Slide Presentation. Management of HCV Coinfection Susanna Naggie, MD, MHS

Transcription

1 Slide Presentation Management of HCV Coinfection Assistant Professor of Medicine Duke University School of Medicine & Durham VA Medical Center Director of Infectious Diseases Duke Clinical Research Institute Disclosure Research support: AbbVie, Anadys, Bristol-Myers Squibb, Gilead, Medtronic, Scynexis, Achillion, and Vertex Scientific adviser/consultant: Abbott, AbbVie, Boehringer Ingelheim, Gilead, Janssen, Achillion, and Vertex (Updated 3/13/14) **Off-label use of FDA approved medications Treatment of Hepatitis C Virus Infection in the HIV-Infected Patient: Everybody s Doing It

2 Natural History HIV and HCV HIV 4 million Hepatitis C 18 million 1 million people worldwide 3% of US patients with HIV have HCV Epidemic in HIV+ MSM 14.5% of deaths liver related Staples CT. Clin Infect Dis 1999 DAD Study Group, Arch Intern Med 26 HAART Era: Cirrhosis Risk Overall RR 2.11 Pre-HAART era RR 2.49 HAART era RR year, 3-year rates 25%, 54% HCV monoinfection HIV/HCV coinfection Thein et al. AIDS 28; 22:1979

3 Accelerated Liver Disease in HIV Kirk et al. Ann Intern Med 213; 158: Clinical Management HCV Screening in HIV+ Patients CDC STD Treatment Guidelines, Dec 21: To detect acute HCV among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing should be considered. Q6 mo GI panel, Q12 mo anti-hcv GI panel and anti-hcv 3 months after dx with new STD Liver enzyme elevation = HCV RNA MMWR, Dec 21, 59(RR-12) NEAT Consensus Conference AIDS 211; 25: last accessed 3/21/14

4 Education and Prevention Launay et al. JAMA 211; 35: Fonseca et al. Vaccine 25: 23:292-8 CDC Pink Book Carrieri et al. J Hepatol 214; 6:46-53 Staging of Liver Disease Sensitivity Assessing Fibrosis: AUROC SROC Curve: APRI for Cirrhosis Symmetric SROC AUC =.8265 SE(AUC)=.13 Q*=.7594 SE(Q*)= specificity The size of the dots for 1-specificity and sensitivity of the single studies in the ROC space is derived from the respective sample size. Lin et al. Hepatology 211;53; Sheheen et al. Am J Gastroenterol 27;12; Sheheen et al. HIV Clin Trials 28;9; Chou et al. Ann Intern Med 213;158. APRI (.3, 2.) (F2-4) (cirrhosis, F4) HIV (F4) Fibrotest (.2,.8): (F2-4) (cirrhosis, F4) HIV.86 (F4) SHASTA:.88 Forns :

5 Assessing Fibrosis: Elastography Sensitivity De Ledinghen et al. JAIDS 26;41: Vergara et al. Clin Infect Dis 27;45: F,1 versus F2,3,4 F,1,2 versus F3,4 F,1,2,3 versus F specificity Assessing Fibrosis: Elastography Probability of decompensation De Ledinghen et al. JAIDS 26;41: Vergara et al. Clin Infect Dis 27;45: LSM 9.4 KPa and <14.6 KPa LSM 14.6 KPa P< Number at risk Time (years) Fs cutoff = Fs cutoff = HCV Treatment

6 New Kids on the Block Simeprevir (TMC-435) Multigenotypic NS3/4A PI QD dosing Second-wave PI Low barrier to resistance + DDI with ARVs Rash, photosensitivity HIV not a special pop Sofosbuvir (GS-7977) Pangenotypic NS5B QD dosing Nucleotide analogue Exceptional barrier to resistance No significant DDI No AE Approved for HIV/HCV as special population Drug Interactions: Simeprevir ARV BOC TPV SMV SOF* DCV FDV ATV/r CAUTION STAND CONTRA STAND DCV FDV DRV/r CONTRA CONTRA CONTRA STAND N/A FDV EFV CONTRA TPV CONTRA STAND DCV FDV RPV STAND CAUTION STAND STAND STAND N/A ETV CAUTION CAUTION CONTRA STAND N/A N/A RGV STAND STAND STAND STAND STAND STAND DGV N/A N/A CAUTION STAND N/A N/A Phase III Study: Rilpivirine (15%), Raltegravir (87%), Maraviroc, Enfuvirtide, NRTIs MVC MVC MVC STAND STAND STAND STAND *Tipranavir CONTRA with SOF Ouwerkerk-Mahadevan et al. IDSA 212 Abstract 49; Hulskotte et al. Clin Infect Dis 213; de Kanter et al. CROI 212; Bifano et al. CROI 212; Kirby et al. AASLD 212 Simeprevir QD + P/R: C212 Study Phase III, open-label (TMC435-C212 study) Treatment naïve and experienced (N=16) RGT = <LLOQ week 4 and <LLOD week 12 HCV treatmentnaïve/relapse Partial/null cirrhotic RGT* Week Dieterich et al. CROI 214 Abstract 24 SMV 15mg/PR SMV 15mg/PR SMV 15mg/PR PR Follow-up PR PR Follow-up Follow-up

