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AIDS 2015Vancouver, BC

Session:TUAB02


Session:TUAB02

C-EDGE CO-INFECTED: PHASE 3 STUDY OF GRAZOPREVIR /

ELBASVIR IN PATIENTS WITH HCV/HIV

Jürgen K. Rockstroh, Mark Nelson, Christine Katlama, Jay Lalezari, Josep Mallolas, Mark Bloch, Gail Matthews, Michael S. Saag,

Philippe Zamor, Chloe Orkin, Jacqueline Gress, Melissa Shaughnessy, Stephanie Klopfer, Janice Wahl, Bach-Yen Nguyen, Eliav Barr,

Heather L. Platt, Michael Robertson, Mark Sulkowski


Session:TUAB02BACKGROUND

• HCV NS3/4A inhibitor, 100 mg

Grazoprevir(MK-5172)

Elbasvir(MK-8742)

• HCV NS5A inhibitor, 50 mg

Broad genotypic activity1-3

Retains activity against many clinically relevant RAVs1-3

All-oral, once-daily regimen1. Summa V, et al. Antimicrobial Agent Chemother 2012:56;4161-672. Coburn CA, et al. ChemMedChem 2013; 8: 1930–403. Harper S, et al. ACS Med Chem Lett. 2012 Mar 2;3(4):332-6.


Session:TUAB02BACKGROUND AND AIM

• HCV infection is a leading cause of morbidity and mortality among patients with HIV-11-3 – rapid progression of liver disease– increased risk of cirrhosis, end-stage liver disease, and

HCC4,5

• The aim of the phase 3 C-EDGE Co-infection study was to evaluate the efficacy, safety and tolerability of the HCV regimen, grazoprevir / elbasvir fixed-dose combination in patients with HIV/HCV coinfection

1. Monga HK, et al. Clin Infect Dis 2001;33(2):240-247. 2. Konerman MA, et al. Hepatology 2014;59(3):767-7753. Pinchoff J, et al. Clin Infect Dis 2014;58(8):1047-1054. 4. Lo Re V, III, et al. Ann Intern Med 2014;160(6):369-379.5. Rockstroh JK, et al. J Hepatol 2013;59(2):213-220.


Session:TUAB02STUDY DESIGN

• An open-label, single-arm, multicenter study across Europe, The US and Australia

• Primary endpoint: SVR12 (HCV RNA <15 IU/mL*)• Treatment-naive patients with HCV GT1, 4 or 6 infection with or without

cirrhosis• Co-infected with HIV-1:

– Naive to ART with CD4+ >500 cells/mm3 and HIV RNA <50,000 copies/mL – On stable on ART† for ≥8 weeks and CD4+ >200 cells/mm3 and undetectable

HIV RNA

GZR 100 mg / EBR 50 mg

D1 TW4 TW8 TW12 FUW4 FUW8 FUW12

n=218

*COBAS TaqMan v2.0 [LLoQ <15 IU/mL]† Stable antiretroviral therapy (ART) included tenofovir or abacavir, and either emtricitabine or lamivudine plus raltegravir, dolutegravir, or rilpivirine

Follow-up


Session:TUAB02DEMOGRAPHICS: HCV DISEASE

All PatientsN = 218

Age, years mean (SD) 48.7 (8.9)Sex, n (%)

Male, 183 (83.9)Female 35 (16.1)

Race, n (%) White 167 (76.6)Black or African-American 38 (17.4)Asian 6 (2.8)Other 7 (3.2)

Ethnicity, n (%) Hispanic / Latino 14 (6.4)Not Hispanic / Latino 194 (89.0)Not reported 10 (4.6)

HCV genotype, n (%) 1a 144 (66.1)1b 44 (20.2)4 28 (12.8)6 2 (1.0)

Baseline HCV RNA >800,000 IU/mL, n (%) 130 (59.6)Cirrhotic*, n (%) 35 (16.1)IL28B CC (%) , n (%) 77 (35.3)

*Of the 35 patients (16.1%) with cirrhosis, 27 were diagnosed by Fibroscan, 6 by biopsy, and 2 by Fibrotest and APRI.


