Potential Issues in Treating HIV/HCV co-infection with new HCV antivirals

Transcription

1 State of the Art in Hepatitis C Virus Infection in HIV/HCV-Coinfected Patients FORMATTED: 11/17/15 David L. Wyles, MD Associate Professor of Medicine University of California San Diego San Diego, California New Orleans, Louisiana: December 15-17, 2015 Learning Objectives After attending this presentation, participants will be able to: Describe the impact of HIV co-infection on the natural history of HCV Describe the impact of drug-drug interactions on selection of HCV therapy in those with HIV on ART Acquire the knowledge base to initiate HCV therapy in HCV/HIV patients using HCV DAAs Slide 3 of 36 Slide 4 of 36 Potential Issues in Treating HIV/HCV co-infection with new HCV antivirals Efficacy Access/ Providers HCV Therapy in HCV/HIV D-D-I Liver Disease Progression New Orleans, Louisiana: December 15-17,

2 Liver disease remains a prominent cause of mortality in HIV. Cause of death 13% AIDS Liver CVD Cancer Other Slide 6 of 36 Smith CJ. Lancet Age and HIV co-infection adversely impact HCV progression. Slide 7 of 36 HIV/HCV HCV Kirk G. Ann Intern Med, HIV treatment does not completely abrogate the negative effect Slide 8 of 36 ART decreases hepatic decompensation events: 0.72 ( ). Lo Re V. Ann Intern Med Anderson JP. CID New Orleans, Louisiana: December 15-17,

3 Slide 9 of 36 Treating HCV is a good thing whether you are co-infected or not. SVR vs. non-svr Hill A. AASLD Unique Aspects in the Evaluation of the Co-Infected Patient A detailed ART history is critical Regimens, virologic failures (How likely is an M184V?) Resistance genotypes when available Role for Archive resistance testing? HIV VL as a built in measure of adherence of course, you can still be fooled Staging- the options are the same Required for medication approval FIB-4 evaluated in co-infection (Berenguer J. CID 2015) >3.25 suggestive of advanced fibrosis ATV can impact directed biomarker tests Know when to refer and don t forget HCC screening! Slide 10 of 36 Slide 11 of 36 EFFICACY OF DAA THERAPIES IN CO-INFECTION New Orleans, Louisiana: December 15-17,

4 Creatinine Clearance (ml/min), mean SD SVR12 (%) Slide 13 of 36 SOF/LDV in HIV Co-Infection: ION-4 N=335 HCV GT 1 or 4 Naïve or experienced Cirrhosis up to 20% TDF/FTC plus EFV RAL RPV Wk 0 Wk 12 Wk 24 LDV/SOF Subjects 82% male 34% African/Amer 98% GT1 (75% 1a) 55% experienced 20% cirrhosis SVR12 Naggie S. NEJM High SVR with 12 weeks of SOF/LDV Overall Naïve Exper No Cirr Cirr Failures: 10 relapses 2 on-treatment 1 lost 1 death Safety and tolerability: 2% Serious AEs No discontinuations due to AEs 1 death 10 relapses: All African-American; 8/10 on EFV. Naggie S. NEJM Slide 14 of Creatinine levels on study EFV+FTC+TDF (n=160) RAL+FTC+TDF (n=146) RPV+FTC+TDF (n=29) BL FU-4 Week 4 patients (1%) had change in creatinine 0.4 mg/dl 2 completed treatment with no ART change 1 had dose reduction of TDF, 1 discontinued TDF Naggie S. NEJM Slide 15 of 36 New Orleans, Louisiana: December 15-17,

5 SVR12( %) SOF/DCV in HIV Co-Infection: ALLY-2 Naive Randomize 2:1 Experienced N DCV 30/60/90 mg + SOF 400 mg QD DCV 30/60/90 mg + SOF 400 mg QD DCV 30/60/90 mg + SOF 400 mg QD Week 0 8 GT 1-6 (1-4 enrolled) Naïve/experienced CD4 >100 CrCl >50 Most ARV regimens allowed 12 SVR12 24 Subjects 87% male 34% African/Amer 69% GT 1a 6% GT 3 14% cirrhosis 29% in experienced arm Wyles D. NEJM Slide 16 of High SVR with 12 weeks of SOF/DCV Week Naive GT 1 (N = 168) Week Experienced 8-Week Naive Failures (12 week arms): 1 withdrawal at week 1 1 detectable HCV RNA at EOT 2 relapses Safety and tolerability: 2% Serious AEs No discontinuations due to AEs 1 death 2 HIV VL >400 copies on study 100% SVR12 in 1b and non-gt1 with 12 weeks. Wyles D. NEJM Slide 17 of 36 N=31 N=32 TURQUOISE I: PrOD + RBV in HIV/HCV ABT450/r/ R Weeks ABT450/r/ R Stable ART ATV or RAL (part A) HIV RNA <40 copies/ml CD4 >200 HCV GT1, naïve or experienced Cirrhosis allowed (CPT A) SVR12 12 Week 24 Week Male 94% 91% Naïve 65% 69% Null 16% 16% 1a 87% 91% F4 19% 19% CD Sulkowski M. JAMA Slide 18 of 36 SVR12 New Orleans, Louisiana: December 15-17,

