Management of HIV/HCV Co-infected Patients

Management of HIV/HCV Co-infected Patients David Wyles, MD Associate Professor of Medicine Division of Infectious Diseases University of California, San Diego San Diego, California

Disclosures Grants/Research Support: AbbVie, Bristol-Myers Squibb, Gilead, Merck, Tacere Therapeutics Consultant/Speaker Bureau: AbbVie, Bristol- Myers Squibb

Potential Issues in Treating HIV/HCV Co-Infection with New HCV Antivirals Efficacy HCV Therapy in HCV/HIV Drug Interactions Access/P roviders Disease Progression

Liver Disease Remains a Major Cause of Mortality in HIV 13% Smith CJ. Lancet 2014.

HIV Treatment Does Not Completely Abrogate the Negative Effect of HIV on HCV ART decreases hepatic decompensation events: 0.72 (0.54-0.94). Lo Re V. Ann Intern Med 2014. Anderson JP. CID 2014.

When and in Whom to Initiate Therapy High Priority for Treatment Owing to High Risk for Complications hcvguidelines.org Fibrosis (Metavir F2) Rating: Class I, level B HIV-1 coinfection Rating: Class 1, level B

Evaluation of the Co-Infected: Unique Aspects A detailed ART history is critical: Regimens, virologic failures (How likely is an M184V?) Resistance genotypes when available Unique role for Archive resistance testing? Use HIV VL as a built in measure of adherence of course, you can still be fooled Staging- the options are the same Likely required for medication approval FIB-4 evaluated in co-infection (Berenguer J. CID 2015) >3.25 suggestive of advanced fibrosis ATV can impact FibroSure Know when to refer and don t forget HCC screening!

Efficacy of DAA Therapies in Co-Infection

SOF/LDV in HIV Co-Infection: ION-4 Wk 0 Wk 12 Wk 24 N=335 LDV/SOF SVR12 HCV GT 1 or 4 Naïve or experienced Cirrhosis up to 20% TDF/FTC plus EFV RAL RPV Subjects 82% male 34% African/Amer 55% experienced 20% cirrhosis Naggie S. #LB-152 CROI 2015.

High SVR with 12 Weeks of SOF/LDV 335 Failures: 10 relapses 2 on-treatment VF 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. #LB-152 CROI 2015.

Creatinine Clearance (ml/min), mean ± SD Creatinine Levels on Study LDV/SOF + EFV+FTC+TDF (n=160) RAL+FTC+TDF (n=146) RPV+FTC+TDF (n=29) BL 1 2 4 6 8 10 12 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. #LB-152 CROI 2015.

SOF/DCV in HIV Co-Infection: ALLY-2 Naive Randomize 2:1 N 101 50 DCV 30/60/90 mg + SOF 400 mg QD DCV 30/60/90 mg + SOF 400 mg QD SVR12 Experienced 52 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 Wyles D. #LB-151 CROI 2015. 12 24 Subjects 87% male 34% African/Amer 69% GT 1a 6% GT 3 14% cirrhosis 29% in experienced arm

HIV Characteristics Parameter Naive 12 Week N = 101 Experienced 12 Week N = 52 Naive 8 Week N = 50 HIV RNA < 50 copies/ml, n/n (%) 94/100 (94) 47/49 (96) 45/48 (94) CD4 cells/mm 3, median (range) 520 (122 1147) 636 (262 1470) 575 (157 1430) Receiving HIV treatment, n (%) 100 (99) 51 (98) 48 (96) PI regimens* NNRTI regimens Other regimens Darunavir/r 19 (19) 11 (21) 21 (42) Atazanavir/r 19 (19) 12 (23) 5 (10) Lopinavir/r 9 (9) 0 3 (6) Efavirenz 18 (18) 8 (15) 8 (16) Nevirapine 5 (5) 3 (6) 1 (2) Rilpivirine 5 (5) 1 (2) 1 (2) Raltegravir 22 (22) 10 (19) 8 (16) Dolutegravir 3 (3) 4 (8) 1 (2) Nucleosides only 0 2 (4) 0 Wyles D. #LB-151 CROI 2015.