Session:TUAB02DEMOGRAPHICS: HIV DISEASE

All PatientsN = 218

Antiretroviral therapy, n (%) Receiving ART with undetectable HIV

RNA211 (96.8)

Naïve to ART 7 (3.2)Baseline CD4 count (cells/µL)

Mean (SD)Median (1st quartile – 3rd quartile)

613 (0.57)

568 (424-766)Antiretroviral therapy, n (%)

Abacavir containing regimen 47 (21.6)Tenofovir containing regimen 164 (75.2)Raltegravir 113 (51.8)Dolutegravir 59 (27.1)Rilpivirine 38 (17.4)


Session:TUAB02SVR12

Discontinued unrelated to VF 1 0 1 0Relapse 5 4 0 1Reinfection 2 1 1 0

*2 patients with GT6 infection were also included; both patients achieved SVR12.GT = genotype

210/217*

96.3% 96.5% 95.5% 96.4%

0%

25%

50%

75%

100%

Full AnalysisSet

GT1a GT1b GT4

Patie

nts,

%

139/144

42/44

210/218*

27/28


Session:TUAB02

SVR12

Variable n/m % (95% CI)

ALL 210/218 96.3 (92.9, 98.4)

GenderMale 175/183 95.6 (91.6, 98.1)

Female 35/35 100.0 (90.0, 100.0)

Age<65 years 204/212 96.2 (92.7, 98.4)

≥65 years 6/6 100.0 (54.1, 100.0)

Race

White 161/167 96.4 (92.3, 98.7)

African American 36/38 94.7 (82.3, 99.4)

Asian 6/6 100 (54.1, 100.0)

IL28B genotype

CC 76/77 98.7 (93.0, 100.0)

Non-CC 134/141 95.0 (90.0, 98.0)

CirrhosisNo 175/183 95.6 (91.6, 98.1)

Yes 35/35 100 (90.0, 100.0)

Baseline viral load

≤800,000 IU/mL 89/91 97.8 (92.3, 99.7)

>800,000 IU/mL 121/127 95.3 (90.0, 98.2)

SVR12 – SUBGROUP ANALYSES FULL ANALYSIS SET

80 90 100SVR12 (95% CI)


Session:TUAB02

SVR12

Variable n/m % (95% CI)

ALL 210/218 96.3 (92.9, 98.4)

ART regimenAbacavir-containing 44/47 93.6 (82.5, 98.7)

Tenofovir-containing 160/164 97.6 (93.9, 99.3)

ART third agent

Raltegravir 109/113 96.5 (91.2, 99.0)

Dolutegravir 59/59 100.0 (93.9, 100.0)

Rilpivirine 36/38 94.7 (82.3, 99.4)

SVR12 ACCORDING TO ART REGIMEN FULL ANALYSIS SET

80 90 100

SVR12 (95% CI)


Session:TUAB02RELAPSE AND REINFECTION

• 5 patients relapsed– All noncirrhotic– GT1a n=4; GT4 n=1– Four patients were receiving ART

• Tenofovir-based ART n=3• Abacavir-based ART n=1

• 2 patients were reinfected– One patient with GT1a at enrolment; GT3 at FW12– One patient with GT1b at enrolment; GT3 at FW12– Per protocol, these patients was classified as a failure for analysis, but

sequencing and phylogenetic data are consistent with post-treatment reinfection


Session:TUAB02RESISTANCE ASSOCIATED VARIANTS IN PATIENTS WITH RELAPSE OR REINFECTION

BaselineHCV GT ARV regimen

Resistance Associated Variants

At baseline At failure

NS3 NS5A NS3 NS5A

RELAPSES

56 yr black/AA male 1a tenofovir, emtricitabine, rilpivirine V36M/L L31M/L Q80K, D168A Q30K, L31M

63 yr black/AA male 1a None Q80K Y93S Q80K, D168A Q30R, Y93S

37 yr white male 1a tenofovir, emtricitabine, raltegravir WT WT WT Q30R/Q

43 yr white male 1a abacavir, lamivudine, raltegravir WT WT WT WT

53 yr white male 4 tenofovir, emtricitabine, raltegravir WT WT WT L28S

REINFECTIONS

35 yr white male 1b abacavir, lamivudine, raltegravir WT WT (GT3) (GT3)

43 yr white male 1a tenofovir, emtricitabine, rilpivirine V55A/V WT (GT3) (GT3)

Bold indicates RAV detected at virologic failure not previously detected at baseline.