6 PHOTON-2 PHOTON-1 SVR12 (%) TURQUOISE I: PrOD + RBV in HIV/HCV SVR SVR12 12 wk 24 wk 2 Virologic failures 1a cirrhotic null responders Relapse in 12-wk arm BT at week 16 2 Re-infections Well tolerated No discontinuation due to AEs 5 HIV VL 40 copies/ml None 200 copies/ml All re-suppressed Sulkowski M. JAMA Slide 19 of 36 SOF/SMV in Co-Infection. Cohorts based on limited numbers Comparable response rates 77-95% SVR12 93% (14/15) in a cohort previously treated with HCV PIs Excellent tolerability Major issue is drug interaction with SMV Slide 20 of 36 Gilmore J. #645 CROI Christensen S. #646 CROI Grant J. #649 CROI Marks K. #644 CROI Slide 21 of 36 PHOTON: SOF/RBV FOR HIV/HCV GT1 TN GT 2,3 TN GT 2,3 TE GT 2 TN GT 2,3 TE GT 1,3,4 TN SOF/RBV (n=114) SOF/RBV (n=68) SOF/RBV (n=41) SOF/RBV (n=19) SOF/RBV (n=55) SOF/RBV (n=200) 12 Weeks 36 Cirrhosis permitted Most ART allowed CD 4 >500 not on ART CD 4 >200 on ART Sulkowski M. JAMA Molina J-M. IAS New Orleans, Louisiana: December 15-17,

7 SVR12 (%) PHOTON: SOF/RBV FOR HIV/HCV PHO-1 40 PHO GT1/4 GT2 TN GT3 TN GT2 TE GT3 TE Slide 22 of 36 PHOTON 2: 65% (11/17) GT1 cirrhosis; 78% (18/23) GT 3 TE, cirrhosis Sulkowski M. JAMA Molina J-M. IAS Treatment naïve GT1 Recommended Slide 23 of 36 GT1a GT1b Cirrhosis Noncirrhotic Noncirrhotic SOF/LDV OBV/PTV/r+DSV SOF/SMV SOF/DCV + RBV +RBV 24 wks 24 wks* ( RBV) 24 wks ( V Cirrhosis * Unclear role of Q80K testing. 24 wks ( V 24 wks ( V hcvguidelines.org Treatment experienced GT1 Failed PEG/RBV PEG/RBV + PI PEG/RBV + SOF (or SOF/RBV) Cirrhosis status SOF/LDV PrOD (1a/1b) SOF+SMV SOF+DCV NC R/ C 12 + R or R/12 # 24 ( RBV) * 24 ( RBV) NC 12 NR NR 12 C 12 + R or 24 NR NR 24 ( RBV) NC 12 (+R) 12+R/ (+R) C 12 + R or R/12 # 24 ( RBV) * 24 ( RBV) #TURQ-III: 100% SVR12 in GT1b without RBV (n=60) Feld JJ. 15 th ISHVLD *Role of Q80K unclear; associated with lower response rate with 12 weeks of therapy. hcvguidelines.org Slide 24 of 36 New Orleans, Louisiana: December 15-17,

