

32 Child-Pugh Interpretation of Hepatic Function in a Patient with Cirrhosis C-P Score (Class) Liver Function 5-6 (A) Mild Dysfunction 7-9 (B) > 9 (C) Moderate Dysfunction Moderate dose reduction (~25%) for drugs that are mostly hepatically metabolized Severe Dysfunction Significant dose reduction (~50%) for drugs that are mostly hepatically metabolized Note: Child Pugh Score is calculated only for patients with cirrhosis

33 Liver Biopsy is Gold Standard but Liver biopsy is not reliable gold standard Sampling error leads to misinterpretation in 10-15% of cases Can miss the diagnosis of cirrhosis Invasive procedure with complications Expensive Poor patient acceptance Interpretation has significant inter observer variability Seeff LB, et al. Clin Gastroenterol Hepatol. 2010;8: The French METAVIR Cooperative Study Group. Hepatology. 1994;20:15-20

34 Hepatocellular Carcinoma Incidence of HCC is estimated at 2-8% per year in patients with chronic HCV and advanced fibrosis/cirrhosis All patients with cirrhosis should be screened for HCC and continue with HCC surveillance every 6 months (indefinitely) Abdominal ultrasound plus AFP Biomarkers MRI or CT for suspicious lesions or concerns for HCC

35 Natural History of Chronic Liver Disease Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Death Development of complications: Variceal hemorrhage Ascites Encephalopathy Jaundice

36 Evaluating Patients with Cirrhosis: Related Complications Physical exam for edema, muscle wasting, encephalopathy, and/or ascites Endoscopy for presence of esophageal varices and need for esophageal banding/prophylaxis Additional info at AASLD guidelines:

37 Probability of Survival Patients with Cirrhosis Decompensation Shortens Survival All patients with cirrhosis Median survival~ 9 years 20 Decompensated cirrhosis Median survival~ 1.6 years Months Source: Ginés P, et al. Hepatology 1987; 7:122-8.

38 Indications for Referral to Hepatologist and for Liver Transplantation Periodic assessment of cirrhotic patients using a validated prognostic tool such as MELD score (Model for End-Stage Liver Disease) can predict mortality and is used as indicator for liver transplantation Patients with a score of 15 or higher should be considered for evaluation of liver transplant

39 MELD Calculator and Interpretation

40 Alcohol and On-going Substance Abuse No indications to withhold HCV therapy based on active alcohol or substance use Tobacco- can increase risk of HCC Marijuana- daily use associated with increased fibrosis Alcohol- hepatotoxic

41 Disease States Potentiating Fibrosis NASH NAFLD Fibrosis Alcohol Patient should be counseled on maintaining a healthy diet and normal BMI (<25 kg/m 2 ) Viral Hepatitis HIV Autoimmune

42 Mental health assessment Patients with HCV have higher rates of depression Underlying depression can affect medication adherence

43 When Will There Be Good News? Coffee and tea may be liver protective Statins may be hepatoprotective and may decrease the risk of HCC Jaruvongvanich V., et al Clin Res Hepatol Gastroenterol.

44 Summary: Pre-Treatment Laboratories (within 60 days of start of treatment) CBC with differential Chem 7 Liver enzymes: ALT, AST, alkaline phosphatase Liver function tests: albumin, total and direct bilirubin, INR Vitamin D 25-OH Urine or serum pregnancy test for women of childbearing capacity (ribavirin only) Alpha fetoprotein (if cirrhosis) HIVRNA and CD4 count (if HIV infected) The following labs should be current within the past 12 months*: HCV-RNA Quant Patients must have documentation of the following labs: HCV GT and subtype HBsAg, anti-hbs, anti-hbc (irrespective of vaccine history) HAV Ab (unless documentation of vaccination) HIV Ab *For non-cirrhotic, treatment naïve patients with genotype 1, an HCV-RNA within 6 months of starting therapy must be available for consideration of an 8 week course of treatment.