7 SVR12: Treatment History HCV RNA Undetectable (%) /16 42/53 13/15 7/1 16/28 Overall Naïve Relapse Partial Null Dieterich et al. CROI 214 Abstract 24 C212: Subpopulations HCV RNA Undetectable (%) Overall 1b 1a - Q8K SVR /16 16/18 2/3 36/45 14/22 7/93 8/ F-2 F3/4 on ART off ART Dieterich et al. CROI 214 Abstract Weeks: Simeprevir QD + P/R Co-infection Monoinfection 6/67 (89%) met RGT criteria and ended treatment at Week 24 (noncirrhotic) SVR4 or SVR12 (%) Dieterich et al. CROI 214 Abstract 24

8 Safety Summary SMV + P/R (N=16) Patients, % First 12 weeks Entire treatment AEs in >25% of patients Fatigue Headache Nausea AEs of special interest 11 9 Pruritis 2 2 Rash Sunburn/Photosensitivity 3/2 4/2 Grade 3-4 AEs Serious AEs 6 1 Treatment D/C due to AEs 4 4 Dieterich et al. CROI 214 Abstract 24 New Kids on the Block Simeprevir (TMC-435) Multigenotypic NS3/4A PI QD dosing Second-wave PI Low barrier to resistance + DDI with ARVs Rash, photosensitivity HIV not a special pop Sofosbuvir (GS-7977) Pangenotypic NS5B QD dosing Nucleotide analogue Exceptional barrier to resistance No significant DDI No AE Approved for HIV/HCV as special population Drug Interactions: Sofosbuvir ARV BOC TPV SMV SOF* DCV FDV ATV/r CAUTION STAND CONTRA STAND DCV FDV DRV/r CONTRA CONTRA CONTRA STAND N/A FDV EFV CONTRA TPV CONTRA STAND DCV FDV RPV STAND CAUTION STAND STAND STAND N/A ETV CAUTION CAUTION CONTRA STAND N/A N/A RGV STAND STAND STAND STAND STAND STAND Phase III Study: Rilpivirine (15%), Raltegravir (87%), Maraviroc, Enfuvirtide, NRTIs DGV N/A N/A CAUTION STAND N/A N/A MVC MVC MVC STAND STAND STAND STAND *Tipranavir CONTRA with SOF Ouwerkerk-Mahadevan et al. IDSA 212 Abstract 49; Hulskotte et al. Clin Infect Dis 213; de Kanter et al. CROI 212; Bifano et al. CROI 212; Kirby et al. AASLD 212

9 The NEUTRINO Regimen in HIV/HCV HCV RNA <LLOQ (25 IU/mL) SVR /19 13/15 4/4 1 1a 1b Rodriguez-Torres et al. IDW 213 Abstract 714 PHOTON-1: Study Design GT 1 TN Wk Wk 12 Wk 24 Wk 36 SOF + RBV, n=114 Wk 48 GT 2/3 TN SOF + RBV, n=68 SVR 12 SVR 24 GT 2/3 TE SOF + RBV, n=41 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 count > 2 cells/mm 3 and HIV RNA < 5 c/ml ART untreated: CD4 count > 5 cells/mm 3 Naggie et al. CROI 214 Abstract 26 Virologic Response: Genotype 1 Patients with HCV RNA <LLOQ (%) * 11/114 13/13 87/114 86/114 Week 4 EOT SVR12 SVR24 Naggie et al. CROI 214 Abstract 26

