New York State HCV Provider Webinar Series. Side Effects of Therapy and Drug-Drug Interactions

Transcription

1

2 New York State HCV Provider Webinar Series Side Effects of Therapy and Drug-Drug Interactions

3 Case Presentation

4 Case 56 year-old lady with Genotype 1A Hepatitis C, Treatment-naive Noninvasive fibrosis testing consistent with mild fibrosis Good candidate for treatment PMH: Atrial Fibrillation, Chronic Kidney Disease (GFR ~ 20 ml/min) Medications: ASA, Amiodarone What elements of her history impact which regimen you choose to treat her with?

5 New York State HCV Provider Webinar Series Part 1: Side Effects of Therapy

6 Objectives Review the currently available regimens for treatment of HCV Appreciate side effects related to specific medications Become aware of general side effects related to clearance of HCV

7 Currently Available Therapies

8 Currently Available Therapies Combination Therapies Trade Name Elbasvir/Grazeprevir GZR/EBR Zepatier Glecaprevir/Pibrentasvir GLE/PIB Mavyret Ledipasvir/Sofosbuvir LDV/SOF Harvoni Sofosbuvir/Velpatasvir SOF/VEL Epclusa Sofosbuvir/Velpatasvir/ Voxilaprevir SOF/VEL/VOX Vosevi

9 Medication-Specific Side Effects

10 Common DAA Side Effects Overview Generic Name Fatigue Headache Nausea Diarrhea Rash Insomnia Ledipasvir/ Sofosbuvir Sofosbuvir/ Velpatasvir Sofosbuvir/ Velpatasvir/ Voxilaprevir Glecaprevir/ Pibrentasvir Elbasvir/ Grazeprevir X X X X X X X X X X X X X X X X X X X X X X X X X X X Zepatier Package Insert MED Ireland 1/16;; Harvoni package insert Gilead 6/16; Epclusa package insert Gilead 6/16; Vosevi PI Gilead 2017; Mavyret PI Abbvie 2017

11 Sofosbuvir Containing Regimens Contraindicated in severe renal impairment (GFR < 30 or dialysis) Causes increased exposure to potentially nephrotoxic breakdown product (Package Insert)

12 Elbasvir/Grazoprevir Contraindicated in moderate-severe liver dysfunction, Child-Pugh B and C cirrhosis (Merck Package Insert)

13 General Side Effects

14 Reactivation of Hepatitis B Patients with prior, resolved, or active HBV infection are at risk of reactivation on DAA therapy FDA issued black box warning in reactivations reported since died, 1 required liver transplant Mechanism of reactivation unknown

15 Reactivation of Hepatitis B Prior to initiating DAA therapy, test for HBV coinfection with HBsAg, anti-hbs, and anti-hbc HBV vaccinate all susceptible patients Check HBV DNA PCR in patients who are sag positive or cab positive/sab negative Start HBV treatment prior to HCV treatment in those who meet criteria for treatment Follow HBV DNA PCR regularly (monthly) in those with low detectable HBV DNA or possibly those who are cab positive but DNA negative at treatment start

16 Recurrence of Hepatocellular Carcinoma (HCC) HCV eradication is associated with decreased incidence of HCC long-term Recent studies have indicated higher risk of HCC recurrence or development of new HCC in the first 4 months following DAA therapy

17 Suggested Monitoring for HBV Reactivation During DAA for HCV Test HBV Markers in All DAA Candidates: 1) HBsAg, 2) An,-HBc, 3) An,-HBs HBV Markers NEGATIVE HBsAg POSITIVE HBsAg NEGATIVE an<-hbc POSITIVE (± an<-hbs) HBV DNA Detectable HBV DNA Low or UD VACCINATE Meets AASLD criteria for ini,a,on of HBV therapy Treat with HBV drug HBVr Standard Defini<on: q Marked increased in HBV DNA (>/=2 log increase from baseline levels) OR q New appearance of HBV DNA to a level of > 100 IU/mL in a person with previously stable or undetectable levels. Ini,ate prophylac,c an,viral therapy un,l 12 weeks axer DAA comple,on OR Monitor for HBVr: q Check HBV DNA + LFTs q2 weeks during & axer DAA therapy Start HBV Therapy if: q HBV DNA >10-fold above baseline or q HBV DNA >1000 IU/mL Specific HBV monitoring not required unless change in liver enzymes or clinical status Lieber and Fried, 2017 Adapted from AASLD Guidelines

18 New York State HCV Provider Webinar Series Part 2: Drug-Drug Interactions

19 Objectives Detail medications contraindicated with all DAA regimens Detail medications contraindicated with specific DAA agents Briefly review drug-drug interactions of the HCV DAA medications with HIV anti-retrovirals

20 Medications Contraindicated with All Regimens P-glycoprotein inducers St John s Wart, rifampin, rifabutin, rifapentine Anticonvulsants (strong cytochrome p450 [CYP] inducers) Carbamazepine, oxcarbazepine, phenytoin (CYP3A4, CYP2C19), phenobarbital Levetiracetam and gabapentin are okay no DDI s

21 Individual Drug Interactions

22 Sofosbuvir Drug-Drug Interactions With all sofosbuvir containing regimens including sofosbuvir alone, ledipasvir/sofosbuvir, and sofosbuvir/velpatasvir Amiodarone causes severe symptomatic bradycardia (unclear effect on sofosbuvir concentrations) Tipranivir/ritonavir-decreases sofosbuvir concentrations Sovaldi package insert 8/2015.