SVR12 (%) High SVR with 12 Weeks of SOF/DCV GT 1 (N = 168) Failures (12 week arms): 1 withdrawal at week 1 1 detectable HCV RNA at EOT 2 relapses 83 44 41 12-Week Naive 12-Week Experienced 8-Week Naive Safety and tolerability: 2% Serious AEs No discontinuations due to AEs 1 death 2 HIV VL >400 copies on study Wyles D. #LB-151 CROI 2015. 100% SVR12 in 1b and non-gt1 with 12 weeks.

SVR12 ( %) 8-Week Arm: Response by Baseline Characteristics 10 relapses, 2 missing data. 20/28 15/19 18/18 20/32 27/34 11/16 3/5 34/44 14/21 7/8 8/10 9/11 White Black Race < 2 M 2 M < 6 M 6 M HCV RNA, IU/mL Yes No Cirrhosis DRV Other PI NNRTI Other cart regimen Wyles D. #151LB CROI 2015.

TURQUOISE I: 3D + RBV in HIV/HCV N=31 N=32 PTV/r/OBV + DSV + R PTV/r/OBV + DSV + R SVR12 SVR12 Weeks Stable ART ATV or RAL (part A) HIV RNA <40 copies/ml CD4 >200 HCV GT1, naïve or experienced Cirrhosis allowed (CPT A) 12 24 12 Week 24 Week Male 94% 91% Naïve 65% 69% Null 16% 16% 1a 87% 91% F4 19% 19% CD4 633 625 Sulkowski M. JAMA 2015.

TURQUOISE I: 3D + RBV in HIV/HCV Sulkowski M. JAMA 2015. 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

Real-world SOF/SMV from CROI Cohorts based on limited numbers Comparable response rates 77-95% SVR12 93% (14/15) in a cohort previously treated with HCV PIs Excellent tolerability Gilmore J. #645 CROI 2015. Christensen S. #646 CROI 2015. Grant J. #649 CROI 2015. Marks K. #644 CROI 2015.

Cohort Real-world SOF/SMV from CROI Cohorts based on limited numbers Abstract (Author) 644 (Marks) 645 (Gilmore) 647 ( Del Bello) 649 (Grant) Comparable response 67% 93% 15 100% rates 77-95% SVR12 93% 37 (14/15) 61% in 78% a cohort (30/37) previously (26/33) treated (13/14) with HCV PIs 34 53% 56% Excellent tolerability SVR12 N TE (%) F3/F4 (%) GT1 1a 1b Comments 33 -- (F4 only) 53% (F4 only) (14/15) 81% 90% (26/29) 95% (18/19) -- -- 74% Gilmore J. #645 CROI 2015. Christensen S. #646 CROI 2015. Grant J. #649 CROI 2015. Marks K. #644 CROI 2015. 93% All prior HCV PI failures without detectable resistance ITT analysis; 4/7 failures were lost to f/u. All 4 attained SVR4 -- -- As treated 92% (11/12) 100% (7/7) As treated; 1 pt treated for 24 weeks.

The COSMOS Regimen in Co-Infection: What are the Issues? No clinical trial data in co-infection Limited real world data (3% in TARGET) Efficacy probably not a concern Simeprevir: significant D-D-I potential CYP3A4 substrate (hepatic) CYP3A4 inhibitor (intestinal) Sofosbuvir: low D-D-I potential Not a CYP3A4 substrate/inhibitor P-gp and BCRP substrate

Grazoprevir/Elbasvir in HIV Co-Infection Wk 0 Wk 12 Wk 24 N= 218 HCV GT 1; 4 and 6 Treatment naïve HIV: CD4 >200 cells/mm 3 ; UD HIV RNA >500 cells/mm 3 ; HIV RNA <50,000 TDF or ABC with FTC/3TC RAL (52%) DTG (27%) RPV (17%) Rockstroh J. #PO877 EASL 2015. GZR 100mg/EBR 50mg SVR12 Subjects 84% male 17% African American 66% GT 1a; 13% GT4 16% cirrhosis

