Case 2: Coinfection. Patient Case

Transcription

1 Case 2: Coinfection Jennifer J. Kiser, PharmD Assistant Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Aurora, Colorado FORMATTED: Learning Objectives After attending this presentation, learners will be able to: Identify HCV treatment options for persons with HIV coinfection Describe drug interaction potential with current and future DAAs with ARV agents Determine the management of interactions Slide 2 of XX Patient Case Slide 3 of yo Hispanic male HIV diagnosed 20 years ago HCV diagnosed 2 years ago Insomnia ½ ppd smoker x 20 years Occasional EtOH History of substance abuse in remission x 4 years History of depression while using drugs 1

2 HIV History Slide 4 of 54 Most recent VL and CD4 (1/14) HIV RNA 59 copies/ml (30 copies/ml in 10/13) CD4 768 cells/µl (24%) CD4 nadir = 6 cells/µl (has had PCPx2, thrush) ARV History Reports taking ARV since diagnosis except for ~1 year during period of active substance abuse Currently taking TDF/FTC 300mg/200mg QD and ATV/r 300/100 QD Had a viral load of 2200 copies/ml in July, genotype performed with no evidence of resistance HCV History Slide 5 of 54 Treatment naive Genotype 1b HCV RNA (7/13) 4,650,000 IU/mL (6.67 log 10 IU/mL) Liver biopsy (12/13): Chronic hepatitis with mild activity and multifocal delicate bridging fibrosis, consistent with history of hepatitis C (Grade 2, Stage 3) Minimal macrovesicular steatosis Abdominal CT ( AFP 28.4 ng/ml, ref range 0 9 ng/ml), 1/14: No arterially enhancing hepatic lesion or other findings of concern for hepatocellular carcinoma Although the liver is unremarkable in size and morphology, recannulization of the umbilical vein, mild splenomegaly and slight prominence of the retroperitoneal nodal tissues are suggestive of portal hypertension Clinical Labs Slide 6 of 54 ALT 52 U/L (0 47) AST 41 U/L (0 47) Alk Phos 84 U/L (39 117) Tbili 3.3 mg/dl (0 1.3)* Albumin 4.0 g/dl (3.4 5) INR 1.0 ( ) SCr 1.08 mg/dl ( ) Wt 87 kg, Ht 5 7 CrCl ~87 ml/min WBC /L (4 11.1) ANC /L ( ) RBC /L ( ) Hgb 16.8 g/dl ( ) Hct 48.2% (39.2 to 50.2) Platelet /L ( )* 2

3 Current Medications Slide 7 of 54 TDF/FTC 300/200mg po QD ATV/r 300/100mg po QD Trazodone 50mg po QHS prn Zolpidem 5mg po QHS Audience Response #1: Given this patient s current and past medical history, I would treat with: Slide 8 of Peginterferon plus ribavirin plus sofosbuvir x 12 weeks 2. Sofosbuvir plus ribavirin x 24 weeks 3. Peginterferon plus ribavirin plus simeprevir x 12 weeks, followed by peginterferon plus ribavirin 4. Sofosbuvir plus simeprevir with or without ribavirin x 12 weeks 5. I would not treat this patient s HCV now Slide 9 of 54 If we treat now what s the data? 3

