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Treatment of HCV Coinfection: Navigating the Interactions

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1 Treatment of HCV Coinfection: Navigating the Interactions
Jennifer J. Kiser, PharmD Assistant Professor Department of Pharmaceutical Sciences University of Colorado School of Pharmacy Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

2 Bermuda Triangle HCV Treatment: A Journey DDI: Basic Principles
BOC and TVR Pharmacology Managing the Interactions Bermuda Triangle SVR Identifying Interactions with Concomitant Medications Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy Identifying Interactions with Antiretroviral Agents From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

3 Slide 3 of 39 Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; CYP450; metabolism; substrates From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

4 CYP450 Inhibition Inhibiting drug added Drug Concentration Time
Slide 4 of 39 CYP450 Inhibition Drug Concentration Inhibiting drug added Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; CYP450; inhibitor Time

5 CYP450 Induction Drug Concentration Inducing drug added Time
Slide 5 of 39 CYP450 Induction Drug Concentration Inducing drug added Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; CYP450; induction Time

6 BOC and TVR are CYP3A substrates
BOC and TVR PK affected by CYP3A inhibitor (ketoconazole) and inducer (efavirenz) Data presented as geometric mean ratios (GMR), i.e., ratio of concentrations A+B vs. A alone AKR inhibitors, diflunisal1 and ibuprofen4, do not increase BOC exposures BOC GMR TVR GMR Cmax AUC Cmin Ketoconazolea 1.411 2.311 NR 1.242 1.622 Efavirenzb 0.921 0.811 0.561 0.913 0.743 0.533 Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; telaprevir; TVR; CYP3A; substrates; ketoconazole; efavirenz; EFV a BOC: ketoconazole 400mg BID x 6 days, BOC single 400mg dose TVR: ketoconazole single 400mg dose, TVR single 750mg dose b BOC: EFV 600mg QD x 16 days, BOC 800mg TID x 6 days TVR: EFV 600mg QD x 20 days, TVR 750mg Q8H x 10 days 1Kassserra C, et al. CROI 2011, Abstract 118, 2Garg V, et al. 6th IWCP Hepatitis Therapy, 2011, abstract PK-13, 3van Heeswijk R, 18th CROI 2011, abstract 119, 4boceprevir prescribing information From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

7 BOC and TVR are CYP3A Inhibitors
TVR a more potent CYP3A inhibitor Midazolam GMR Atorvastatin GMR AUC Cmax BOC AUC12 = 5.31 2.81 2.33 2.73 TVR AUC24 = 9.02 2.92 7.94 10.64 1BOC: midazolam single 4mg oral dose, BOC 800mg TID x 6 days 2TVR: midazolam single 2mg oral dose, TVR 750mg Q8H x 11 days, 340mg single dose 420mg daily Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; telaprevir; TVR; CYP3A; inhibitor; midazolam; atorvastatin 1Kassserra C, et al. CROI 2011, Boston, MA, Abstract 118, 2Garg V, J Clin Pharm 2012 Jan 26 [Epub ahead of print], 3Hulskotte EGJ, et al. HepDART 2011,4Lee JE, et al. AAC 2011;55(1): From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

8 Drug Transporters Systemic Circulation NTCP ABCG5/G8 BCRP OATP1B1 MRP3
Slide 8 of 39 Systemic Circulation Sinusoidal Membrane Bile NTCP OAT2 OCT1 P-gp MRP2 MRP3 MRP4 BCRP ABCG5/G8 BSEP MDR3 Canalicular Membrane OATP1B1 Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; transporters

9 Concept of a Therapeutic Index
Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; therapeutic index; toxicity From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

10 Approach to Identifying and Managing Drug Interactions in HCV Treatment
Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted] From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

11 Patient Case 57 yo African American female being considered for triple therapy for HCV HIV Diagnosed 2005, sexually acquired, CD4 nadir~200 HIV RNA = target not detected, CD4=1000 (40%) (Feb 2013) Hepatitis C 1a Treatment naïve Biopsy (June 2012) grade 2 inflammation, stage 2 fibrosis HCV RNA = 3,270,000 (Aug 2012) GERD Hypertension Chronic Pain Schizoaffective Disorder Personality Disorder Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; case From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