Grazoprevir/Elbasvir in HIV Co-Infection 4 pts were lost to f/u Virologic failures: 6 relapses (4/6 GT1a) 1 re-infection 3% SAEs with no discontinuations 144 44 28 Treatment was well tolerated with no loss of HIV virologic control. 100% SVR12 (35/35) in those with cirrhosis. Rockstroh J. #PO877 EASL 2015.

PHOTON-2 PHOTON-1 PHOTON: SOF/RBV FOR HIV/HCV GT1 TN SOF/RBV (n=114) GT 2,3 TN GT 2,3 TE SOF/RBV (n=68) SOF/RBV (n=41) 12 Weeks 36 GT 2 TN GT 2,3 TE GT 1,3,4 TN SOF/RBV (n=19) SOF/RBV (n=55) SOF/RBV (n=200) Cirrhosis permitted CD 4 >500 not on ART CD 4 >200 on ART Sulkowski M. JAMA 2014. Molina J-M. IAS 2014.

PHOTON: SOF/RBV FOR HIV/HCV PHOTON 2: 65% (11/17) GT1 cirrhosis; 78% (18/23) GT 3 TE, cirrhosis Sulkowski M. JAMA 2014. Molina J-M. IAS 2014.

Significant Potential for Drug-Drug Interactions SOF SMV LDV DCV 3D/r CYP No 3A4 No 3A4 3A4 2C8- Dasa P-gp Substrate Substrate Substrate Inhibitor Substrate Inhibitor Substrate Other transporters BCRP (S) OATP1B1/3 (S) BCRP (S/I) BCRP OATP1B1 (S/I) BCRP (S) OATP1B1/3 (S/I) S=substrate, I=inhibitor

How Often is a Change in ART Needed with Current HCV DAA Regimens? Retrospective chart review (n=127) ART Switch Required N (%) ART Switch Not Required N (%) Simeprevir 97 (76%) 30 (24%) Ledipasvir 81 (64%) 46 (36%) Paritaprevir/r 91 (72%) 36 (28%) 18 required a switch but was felt not feasible Cope R. #651 CROI 2015. All on ritonavir boosted HIV PIs

How Often is a Change in ART Needed with Current HCV DAA Regimens? Retrospective chart review (n=127) ART Switch Required N (%) ART Switch Not Required N (%) Simeprevir 97 (76%) 30 (24%) Ledipasvir 81 (64%) 46 (36%) 36 (28%) Paritaprevir/r 91 (72%) 36 (28%) 18 required a switch but was felt not feasible Cope R. #651 CROI 2015. All on ritonavir boosted HIV PIs

SOF/LDV DDIs with Antiretrovirals LDV exposure increased 100-150% No change in DRV exposure seen TFV German P. CROI 2015.

3D D-D-I: RAL, RPV, EFV Healthy volunteer study 3D regimen with RAL, TDF/FTC, RPV 25mg 2D regimen (ABT-450/r, Dasabuvir) with EFV EFV arm discontinued prematurely RPV exposure similar to 75mg (QTc 10s) No significant impact on 3D regimen Katri A. ICAAC 2014.

3D DDIs: LPV, ATV, DRV Healthy volunteer study of 3D regimen with: ATV/r 300/100mg QAM or QPM rit omitted if given in AM with 3D regimen DRV/r 800/100mg QAM or QPM or 600/100mg BID rit omitted if given in AM with 3D regimen LPV/r 800/200mg QPM or 400/100mg BID Katri A. ICAAC 2014.