4 Slide 10 of 54 SOF+RBV in HIV/HCV (PHOTON) Study Design Wk 0 Wk 12 Wk 24 Wk 36 Wk 48 GT 1 TN SOF + RBV, n=114 GT 2/3 TN GT 2/3 TE SOF + RBV, n=68 SOF + RBV, n=41 SVR 12 SVR 24 Broad inclusion criteria Cirrhosis permitted with no platelet cutoff Hemoglobin: 12 mg/dl (males); 11 mg/dl (females) Wide range of ART regimens allowed Undetectable HIV RNA for >8 weeks on stable ART regimen Baseline CD4 count ART treated: CD4 T-cell count >200 cells/mm 3 and HIV RNA < 50 c/ml ART untreated: CD4 T-cell count >500 cells/mm 3 Slide 11 of 54 PHOTON Baseline Demographics Treatment Naive GT 1 n=114 GT 2/3 n=68 Treatment Experienced GT 2/3 n=41 Mean age, y (range) 48 (25-70) 49 (24-71) 54 (34-68) Male, n (%) 93 (82%) 55 (81%) 37 (90%) Black, n (%) 37 (32%) 8 (12%) 7 (17%) Hispanic, n (%) 25 (22%) 19 (28%) 10 (24%) Mean BMI, kg/m 2 (range) 27 (18-46) 27 (20-43) 27 (19-40) Genotype 1a, n (%) 90 (79) NA NA Genotype 2, n (%) NA 26 (38) 24 (59) Genotype 3, n (%) NA 42 (62) 17 (41) IL28B CC, n (%) 30 (27) 25 (37) 20 (49) Mean HCV RNA, log 10 IU/mL (range) 6.6 ( ) 6.3 ( ) 6.5 ( ) Cirrhosis, n (%) 5 (4) 7 (10) 10 (24) On ART, n (%) 112 (98) 61 (90) 39 (95) CD4 T cell count (cells/μl), mean (SD) 636 (251) 585 (246) 658 (333) SOF+RBV x 24 wks in HIV/HCV Virologic Response: Genotype 1 Slide 12 of 54 Patients with HCV RNA <LLOQ (%) 110/ /103 87/114 22/23 virologic failures were by relapse, 1 with breakthrough was presumed nonadherent 86/114 Week 4 EOT SVR12 SVR24 4

5 Slide 13 of 54 SMV x 12 wks + PegIFN/RBV x wks: HIV/HCV Geno 1 (Study C212) 88% naives eligible for RGT (87% SVR12) G1b SVR 89% vs G1a(d) 71% Il28CC favorable predictor Dieterich, CROI, 2014 SOF + PegIFN/RBV x 12 wks (NEUTRINO) HCV-monoinfected Ph III, Rx-naive, GT1,4,5,6 Slide 14 of 54 n=327 n=292 n=28 n=7 All GT1 GT4 GT5,6 SVR 80% in cirrhotics SVR 71% if multiple bad prognostic factors (G1, F3/F4, IL28 non CC, HCV RNA>800k) Lawitz et al. NEJM 2013 Slide 15 of 54 SOF + PegIFN/RBV x 12 wks in Coinfected (n=23) 2/23 without SVR 1 relapse 1 early d/c at wk 6 Included only Rx naïve, no cirrhosis, cd4>200 Included geno 1a,>1b>3> 2 Rodriguez-Torres, et al. ID Week

6 Slide 16 of 54 HCV versus HIV/HCV GT1 in Clinical Trials (Not head to head comparisons) SVR Rate 40/64 28/38 13/15 16/28 42/53 206/260 15/23 9/17 419/521 7/10 260/292 17/1 9 17/2 87/ Poordad F et al, NEJM 2011; 364: vs. Sulkowski et al. Lancet Infect Dis 2013; 13(7): Jacobson I et al, NEJM 2011; 364: vs. Sulkowski et al. Ann Intern Med 2013; 159(2): Antiviral Drugs Advisory Committee Meeting, FDA review, 10/24/13 C208, C216, C206, C212, HPC3007, Dieterich, 14 th European AIDS Conference, 2013 Lawitz et al. NEJM 2013 versus Torres Rodriguez et al., IDSA 2013 Osinusi et al., JAMA 2013;310(8): versus Sulkowski et al. AASLD 2013 (PHOTON) Slide 17 of 54 COSMOS: Nucleotide + Protease inhibitor Cohort 1 GT1 null F0 F2 78% 1a 50% Q80K 6% CC N=24 N=15 N=27 N=14 SOF/SMV/r SOF/SMV SOF/SMV/r SOF/SMV Weeks N=30 N=16 N=27 N=14 Cohort 2 GT1 naïve/null (54% null) F3 F4 (47% F4) 78% 1a 40% Q80K 21% CC SOF 400mg QD + SMV 150mg QD +/ RBV (weight based) Sulkowski M. EASL Lawitz E. EASL Response (%) Slide 18 of 54 COSMOS: Nucleotide + Protease inhibitor Cohort 1 Cohort 2 100% % % 60 40% 40 20% 20 0% 24 R 24 No R 12 R 12 No R SVR12 Lost Relapse 3 relapses: all 1a with Q80K 0 24 R 24 No R 12 R 12 No R SVR12 Lost Relapse 3 relapses: all 1a with F3 or F4 Sulkowski M. EASL Lawitz E. EASL

