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

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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 Classes of Medications Used for Treatment NS3-4A Protease Inhibitors ( previr ) NS5A Inhibitors ( asvir ) NS5B Inhibitors: ( buvir ) Nucleoside Analogues Non-Nucleoside Analogues Other Grazoprevir Daclatasvir Sofosbuvir Dasabuvir Ribavirin Paritaprevir Simeprevir Elbasvir Ledipasvir Ombitasvir Velpatasvir Combination Therapies Grazoprevir/Elbasvir Paritaprevir/Ombitasvir/Dasabuvir Sofosbuvir/Ledipasvir Sofosbuvir/Velpatasvir Trade Name Zepatier Viekira XR Harvoni Epclusa

9 Medication-Specific Side Effects

10 Common DAA Side Effects Overview Generic Name Fatigue Headache Nausea Diarrhea Insomnia Pruritus Sofosbuvir X X Hemolytic Anemia Cough Rash Teratogenicity Ledipasvir/Sofosbu vir X X Sofosbuvir / Velpatasvir X X Daclatasvir X X X X Paritaprevir/ Ritonavir/ Ombitasvir/ Dasabuvir Elbasvir/Grazepr evir X X X X X X X Ribavirin X X X X X Zepatier Package Insert MED Ireland 1/16; Viekira XR package insert Abbvie 7/16; Harvoni package insert Gilead 6/16; Epclusa package insert Gilead 6/16; Daklinza package insert BMS 4/16.

11 Ledipasvir/Sofosbuvir Side Effects* Adverse reactions reported in 5% Fatigue 13-18% Headache 11-17% Nausea 6-9% Insomnia 3-6% (Package Insert)

12 Ledipasvir/Sofosbuvir Side Effects* Adverse Reactions in Cirrhotics Asthenia (abnormal weakness) 31% vs. 23% placebo Headache 29% vs. 16% placebo Fatigue 18% vs. 1% placebo Cough 5% vs. 1% placebo Myalgia 9% vs. 0% placebo Dyspnea 3% vs. 1% placebo Irritability 8% vs. 1% placebo Dizziness 5% vs. 0% placebo (Package Insert)

13 Ledipasvir/Sofosbuvir Side Effects* Contraindicated in severe renal impairment (GFR < 30 or dialysis) Causes increased exposure to sofosbuvir (Package Insert)

14 Sofosbuvir/Velpatasvir Side Effects Adverse reactions reported in 10% Fatigue Headache Contraindicated in severe renal impairment (GFR < 30 or dialysis) Causes increased exposure to sofosbuvir (Package Insert)

15 Elbasvir/Grazoprevir Side Effects Serious adverse reactions ALT elevations, although usually mild and asymptomatic Discontinuation advised if ALT persist > 10x ULN or if accompanied by signs/sx of liver inflammation, increasing conjugated bilirubin, alkaline phosphatase, or INR Adverse reactions reported in 5% Fatigue 5% Headache 11% Nausea 11% Contraindicated in moderate-severe liver dysfunction, Child-Pugh B and C cirrhosis Causes increased grazoprevir exposure (Merck Package Insert)

16 Paritaprevir/Ritonavir/Ombitasvir/ Dasabuvir Side Effects Serious adverse reactions Risk of hepatic failure or decompensation, including fatal outcomes Contraindicated in moderate-severe liver dysfunction, Child-Pugh B and C cirrhosis For patients with cirrhosis: Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage). Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated. Discontinue in patients who develop evidence of hepatic decompensation ALT elevation >5x ULN in 1% (AbbVie Package Insert)

17 Paritaprevir/Ritonavir/Ombitasvir/ Dasabuvir Side Effects Adverse reactions Fatigue 34% vs. 26% placebo Nausea 22% vs. 15% placebo Pruritus 18% vs. 7% placebo Skin reactions 16% vs. 9% placebo Insomnia 14% vs. 8% placebo Asthenia (abnormal weakness) 14% vs. 7% placebo (AbbVie Package Insert)

18 Daclatasvir Side Effects Serious adverse reactions None related to daclatasvir, but be aware of sofosbuvir-amiodarone interaction (symptomatic bradycardia) Adverse reactions reported in 5% Fatigue 14% Headache 14% Nausea 8% Diarrhea 5% (BMS Package Insert)

19 General Side Effects

20 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

21 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

22 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

23 Recurrence of Hepatocellular Carcinoma (HCC) Table 1: Studies, which reported naïve HCC or HCC recurrence after receiving direct agent antiviral. Author, Year Target Population HCC Development or Recurrence Primary End Point Whole Cohort (n) Incidence % HCC Recurrence % Temporal Association Between DAA and HCC Development or Recurrence Risk of Recurrence HR (95%IC)* Reig, Mariño, 2016 (6) Conti, 2016 (7) HCC treated patients with CR HCC treated patients with CR No HCC patients Yes NA NA Yes NR Yang, 2016 (9) Pre-LT patients Kozbial, 2016 (8) Pol, 2016 (10) No HCC patients HCC patients treated with CR HCC patients treated with CR HCC patients treated with CR NR No 189 Yes 79 NA NA 0.73/100 person-month 1.11/100 person-month NR 1.21 ( ) 0.41 ( ) LT-patients No Yes NR *Related to patients not receiving DAA. HCC: hepatocellular carcinoma; CR: complete radiologic response; LT: liver transplantation; NR: not reported. Bruix J.

24 Recurrence of Hepatocellular Carcinoma (HCC) Consider completing HCC treatment prior to HCV treatment Close surveillance for HCC recurrence in those who have previously been treated Lifetime screening for HCC in those with cirrhosis and advanced fibrosis prior to HCV eradication

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

26 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

27 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

28 Individual Drug Interactions

29 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.

30 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:

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

32 Ledipasvir/Sofosbuvir and Acid Suppressors Recommendation is no more than 20 mg omeprazole daily due to reduced levels of ledipasvir H2 blockers 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 HARVONI US Full Prescribing Information. Gilead Sciences. February 2016.

33 Real World Data of PPI and LED/SOF Published Dec 2016 in Hepatology 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;

34 HCV DAA and Antiretroviral DDI s SOF, sofosbuvir; SOF/LDV, sofosbuvir plus ledipasvir; SOF/VEL, sofosbuvir plus velpatasvir; 3D, ritonavir-boosted paritaprevir, plus ombitasvir and dasabuvir; G grazoprevir plus elbasvir; DCV, daclatasvir; SIM, simeprevir; r, ritonavir. EASL Recommendations: Journal of Hepatology

35 hep-druginteractions.org

36 Case Revisited

37 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?

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

39 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

40 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

41 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