Session:TUAB02NS5A PHYLOGENETIC ANALYSIS OF REINFECTION:AN191535

Day 1

At failure


Session:TUAB02NS5A PHYLOGENETIC ANALYSIS OF REINFECTION:AN191554

Day 1

At failure


Session:TUAB02ADVERSE EVENTS

Patients with:

All PatientsN = 218

Serious AE, n (%) 8* (2.8)Serious drug-related AE, n (%) 0 (0)Discontinuation due to AE, n (%) 0 (0)Deaths, n (%) 0 (0)Any adverse event†, n (%) 167 (76.6)

Fatigue 29 (13.3)Headache 27 (12.4)Nausea 20 (9.2)

Late ALT or AST >5.0 x ULN‡, n (%) 2 (0.9) Lowest hemoglobin on treatment, n (%)

≥8.5 to <10 g/dL 1 (0.5)Elevation of total bilirubin¶, n (%)

>2.5 – 5.0 × baseline 8 (3.7)>5.0 × baseline 1 (0.5)

Creatinine >2.5 x baseline, n (%) 0 (0)

*2 SAEs were reported during the treatment period (convulsion and pneumonia) and 6 SAEs were reported during follow-up (erysipelas; acute psychosis and urinary retention; ulnar fracture; spontaneous bacterial peritonitis, cellulitis, and urinary retention)†All AEs, regardless of relationship to study drug reported in >5% of patients.‡ALT/AST >5× ULN after TW4 with an ALT/AST ≤ ULN between TW2 and TW4¶ Bilirubin elevations were not associated with simultaneous ALT increases


Session:TUAB02HIV PARAMETERS

• Two patients receiving ART experienced transient HIV viremia during treatment – Both patients subsequently achieved undetectable HIV RNA with

additional compliance education, and without a change in ARV regimen.

• No notable change in CD4+ cells from baseline compared to TW12– Mean change of 52.9 cells/µL (SD 156.14, n=207)


Session:TUAB02CONCLUSIONS

• High rates of SVR were achieved in patients with HCV GT1, 4 and 6 and HIV co-infection receiving the all-oral, fixed-dose combination of GZR / EBR – Comparable response rates to other studies in HCV mono-infected patients– Comparable response rates across all patient subgroups, including

black/African American– Comparable response rates in cirrhotic and non-cirrhotic patients– Generally well tolerated with few SAEs, and no discontinuation

• Low rates of adverse events, once-daily administration, and suitability for use in patients also receiving antiretroviral therapy suggest GZR / EBR may represent a highly effective treatment option for patients with HCV/HIV co-infection.


Session:TUAB02PUBLISHED 09-JULY-15


Session:TUAB02ACKNOWLEDGEMENTS

• We extend our gratitude to the patients, their families, investigators and site personnel who participated in this study.– Australia: Gail Matthews, Mark Theo Bloch– Canada: Jason Brunetta, Brian Conway– Denmark: Jan Gerstoft, Nina Weis, Alex Lund Laursen– France: Marc Bourliere, Christine Katlama, Stanislas Pol– Germany: Stefan Mauss, Jürgen K. Rockstroh, Michael Sabranski– Israel: Yaacov Baruch, Oren Shibolet, Ziv Ben Ari– Spain: Juan Gonzalez Garcia, Josep Mallolas, Christina Tural– United Kingdom: Mark Nelson, Chloe Orkin– United States: David Michael Asmuth, Michael David, Laveeza Bhatti, Edwin DeJesus,

Princy N. Kumar, Jacob Paul Lalezari, Kristen Marks, Frederick Nunes, Ponni Perumalswami, Peter Jerome Ruane, Alyssa So Young Shon, Mark S. Sulkowski, David Wyles, Philippe J. Zamor, David J Prelutsky, Michael S Saag, Anthony Mills.

• This study and medical writing support by ApotheCom were funded by Merck & Co., Inc


Session:TUAB02CONCLUSIONS

• High rates of SVR were achieved in patients with HCV GT1, 4 and 6 and HIV co-infection receiving the all-oral, fixed-dose combination of GZR / EBR – Comparable response rates to other studies in HCV mono-infected patients– Comparable response rates across all patient subgroups, including

black/African American– Comparable response rates in cirrhotic and non-cirrhotic patients– Generally well tolerated with few SAEs, and no discontinuation

• Low rates of adverse events, once-daily administration, and suitability for use in patients also receiving antiretroviral therapy suggest GZR / EBR may represent a highly effective treatment option for patients with HCV/HIV co-infection.


Session:TUAB02

BACK UP SLIDES


Session:TUAB02BACKUP SLIDES

Treatment N n (%) 95% Confidence

Interval†

p-Value‡

GZR/EBR for 12 Weeks 218

210 (96.3)

(92.9, 98.4)

<.001

†Based on Clopper-Pearson method. ‡Based on a one-sided exact test for a binomial proportion. A one-sided p-value<0.025

supports a conclusion that the true SVR12 is >70%.

N = Number of subjects included in the analysis. n (%) = Number of subjects who achieved SVR12 and the percentage calculated as (n/N)*100.

LLoQ is 15 IU/mL.

