July 9, 2013
The 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) took place from June 30-July 3 in Kuala Lumpur and featured a pre-conference symposium and several sessions on HIV cure research. Webcasts and powerpoints of at least some presentations are being made available on the conference website (see links below).
The major news to emerge from the meeting came from a late breaker presentation by Timothy Henrich from Brigham and Women's Hospital, who provided an update on two individuals with HIV who received stem cell transplants to treat cancers. Henrich first discussed these cases at the IAS Towards a Cure Symposium in 2012, and they were subsequently described in detail in a paper in the Journal of Infectious Diseases published earlier this year (the paper is open access). Both individuals received "reduced intensity" immunosuppressive drug regimens to facilitate the transplants and remained on antiretroviral therapy (ART) throughout the procedures. Both also subsequently experienced graft-versus host disease (GVHD), which involves the newly transplanted immune system cells attacking and eliminating the original host cells. Follow-up testing during the months after the transplants showed that HIV reservoirs were no longer detectable. Unlike Timothy Brown, who received a stem cell transplant from a donor homozygous for the CCR5-Δ32 mutation, rendering his immune system largely resistant to HIV, Henrich's patients were originally heterozygous for CCR5-Δ32 and received transplants from individuals who lacked the mutation. Henrich hypothesized that continuous ART served to protect the newly transplanted immune system from HIV, while the GVHD eliminated the prior reservoir of infected cells. Immunosuppressive treatment, notably the drug sirolimus, has also been suggested as potentially playing a role (it has been associated with reductions in HIV DNA levels in another study involving kidney transplant recipients).
At the time of these initial reports, Henrich noted that plans were underway to conduct ART interruptions to assess if HIV became detectable again. At IAS 2013, it was revealed that the two individuals have now been off ART for 7 and 15 weeks, respectively. As yet, no rebound in HIV has occurred and reservoirs remain undetectable, an encouraging sign that a cure might have been achieved. However, researchers are stressing that longer-term follow-up is needed and that a delayed rebound could still occur. The story has been widely covered in the mainstream media, with perhaps the best and most detailed article authored by Donald G. McNeil Jr. in the New York Times. Keith Alcorn also posted a comprehensive report on Henrich's presentation for AIDSMap as part of their IAS 2013 coverage. As many of the stories stress, there is a high risk of mortality (20-30%) associated with stem cell transplantation and so it is only appropriate for HIV-positive individuals with cancer diagnoses requiring the procedure. It is hoped, however, that these cases can provide important clues as to how a more broadly applicable HIV cure can be achieved.
The conference also featured a case report from Jan van Lunzen and colleagues in Germany, describing an individual treated with ART very soon after infection who subsequently interrupted therapy and has maintained undetectable levels of HIV for nine years and counting. Jan van Lunzen previously mentioned this case briefly in a presentation at the 2011 HIV Persistence Workshop. Although HIV DNA and RNA cannot be detected, experiments involving the transfer of purified CD4 T cells to humanized mice have revealed the presence of replication-competent virus. The presentation was covered by AIDSMap and the abstract and figures are available on Jules Levin's National AIDS Treatment Advocacy Project (NATAP) website.
Jan van Lunzen's case appears to have some similarities with the 14 individuals in the well-publicized 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 an important and arguably somewhat neglected issue in HIV cure research: the need to create more rigorous definitions of the terms that are being used, and 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 publicized 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 was published in the New England Journal of Medicine in 1999 and he was reported to still be off ART in 2003 (during a presentation by Bruce Walker at IAS 2003); to my knowledge 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:
Researchers and clinicians are encouraged to email firstname.lastname@example.org if they may have candidates 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 viremia 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. Slides from the presentation are posted on the NATAP website. 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.
Sources of IAS 2013 news coverage:
Towards an HIV Cure Symposium:
IAS 2013 Sessions:
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.