45 Pre-Treatment Resistance Testing All patients with HCV GT1a when considering use of elbasvir/grazoprevir require pre-treatment resistance testing for NS5A resistance associated substitutions (RASs) All patients with HCV GT3 who have cirrhosis and/or are treatment experienced when using sofosbuvir/velpatasvir or sofosbuvir plus daclatasvir should have RAS testing for HCV GT3- looking for Y93 mutation

46 Changes in HCV Therapy

47 Goals of HCV Therapy Cure Defined as sustained virologic response (SVR) Improvements in liver function Improvements in fibrosis, reversal of cirrhosis? Improvements in extrahepatic manifestations of HCV

48 Differences in Therapy Interferon Based Injectable Long duration of treatment High side effect profile Multiple laboratory abnormalities Low cure rates Direct Acting Antivirals Oral Short durations Minimal side effects Minimal laboratory abnormalities High cure rates

49 Treatment Terminology Treatment naïve (TN): no prior HCV therapy Treatment experienced (TE): prior HCV therapy- important to clarify which prior treatment Interferon Direct acting antivirals only Sustained virologic response (SVR): cure, defined as undetectable HCV RNA at least 12 weeks after end of treatment (EOT) Durable Relapser: patient who achieves an undetectable HCV RNA on treatment but has a detectable HCV RNA after treatment is completed

50 The Evolution of Highly Effective Treatment IFN 6 mos PegIFN RBV 12 mos IFN 12 mos IFN/ RBV 12 mos Standard IFN RBV PegIFN 1991 BOC and TPV PegIFN/ RBV/ BOC or TPV 6-12 mos IFN/ RBV 6 mos SOF 89+ SMV 80+ PegIFN/ RBV/ SMV wks PegIFN/ RBV/ SOF wks 2014 LDV/ SOF >90 >90 PrOD LDV/ SOF 8-12 wks PrOD + RBV wks EBR/ GZR wks SOF + DCV 12 wks DCV+ SOF EBR/ GZR 2016 >90 >90 SOF/ VEL >90 SOF/ VEL 12 wks SOF/ VEL/ VOX 2017 GLE/ PIB >90 >90 GLE/ PIB 8-12 wks SOF/ VEL/ VOX 12 wks

51 HCV Direct Acting Antivirals (DAAs) Target NS3/4A: Protease Inhibitors (-previr) NS5A: Replication Complex Inhibitors (-asvir) NS5B: Polymerase Inhibitors (-buvir) Boceprevir Telaprevir Simeprevir Paritaprevir Grazoprevir Glecaprevir Voxilaprevir Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatavir Pibrentasvir Nucleotide: Sofosbuvir Non-nucleoside: Dasabuvir

52 HCV Direct Acting Antivirals (DAAs) Generic Name Elbasvir/ Grazoprevir Glecaprevir/Pibrentasvir Ledipasvir/Sofosbuvir Paritaprevir/ritonavir/Ombitasvir Paritaprevir/ritonavir/Ombitasvir with Dasabuvir Sofosbuvir/ Velpatasvir Sofosbuvir/ Velpatasvir/Voxilaprevir Other Therapies Ribavirin Single Agent Therapies Daclatasvir Simeprevir Sofosbuvir Brand Name Zepatier Mavyret Harvoni Technivie Viekira Pak Epclusa Vosevi Ribasphere, RibaPak, Copegus, Rebetol Daklinza Olysio Sovaldi

53 What Predicts Treatment Success or Failure? Patients who are treatment naïve and non-cirrhotic have very high SVR rates Underlying cirrhosis can decrease SVR Medication adherence

54 Overview of HCV Therapies

55 Joint guidelines of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) Updated frequently- check online for most current version of guidelines Available at:

56 Ledipavir/Sofosbuvir Combination of NS5B polymerase inhibitor (Sofosbuvir); NS5A inhibitor (ledipasvir) Administration One tablet once daily with food or without food Requires acidic environment for absorption Indicated for GT 1 and 4 Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.

