TAG HIV Basic Science, Vaccines, and Cure Project Blog

Sad News Regarding Attempt to Duplicate the Cure Achieved in Timothy Brown

In April, doctors at the University of Minnesota announced that they were attempting to reproduce the cure achieved in Timothy Brown in a 12-year old boy with HIV and leukemia who required a stem cell transplant. Due to the challenges associated with identifying appropriate adult stem cell donors homozygous for CCR5Δ32 (as was done for Brown), the Minnesota team—led by Dr. John Wagner—obtained cord blood stem cells from the limited available supplies that have been screened for the mutation (the current status of screening efforts is described in a recent review article). Permission was obtained from the Food and Drug Administration (FDA) to conduct the procedure, and it was performed on April 23rd.

On July 12th, the University of Minnesota reported that the boy, Eric Blue, died July 5th from complications associated with transplant. Blue developed severe graft-versus host disease (GVHD), a known risk associated with stem cell transplantation. In the news stories, the doctors express their commitment to honoring Blue's bravery by learning from his case, and highlight the need to expand screening of stored cord blood units for CCR5Δ32 in order to increase the possibility of identifying sources that are suitably HLA-matched for potential HIV-positive recipients.

Cord blood stem transplantation is an evolving field, but current practice is based on matching 6 HLA antigens (fewer than are required for adult stem cell transplants), with a 6:6 match typically viewed as ideal and 4:6 as the minimum acceptable (although some resource websites cite 3:6 as “unlikely, but possible”). There are additional complexities related to the direction of the mismatch and the dose of cord blood that is available. Although the issue does not yet seem to be entirely resolved, it has also been reported that limited mismatches may lead to superior anti-cancer effects under some circumstances. One aspect of Eric Blue’s procedure that has not been specifically addressed in the news stories or the University of Minnesota’s coverage is the extent to which the CCR5Δ32 homozygous cord blood source was HLA-matched. In order to provide guidance for future attempts to cure HIV-positive people with cancers using CCR5Δ32 homozygous cord blood, it will be important for the doctors and researchers that were involved to report the details of the case. 

Lack of Efficacy and Safety Concerns Blight Adenovirus Vaccine Vectors

Vaccine vectors based on adenoviruses—which are common in nature and cause severe colds—were once viewed as promising for HIV and other intractable diseases due to their ability to induce antigen-specific CD8 T cell responses in the majority of recipients. The subsequent Icarus-like trajectory of the approach in HIV has been covered in some detail on this blog, starting with the results of the first efficacy trial of Merck’s now-discontinued adenovirus serotype 5 (Ad5) candidate (the Step study), which showed that the vaccine significantly increased the risk of HIV acquisition and did not significantly lower viral load or preserve CD4 T cell counts in participants who became infected.

The HIV vaccine section of TAG’s new 2013 Pipeline Report covers the latest round of grim news, which emerged earlier this year with the announcement that immunizations in the lone ongoing HIV vaccine efficacy trial, HVTN 505, were being stopped at the recommendation of the Data Safety Monitoring Board (DSMB). An interim analyses conducted by the DSMB on April 22, 2013 found that the vaccine regimen—comprised of three priming immunizations with a DNA vaccine and a booster shot with an Ad5 vector (both designed by the NIH’s Vaccine Research Center)—did not show efficacy either in terms of preventing HIV infection or lowering post-infection viral load set points, and there was no possibility of efficacy being demonstrated if the trial ran to completion. The total number of infections was greater in the vaccine arm compared to placebo (41 vs. 30), but many of these infections occurred prior to the administration of the Ad5 boost and the difference was not statistically significant. Post-boost, there were 27 infections in the vaccine arm and 21 in the placebo arm.

On the heels of this announcement came word that extended follow up from the second efficacy trial of Merck’s Ad5-based HIV vaccine, the Phambili trial in South Africa, had documented significantly more infections among vaccine recipients compared to placebo recipients. The data were described by principal investigator Glenda Gray at the HIV Vaccine Trials Network meeting in Washington DC on May 7th, and reported by Jon Cohen in Science on May 10th. Although it went largely unnoticed at the time, on May 14th the National Institute of Allergy and Infectious Diseases (NIAID) issued a bulletin reporting that regulatory authorities had been notified of the Phambili findings. The bulletin notes that while the initial published analysis of the trial results did not reveal significant differences between vaccine and placebo arms, “in the current analysis of the full 3.5 year follow-up period, the researchers found that 100 study participants became HIV-infected: 63 participants who received the investigational vaccine and 37 participants who received a placebo injection. The increased number of HIV infections among the vaccinated recipients was greatest among men and more pronounced roughly 30 months after initial vaccination.” There are some potential caveats: the additional infections occurred after the study was unblinded, and there was a substantial drop-out rate that was slightly greater in the placebo arm. Also, in contrast to the Step trial where the enhanced HIV risk has been reported to have waned over time, the increased rate of infection occurred late (>2 years post vaccination). 

The accumulation of negative data has left a cloud of suspicion hanging over all investigational adenovirus-based vaccines, including those based on alternate human serotypes to Ad5 and chimpanzee-derived adenovirus serotypes. The mechanism of the apparent enhancement of HIV acquisition risk in the Step and Phambili trials remains unclear. Importantly, it is not yet known if the adenovirus vectors were somehow solely responsible or if the effect was interlinked with the immune responses to HIV that were induced by the constructs (as one small but as yet unconfirmed macaque study has suggested). Complicating matters further, evidence from the Step study indicated that the degree of pre-existing immunity to natural Ad5 (as measured by antibody titers) was correlated with the magnitude of the vaccine-associated enhancement of HIV risk. In the absence of clarity regarding these issues, there remains the worrying possibility that experimental adenovirus-based vaccines for other diseases (such as TB, malaria, and hepatitis C) could place recipients at increased risk of becoming HIV infected if they are exposed to the virus.

Currently the various stakeholders in the development of adenovirus-based vaccine candidates, including major sponsors such as NIAID and the International AIDS Vaccine Initiative (IAVI), are conducting meetings to discuss the new findings and their implications for the future. It is not yet known if planned or ongoing trials will be affected. In a related development—as reported by Mike Frick in the TB vaccine section of TAG’s Pipeline Report—plans for a large efficacy trial of an Ad35-based TB vaccine candidate have been significantly scaled back due to the observation that the approach is less immunogenic than preliminary results had suggested.

HIV Cure Research Capsules from IAS 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:

• 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 are encouraged to email [email protected] 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:

AIDSMap

HIVandHepatitis.com

i-Base

NATAP

The Body Pro

Towards an HIV Cure Symposium:

Website

Abstract book

IAS 2013 Sessions

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 - D. Persaud, United States (rapporteur summary only)

WELBA Late Breaker Track A