12 Patient Case HIV GERD Chronic Pain Psychotropics Hypertension
Raltegravir 400mg BID Tenofovir DF 300mg QD Emtricitabine 150mg QD GERD Omeprazole 20mg QD Chronic Pain Oxycodone 5-10mg Q6H prn Psychotropics Sertraline 50mg QD Quetiapine 300mg QHS Hypertension Amlodipine 5mg QD Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; case; raltegravir; tenofovir; emtricitabine; omeprazole; oxycodone; sertraline; quetiapine; amlodipine From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

13 Antihypertensives ACE inhibitors and diuretics ok
Metabolized to some extent by CYP3A, so consider dose reductions Beta blockers: carvedilol and nebivolol ARBs: irbesartan and losartan Calcium channel blockers Amlodipine Cmax and AUC increased and 2.79-fold by TVR, so a reduced dose should be considered Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; antihypertensive; CYP3A carvedilol; nebivolol; irbesartan; losartan; amlodipine Kiser JJ, et al. Hepatology 2012;55(5):1620 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

14 Antidepressant Exposures Likely Reduced by BOC and TVR
Escitalopram AUC ↓21% by BOC (t1/2 ↓ from 31 to 22 hrs)1 Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; antidepressant; boceprevir; BOC; telaprevir; TVR; paroxetine; sertraline With HIV protease inhibitors, paroxetine and sertraline exposures are reduced.3,4 1Hulskotte EGJ, et al. HepDART 2011 3Best BM, et al. 14th CROI 2007, abstract 574 4Sekar V, et al. 8th International Congress on Drug Therapy in HIV Infection 2006, abstract P295 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

15 Antipsychotics Quetiapine ↑ 335% with potent CYP3A inhibitor ketoconazole Cases of toxicity with HIV PIs Avoid quetiapine Dosage of aripiprazole and iloperidone should be halved Grimm SW, et al. Br J Clin Pharmacol 2006;61:58 Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; antipsychotic; ketoconazole; quetiapine; aripiprazole; iloperidone Kiser JJ, et al. Hepatology 2012;55(5):1620 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

16 Opioids Primarily metabolized by CYP3A, so may require dose reduction:
Oxycodone Tramadol Fentanyl Hydrocodone, codeine, morphine, hydromorphone, oxymorphone okay Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; opioid; CYP3A; oxycodone; tramadol; fentanyl; hydrocodone; codeine; morphine; hydromorphone; oxymorphone Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted] From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

17 Interaction Potential of Concomitant Medications with BOC and TVR
Avoid or Use With Caution (Requires Investigation) Safe Oral Contraceptives Psychotropics Gastric Acid Modifiers Phosphodiesterase Inhibitors Herbal Supplements Opioid Replacements HMG-CoA Reductase Inhibitors Pain Medications Antiretroviral Drugs Cardiovascular Immunosuppressants Corticosteroids Anxiolytics Antimycobacterials Anticonvulsants Antifungals Ergot Derivatives Alpha-1 adrenoreceptor antagonist Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; telaprevir; TVR; oral contraceptive; psychotropic Kiser JJ, et al. Hepatology 2012;55(5):1620, Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted] From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

18 Mean HIV PI PK Profiles LPV/r ATV/r DRV/r fAPV/r Slide 18 of 39
Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119 Mean HIV PI PK Profiles 12000 LPV/r 4000 3000 2000 1000 ATV/r PI alone PI + TVR n=19 8000 LPV concentration (ng/mL) n=12 ATV concentration (ng/mL) n=7 4000 PI alone PI + TVR n=11 Cmin ↔ AUC  Cmin ↑ 85% AUC 17% Time (hours) Time (hours) DRV/r fAPV/r 6000 4000 2000 PI alone PI + TVR PI alone PI + TVR Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; protease inhibitor; PI; lopinavir; LPV; atazanavir; ATV; darunavir; DRV; fosamprenavir; fAPV; ritonavir; telaprevir; TVR 4000 3000 2000 1000 n=20 n=16 DRV concentration (ng/mL) APV concentration (ng/mL) Cmin ↓ 42% n=11 n=18 AUC 40% Cmin ↓ 56% AUC 47% From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Time (hours) Time (hours) APV = amprenavir

19 TVR concentration (ng/mL)
Slide 19 of 39 Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119 Mean TVR PK Profiles 2 4 6 8 2 4 6 8 LPV ATV DRV fAPV n=14 n=17 n=16 n=20 3000 TVR alone 2000 TVR concentration (ng/mL) TVR + ARV Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; telaprevir; TVR; lopinavir; LPV; atazanavir; ATV; darunavir; DRV; fosamprenavir; fAPV 1000 n=12 n=14 n=11 n=18 Cmin ↓ 52% Cmin ↓ 15% Cmin ↓ 32% Cmin ↓ 30% AUC 54% AUC 20% AUC 35% AUC 32% 2 4 6 8 2 4 6 8 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Time (hours) AUC = area under the curve

20 BOC and RTV-boosted PI DDI Study
ATV AUC ↓ 35%, Cmin ↓ 49% LPV AUC ↓ 34%, Cmin ↓ 43% Coadministration with BOC also decreased the AUC of ritonavir in all three groups with ritonavir AUC decreasing 34%, 22%, and 27% in the ATV, LPV, and DRV cohorts respectively. DRV AUC ↓ 44%, Cmin ↓ 59% Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; ritonavir; RTV; protease inhibitor; PI; atazanavir; ATV; lopinavir; LPV; darunavir; DRV; didanosine; ddi BOC PK AUC Cmax Cmin w/ ATV/r ↓5% ↓7% ↓12% w/ LPV/r ↓45% ↓50% ↓57% w/ DRV/r ↓32% ↓25% ↓35% Hulskotte EGJ. CROI, March 5-8, 2012, Seattle, WA, abstract 771LB From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

21 Summary of Interactions with BOC and TVR and RTV-boosted HIV PI
ATV/r DRV/r fAPV/r No data LPV/r Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; telaprevir; TVR; ritonavir; RTV; protease inhibitor; PI; atazanavir; ATV; darunavir; DRV; fosamprenavir; fAPV; lopinavir; LPV Inconsistent Unexpected Difficult to Explain Possibly Multifactorial From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

22 Possible Mechanisms for Interactions with HIV/HCV Protease Inhibitors
Enzyme Induction? Decrease in Bioavailability? Altered Protein Binding? Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

23 NNRTI Interactions with BOC and TVR
RPV ↑39%1 ↔1 ↑79%2 ↔2 ETV ↓29%3 ↔3 ↓25%2 Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; NNRTI; boceprevir; BOC; telaprevir; TVR; rilpivirine; RPV; etravirine; ETV 1Rhee E, et al. 20th CROI, 2013 Atlanta, GA 2Kakuda TN, et al. 7th Int Workshop on Clin Pharm HIV Therapy, 2012 Barcelona, Spain 3Hammond KP, Kiser JJ, JAIDS 2013;62(1):67 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

24 BOC and TVR okay with RAL
RAL AUC ↔ TVR1: RAL and RAL-glucuronide AUC increased 31% and 37%, respectively by TVR Similar changes in RAL-glucuronide suggest no effect of TVR on UGT1A1 ↑ RAL likely due to P-gp inhibition by TVR Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; telaprevir; TVR; raltegravir; RAL 1Van Heeswijk R, et al. 51st ICAAC, Chicago, IL, Sept 17-20, 2011, abstract 1738a 2de Kanter CTMM, et al. 19th CROI, Seattle, WA, March 5-8, 2012, abstract 772LB From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

25 Maraviroc Interaction with BOC and TVR vs. HIV PI
Greatest to least effect on MVC AUC Co-administered drug (dose) N Ratio (90% CI) of maraviroc PK parameters with/without co‑administered drug (no effect=1.00) AUCtau Cmax Cmin Saquinavir/r (1000/100 mg BID) 11 9.77 (7.87, 12.14) 4.78 (3.41, 6.71) 11.3 (8.96, 14.1) Telaprevir (750 mg TID) 14 9.49 (7.94, 11.34) 7.81 (5.92, 10.32) 10.17 (8.73, 11.85) Ketoconazole (400 mg QD) 12 5.00 (3.98, 6.29) 3.38 (2.38, 4.78) 3.75 (3.01, 4.69) Atazanavir/r (300/100 mg QD) 4.88 (4.40, 5.41) 2.67 (2.32, 3.08) 6.67 (5.78, 7.70) Darunavir/r (600/100 mg BID) 4.05 (2.94, 5.59) 2.29 (1.46, 3.59) 8.00 (6.35, 10.1) Lopinavir/r (400/100 mg BID) 3.95 (3.43, 4.56) 1.97 (1.66, 2.34) 9.24 (7.98, 10.7) Atazanavir (400 mg QD) 3.57 (3.30, 3.87) 2.09 (1.72, 2.55) 4.19 (3.65, 4.80) Boceprevir (800 mg TID) 3.02 (2.53, 3.59) 3.33 (2.54, 4.36) 2.78 (2.40, 3.23) Ritonavir (100 mg BID) 8 2.61 (1.92, 3.56) 1.28 (0.79, 2.09) 4.55 (3.37, 6.13) Fosamprenavir/r (700/100 mg BID) 2.49 (2.19, 2.82) 1.52 (1.27, 1.82) 4.74 (4.03, 5.57) Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; telaprevir; TVR; protease inhibitor; PI; saquinavir; darunavir; lopinavir; ritonavir; fosamprenavir AUCtau, area under the plasma concentration-time curve over the dosage interval; Cmin, minimum plasma concentration; DDI, drug-drug interaction; Cmax, maximum plasma concentration; QD, once daily Vourvahis M, et al. Int Workshop on Clin Pharm HIV Therapy, Amsterdam, Netherlands, 2013 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