10 SVR12 by GT 1 Patient Subgroups Overall HCV GT 1a 1b SVR12 Rate, % (95% CI) HCV RNA level <6 log 1 IU/mL 6 log 1 IU/mL IL28B Cirrhosis CC Non-CC No Yes Nonblack Race Black Female Gender Male <5 Age 5 Naggie et al. CROI 214 Abstract Virologic Response: Genotype 2 Patients with HCV RNA <LLOQ (%) 25/26 25/26 23/26 23/26 24/24 23/23 22/24 22/24 Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24 Treatment Naïve 12 Weeks SOF + RBV Treatment Experienced 24 Weeks SOF + RBV Naggie et al. CROI 214 Abstract 26 Virologic Response: Genotype 3 Patients with HCV RNA <LLOQ (%) 41/41 39/4 28/42 28/42 17/17 17/17 16/17 15/17 Week 4 EOT SVR12 SVR24 Week 4 EOT SVR12 SVR24 Treatment Naïve 12 Weeks SOF + RBV Treatment Experienced 24 Weeks SOF + RBV Naggie et al. CROI 214 Abstract 26

11 Safety Summary SOF + RBV Patients, % 24 Weeks (n=155) 12 Weeks (n=68) AEs AEs in 1% of patients Fatigue Insomnia Headache Nausea Diarrhea 11 9 Irritability 1 1 URI Grade 3-4 AEs 12 1 Serious AEs 6 7 Treatment D/C due to AEs* 3 4 Death 1 * Weight loss, insomnia/agitation, pneumonia, suicide attempt, foreign body sensation in throat, increased anxiety, dyspnea. Suicide 9 days after completing study treatment; patient had history of depression and was being treated for ADHD and insomnia before entering study. Naggie et al. CROI 214 Abstract 26 Laboratory Abnormalities SOF + RBV n (%) 24 Weeks (n=155) 12 Weeks (n=68) Any Grade 3 33 (21) 8 (12) Grade 3 hyperbilirubinemia (indirect) 28 (18) 4 (6) Taking atazanavir* 26 (17) 4 (6) Not taking atazanavir 2 (1) Grade 3 elevated lipase 3 (2) Hemoglobin <1 mg/dl 27 (17) 7 (1) <8.5 mg/dl 2 (1) 1 (1) *4 patients changed ARV regimens from atazanavir to darunavir due to hyperbilirubinemia; 43 (19%) required ribavirin dose reduction during study; epoetin alfa was not permitted. Naggie et al. CROI 214 Abstract 26 Recommended for HIV/HCV Treatment Naïve/Relapse 76% SVR12 >9% SVR12 89% SVR12

12 Recommended for HIV/HCV Treatment Experienced >9% SVR12 ~72% SVR12 Recommended for HIV/HCV Genotype 2 and 3 88% SVR % SVR12 *Consider addition of PEG to SOF/RBV for 12 weeks for treatment-experienced cirrhotics (LONESTAR-2) What s Next? Patients with SVR12 (%) Naïve Experienced Gane et al. AASLD 213 Abstract 73; Lawitz et al. AASLD 213 Abstract 215/1844; Sulkowski et al. NEJM 214; 37:211-21; abbvie.mediaroom.com/press_release SOF/LDV(P3) ABT QUAD(P3) DCV/SOF(P2)

