In the spring of 2013, a wildly inaccurate Daily Telegraph story about HIV cure research claiming “there will be a breakthrough in finding a cure for HIV within months” was amplified around the Internet, understandably receiving a massive amount of attention and interest. To their credit, the researchers whose work prompted the piece published a statement addressing the inaccuracies, and eventually the Telegraph made extensive corrections. Recently, in the debut issue of The Lancet’s new online HIV journal, results from the trial at the center of the story were published - to no fanfare whatsoever.
The drug being tested was the HDAC inhibitor panobinostat, which has been reported to reverse HIV latency in laboratory experiments. In the 15-person phase I trial, a small but significant increase of approximately 2-3 fold in cell-associated HIV RNA was documented, and plasma viremia was more frequently detected compared to baseline. A transient decrease in the amount of total HIV DNA in the blood was captured at day 14 of the study, but otherwise no measures of the HIV reservoir (including levels of replication-competent virus) were altered by panobinostat. A subset of nine study participants subsequently underwent an analytical treatment interruption, and HIV viral load rebounded to over 1,000 copies in all cases within a median of 17 days (range 14–56). The main side effect of the drug was fatigue, and no adverse events of greater than grade 1 occurred. However, as noted in an accompanying commentary by Stephen Kent and Miles Davenport, HDAC inhibitors have been shown to cause long-term changes in expression of multiple genes, so long-term safety will need to be carefully monitored.
The results appear consistent with clinical trials of the HDAC inhibitors vorinostat and romidepsin, which also indicated that the drugs could activate at least some latent HIV. The romidepsin trial results were presented by Dr. Ole Søgaard at the International AIDS Society Towards an HIV Cure Symposium in July, and both the powerpoint presentation and an audio file are available online. The lack of a significant reduction in the HIV reservoir supports the proposal that additional interventions are needed to promote clearance of HIV-infected cells after latency is reversed, and Søgaard and colleagues are now exploring this possibility by combining romidepsin with therapeutic vaccination.
The panobinostat paper does offer a hint of a greater effect of the drug in four participants, but these types of post-hoc (not planned in the original study protocol) subset analyses have to be interpreted with great caution. In these individuals, a decline in total HIV DNA levels of around 67–84% is reported to have persisted, and was correlated with a slightly longer time to viral load rebound during the analytical treatment interruption. At the recent Strategies for an HIV Cure meeting, which took place at the National Institutes of Health in Bethesda in October, Mathias Lichterfeld presented some preliminary data associating this delayed time to viral load rebound with interferon-stimulated gene expression and natural killer cell activity, suggesting a role for innate immunity. Given the small number of participants and the fact that the analyses are all post-hoc, these results can only be considered exploratory and require confirmation.
Beyond the results obtained with individual candidates, there is a notable larger issue that looms over latency-reversing approaches generally. The experience of the Boston patients has demonstrated that significant HIV reservoir reductions of around 3 logs (1,000-fold) can lead to delayed viral load rebound after ART interruption, but not a cure. This is in line with mathematical modeling by Alison Hill (published recently in PNAS) which estimates that an HIV reservoir reduction more on the order of 5-6 logs (100,000-1 million-fold) would be needed to achieve a long-term cure in most people. In this context, the fact that no latency-reversing strategy has yet had any significant effect on HIV reservoir levels does not seem very encouraging. But, in case that sounds like doom saying, it’s also true that the work is at an early stage, and latency reversal is just one of many strategies being pursued in HIV cure research.
The Lancet HIV, Volume 1, Issue 1, Pages e13 - e21, October 2014
Published Online: 16 September 2014
Dr Thomas A Rasmussen MD a , Martin Tolstrup PhD a, Christel R Brinkmann PhD a, Rikke Olesen PhD a, Christian Erikstrup MD b, Ajantha Solomon c, Anni Winckelmann a, Sarah Palmer PhD d, Prof Charles Dinarello MD e, Maria Buzon PhD f g, Mathias Lichterfeld MD f g, Prof Sharon R Lewin PhD c h, Prof Lars Østergaard DMSc a, Ole S Søgaard MD a
a Department of Infectious Diseases, Aarhus University Hospital, Denmark
b Department of Clinical Immunology, Aarhus University Hospital, Denmark
c Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia
d Westmead Millennium Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
e Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, Aurora, CO, USA
f Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA
g Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA
h Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia
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 significantly 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 effectively 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 significantly affect the latent HIV reservoir.
The Lancet HIV, Volume 1, Issue 1, Pages e2 - e3, October 2014
Published Online: 16 September 2014
Stephen J Kent, Miles P Davenport
Purging latent HIV with reactivating drugs is one of the most promising approaches to curing HIV infection. In The Lancet HIV , Thomas Rasmussen and colleagues report results of a phase 1/2 trial 1 of panobinostat, a histone deacetylase inhibitor, to reactivate latent HIV. They show that the drug was well tolerated in the short term and the treatment increased both the amount of cell-associated HIV RNA and low-level transient HIV viraemia. There was, however, no overall change in measurements of the HIV reservoir after 8 weeks of panobinostat treatment.