57 SVR12 (%) ION Phase 3 Program (ION-1, ION-2, ION-3) Efficacy Summary LDV/SOF LDV/SOF+RBV / / / / Weeks 24 Weeks 8 Weeks 12 Weeks 12 Weeks 24 Weeks ION-1 GT 1 treatment-naïve including cirrhotics 202/ / / 216 ION-3 GT 1 treatment-naïve non-cirrhotic 102/ / / / 111 ION-2 GT 1 treatment-experienced including cirrhotics and PI failures 97% (1886/1952) overall SVR rate Error bars represent 95% confidence intervals. Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print] Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print] Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]

58 Elbasvir/ Grazoprevir (EBR/GZR) Fixed-dose combination tablet 50 mg elbasvir (NS5A replication complex inhibitor) 100 mg grazoprevir (NS3/4A protease inhibitor) Dosing: 1 tablet per day with or without food Approved Feb Indicated for HCV genotypes 1 and 4 Patients with GT 1a require pre-treatment resistance testing If present, must add ribavirin and extend treatment duration to 16 weeks

59 Laboratory Abnormalities and Adverse Effects Increased risk of ALT elevations 5x ULN in 1% of patients 2% in women, Asian race, or patients aged 65 years or older Occurred at treatment week 8 or later Mostly asymptomatic Resolved with ongoing or completed therapy Monitor LFTs every 4 weeks or as clinically indicated Adverse effects: Fatigue, headache, and nausea

60 Elbasvir-Grazoprevir in Treatment-Naïve HCV GT 1, 4 or 6 C-EDGE TN: Results C-EDGE TN: SVR12 Results by Genotype 299/ / /131 18/18 8/10 Primary efficacy analysis included all patients who received 1 dose of drug. Source: Zeuzem S, et al. Ann Intern Med. 2015;163:1-13. Slide courtesy of HCV Online; H. Nina Kim MD, MSc and David Spach MD

61 Sofosbuvir/Velpatasvir Fixed-dose combination of sofosbuvir (NS5B inhibitor) and velpatasvir (NS5A inhibitor) Approved June 28, 2016 for chronic HCV genotypes 1, 2, 3, 4, 5, or 6 Treatment naïve Treatment experienced (Peg- IFN/RBV with or without PI) Epclusa [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2016.

62 SVR12 (%) ASTRAL-1: SOF/VEL STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-Infected Patients SVR12 by Cirrhosis Status or Treatment History / / / /423 Total Non-Cirrhotic Cirrhotic Treatment- Naïve 200/201 Treatment- Experienced Error bars represent 95% confidence intervals. Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med DOI: /NEJMoa

63 Sofosbuvir/Velpatasvir/Voxilaprevir Combination of NS5B polymerase inhibitor (Sofosbuvir); NS5A inhibitor (Velapatasvir); NS3/4A protease inhibitor (Voxilaprevir) Administration One tablet once daily with food Approved July 18, 2017 Vosevi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.

64 Indications: DAA Treatment Experienced Patients Patients with genotype 1, 2, 3, 4, 5, or 6 who were previously treated with an NS5A inhibitor Patients with genotype 1a or 3 infection previously treated without an NS5A inhibitor No advantage of using sofosbuvir/velpatasvir/voxilaprevir over sofosbuvir/velpatasvir for retreatment of patients with GT 1b, 2, 4, 5, or 6

65 SVR12, % POLARIS-1: SOF/VEL/VOX for 12 Weeks in NS5A Inhibitor-Experienced HCV GT 1 6 SVR12 Results Overall and by Cirrhosis Status relapses 1 on-treatment failure** 2 withdrew consent 1 LTFU 1 withdrew consent 1 LTFU 6 relapses 1 on-treatment failure** 1 withdrew consent / / /121 Overall* No Cirrhosis Cirrhosis * p <0.001 for superiority compared with prespecified 85% performance goal for SOF/VEL/VOX ** Exposure was consistent with non-adherence Bourliere M, AASLD 2016, Oral 194

66 SVR12, % POLARIS-1: SOF/VEL/VOX for 12 Weeks in NS5A Inhibitor-Experienced HCV GT 1 6 SVR12 by Genotype and Cirrhosis Status No Cirrhosis Cirrhosis * Overall GT 1 GT 1a GT 1b GT 2 GT 3 GT 4/5/ *1/1 patient with GT unknown achieved SVR12; 4/4 patients with GT 1 other (cirrhosis, n=2; no cirrhosis, n=2) achieved SVR12; Includes only GT 4 patients. Data on file, Gilead Sciences 66