7 AASLD/IDSA/IAS USA Guidance Recommendations for GT1 Treatment naïve and prior relapser PEG/RBV + SOF x 12 weeks in those who can tolerate interferon SOF/RBV x 24 weeks or SOF/SIM x 12 weeks for interferon ineligible/unwilling Treatment experienced: SOF/SIM x 12 weeks Slide 19 of 54 Slide 20 of 54 IFN ineligible is defined as one or more: Intolerance to IFN Autoimmune hepatitis and other autoimmune disorders Hypersensitivity to PEG or any of its components Decompensated hepatic disease History of depression, or clinical features consistent with depression Baseline Cytopenias neutrophil count below 1500/μL platelet count below 90,000/μL hemoglobin below 10 g/dl A history of preexisting cardiac disease Simeprevir Clinical Pharmacology Slide 21 of 54 HCV Protease Inhibitor Food exposures ~60% 99.9% protein bound primarily to albumin Primarily metabolized by CYP3A Eliminated via biliary excretion, less than 1% renal elimination 7

8 Slide 22 of 29 Simeprevir in Hepatic Impairment Compared with healthy matched controls, simeprevir AUC in moderate and severe hepatic impairment is 2.4 and 5-fold higher, respectively BUT only 1.3 and 2.8-fold higher than concentrations observed in Child-Pugh A cirrhotics in OPERA-1 study. Ouwerkerk-Mahadaven S. et al. EASL 2013 Simeprevir Interaction Potential Slide 23 of 54 Victim CYP3A substrate P gp and OATP1B1/3 substrate Perpetrator Mild inhibitor of CYP1A2 and intestinal 3A4 Inhibitor of OATP1B1/3, P gp, and MRP2 Slide 24 of 54 Transporter Mediated Interactions Like enzymes, transporter expression can be induced and transporter function can be inhibited. OATP1B1 Hepatocyte P gp, MRP2, BCRP, BSEP 8

9 Sofosbuvir Clinical Pharmacology Slide 25 of 54 NS5B Polymerase Inhibitor Uridine nucleotide analog 61 65% protein bound Renally eliminated In plasma, SOF accounts for only ~4% of the drug related material, majority (>90%) is GS Plasma Sofosbuvir Sofosbuvir Hepatocyte GS Slide 26 of 54 hce1,cata GS GS ACTIVE FORM GS HINT1 GS MP TP DP MP GS GS Made from: Mathias A, et al. 63 rd AASLD, Nov 9 13, 2012, abstract 1869, Sofia MJ, et al. J. Med. Chem. 2010, 53, , Murakami E, et al. J Biol Chem 2010;285: Renal Impairment Slide 27 of 29 Cornpropst M, et al. EASL

10 Sofosbuvir Interaction Potential Slide 28 of 54 Victim P gp and BCRP substrate Perpetrator Very low potential for altering PK of other agents In vitro not an inhibitor or inducer of CYP450, UGT1A1, P gp, BCRP, OATP1B1, OCT1, BSEP Slide 29 of 54 No significant PK interactions between SOF and common ART Kirby AASLD 2012 SOF and 007 Pharmacokinetics with ARV Slide 30 of 54 Kirby AASLD

