Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals initiating ART during acute HIV infection

Background: Individuals who initiate antiretroviral therapy (ART) during acute HIV infection (AHI) have a lower frequency of latently infected cells and could have a greater chance for viremic control after treatment interruption (TI).
Methods: A randomized study of vorinostat/hydroxychloroquine/maraviroc (VHM, n= 10; 8 Fiebig III/ 2 Fiebig IV) plus ART vs. ART alone (n=5; all Fiebig III) given for 10 weeks, followed by TI at week 10 was conducted in individuals treated since AHI with viral load (VL) suppression for >48 weeks and CD4 ≥ 450 cells/mm3. The VHM arm received 3 cycles of vorinostat 400mg/day (14 days on/14 days off) plus hydroxychloroquine (400mg/day) and maraviroc (1200mg/day). VL was monitored weekly after TI. ART was resumed when confirmed VL >1000 copies/ml.
Results: The participants were mainly male who were treated during Fiebig III AHI with high CD4 and about 3 years of VL suppression. Two individuals in the VHM arm had serious adverse events, and one withdrew from the study for renal insufficiency and thrombocytopenia.

Fourteen participants underwent TI (9 VHM+ART, 5 ART) and all experienced VL rebound with no difference between arms (range: 2-11 weeks). One participant in the ART arm had viremic control for 11 weeks. None had acute retroviral syndrome. All achieved VL suppression following ART and there was no change in genotypic resistance profile.



Characteristics, median (range)VHM+ARTART
Age at randomization, years/ Gender28 (22 - 51)/ 9 male :1 female26 (24 - 34)/ 4male :1 female
ART duration, weeks224 (79 - 294)155 (100 - 295)
CD4 count, cells/mm3634 (501 - 1,106)1079 (537 - 1,612)
Total HIV DNA (copies/10E6 PBMCs) 837 (0 - 2,323)594 (19 - 1,878)
POST-TREATMENT INTERRUPTION
Time from treatment interruption to VL detection, weeks3 (2 - 5)3.1 (3 -11)
VL levels at first detection, copies/ml222 (33 - 41,822)156 (52 - 395)
Time from first VL detection to ART resumption, weeks1 (0.1 - 4.1)2 (1 - 5.3)
Time from ART resumption to VL suppression, weeks2.9 (0.9 - 10.9)2 (1.9 - 3.9)
[Characteristics at randomization and after TI in VHM+ART vs. ART arms]



Viral load kinetics following treatment interruption in VHM+ART vs. ART arms
[Viral load kinetics following treatment interruption in VHM+ART vs. ART arms]


Conclusions: In this proof-of-concept study, all 14 individuals who initiated ART during Fiebig III/IV AHI experienced VL rebound following treatment interruption regardless of VHM treatment.

E. Kroon1, J. Ananworanich1,2,3, K. Eubanks4, J. Intasan1, S. Pinyakorn2,3, N. Chomont5, S.R. Lewin6,7, S. Palmer8,9, L. Trautmann2,3, H. Yang4, N. Chomchey1, N. Phanuphak1, K. Cooper4, P. Phanuphak1,10, M. de Souza4,10, on behalf of the SEARCH 019 study group
1Thai Red Cross AIDS Research Centre, SEARCH, Bangkok, Thailand, 2Walter Reed Army Institute of Research, U.S. Military HIV Research Program, Bethesda, United States, 3Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, United States, 4Cooper Human Systems, Cambridge, United States, 5Universite de Montreal, CRCHUM and Department of Microbiology, Infectiology and Immunology, Montreal, Canada, 6University of Melbourne, The Peter Doherty Institute for Infection, Melbourne, Australia, 7The Royal Melbourne Hospital, Melbourne, Australia, 8The University of Sydney, Sydney, Australia, 9The Westmead Institute for Medical Research, Sydney, Australia, 10Thai Red Cross AIDS Research Centre, HIV-NAT, Bangkok, Thailand