67 SVR12, % POLARIS-4: SOF/VEL/VOX or SOF/VEL for 12 Weeks in Non-NS5A Inhibitor DAA- Experienced HCV GT 1 4 SVR12 by Genotype and Cirrhosis Status No Cirrhosis Cirrhosis SOF/VEL/VOX 12 Weeks Overall SVR12 97% SOF/VEL 12 Weeks Overall SVR12 90% GT 1a GT 1b GT 2 GT 3 GT GT 1a GT 1b GT 2 GT 3 GT Data on file, Gilead Sciences 67

68 Adverse Reactions and Laboratory Abnormalities Adverse reactions: Headache Fatigue Diarrhea Nausea Laboratory abnormalities: increases in total bilirubin Voxilaprevir can inhibit bilirubin transporters

69 Glecaprevir/Pibrentasvir Combination of Glecaprevir an NS3/4A protease inhibitor Pibrentasvir an NS5A inhibitor Dosage and administration: 3 tablets once daily with food Approved Aug. 3, 2017

70 Glecaprevir/Pibrentasvir: Indications and Duration of Therapy HCV Genotype Prior Treatment Experience Without Cirrhosis 1,2,3,4,5,6 Naïve 8 weeks 12 weeks 1,2,4,5,6 Pegylated interferon, ribavirin and/or sofosbuvir 3 Pegylated interferon, ribavirin and/or sofosbuvir 8 weeks 12 weeks 16 weeks 16 weeks With Compensated Cirrhosis 1 NS3/4A (NS5A naïve) 12 weeks 12 weeks NS5A (NS3/4A naïve) 16 weeks 16 weeks

71 Patients (%) with SVR 12 Glecaprevir-Pibrentasvir for 8 or 12 weeks in Non-Cirrhotic GT 1 ENDURANCE-1: Baseline Characteristics GLE-PIB x 8 Weeks GLE-PIB x 12 Weeks / / / /332 ITT-PS ITT-PS-PP ITT-PS population: ITT excluding patients with HIV coinfection or treatment experience with sofosbuvir ITT-PS-per protocol (PP) population: ITT-PS excluding patients with premature discontinuation of study drug, virologic failure before Week 8, and missing SVR12 data Source: Zeuzem S, et al. AASLD 2016.Abstract 253.

72 Patients with SVR 12 (%) Glecaprevir-Pibrentasvir in Treatment-Naïve Non-Cirrhotic GT 3 ENDURANCE-3 Study: Results ION-3: SVR 12 by Treatment Duration and Regimen (ITT Analysis) / / /157 GLE-PIB SOF + DCV GLE-PIB 12-Week Regimens 8-Week Regimen GLE-PIB = glecaprevir-pibrentasvir; SOF = sofosbuvir; DCV = daclatasvir ITT = Intent-to-treat Source: Foster G, et al. EASL Abstract GS-007.

73 Patients with SVR12 (%) Glecaprevir-Pibrentasvir in Genotype 1-6 with Renal Disease EXPEDITION-4: Results SVR12 by Type of Analysis discontinuation 1 lost to follow-up / /102 ITT mitt ITT, intent-to-treat analysis; mitt, modified intent-to-treat analysis Source: Gane E, et. al, AASLD Abstract 935.

74 Adverse Reactions and Laboratory Abnormalities Adverse reactions reported: Headache, fatigue, nausea, diarrhea Rates similar to placebo Laboratory abnormalities: Serum bilirubin abnormalities in approximately 3% of patients Glecaprevir/pibrentasvir can affect bilirubin transporters

75 Ribavirin Still utilized in combination with other HCV therapies in more difficult to treat patient populations and/or when specific RAS concerns exist Well-known to cause toxicity profile Hemolytic anemia Occurs within 1-2 weeks and peaks after 4-6 weeks Can see increase in indirect bilirubin Teratogenic Pregnancy category X

76 Case This is a 61-year old male with hepatitis C, genotype 1a Currently on furosemide and spironolactone for ascites Recommended treatment: ledipasvir/sofosbuvir plus 1200 mg ribavirin for 12 weeks What is this person s level of liver disease? What laboratory abnormalities do you anticipate on treatment?