Analysis of Sustained Virologic Response (HCV RNA < LLoQ) at Follow-up Week 12 Visit (SVR12) in Treatment-Naïve Subjects

Full Analysis Set

Full Analysis Set: 210/218• 5 relapses• 2 reinfections• 1 discontinuation


Session:TUAB02BACKUP SLIDES

Treatment N n (%) 95% Confidence Interval†

GZR/EBR for 12 Weeks 217 210 (96.8)

(93.5, 98.7)

†Based on Clopper-Pearson method. N = Number of subjects included in the analysis. n (%) = Number of subjects who achieved SVR12 and the percentage calculated as

(n/N)*100. LLoQ is 15 IU/mL.Data Source: [16.4]

Analysis of Sustained Virologic Response (HCV RNA < LLoQ) at Follow-up Week 12 Visit (SVR12) in Treatment-Naïve Subjects

Per Protocol

Per Protocol Analysis: 210/217• 5 relapses• 2 reinfections


Session:TUAB02BACKUP SLIDES: SUBGROUP ANALYSIS

GZR/EBR for 12 Weeks N n (%) 95% Confidence

Interval†

Gender

Male 183 175 (95.6)

(91.6, 98.1)

Female 35 35 (100.0)

(90.0, 100.0)

Age

<65 212 204 (96.2)

(92.7, 98.4)

>=65 6 6 (100.0)

(54.1, 100.0)

Race

White 167 161 (96.4)

(92.3, 98.7)

African American

38 36 (94.7)

(82.3, 99.4)

Asian 6 6 (100.0)

(54.1, 100.0)

Other 7 7 (100.0)

(59.0, 100.0)

Ethnicity

Hispanic or Latino

14 14 (100.0)

(76.8, 100.0)

Not Hispanic or Latino

194 186 (95.9)

(92.0, 98.2)

Other 10 10 (100.0)

(69.2, 100.0)

Genotype

1a 144 139 (96.5)

(92.1, 98.9)

1b 44 42 (95.5)

(84.5, 99.4)

1-other 0 0 (0.0)

NA

4 28 27 (96.4)

(81.7, 99.9)

6 2 2 (100.0)

(15.8, 100.0)

IL28B CC genotype

CC genotype 77 76 (98.7)

(93.0, 100.0)

Non-CC genotype

141 134 (95.0)

(90.0, 98.0)

Fibrosis Stage

Non-Cirrhotic 183 175 (95.6)

(91.6, 98.1)

Cirrhotic 35 35 (100.0)

(90.0, 100.0)

Baseline HCV RNA

<=800,000 IU/mL

91 89 (97.8)

(92.3, 99.7)

>800,000 IU/mL

127 121 (95.3)

(90.0, 98.2)

<=2,000,000 IU/mL

135 131 (97.0)

(92.6, 99.2)

>2,000,000 IU/mL

83 79 (95.2)

(88.1, 98.7)

<=10,000,000 IU/mL

214 206 (96.3)

(92.8, 98.4)

>10,000,000 IU/mL

4 4 (100.0)

(39.8, 100.0)

Prior Treatment

Summary of Sustained Virologic Response (HCV RNA < LLoQ) at Follow-up Week 12 Visit (SVR12) by Subgroup

Full Analysis Set


Session:TUAB02BACKUP SLIDES: SUBGROUP ANALYSIS CONTINUED

GZR/EBR for 12 Weeks N n (%) 95% Confidence

Interval†

Naïve 194 186 (95.9)

(92.0, 98.2)

Naïve – Interferon Ineligible 11 11 (100.0)

(71.5, 100.0)

Naïve – Interferon Unwilling 13 13 (100.0)

(75.3, 100.0)

Antiretroviral therapy with NRTI backbone

Abacavir containing regimen‡ 47 44 (93.6)

(82.5, 98.7)

Tenofovir containing regimen 164 160 (97.6)

(93.9, 99.3)

Antiretroviral therapy with 3rd agent in ARV Regimen

Raltegravir 113 109 (96.5)

(91.2, 99.0)

Dolutegravir 59 59 (100.0)

(93.9, 100.0)

Rilpivirine 38 36 (94.7)

(82.3, 99.4)

†Based on the Clopper-Pearson method. ‡Includes one subject who was on abacavir, lamivudine, and tenofovir. N = Number of subjects included in the analysis. n (%) = Number of subjects who achieved SVR12 and the percentage calculated as (n/N)*100.

LLoQ is 15 IU/mL.Data Source: [16.4]


Session:TUAB02PHYLOGENETIC DATA


Session:TUAB02NS5A PHYLOGENETIC TREE


Session:TUAB02NS3 PHYLOGENETIC TREE

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