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AIDS 2016: Seeking a Cure, Doctors Document Bone Marrow Transplant Recipients with HIV

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The "Berlin patient," Timothy Ray Brown, has now survived 7 years off antiretroviral therapy (ART) with no sign of HIV reappearing in his body, and as time passes his position as "the person cured of HIV" becomes more secure. However, participants at the 2016 Towards a Cure Symposium, held in advance of the recent 21st International AIDS Conference (AIDS 2016) in Durban, heard about the work of a consortium of physicians and researchers who are searching for, and documenting, the fates of patients with HIV who, like Brown, have been given stem cell transplants for cancer, in an effort to abolish Brown’s distinction as the only person to be cured of HIV.

[Produced in collaboration with Aidsmap.com]

There have been disappointments along the way in the search for more cured patients. It appeared in 2013 that we might have 2 more stem cell transplant recipients who were controlling HIV off treatment, but there was disappointment in 2014 it was revealed that in both cases, their virus had reappeared.

Stem cell transplantation will almost certainly never be a cure option for most people with HIV. It is a highly risky procedure itself, as it involves basically deleting or nearly deleting the patient’s immune system with radiation and chemotherapy. It is only a last-resort option for patients with cancers of the immune system like lymphoma or leukemia; Brown nearly died from the procedure himself.

With the patient’s immune cells thus "ablated," they are then replaced with a donation of the stem cells that are the progenitors of all other immune system cells. These stem cells come either from bone marrow from adult donors or from blood taken from the umbilical cords of newborn babies, who have them in abundance. The advantage of cord blood cells is that they do not have to be matched genetically to their recipients; adult ones must be, to avoid rejection.

In some cases, including Brown’s, the donor cells have come from the 1.0% to 1.5% of people of northern European descent (less than 0.2% elsewhere) who happen to have the CCR5-delta-32 double-deletion (homozygous) mutation, which confers resistance to HIV infection. These people lack the CCR5 receptor on their T-cells that the vast majority of HIV viruses must latch on to in order to infect the cell. People may also have a single-deletion (heterozygous) mutation, which does not confer immunity to HIV but does lead to a slower rate of disease progression in untreated people.

It is not certain, though, if using HIV-resistant stem cells this is a necessary condition for a cure. Another theory is that a phenomenon called graft-versus-host disease, in which the engrafted cells destroy remaining host cells, and which is normally an undesirable complication of transplantation, may be necessary.

The EpiStem consortium is a group of European researchers based at 7 clinics in 5 countries. Annemarie Wensing from Utrecht University in the Netherlands said that EpiStem was set up with aims that include guiding doctors on clinical procedures to use for HIV-positive bone-marrow recipients, sharing the hypersensitive assays used in cure research, exploring the ethical issues involved in procedures that could potentially cure HIV but are themselves very risky and performed on very sick patients, and searching for donors and screening them for the CCR5-delta-32 mutation. The other main aim is to study patients who have been given or are being considered for stem-cell transplants and evaluate their viral responses.

Nearly 30,000 cord blood units in multiple European blood banks and more than 1,000,000 adult donors have been genotyped for CCR5 to generate a registry of available donors with the CCR5-delta-32 deletion.

EpiStem has identified 24 HIV-positive patients so far, 15 who have had transplants. So far they have come from Belgium, Canada, Germany, Italy, the Netherlands, Spain, and the U.K., Spain, with other possible patients identified in Brazil, Serbia, and Sweden.

To underline how sick these patients are, and the gravity of the decision to give them a stem cell transplant, only 6 of the 15 identified patients are currently still alive; 8 died within 4 months of receiving their transplant and another 2.5 years afterwards. Patients either die directly from uncontrolled cancer or from opportunistic infections brought on by immune suppression pre- and post-transplant.

Of the 6 not dead, 1 is alive at 5 months, 1 at 14 months, 3 at approximately 3 years, and 1 at 5 years after transplantation. They all show signs of very low HIV DNA in their cells, as did most of the patients who did not survive. Only 2 of these 6 patients had transplants of cells with the CCR5-delta-32 double-deletion mutation, the other 4 received "wild type" cells.

Typical HIV-positive patients starting ART see a decline in HIV DNA in their peripheral blood lymphocytes (the class of cells that includes T-cells) from an average of 900 to about 400 copies per million cells during the first few years, but this soon levels out and declines no further.

There is great natural individual variability in the amount of HIV DNA "seeded" in cells, and among the 15 EpiStem patients, the amount at day 1 varied from 2 to 2000 copies per million cells. However, by 3 months after transplantation (most still being alive at that point), nearly all had no measurable HIV DNA in their cells (i.e., less than 1 copy per million cells), and after 200 days, there was only 1 detectable DNA reading in any patient.

Wensing reviewed the 3 longest-surviving patients in detail, 2 who have survived more than 3 years post-transplant and 1 more than 5 years. One of them received cord blood stem cells and 2 received matched-donor bone marrow cells. Only 1 of them received cells with the CCR5-delta-32 double-deletion mutation, the other 2 received wild type. The 2 matched-donor cell recipients -- 1 with CCR5-delta-32 double-deletion, 1 with wild-type cells -- have undetectable HIV DNA in all their samples.

So far, however, none of these patients has been taken off ART. As with another study presented at the cure symposium looking at women treated during very early infection, this will be the crucial moment when we find out whether the patients can control HIV without ART, or indeed have any HIV at all.

Clearly we hope for another Timothy Ray Brown, and it would be even more exciting if wild-type stem cell recipients stay undetectable after treatment interruption, but researchers have not yet set criteria or a date for stopping.

8/2/16

Reference

AM Wensing. Allogeneic stem cell transplantation in HIV-1-infected individuals; the EPISTEM consortium. IAS Towards a Cure Symposium, 21st International AIDS Conference. Durban, July 18-22, 2016. Abstract OA3-1.