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79 Summary: Side Effect Profile of DAAs Overall very well tolerated Most commonly reported side effects: Headache Fatigue Nausea Diarrhea (reported with voxilaprevir)

80 Summary: Laboratory Abnormalities with DAAs Overall not common Most common laboratory abnormalities: ALT elevations Concomitant use of ethinyl-estradiol with PrOD or glecaprevir/pibrentasvir Elbasvir/grazoprevir Bilirubin elevations Many DAAs inhibit bilirubin transporters Anemia with concomitant use of ribavirin Ribavirin causes hemolytic anemia

81 What About Medications in Patients with HCV? In patients undergoing HCV therapy Avoid herbals Verify potential drug interactions using Liverpool website In patients with cirrhosis Avoid NSAIDs Acetaminophen preferred for short-term pain management at <2 grams per day

82 Other Main Drug Interaction Concerns for DAAs Statins: Interactions vary by DAA and statin Acid suppressive therapy: Ledipasvir and velpatasvir require acidity for absorption greatest concern with velpatasvir Avoid amiodarone Amiodarone with sofosbuvir and other DAA: Serious symptomatic bradycardia

83 Major Drug-Drug Interactions for all Direct Acting Antivirals Carbamazepine Oxcarbazepine Phenytoin Phenobarbital Rifampin Expected to concentrations DO NOT USE WITH HCV THERAPY!

84 Case Study: Managing Interactions 44 yo female who is treatment naïve with HCV GT 1a Current medications: Amlodipine Atorvastatin Omeprazole Fluticasone nasal

85 Also available as an app: hepichart

86 Use of HCV Therapies in Special Populations

87 Use of HCV DAAs in Renal Insufficiency and Cirrhosis Ledipasvir/ sofosbuvir Elbasvir/gra zoprevir Sofosbuvir/ velpatasvir Sofosbuvir/ velpatasvir/ voxilaprevir Glecaprevir/ pibrentasvir Use in renal impairment or endstage renal disease? > 30 ml/min Safe to use in all levels of renal impairment including dialysis > 30 ml/min > 30 ml/min Safe to use in all levels of renal impairment including dialysis Use in cirrhosis? Childs Class A, B or C Child Class A Childs Class A, B or C Child Class A Child Class A

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94 Treatment Flowsheet Example

95 Treatment Flowsheet Example: With Ribavirin

96 Resources AASLD/IDSA HCV Treatment Guidelines: Available at: HCV Drug Interactions (University of Liverpool): Available at: Educational material, clinical calculators, HCV therapy summaries (University of Washington) Available at:

97 HCV ECHO WESTERN STATES End of Presentation Questions?

98 POOR CORRELATION OF AMMONIA LEVELS WITH PRESENCE OR SEVERITY OF HEPATIC ENCEPHALOPATHY Poor Correlation of Ammonia Levels With Presence or Severity of Encephalopathy Venous total ammoni a mmol/l Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Severity of Hepatic Encephalopathy Ong et al., Am J Med 2003; 114:188

99 Can Active Drug Users Adhere to HCV Therapy and Achieve Cure? Immediate Treatment Group Deferred Treatment Group Mean Drug Adherence (%) SVR12, n/m (%) Mean Drug Adherence (%) SVR12, n/m (%) All patients /201 (91.5) /95 (89.5) Patients with positive UDS at Day 1 Opioids /44 (84.1) /19 (84.2) Amphetamine /10 (90) /6 (83.3) Cocaine /20 (95) /10 (80) Benzodiazepin es /51 (90.2) /26 (88.5) Cannabinoids /60 (93.3) /27 (99.6) n= number of all randomized patients achieving SVR12; m= number of all randomized patients with positive UDS for the indicated drug at day 1 Dore et al. Ann Intern Med. 2016;165: