Next generation DAAs: Combining efficacy and safety profile. Jiannis Vlachogiannakos

Transcription

1 Next generation DAAs: Combining efficacy and safety profile. Jiannis Vlachogiannakos Associate Professor of Gastroenterology, Academic Department of Gastroenterology, National and Kapodistrian University of Athens, Medical School, Laiko General Hospital 1

2 Disclosures Speaker in Satellite Symposiums, Participant in Advisory Boards (Abbvie, Bristol, Janssen, Gilead, MSD, Roche)

3 EFFICACY SVR > 95%

4 Treatment Goals

5 DAAs combinations Sofosbuvir Sofosbuvir Sofosbuvir Sofosbuvir Sofosbuvir Paritaprevir /Ritonavir +Ombitasvir Grazoprevir +Elbasvir Ledipasvir Velpatasvir ± Ριμπαβιρίνη Simeprevir Daclatasvir Dasabuvir

6 Ribavirin Anaemia Rash Cough - Nausea

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8 What should be included in the term «SAFETY» Side effects Unexpected toxicity HBV reactivation Deterioration of liver disease HCC development DDIs

9 TREATMENT PRIORITIES Patients who must be treated with the new drugs F3-F4 Decompensated cirrhosis Transplanted patients HIV co-infection Severe extra-hepatic manifestations(cryoglobulinaemia, proteinouria, nephrosic syndrome etc) Patients who should take the new drugs F2 ΚΕΕΛΠΝΟ 2015

10 Safety Data from Clinical Trials

11 SIDE EFFECTS

12 NEW COMBINATIONS

13 REAL-WORLD DATA

14 HCV-TARGET: Serious AEs Patients, % Serious adverse events SOF + PR (n = 384) SOF + RBV (n = 667) SOF + SMV (n = 784) SOF + SMV + RBV (n = 228) Total (N = 2063) deaths, 9 in cirrhotic patients Causes of death SOF + PR: Sepsis SOF + RBV: Multiorgan failure, cardiac arrest (n = 2) SOF + SMV: Stroke, liver failure (n = 2), renal and liver failure, pneumonia from aspiration, cardiovascular shock. SOF + SMV + RBV: unknown, suicide Jensen D, et al. AASLD Abstract 45.

15 1. Hinrichsen H, et al. EASL Abstract GS Zuckerman E, et al. EASL Abstract PS004. Real-World Use of 3D ± RBV German Hepatitis C Registry cohort [1], Israeli cohort (12 treatment centers in Israel) [2] Common side-effects Fatigue, itching, insomnia, headache, nausea, anaemia Serious adverse events: 2% - 4% Discontinuation due to side-effects: 1.5% - 3% 3 deaths non associated with treatment: stroke, AMI, Multiorgan failure Factors associated with decompensation in the Israeli study. Factor P Value Age > Platelets < 90,000/mL.03 Albumin < 3.5 g/dl.048 Child-Pugh score 7.07 MELD score > History of decompensation <.001

16 Patients with decompensated cirrhosis

17 Serious side-effects- Deaths

18 SOLAR-1: Safety in patients with decompensated cirrhosis according to Child-Pugh score Child-Pugh B Child-Pugh C Patients, n (%) 12 Wks (n = 30) 24 Wks (n = 29) 12 Wks (n = 23) 24 Wks (n = 26) AE 29 (97) 27 (93) 23 (100) 26 (100) SAE 3 (10) 10 (34) 6 (26) 11 (42) Treatment-related SAEs 2 (7) (8) Treatment discontinuation due to AE 0 1 (3) 0 2 (8) Flamm SL, et al. AASLD Abstract 239.

19 SOLAR-1 and SOLAR-2 MELD Score Change from Baseline to FU-24 in CTP B/C Patients Who Achieved SVR12 Gane, AASLD, 2015, 1049

20 Patients with chronic renal failure

21 Metabolism of Sofosbuvir

22 HCV in patients with CKD Dose of drugs in reduced CrCl Sofosbuvir Sofosbuvir/Ledipasvir Sofosbuvir/Veltapasvir No change if CrCl 30 ml/min Not reccommended if CrCl <30 ml/min (200 mg/24h or 400 mg/48h) No change if CrCl 30 ml/min Not reccommended if CrCl <30 ml/min (1/2 tablet/24h or 1 tablet/48h?) No change if CrCl 30 ml/min Not reccommended if <30 ml/min (1/2 tablet/24h or 1 tablet/48h?) Simeprevir Daclatasvir Paritaprevir/r/Ombitasvir, Dasabuvir Grazoprevir/Elbasvir No change No change No change No change

23 Unexpected post-market reports

24 Reig M et al. J Hepatol 2016

25 HCC in patients with HCV cirrhosis who received treatment with SOFO-based DAAs Follow-up: weeks 17/59 26/344 9/285 Conti F et al. J Hepatol 2016