8 Slide 25 of 36 GT2/3 Guideline Recommendations Option-1 Option-2 Option-3 GT2 GT3 Naïve Exp Naive Exp SOF/RBV wks SOF/RBV wks SOF/PEG/RBV SOF/PEG/RBV () SOF/DCV SOF/PEG/RBV SOF/DCV weeks SOF/DCV ( V weeks -- SOF/DCV ( V 24 weeks SOF/RBV 24 wks (alternative) GT3: Patients with cirrhosis are recommended to receive 24 weeks of SOF/DCV due to lower response with just 12 weeks pending additional data. hcvguidelines.org Slide 26 of 36 DRUG-DRUG INTERACTION WITH ANTIRETROVIRALS Slide 28 of 36 Potential for drug-drug interactions SOF SMV LDV DCV PrOD/r CYP No 3A4 No 3A4 P-gp Substrate Substrate Other transporters Substrate Inhibitor BCRP (S) OATP1B1/3 (S) BCRP (S/I) Substrate Inhibitor BCRP (S) OATP1B1 (S/I) 3A4 2C8 Substrate BCRP (S) OATP1B1/3 (S/I) New Orleans, Louisiana: December 15-17,

9 Slide 29 of 36 How frequent are significant interactions? Retrospective analysis of HIV/HCV patients (n=125) 81% TDF, 35% RAL, 16% EFV, 40% PI/r 100% 80% None 60% Moderate 40% Severe 20% 0% SOF/SMV SOF/LDV SOF/DCV PrOD Langness J. 16th HIV and Hep Clin Pharm Workshop Slide 30 of 36 SOF/LDV DDIs with antiretrovirals LDV exposure increased % No change in DRV exposure seen TFV German P. CROI LDV/SOF and TAF LDV/SOF + E/C/F/TAF n=30 E/C/F/TAF n=30 GMR (90% CI) Slide 31 of 36 TFV Mean(%CV) AUC ng. h/ml 397 (15.9) 315 (18.7) 1.27 (1.23, 1.31) C maxng/ml 20.7 (16.1) 17.8 (20.4) 1.17 (1.12, 1.22) C tau ng/ml 15.5 (16.6) 11.7 (20.0) 1.33 (1.28, 1.38) TAF Mean (%CV) AUC last, ng. h/ml 195 (29.2) 239 (45.9) 0.86 (0.78, 0.95) C taung/ml 148 (48.2) 166 (50.8) 0.90 (0.73, 1.11) Conclusions Safe to administer E/C/F/TAF with LDV/SOF increases in COBI and EVG levels not considered clinically significant Monitor for TFV toxicity when using DTG-FTC/TDF with LDV/SOF Garrison et al. 16 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy New Orleans, Louisiana: December 15-17,

10 TDF SOF SOF/LDV SMV DCV PrO-D GZP/EBR RAL/DTG HIV PI/EFV ( TDF) EFV ( TDF) SMV RLP RAL/DTG ATV/r DRV/r EVG/c/FTC/TDF Drug interaction scorecard ABC TDF ABC TDF SMV DCV 90mg DCV 30mg RLP GZP GZP SMV DRV GZP SMV* DCV 30mg* GZP Slide 32 of 36 *not studied, based on predicted interactions. EVG/c/FTC/TAF No data A cautionary tale on switching. Slide 33 of 36 Combined <50copies/ml week 24: RAL 84.4%, LPV 90.6% (-6.2%; to -1.3) Reported history of virologic failure RAL LPV-rit Eron JJ. Lancet Slide 34 of 36 Regimen Switching in the Setting of Viral Suppression Prior to Starting HCV Treatment Concepts: 1. Cardinal principle of regimen switching Maintain viral suppression 2. Virologic failure with emergence of new resistance mutations Potential for more complex, toxic, or expensive regimens DHHS. Revision May 1, To do: 1. Review ART history and resistance Infer resistance if no data 2. Characterize the switch Don t be afraid to ask for help 3. Monitor closely after switch Compliance/tolerability Viral suppression (4 wks) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014; New Orleans, Louisiana: December 15-17,

11 5-year re-infection rate (%) Slide 35 of 36 How big of an issue is re-infection? 2/63 subjects 4.1 years 25 in Turquoise I by SVR12 20 Both SVR4 15 No resistance mutations on relapse patients 1203 patients 5.0 years 1285 patients 3.3 years 21.8% Low risk IVDU/prisoner HIV co-infected Hill A. CROI Sulkowski M. JAMA Summary HCV treatment should be a priority in those with HIV Efficacy is not an issue when considering treatment for HCV in those with HIV I would not use 8 weeks in those with HIV Keep a Pharmacist close by drug interactions are the major consideration Carefully review HIV treatment history before switching to accommodate HCV therapy Re-infection can and will happen counsel your patients on re-infection risks. Slide 36 of 36 New Orleans, Louisiana: December 15-17,