26 HCV PI:ARV Interaction Scorecard
Boceprevir Telaprevir ATV/r BOC ↔; ATV ↓ TVR ↓; ATV ↑ DRV/r BOC ↓; DRV ↓ TVR ↓; DRV ↓ fAPV/r No data TVR ↓; APV ↓ LPV/r BOC ↓; LPV ↓ TVR ↓; LPV ↔ NFV EFV BOC ↓; EFV ↔ TVR ↓*; EFV ↔ RPV BOC ↔; RPV ↑ TVR ↔; RPV ↑ ETV BOC ↔; ETV ↓ TVR ↓; ETV ↔ RAL BOC ↔; RAL ↔ TVR ↔; RAL ↑ ELV/cobi MVC BOC ↔; MVC ↑** TVR ↔; MVC ↑** Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; protease inhibitor; PI; atazanavir; ATV; darunavir; DRV; fosamprenavir; fAPV; lopinavir; LPV; nelfinavir; NFV; efavirenz; EFV; rilpivirine; RPV; etravirine; ETV; raltegravir; RAL; MVC; maraviroc; elvitegravir; cobicistat *TVR dose 1125mg Q8H, **Use MVC 150mg BID From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

27 Resources for Drug Interactions
Not specific to ARV University of Liverpool Toronto General Hospital University of Buffalo ACTG Pharmacology Support Laboratory Specific to ARV DHHS Guidelines Drug Interaction Tables Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; DHHS From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

28 Pharmacology and Interaction Potential of Phase 3 Agents
CYP3A substrate? Interaction Potential ARV DDI data Faldaprevir (PI) Moderate ᴓ CYP3A, weak ᴓ CYP2C9,1 ᴓ UGT1A12 DRV/r ↑FDV 130% EFV ↓ FDV 35% TDF ↓ FDV 22%3 Simeprevir (PI) Mild ᴓ CYP1A2 and intestinal 3A4,4 ᴓ OATP1B1 and MRP25 EFV ↓ SPV 71%, DRV/r ↑ SPV 360%, ↔TDF, RPV, and RAL6 Daclatasvir (NS5A) Substrate and ᴓ of P-gp ATV/r ↑ DCV EFV ↓ DCV TDF ↔ DCV7 Sofosbuvir (NI) X Transporters? Intracellular phosphorylation? DRV/r, RAL, RPV, TDF/FTC/EFV + SOF and uridine plasma metabolite largely unchanged8 Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; CYP3A; substrate; PI; protease inhibitor; NS5A; faldaprevir; simeprevir; daclatasvir; sofosbuvir 1Sabo JP, 52nd ICAAC 2012, 2Sane R, 46th EASL 2011, 3Sabo JP, CROI 2013, 4Sekar V, 45th EASL 2010 , 5Huisman MT, 61st AASLD 2010, 6Ouwerkerk-Mahadevan S, IDSA 2012, 7Bifano M, 19th CROI 2012, 8Kirby B, AASLD 2012 From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.

29 Conclusion BOC and TVR have complex pharmacology
Interactions are not easily predicted Identification and management of interactions is critical with these agents Next “batch” of Hepatitis C agents less likely to act as perpetrators in interactions but still victims Keywords: Jennifer J. Kiser, PharmD; HCV; hepatitis C virus; HCV; HIV; coinfection;; Chicago 2013; drug interactions; antiretroviral therapy; boceprevir; BOC; telaprevir; TVR From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.


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