Drug interactions in HCV: a case discussion

Transcription

1 Drug interactions in HCV: a case discussion Antonio Craxì GI & Liver Unit, Di.Bi.M.I.S. University of Palermo, Italy antonio.craxi@unipa.it Disclosure of potential COIs (advisory boards, speakers bureau, research grants) related to this presentation: Abbott, Achillion, Anadys, Boehringer-Ingelheim, Bristol Myers Squibb, Genentech, Gilead, Glaxo Smith Kline, Inhibitex, Janssen- Cilag, Merck Sharp & Dohme, Novartis, Pharmasset, Roche, Tibotec, Vertex.

2 2007: G.M., male caucasian, accountant, 64 years History 1987: Car accident, multiple blood transfusions 1993: Found anti-hcv and positive with ALT 2 x u.l.n. No treatment suggested. Since then ALT 2 to 3 x u.l.n. 1993: Arterial hypertension, starts ACE inhibitors Clinical presentation (2007) BMI Biopsy: 29 Kg/m 2, WC Chronic 103 cm. No alcohol hepatitis since 1993, with non-smoker Anti-HCV positive, 1,850,000 IU/ml, genotype 1b moderate HBsAg and anti-hiv necroinflammatory negative activity ALT 3 x u.l.n., γgt 3 x u.l.n., glucose 105 mg/dl, HOMA 3.5, PLT and , portal other fibrosis. LFTs normal Steatosis 20% (METAVIR: US steatosis, without Grading signs of cirrhosis 2/3; or Staging portal hypertension 2/4). (portal vein mm 10; spleen DL cm 12)

3 2007: G.M., male caucasian, accountant, 64 years 1,850,000 IU PEG IFN alfa2a 180 µg/wk plus RBV 1200 mg/da Null responder: 250,000 IU 220,000 IU STOP THERAPY at 12 weeks Weeks

4 G.M. Gt 1 Null Responder: AST/ALT 110/ /150 99/100 85/90 (NV<41 UI) PLT/mmc 212, , , ,000 BMI Glucose Ultrasonography Steatosis Steatosis Steatosis + scarring Steatosis + scarring + spleen 14 cm LSM (KPa)

5 G.M., male, 69 years old (2012) IL28B: T/T 2,750,000 IU AST/ALT 90/92 UI/L GGT 306 UI/L Total/direct bilirubin 1.5/0.7 mg/dl Normal INR and albumin PLT /mmc Glucose 130 mg/dl; HbAC 7% HOMA-IR 4.1 Total/LDL cholesterol 289/170 mg/dl

6 2012: G.M. Gt 1 Null Responder, 69 yrs US: finely hyperechoic, dishomogeneous structure Irregular margins Portal vein 12 mm Reduced respiratory variations Spleen 14 cm EGDS Fibroscan Height 167; Weight 88; BMI 31,5 LSM: 13 KPa IQR (KPa): 1.30 Success Rate: 67% F1 Esophageal Varices

7 2012: G.M. Gt 1 Null Responder, 69 yrs, metabolic syndrome Hepatology 2012 May;55(5): doi: /hep Epub 2012 Apr 4. Bilateral carotid atherosclerotic plaques stenosing 20%-30% of vascular lumen

8 Gt1 CHC Patient with Child A5 Cirrhosis, with F1 Esophageal Varices, Null Responder to Dual Therapy Awaiting for triple therapy with protease Inhibitors (unsuitable for RCTs) Obese, Hypertensive, Insulin Resistant, Diabetic Patients, with Carotid Atherosclerosis Attempts lifestyle changes. Started on metformin, atorvastatin and low-dose aspirin

9 G1 CHC Patients with Child A5 Cirrhosis, with F1 Esophageal Varices, Null Responder to Dual Therapy Pros of TT Cons of TT Previous Null Responder Higher SVR of TT vs DT Late 2011 Cirrhosis Availability Benefit of SVR of BOCEPREVIR Age through EAP in Italy Metabolic Dysfunctions? Co-morbities and drug-interactions Obese, Hypertensive, Insulin Resistant, Diabetic Patients, with Carotid Atherosclerosis