11 ARV Pharmacokinetics Slide 31 of 54 Kirby AASLD 2012 Audience Response #2: If we include simeprevir in our HCV regimen what ARV changes are needed? Slide 32 of None, there are no clinically significant interactions with simeprevir and his ARV regimen 2. The patient could be switched to TDF/FTC plus efavirenz 3. The patient could be switched to TDF/FTC plus raltegravir 4. I would do something else Slide 33 of 54 Darunavir/Ritonavir Increases Simeprevir Exposures 2.6 fold even after reducing the simeprevir dose by 2/3 Ouwerkerk Mahadaven S, et al. IDWeek

12 Efavirenz Reduces Simeprevir Exposures by 71% Slide 34 of 54 Ouwerkerk Mahadaven S, et al. IDWeek 2012 Slide 35 of 54 Raltegravir Does Not Affect Simeprevir (and Vice Versa) Ouwerkerk Mahadaven S, et al. IDWeek 2012 ARV Interaction Score Card Slide 36 of 54 Simeprevir Sofosbuvir ATV/r No data No data DRV/r SIM ; DRV SOF ; DRV LPV/r No data No data TPV/r No data No data EFV SIM ; EFV SOF ; EFV RPV SIM ; RPV SOF ; RPV ETV No data No data RAL SIM ; RAL RAL ELV/cobi No data No data DLG No data No data MVC No data No data 12

13 Tipranavir is a P-gp Inducer SQV/r 1000/200 APV/r 600/200 LPV/r 400/100 ATV/r 300/100 ETV 800/ AUC Cmin Leith J, et al. 5 th Clin Pharm Workshop, Rome, Italy. April 1-3, Abs 34 Schoeller M, et al. 13th CROI 2006; abstract 583, Sabo J, et al. 7th PK Workshop, April 2006 abstract 41. Psychotropics Slide 38 of 54 Trazodone Metabolized by CYP3A Monitor for nausea, dizziness, hypotension, and syncope Zolpidem Multiple routes of metabolism hydroxylation and oxidation by CYP3A4, CYP2C9, CYP1A2, CYP2D6 and CYP2C19 No pre emptive dose reductions for psychotropics, monitor for psychotropic toxicities Audience Response #3: Which of the following agents could conceivably interact with sofosbuvir? 1. Rifampin 2. Carbamazepine 3. St John s Wort 4. All of the above Slide 39 of 54 13

14 Slide 40 of 54 Other Therapeutic Classes to Consider Low Potential for Interactions with Either Simeprevir or Sofosbuvir Potential or Documented Interactions with Simeprevir Potential Interactions with Sofosbuvir Methadone Rifamycins Rifamycins Opioids Antiepileptics Antiepileptics Oral contraceptives Herbals Herbals Immunosuppressants* HMG Co A reductase inhibitors Warfarin Calcium Channel Blockers Inhaled/intranasal corticosteroids Gastric Acid Modifiers Phosphodiesterase Inhibitors for ED * Still perform therapeutic drug monitoring for the immunosuppressants Slide 41 of 54 Resources for Drug Interactions University of Liverpool druginteractions.org Toronto General Hospital University of Buffalo ACTG Pharmacology Support Laboratory Specific to antiretroviral interactions DHHS Guidelines Drug Interaction Tables Slide 42 of 54 What if we wait a few months? 14

15 Slide 43 of 54 Risk of Liver Decompensation in HIV/HCV w/ Advanced Fibrosis The incidence of decompensation was 1.4 (95% CI, 0.7 2) per 100 personyears for subjects with fibrosis stage 3 vs 3.1 (95% CI, ) per 100 personyears for patients with cirrhosis. The incidence of decompensation was 0.9 (95% CI,.4 2) per 100 personyears for subjects with LSM 9.5 kpa and <14.6 kpa and 4 (95% CI, 3 5.2) per 100 person years for patients with LSM 14.6 kpa. Macias et al, CID, 2013 Slide 44 of 54 Preliminary Results: SOF/LDV in Persons with HCV/HIV Coinfection ERADICATE. Osinusi A, EASL 2014 Slide 45 of 54 Preliminary Results: SOF/LDV in Persons with HCV/HIV Coinfection ERADICATE. Osinusi A, EASL