13 Drug Interactions: Faldaprevir and Daclatasvir ARV BOC TPV SMV SOF* DCV FDV ATV/r CAUTION STAND CONTRA STAND DCV FDV DRV/r CONTRA CONTRA CONTRA STAND N/A FDV EFV CONTRA TPV CONTRA STAND DCV FDV RPV STAND CAUTION STAND STAND STAND N/A ETV CAUTION CAUTION CONTRA STAND N/A N/A RGV STAND STAND STAND STAND STAND STAND Phase III Study: Rilpivirine (15%), Raltegravir (87%), DGV N/A N/A CAUTION STAND N/A N/A MVC MVC MVC STAND Maraviroc, Enfuvirtide, NRTIs STAND STAND STAND *Tipranavir CONTRA with SOF Ouwerkerk-Mahadevan et al. IDSA 212 Abstract 49; Hulskotte et al. Clin Infect Dis 213; de Kanter et al. CROI 212; Bifano et al. CROI 212; Kirby et al. AASLD 212 In a nutshell... Response to HCV treatment is no longer different. IFN-free regimens approved in GT 2/3. IFN inclusive still recommended for GT 1 patients who can tolerate IFN. IFN-free for GT 1 is recommended but can be hard to get. FDA-approved all-oral treatments are months away! 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 (25-7) 49 (24-71) 54 (34-68) Male, n (%) 93 (82%) 55 (81%) 37 (9%) Black, n (%) 37 (32%) 8 (12%) 7 (17%) Hispanic, n (%) 25 (22%) 19 (28%) 1 (24%) Mean BMI, kg/m 2 (range) 27 (18-46) 27 (2-43) 27 (19-4) Genotype 1a, n (%) 9 (79) NA NA Genotype 2, n (%) NA 26 (38) 24 (59) Genotype 3, n (%) NA 42 (62) 17 (41) IL28B CC, n (%) 3 (27) 25 (37) 2 (49) Mean HCV RNA, log 1 IU/mL (range) 6.6 ( ) 6.3 (5.-7.4) 6.5 ( ) Cirrhosis, n (%) 5 (4) 7 (1) 1 (24) On ART, n (%) 112 (98) 61 (9) 39 (95) CD4 T-cell count (cells/μl), mean (SD) 636 (251) 585 (246) 658 (333) 4

14 Antiretroviral Regimens Treatment Naive Treatment Experienced Regimen, n (%) GT 1 n=114 GT 2/3 n=68 GT 2/3 n=41 On ART 112 (98) 61 (9) 39 (95) Tenofovir DF/emtricitabine plus Efavirenz 42 (37) 2 (33) 16 (41) Atazanavir/ritonavir 24 (21) 7 (11) 8 (21) Darunavir/ritonavir 15 (13) 17 (28) 2 (5) Raltegravir 21 (18) 8 (13) 7 (18) Rilpivirine 7 (6) 5 (8) 2 (5) Other 3 (3) 4 (7) 4 (1) 41 Patient Disposition Treatment Naive Treatment Experienced Regimen, n (%) GT 1 n=114 GT 2/3 n=68 GT 2/3 n=41 Completed 13 (9) 62 (91) 4 (98) Discontinued 11 (1) 6 (9) 1 (2) Reason for discontinuation AE 3 (3) 3 (4) 1 (2) Withdrew consent 2 (2) 1 (1) Protocol violation* 4 (4) Investigator decision 1 (<1) 1 (1) Efficacy failure 1 (<1) Lost to follow-up 1 (1) *Three GT1 subjects inadvertently discontinued after 12 weeks; one GT 1 subject did not adhere to study visits 42 Virologic Outcome Treatment Naive Treatment Experienced GT 1 GT 2 GT 3 GT 2 GT 3 Outcome, n (%) n=114 n=26 n=42 n=24 n=17 SVR12 87 (76) 23 (88) 28 (67) 22 (92) 16 (94) HCV virologic failure 26 (23) 1 (4) 12 (29) 1 (4) 1 (6) Relapse 25 (22) 12 (29) 1 (4) 1 (6) Completed study drug Did not complete study drug HCV viral breakthrough* 1 (<1) 1 (4) Other 1 (<1) 2 (8) 2 (5) 1 (4) *Both patients with HCV breakthrough were nonadherent to SOF, confirmed by PK analysis. 43

15 Safety of Sofosbuvir Safety Outcome Total (N=775) No Peg (N=331) Yes Peg (N=444) Grade 3 AE, N(%) 88 (11) 17 (5) 71 (16) SAE, N(%) 28 (3.6) 12 (3.6) 16 (3.6) Leading to d/c, N(%) 38 (5) 4 (1.2) 34 (7.6) Grade 3/4 anemia 146 (19) 24 (7) 122 (27.5) Grade 3/4 neutropenia 93 (12) 93 (21) Grade 3/4 lymphopenia 35 (4.5) 7 (2) 28 (6.3) Grade 3/4 thrombocytopenia 4 (1) Grade 3/4 hyperbilirubinemia 8 (1) 5 (1.5) 3 (.6) Kowdley KV et al. EASL 213 Abstract C212: Sub-hoc Analyses HCV RNA <LLOQ (25 IU/mL) on ART SVR12 62 not on ART SVR CD4 5/mm3 CD>5/mm3 Dieterich et al. CROI 214 Abstract 24; NCT