HIV cure research: further capsules at IAS 2013
Richard Jefferys, TAG
In addition to the cases of treatment discontinuation following stem cell transplantation (Hendrich et al, reported) the focus on cure research was one of the strong themes on the conference and it featured in many of the sessions.
A case report from Jan van Lunzen and colleagues in Germany, described a 67 year-old man who was treated with ART three months after infection and one month after seroconversion (when his CD4 was <500 cells/mm3 and viral load was > 1 million/copies/mL). In 2004, after 5.5 years on ART he stopped therapy and has maintained undetectable viral load (<20 copies/mL) for nine years and currently has a stable CD4 count >900 cells/mm3. 
This case had previously been briefly described in a presentation at the 2011 HIV Persistence Workshop.  Although HIV DNA and RNA cannot be detected in plasma, PBMC, gut or CSF, experiments involving the transfer of purified CD4 T cells to humanised mice have revealed the presence of replication-competent virus.
Jan van Lunzen’s case appears to have some similarities with the 14 individuals in the well-publicised VISCONTI cohort, in that it involves post-treatment control of HIV.  However, HIV DNA remains detectable in all VISCONTI participants and they have been reported to have weak HIV-specific CD8 T cell responses. In contrast, van Lunzen found broadly directed HIV-specific CD8 T cells along with strong HIV-specific CD4 T cell responses—as measured by proliferation—in his case (no data on HIV-specific CD4 T cell responses in the VISCONTI cohort has been reported yet). The German research group also opted to designate the outcome as a “functional cure” whereas the researchers involved in VISCONTI have more conservatively described their study subjects as achieving “virological remission.”
This semantic tangle highlights important and arguably somewhat neglected issues in HIV cure research: the need to create more rigorous definitions of the terms being used and the need to obtain broader consensus about their appropriate application. It should also be noted that reports of post-treatment control are not new; one of the first widely publicised instances was an individual in Berlin (the first so-called “Berlin patient”) who was treated during acute infection and maintained viral load below 50 copies/mL after a subsequent interruption. This case also involved use of hydroxyurea and was published as a letter in the New England Journal of Medicine in 1999. 
Although this person was still off ART in 2003, reported by Bruce Walker during a presentation by at IAS 2003, there have not been any updates recently (although the individual is one of the subjects of a forthcoming book along with the person now more associated with the Berlin patient moniker, Timothy Brown).  There have also been a smattering of other reports such as those from Renslow Sherer and colleagues at the 2000 CROI,  but the extent of the virological control in these individuals appears to have been variable and it is unclear how they might compare to newer cases. The term “virological remission” shows up as far back as 1996 in an abstract from the 11th International AIDS Conference. 
To address the shortcomings in current knowledge of post-treatment control, the VISCONTI researchers (led by Asier Sáez-Cirión) announced at an IAS 2013 satellite symposium that they are launching an international collaborative effort to collect data on individuals maintaining low or undetectable levels of HIV off ART. 
The inclusion criteria are:
- Treatment initiation with VL >2000 HIV-RNA copies/mL, whatever the timing of infection
- Treatment for more than 12 months
- Viral control after treatment interruption below 400 copies/mL for at least 12 months
Researchers and clinicians who may have candidates for inclusion are encouraged to email <firstname.lastname@example.org> for inclusion.
One of the anticipated presentations at IAS 2013 was Martin Tolstrup’s first report of data from a phase I trial of an HIV latency-reversing candidate, the HDAC inhibitor panobinostat (earlier this year the trial was the subject of an erroneous but very widely distributed article in the Daily Telegraph claiming that an HIV cure was months away). 
Fifteen individuals on long-term suppressive ART participated in the study, receiving a cyclic dosing regimen of 20mg of panobinostat three times a week, every other week, for a total of eight weeks. The primary endpoint is changes in cell-associated HIV RNA, however that data is reportedly being reevaluated at the current time. Tolstrup was able to present one of the secondary endpoints, changes in low-level HIV viraemia as measured by a qualitative (not quantitative) nucleic acid detection system (the PROCLEIX ULTRIO Plus Assay, which is used for blood screening). The results of this assay indicated a significant increase in the proportion of participants with detectable low-level HIV RNA after receipt of panobinostat. 
While adding to the evidence that HDAC inhibition can coax HIV out of latency, the results are preliminary and do not shed light on the thorny question of what proportion of latently infected cells are responding to the intervention.
Additional presentations on cure research are included below with hyperlinks to the conference website.
- Press Conference: Towards an HIV Cure
- Towards an HIV Cure Symposium
http://www.iasociety.org/Web/WebContent/File/HIV_Cure_Abstract_Book_IAS2013.pdf (PDF of abstract book)
- MOBS01 Immune Activation in HIV
- MOPDA01 Multi-Faceted Aspects of Acute HIV Infection
- MOAA01 What Drives Disease Progression and Limits CD4 Recovery?
- TUAA01 Viral and Immune-Targeted Interventions: Hit Me with Your Best Shot
- TUSY01 The Roles of Secondary Lymphoid Tissues in HIV Infection: What Do We Know and Don’t Know?
- TUSA03 ANRS Satellite Symposium: What Can We Learn from Post-Treatment Controllers?
- WESY0107 Approaches to HIV cure in children and youth with perinatal HIV infection. Persaud D. (not webcast, rapporteur summary only)
- WELBA Late Breaker Track A
- Van Lunzen J et al. Functional cure after long-term HAART initiated during early HIV infection: a comprehensive case study. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Poster abstract TUPE246, Kuala Lumpur, 2013.
- Jefferys R. Workshop report and commentary: 5th HIV persistence and reservoirs workshop. HIV Treatment Bulletin. January/February 2012.
- Sáez-Cirión A et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211.
- Lisziewicz J et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999; 340:1683. (27 May 1999). DOI: 10.1056/NEJM199905273402114
- Holt N. Cured: how the Berlin patients defeated HIV. (in press)
- Sherrer R et al. No detectable HIV RNA in thirteen individuals months after stopping antiretroviral therapy. 7th Conference on Retroviruses and Opportunistic Infections, 30 January – 2 February 2000, San Francisco.
- Saimot AG et al. A triple nucleoside analogue combination in four patients with primary HIV-1 infections: towards complete virological remissions? Int Conf AIDS. 1996 Jul 7-12;11(1):112 (abstract no. Mo.B.1332).
- ANRS Satellite Symposium: What Can We Learn from Post-Treatment Controllers? 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, 2013. Non-commercial satellite.
- Jefferys R. Reviewing Strategies for Draining HIV Reservoirs. TAB basic science blog. (12 April 2013).
- Tolstrup M et al. Cyclic panobinostat (LBH589) dosing in HIV-1 patients: findings from the CLEAR trial. IAS Towards an HIV Cure Symposium 29-30th June 2013, Kuala Lumpur. Invited lecture IS 3-1.
- Dolgin E. Underestimate of HIV reservoirs threatens purging approach. Nature Medicine. Published online 04 April 2013.