TY - JOUR
T1 - Panobinostat, a histone deacetylase inhibitor, for latent virus reactivation in HIV-infected patients on suppressive antiretroviral therapy
T2 - A phase 1/2, single group, clinical trial
AU - Rasmussen, Thomas A.
AU - Tolstrup, Martin
AU - Brinkmann, Christel R.
AU - Olesen, Rikke
AU - Erikstrup, Christian
AU - Solomon, Ajantha
AU - Winckelmann, Anni
AU - Palmer, Sarah
AU - Dinarello, Charles
AU - Buzon, Maria
AU - Lichterfeld, Mathias
AU - Lewin, Sharon R.
AU - Ostergaard, Lars
AU - Søgaard, Ole S.
N1 - Funding Information:
We thank Carsten Schade Larsen, Alex Laursen, and Merete Storgaard for clinical guidance during the study and Henrik Støvring for biostatistical support. Amy Shaw provided technical support and Paul W Denton provided input to the drafting of the report. The study was primarily funded by The Danish Council For Strategic Research, but also received contributions from The Danish AIDS Foundation, The Augustinus Foundation, Frode V Nyegaard Foundation, SSAC Foundation, Aarhus University, Aarhus University Hospital, and the American Fund for AIDS Research. Novartis supplied panobinostat for use in the study. SRL's contribution was supported by an Australian National Health and Medical Research Council project grant 1009533 , an NHMRC Practitioner Fellowship and the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (Delaney AIDS Research Enterprise; U19AI096109 ). We wish to express our sincere gratitude to the study patients for their participation in the study.
PY - 2014
Y1 - 2014
N2 - Background: Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy. Methods: In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094. Findings: We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased signifi cantly at all timepoints when patients were taking panobinostat (p<0·0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3·5-fold (range 2·1-14·4). Panobinostat induced plasma viraemia with an odds ratio of 10·5 (95% CI 2·2-50·3; p=0·0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat. Interpretation: Panobinostat eff ectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to signifi cantly aff ect the latent HIV reservoir. Funding: The Danish Council for Strategic Research and Aarhus University.
AB - Background: Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy. Methods: In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094. Findings: We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased signifi cantly at all timepoints when patients were taking panobinostat (p<0·0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3·5-fold (range 2·1-14·4). Panobinostat induced plasma viraemia with an odds ratio of 10·5 (95% CI 2·2-50·3; p=0·0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat. Interpretation: Panobinostat eff ectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to signifi cantly aff ect the latent HIV reservoir. Funding: The Danish Council for Strategic Research and Aarhus University.
UR - http://www.scopus.com/inward/record.url?scp=84911460971&partnerID=8YFLogxK
U2 - 10.1016/S2352-3018(14)70014-1
DO - 10.1016/S2352-3018(14)70014-1
M3 - Article
AN - SCOPUS:84911460971
SN - 2352-3018
VL - 1
SP - e13-e21
JO - The Lancet HIV
JF - The Lancet HIV
IS - 1
ER -