10 RESPOND-2: SVR according to prior response to DT SVR (%) Prior relapsers Prior partial responders Prior null responders in PROVIDE PR48 BOC RGT BOC44/ PR48 PR48 BOC RGT BOC44/ PR48 BOC44/ PR48 n/n= 15/51 72/105 77/103 2/29 23/57 30/58 SVR was defined as undetectable at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward Boceprevir EU SmPC

11 RESPOND-2: SVR by baseline fibrosis stage and prior response to DT Prior relapsers Prior partial responders Prior null responders PR48 SVR (%) BOC RGT BOC44/PR48 Cirrhosis + Null Response? n/n= 12/38 59/79 58/77 2/10 11/22 15/18 2/23 18/38 23/42 0/5 3/10 6/13 Stage No, minimal or portal fibrosis (F0 F2) Bridging fibrosis / cirrhosis (F3/F4) No, minimal or portal fibrosis (F0 F2) Bridging fibrosis / cirrhosis (F3/F4) Bruno S, et al. J Hepatol 2011;54(Suppl. 1):S4

12 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome Starts Triple Therapy with Boceprevir Peg- IFN + RBV Boceprevir + Peg-IFN + RBV Atorvastatin stopped before starting triple therapy

13 Drug-Drug Interactions and Boceprevir Class Agent EU US Alpha-1 receptor antagonists Antiarrhythmics Anticonvulsants Alfuzosin No recommendation CI Amiodarone, bepridil, quinidine Carbamazepine, phenobarbital, phenytoin Bepridil contraindicated. Caution with amiodarone/quinidine No data available: not recommended Caution warranted; therapeutic monitoring recommended Antimalarials Lumefantrine, halofantrine CI No recommendation Antimycobacterials Rifampicin No data available: not recommended CI Antipsychotics Pimozide CI CI Benzodiazepines Oral midazolam, triazolam CI CI Digestive motility stimulants Ergot rye derivatives Herbal products HMG-CoA reductase inhibitors Cisapride No recommendation CI Dihydroergotamine, ergonovine, ergotamine, methylergonovine St. John s wort (Hypericum perforatum) Atorvastatin, simvastatin, lovastatin CI No recommendation No data available. Therapeutic monitoring recommended (atorvastatin, simvastatin) CI CI CI Lovastatin, simvastatin; CI Atorvastatin: Therapeutic monitoring recommended PDE5 inhibitors* Sildenafil, tadalafil No recommendation CI Tyrosine kinase inhibitors Not specified CI No recommendation Contraceptives Drospirenone Caution warranted CI Italic: removed/not available in all countries; *for pulmonary arterial hypertension 1. Boceprevir EU SmPC; 2. Boceprevir US prescribing information

14 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome 2,750,000 IU Flu-like symptoms Hb 12 g/dl Wbc/Neut 2,400/1,100 mmc PLT 132,000 mmc ALT 2.5 x u.l.n. 1,740,000 IU Peg- IFN + RBV Boceprevir + Peg-IFN + RBV 48

15 SVR According to Lead-in (RESPOND-2, non-black) 100 % of patients with SVR % 33% 34% 79% Cirrhosis <1 log decrease? 1 log decrease 0 BOC/RGT BOC/PR48 (Bacon et al., N Engl J Med 2011;364: )

16 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome 2,750,000 IU 1,740,000 IU Flu-like symptoms, Dysgeusia, Dyspepsia Esomeprazole 40 mg Mild depression Hb 11.1 g/dl Wbc/Neut 1,900/900 mmc PLT 111,000 mmc ALT 1.5 x u.l.n. 96 IU Peg- IFN + RBV Boceprevir + Peg-IFN + RBV 48

17 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome 2,750,000 IU Flu-like symptoms, Dysgeusia Dyspepsia Esomeprazole 40 mg Mild depression Hb 10.1 g/dl Wbc/Neut 1,850/910 mmc PLT 101,000 mmc ALT <1.5 x u.l.n. 1740,000 IU 96 IU 35 IU Peg- IFN + RBV Boceprevir + Peg-IFN + RBV 48