23 Sofosbuvir + Amiodarone = Bradycardia Described by the French National Agency for Medicines and Health Products Safety in January arrhythmias in 1337 patients from compassionate use of daclatasvir and sofosbuvir FDA warning issued about sofosbuvir plus another antiviral drug taken with amiodarone can cause serious slowing of the heart rate 2 NEJM November 2015, reported 3 cases of severe symptomatic bradycardia in patients receiving sofosbuvir (2 also had amiodarone exposure) 3 1. Signal de securite Jan 16,2015; Fontaine H, et al. NEJM 2015; 373:

24 Sofosbuvir + Amiodarone = Bradycardia Effect is reproducible in Guinea Pigs and Rhesus Monkeys Guinea Pigs Rhesus Monkeys Regan CP, et al. Hepatology. 2016:64;

25 PPIs and DAAs SOF/LED no more than 20 mg omeprazole daily due to reduced levels of ledipasvir SOF/VEL and SOF/VEL/VOX Avoid PPIs GLE/PIB No restrictions Harvoni PI Gilead, Epclusa PI Gilead, Vosevi PI Gilead, Mavyret PI Abbvie

26 Real World Data of PPI and LED/SOF Data collection through Trio Health s Innervation Platform 1,566 patients had no PPI vs 468 who had a PPI SVR (ITT analysis): 95.6% w/o PPI vs 94.2% with PPI Completion rate: 98.2% w/o PPI vs 97.1% with PPI Daily PPI (n=410) SVR % BID PPI (n=24) SVR % Hepatology. 2016:64;

27 DAAs and Antacids SOF/LED, SOF/VEL, SOF/VEL/VOX H2 blocker such as ranitidine or famotidine can be taken simultaneously or 12 hours apart, at doses not exceeding 40 mg famotidine twice daily Antacids (such as aluminum and magnesium hydroxide) must be separated from ledipasvir/sofosbuvir by 4 hours GLE/PIB No restrictions Harvoni PI Gilead, Epclusa PI Gilead, Vosevi PI Gilead, Mavyret PI Abbvie

28 Dose Equivalence of PPI and H2 Blockers European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C J Hepatol (2018), jhep

29 DDIs between DAA and Lipid Lowering Drugs European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C J Hepatol (2018), jhep

30 DDIs between DAAs and CNS Drugs European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C J Hepatol (2018), jhep

31 DDIs between DAAs and Cardiovascular Drugs European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C J Hepatol (2018), jhep

32 DDIs between DAAs and antiplatelet and anticoagulants European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C J Hepatol (2018), jhep

33

34

35

36 hep-druginteractions.org

37 Case Revisited

38 Case 56 year-old lady with Genotype 1A Hepatitis C, Treatment-naive Noninvasive fibrosis testing consistent with mild fibrosis Good candidate for treatment PMH: Atrial Fibrillation, Chronic Kidney Disease (GFR ~ 20 ml/min) Medications: ASA, Amiodarone What elements of her history impact which regimen you choose to treat her with?

39 Case 56 year-old lady with Genotype 1A Hepatitis C, Treatment-naive Noninvasive fibrosis testing consistent with mild fibrosis Good candidate for treatment PMH: Atrial Fibrillation, Chronic Kidney Disease (GFR ~ 20 ml/min) Medications: ASA, Amiodarone

40 Case (Continued) What elements of her history impact which regimen you choose to treat her with? Mild fibrosis Protease inhibitors not contraindicated GFR ~ 20 ml/min Sofosbuvir contraindicated Amiodarone Sofosbuvir contraindicated

41 Summary Most DAA side effects are mild and rarely lead to discontinuation Sofosbuvir-containing regimens are contraindicated in patients taking amiodarone and those with GFR < 30 or on dialysis Protease inhibitor-containing regimens are contraindicated in cirrhotic patients with moderate to severe hepatic dysfunction Ribavirin is teratogenic and causes hemolytic anemia that is dose-dependent DAA therapy has been associated with HBV reactivation The risk of HCC recurrence or de novo HCC may be increased shortly after DAA therapy

42 Summary St John s Wart, rifampin, carbamazepine, phenytoin, and oxcarbazepine are not safe to use with any HCV regimen Amiodarone has a significant interaction with sofosbuvir causing symptomatic bradycardia Each HCV regimen has unique drug-drug interactions and a careful review of each patient s medical history and medication list is essential prior to initiating HCV therapy It is essential to consult the package insert or the drug interactions website for potential drug interactions Withhold any vitamins/herbal supplements and statins during HCV treatment