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 96 | SINGLE Week 96 | FLAMINGO Week 48 | SAILING Week 48 | |||||
| DTG QD N=49 | RAL QD N=43 | DTG QD N=28 | Atripla QD N=30 | DTG QD N=26 | DRV/r QD N=20 | DTG QD N=50 | RAL BID N=65 | |
| HCV+ | 92% | 93% | 95% | 88% | 100% | 100% | 100% | 86% |
| HCV- | 95% | 92% | 93% | 93% | 99% | 99% | 93% | 87% |
| HBV+ | 83% | 88% | N/A | N/A | 100% | 100% | 93% | 81% |
| HBV- | 94% | 92% | N/A | N/A | 99% | 99% | 94% | 87% |
Post-Baseline-emergent Grade 2-4 liver enzyme toxicities are presented:
| HBV and/or HCV Co-Infected | No HBV or HCV Infection | |||||||
| ART-Naive | DTG QD N=103 | RAL BID N=43 | Atripla QD N=30 | DRV/r QD N=20 | DTG QD N=959 | RAL BID N=363 | Atripla QD N=385 | DRV/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-exp | DTG QD N=50 | RAL N=65 | DTG QD N=289 | RAL BID N=272 | ||||
| ALT n(%) | 11 (22) | 5 (8) | 10 (3) | 9 (3) | ||||
| AST n(%) | 10 (20) | 12 (18) | 8 (3) | 8 (3) | ||||
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