Efficacy and safety of dolutegravir (DTG) in hepatitis (HBV or HCV) co-infected patients: results from the phase 3 program

Background: DTG Phase 3 studies enrolled hepatitis virus co-infected patients, an important population of HIV patients.
Methods: Patients enrolled in 4 Phase 3 DTG studies (ART-naïve: SPRING-2, SINGLE, FLAMINGO; ART-exp, INI-naïve: SAILING) were assessed. Atripla (SINGLE), darunavir/ritonavir (DRV/r; FLAMINGO) and raltegravir (RAL; SPRING-2, SAILING) were comparators. HBV surface antigen and HCV antibody was performed at Screening or Day 1. HBV subjects were excluded from SINGLE; local standard of care for HBV was otherwise recommended. An exploratory analysis of proportion without failure (efficacy-related discontinuation=failure [ERDF]) was conducted in order to understand the purely virologic efficacy of DTG in the setting of hepatitis co-infection. Graded liver chemistry (ALT, AST, total bilirubin) abnormalities are presented for subjects with/without viral hepatitis.
Results: 153 DTG and 158 comparator subjects had HBV and/or HCV co-infection. ERDF results for co-infected participants showed comparable or better efficacy with DTG:

 SPRING-2 Week 96SINGLE Week 96FLAMINGO Week 48SAILING Week 48
 DTG QD N=49RAL QD N=43DTG QD N=28Atripla QD N=30DTG QD N=26DRV/r QD N=20DTG QD N=50RAL BID N=65
[ERDF in HCV/HBV Co-infected vs. Mono-infected]

Post-Baseline-emergent Grade 2-4 liver enzyme toxicities are presented:

 HBV and/or HCV Co-InfectedNo HBV or HCV Infection
ART-NaiveDTG QD N=103RAL BID N=43Atripla QD N=30DRV/r QD N=20DTG QD N=959RAL BID N=363Atripla QD N=385DRV/r QD N=222
ALT n(%)17 (17)10 (23)7 (23)2 (10)32 (3)14 (4)17 (4)4 (2)
AST n(%)16 (16)6 (14)6 (20)2 (10)42 (4)18 (5)18 (5)7 (3)
ART-expDTG QD N=50RAL N=65  DTG QD N=289RAL BID N=272  
ALT n(%)11 (22)5 (8)  10 (3)9 (3)  
AST n(%)10 (20)12 (18)  8 (3)8 (3)  
[Treatment-emergent, Grade 2-4 Liver Enzymes]

Higher rates of ALT elevations in co-infected, ART-exp DTG subjects occurred concurrently with virologic/immunologic responses, representing more IRIS cases on DTG. Increased bilirubin in ART-naive DTG subjects (3% co-infected, 2% mono-infected) was uncommon but, in ART-exp DTG subjects, was more frequent due to atazanavir (12% in both).
Conclusions: The efficacy/safety profile of DTG in HBV/HCV co-infected subjects was similar to other HIV therapy.

S. Min1, J. Roberts2, S. Almond2, L. Curtis3, C. Stainsby3, J. Lim4, B. Wynne5, G. Nichols1
1GlaxoSmithKline, ID Medicine Development, Research Triangle Park, United States, 2GlaxoSmithKline, Statistics, Mississauga, Canada, 3GlaxoSmithKline, Global Clinical Safety and Pharmacovigilance, Stockley Park, United Kingdom, 4GlaxoSmithKline, Statistics, Stockley Park, United Kingdom, 5GlaxoSmithKline, ID Medicine Development, Upper Providence, United States