16 Slide 46 of 54 Preliminary Results: SOF/LDV in Persons with HCV/HIV Coinfection ERADICATE. Osinusi A, EASL 2014 Slide 47 of 54 Preliminary Results: SOF/LDV in Persons with HCV/HIV Coinfection Preliminary results compare favorably with ION studies in HCV monoinfection ERADICATE. Osinusi A, EASL 2014 AbbVie Phase 3 Results in Monoinfected Patients Slide 48 of 54 Naives 1 Experienced 2 Overall 96% SVR with 12 weeks of ABT450/r + ombitasvir + dasabuvir + RBV SAPPHIRES I and II. 1 Feld JJ, EASL 2014, 2 Zeuzem S, EASL

17 Some Ongoing Coinfection Trials Slide 49 of 54 NCT NCT Drugs ABT450/r + ombitasvir (ABT267/NS5A) + dasabuvir (ABT333/NNI) (TURQUOISE 1) Daclatasvir (DCV)+ Sofosbuvir (SOF) (ALLY 2) Population N=300 genotype 1 12 vs. 24 weeks Treatment naïve and experienced Decompensation exclusion N=200 genotype 1, 2, 3, 4, 5, or 6 8 vs. 12 weeks for treatment naïve 12 weeks for treatment experienced Decompensation exclusion Pharmacology of Investigational DAA CYP3A Interaction Potential substrate? Faldaprevir (PI) Substrate and ᴓ of CYP3A4 and OATP1B1, substrate of P gp and MRP2, ᴓ UGT1A1 ARV DDI data DRV/r FDV* EFV FDV* Daclatasvir (NS5A) Substrate and ᴓ of P gp ATV/r DCV* EFV DCV* Ledipasvir (NS5A) No data P gp substrate, weak ᴓ P gp, BCRP, OATP1B1 Slide 50 of 54 ARVs allowed in ERADICATE study included EFV, RPV, RAL, need data with HIV PIs ABT450/r (PI) No data No data Ombitasvir No data No data No data (ABT267) (NS5A) Dasabuvir (ABT333) (NNI) No data No data No data ᴓ = inhibitor * managed with DAA dose adjustment Patient s Clinical Course 1 st Month Patient treated with PEG/RBV/SOF Within ~9 days of starting treatment platelets dropped to 88 (nadir 83), ANC dropped to 1.3 (nadir 0.8) Hgb dropped to 12.6 g/dl within 3 weeks (baseline 16.8 g/dl), nadir 11 g/dl symptomatic, RBV reduced to 600QD EPO and GCSF added at 1 month HCV RNA at 1 month IU/mL, but patient changed insurance and missed 5 days of sofosbuvir Slide 51 of 54 17

18 Patient s Clinical Course 2 nd Month Slide 52 of 54 Hgb improving, increased RBV to 800mg QD then 1000mg QD Platelets 93, ANC 0.7 By 6 weeks, HCV RNA < 18 IU/mL (TND) RBV Dose Reduction Does Not Compromise SVR with PEG/RBV/SOF Slide 53 of 54 *Hgb<10g/dL Pooled data from NEUTRINO, FISSION, FUSION, VALENCE. Sulkowski MS, HepDART 2013 Conclusions Slide 54 of 54 Efficacy rates appear similar in HIV and HCV coinfected patients Only difference in treating HIV and HCV patients is drug interaction potential with ARV Currently DDI are not a major concern in HCV treatment but don t get too comfortable in near future, DDI identification and management will likely be important 18