26 Reactivation of HBV with 2 nd Generation DAAs 29 cases of HBV reactivation with DAA. Reactivation usually occurred within 4-8 weeks (mean time: 53 days) from the initiation of DAAs. Severity of HBV reactivation ranged from mild to severe fulminant liver injury. Decompensation (n=3: death in 2, and liver transplantation in 1). Test for HBV in all patients beginning DAA regimens (HBsAg, anti- HBs, and anti-hbc). HBV vaccination for all susceptible individuals. Test HBV DNA levels prior to DAA therapy in patients who could be actively replicating (ie, those who are HBsAg positive) Start HBV treatment for active HBV infection (before or same time as DAA therapy)

27 DRUG-DRUG INTERACTIONS (DDIs) + =

28 Side effects PERPETRATOR Side effects VICTIM Loss of efficacy Loss of efficacy The disposition of each drug The therapeutic window of each drug Exposure Response and Exposure Adverse Response relationship to interpret PK data

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30 Chronic Liver disease Age

31 DDIs with novel all oral IFN- free DAAs 261 patients with HCV infection evaluated for initiation of antiviral treatment between

32 DDIs with DAAs The 10 most common Drug Classes in regular outpatient medication list % Proton Pump Inhibitors 24.1 Beta Blockers (selective) 18.4 Aldosterone antagonists 16.9 Thyroid Hormones 16.5 Angiotensin ΙΙ Antagonists 13.0 ΑCE Inhibitors 11.1 Dihydropyridine derivatives 10.7 Thiazides 10.0 Sulphonamides 9.2 Beta Blockers (non selective) 8.0

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34 DDIs between HCV DAAs and HIV antiretrovirals Induction Inhibition Inhibition

35 DDIs between HCV DAAs and HIV antiretrovirals Induction No co-administration with Rtv boosted PIs

36 DDIs between HCV DAAs and HIV antiretrovirals TDF levels

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38 DDIs between HCV DAAs and illicit drugs

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40 DDIs between HCV DAAs and CNS drugs

41 DDIs between HCV DAAs and lipid lowering drugs

42 DDIs between HCV DAAs and lipid lowering drugs

43 DAAs and PPIs

44 HCV-TARGET: Prognostic factors of SVR in patients SVR12 (%) who received Ledipasvir/Sofosbuvir Baseline Predictor Albumin 3.5 g/dl OR (95% CI) 4.59 ( ) Platelet count, /mm 3 ( ) P Value <.001 < SVR According to Baseline PPI Use 98 No PPI 93 PPI Total bilirubin 1.2 mg/dl 3.65 ( ) Hemoglobin, g/dl No cirrhosis Compensated liver disease No baseline PPI 1.22 ( ) 3.87 ( ) 5.49 ( ) 3.02 ( ).030 <.001 < n/n = 0 122/ / 30 8-Wk LDV/SOF 456/ / Wk LDV/SOF Terrault N, et al. AASLD Abstract 94.

45 TRIO Network: Predictors of Response to LDV/SOF by PPI Usage Per protocol analysis (n = 1979) Caution with use of high dose PPIs with LDV/SOF n = 454 P =.799 P =.965 P = % PPI drug Dexlansoprazole (n = 10) Esomeprazole (n = 48) Lansoprazole (n = 26) Omeprazole (n = 288) Pantoprazole (n = 77) Rabeprazole (n = 5) PPI dose Low (n = 282) High (n = 172) PPI frequency Once daily (n = 420) Twice daily (n = 34) Afdhal N, et al. EASL Abstract LBP % 90% 100%

46 DAAs και PPIs Grazoprevir / Elbasvir combination is not influenced by PPIs co-administraton as well as 3D combination.

47 Severe bradycardia with Sofosbuvir and Amiodarone The Medical Letter on Drugs and Therapeutics, 13 Apr 2015

48 Sofosbuvir and Amiodarone 9 cases: 3 SOF/LDV, 5 SOF/DCV, 1 SOF/SIM 6 cases within 24 hours 3 cases within 2 and 12 days from initiation of treatment Amiodarone Class II antiarrhythmic Half life> 50 days Interacts with P-gp (transported by and inhibits) Several potential mechanisms have been put forward

49 Amiodarone toxicity (SPC) Too high a dosage may lead to severe bradycardia and to conduction disturbances. Because of the long half-life of amiodarone, if bradycardia is severe and symptomatic the insertion of a pacemaker should be considered.

50 DDIs between HCV DAAs and cardiovascular drugs

51 Transplanted patients Drug-Drug interactions Sofosbuvir None Simeprevir Not with CsA Daclatasvir None Sofosbuvir/Ledipasvir None Paritaprevir/r/Ombitasvir + Dasabuvir Increase of TAC>CsA levels TAC: 0.5 mg/wk or 0.2 mg/72h, CsA: 20% of previous dose

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55 Conclusions New all oral antiviral drugs are very effective and safe for the majority of patients with chronic hepatitis C. Caution for some potentially serious and unexpected side effects of these drugs, particularly in patients with advanced liver disease and / or comorbidities. Particular attention to the other drugs that probably takes the patient. We need more data that will contribute to the identification of those patients who would not benefit from the response. Patients should be monitored both during and after treatment, particularly those who have developed cirrhosis.

56 We're done with the virus, but we're not done with liver care.

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