3D DDIs: LPV, ATV, DRV HIV PI Levels Paritaprevir Levels Healthy volunteer study of 3D regimen with: ATV/r 300/100mg QAM or QPM rit omitted if given in AM with 3D regimen DRV/r 800/100mg QAM or QPM or 600/100mg BID rit omitted if given in AM with 3D regimen LPV/r 800/200mg QPM or 400/100mg BID Katri A. ICAAC 2014.

3D DDIs: LPV, ATV, DRV Healthy volunteer study of 3D regimen with: ATV/r 300/100mg QAM or QPM rit omitted if given in AM with 3D regimen DRV/r 800/100mg QAM or QPM or 600/100mg BID rit omitted if given in AM with 3D regimen LPV/r 800/200mg QPM or 400/100mg BID Katri A. ICAAC 2014.

3D DDIs: LPV, ATV, DRV Healthy volunteer study of 3D regimen with: ATV/r 300/100mg QAM or QPM rit omitted if given in AM with 3D regimen DRV/r 800/100mg QAM or QPM or 600/100mg BID rit omitted if given in AM with 3D regimen LPV/r 800/200mg QPM or 400/100mg BID DRV C min 43-48% lower DRV/r BID with 3D comparable exposure to DRV/r QD DRV/r QD and BID being evaluated in TURQUOISE I Dasabuvir C min 46% lower with DRV BID (AUC 27%) Katri A. ICAAC 2014.

Daclatasvir: Unique Role in Co-Infection? Substrate of Pgp and CYP3A4 Moderate Pgp inhibitor ATV/r- DCV 20mg: AUC t : 0.70, C 24 : 1.21 30mg (est): AUC t : 1.05, C 24 : 1.83 EFV- DCV 120mg: AUC t : 1.37, C 24 : 0.83 90mg (est): AUC t : 1.03, C 24 : 0.62 TDF- DCV 60mg: AUC t : 01.10, C 24 : 1.17 Bifano M. CROI 2012. Eley T. HIV DART 2014.

Daclatasvir: Unique Role in Co-Infection? Substrate of Pgp and CYP3A4 Moderate Pgp inhibitor ATV/r- DCV 20mg: AUC t : 0.70, C 24 : 1.21 30mg (est): AUC t : 1.05, C 24 : 1.83 EFV- DCV 120mg: AUC t : 1.37, C 24 : 0.83 90mg (est): AUC t : 1.03, C 24 : 0.62 TDF- DCV 60mg: AUC t : 01.10, C 24 : 1.17 DRV/r- DCV 60mg: AUC t : 01.41 (1.32, 1.50) Bifano M. CROI 2012. Eley T. HIV DART 2014.

Drug Interaction Scorecard (Kisergram) TDF SOF SOF/LDV SMV DCV 3D RAL/DTG HIV PI/EFV ( TDF) EFV ( TDF) SMV RLP RAL/DTG ATV/r DRV/r ABC TDF ABC TDF SMV SMV DCV 90mg DCV 30mg RLP DRV No expected issues with co-administration Caution- potentially significant interactions or interactions of unknown significance. Additional monitoring may be necessary. Do not co-administer TDF/FTC/E LV/Cobi *not studied, based on predicted interactions. SMV* DCV 30mg*

A Cautionary Tale Combined <50 copies/ml week 24: RAL 84.4%, LPV 90.6% (-6.2%; -11.2 to -1.3) Reported history of virologic failure RAL LPV-rit Eron JJ. Lancet 2010.

How Big of an Issue is Re-Infection? 2/63 subjects in Turquoise I by SVR12 Both SVR4 No resistance mutations on relapse Hill A. CROI 2015. Sulkowski M. JAMA 2015.

How Big of an Issue is Re-Infection? 2/63 subjects in Turquoise I by SVR12 Both SVR4 No resistance mutations on relapse Hill A. CROI 2015. Sulkowski M. JAMA 2015.

Summary HCV treatment should be a priority in those with HIV Efficacy is not an issue when considering treatment for HCV in those 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 Reinfection can and does occur educate your patients about the risk of re-infection