18 Boceprevir Stopping Rule STOP Treatment-naïve without cirrhosis who achieve undetectable at Weeks 8 and 24 PR lead-in BOC + PR BOC + PR* PR Non-cirrhotic treatment-naïve with detectable at Week 8 but undetectable at Week 24 Non-cirrhotic relapsers and partial responders If 100 IU/mL discontinue all drugs If detectable discontinue all drugs BOC + PR Null responders Patients with cirrhosis Weeks RESPOND-2: stopping rule if detectable at week 12

19 Disposition of the Evaluable Treatment-experienced Patients from RESPOND-2 with Detectable at Week 12

20 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome HCVRNA 2,750,000 IU 1740,000 IU Weakness, Dysgeusia Dyspepsia Esomeprazole 40 mg Bloating, Mild Constipation Mild depression Hb 9.9 g/dl Wbc/Neut 1,920/950 mmc PLT 96,000 mmc ALT <1.5 x u.l.n. 96 IU HCVRNA 35 IU >lod < loq Peg- IFN + RBV Boceprevir + Peg-IFN + RBV 48

21 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome 2,750,000 IU 1,740,000 IU 96 IU HCVRNA 35 IU >lod < loq Weakness, Dysgeusia Dyspepsia Esomeprazole 40 mg Bloating, Mild Constipation Mild depression Hb 10 g/dl Wbc/Neut 1,870/890 mmc PLT 91,000 mmc AST/ALT <1.5 x u.l.n. HCVRNA >lod < loq Peg- IFN + RBV Boceprevir + Peg-IFN + RBV 48

22 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome HCVRNA 2,750,000 IU Weakness, Dysgeusia Dyspepsia Esomeprazole 40 mg Bloating, Mild Constipation Hb 10 g/dl Wbc/Neut 1870/890 mmc PLT mmc AST/ALT <1.5XN HCVRNA 1740,000 IU HCVRNA 96 IU HCVRNA HCVRNA 35 IU >lod < loq HCVRNA >lod < loq 26,530 IU Peg- IFN + RBV Viral breakthrough: Boceprevir + Peg-IFN + RBV STOP all therapy 48

23 2012: G.M., Gt 1 Patient with Child A5 Cirrhosis, Null Responder to Dual Therapy, with Metabolic Syndrome Viral breakthrough Search for RAVs: V36A/M and A156T/V Rule-out: detectable only at wk 24 Telaprevir* (linear) Boceprevir* (linear) V36A /M T54S/ A V55 A Q80R/ K R155K/ T/Q A15 6S A156 T/V Lack of adherence Drug-Drug Interaction D168A/E/G/H /T/Y V170A/T

24 Why did this patient fail to respond to P/R + BOC after an initial slow response? upon repeated questioning, the patient reported taking since week 8 an herbal tea to cure mild depression and dyspepsia.

25 Hypericum, «St John s wort»

26 Drug-Drug Interactions and Boceprevir Class Agent EU US Alpha-1 receptor antagonists Antiarrhythmics Anticonvulsants Alfuzosin No recommendation CI Amiodarone, bepridil, quinidine Carbamazepine, phenobarbital, phenytoin Bepridil contraindicated. Caution with amiodarone/quinidine No data available: not recommended Caution warranted; therapeutic monitoring recommended Antimalarials Lumefantrine, halofantrine CI No recommendation Antimycobacterials Rifampicin No data available: not recommended CI Antipsychotics Pimozide CI CI Benzodiazepines Oral midazolam, triazolam CI CI Digestive motility stimulants Ergot rye derivatives Herbal products HMG-CoA reductase inhibitors Cisapride No recommendation CI Dihydroergotamine, ergonovine, ergotamine, methylergonovine St. John s wort (Hypericum perforatum) Atorvastatin, simvastatin, lovastatin CI No recommendation No data available. Therapeutic monitoring recommended (atorvastatin, simvastatin) CI CI CI Lovastatin, simvastatin; CI Atorvastatin: Therapeutic monitoring recommended PDE5 inhibitors* Sildenafil, tadalafil No recommendation CI Tyrosine kinase inhibitors Not specified CI No recommendation Contraceptives Drospirenone Caution warranted CI Italic: removed/not available in all countries; *for pulmonary arterial hypertension 1. Boceprevir EU SmPC; 2. Boceprevir US prescribing information

27 Was it wort(h)?