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Searching for the next ‘Berlin patient’: doctors document bone-marrow recipients with HIV
Gus Cairns, 2016-08-01 07:40:00
patient’, Timothy Ray Brown, has now survived seven years off antiretroviral therapy
with no sign of HIV reappearing in his body, and as time passes his position
as ‘the person cured of HIV’ becomes more secure.
The 2016 Towards
a Cure Symposium held in advance of the AIDS2016
conference, however, 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 Timothy Brown, have been given stem-cell transplants, in an
effort to abolish Brown’s distinction as the only person to be cured of HIV.
There have been disappointments
along the way: it appeared
in 2013 that we might have two more stem-cell transplant recipients who
were controlling HIV off treatment, but there
was disappointment when in 2014 it was revealed that in both cases,
their viral load had reappeared.
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 near-deleting the patient’s immune system with radio- and chemotherapy. It
is only a last-resort option in patients with cancers of the immune system like
lymphoma and leukaemia; Brown nearly died from the procedure himself.
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 cells come either from bone marrow cells from adult donors, or from stem
cells found in 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
In some cases
including Brown’s, the donor cells have come from the
1.0 to 1.5% of people of north European descent (and less than 0.2% elsewhere)
who happen to have the so-called CCR5-32 double-delete (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 have to latch on to in
order to infect the cell. People may also have the single-delete (heterozygous)
mutation, which does not confer immunity to HIV but does lead to a slower rate
of disease progression in untreated people with HIV.
It is not
certain though if this is a necessary comdition for an HIV cure: another theory is that a phenomenon
called graft-versus-host disease, in which the graft cells destroy remaining
host cells, and which is normally an undesirable complication of
transplantation, may be necessary.
consortium is a group of European researchers based in seven clinics in five
of Utrecht University in the Netherlands said that EPISTEM was set up with four
main aims. Firstly, to guide doctors on clinical procedures to use for HIV
bone-marrow recipients, to share the hypersensitive assays used in cure
research, and to explore the ethical issues involved in procedures that could cure
HIV but are themselves very risky and performed on very sick patients, and to
search for donors and screen them for the delta-32 mutation.
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 CCR5-32-deletion
The other aim
is to study patients who have been given or are being considered for stem-cell
transplants and evaluate their viral responses.
identified 24 patients so far, 15 who have had transplants. So far they have come
from Canada, the UK, Spain, Netherlands, Belgium, Germany and Italy, 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 transplant,
only six of the 15 patients are currently still alive. Eight died within four
months of receiving their transplant and another one 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 six not
dead, one is alive five months, one 14 months, three approximately three years,
and one five years after transplant. They all show signs of very low HIV DNA in
their cells, as did most of the patients who did not survive.
Typical HIV-positive patients starting ART see a decline in the HIV DNA in
their 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 variability in the amount of HIV DNA ‘seeded’ in cells
and in the 15 EPISTEM patients, the amount of RNA at day one varied from 2 to
2000 copies per million cells. However by three months after transplantation (most
still being alive at that point), nearly all had no measurable HIV DNA in their
cells (i.e. less than one copy per million cells), and after 200 days, there
was only one detectable DNA reading in any patient.
Only two of
these six patients had transplants of cells with the CCR5-32 double-delete
mutation, the other four were ‘wild type’.
reviewed the three longest-surviving patients in detail, two who have survived
more than three years post-transplant and one more than five years. One of them
received cord blood stem cells and two matched-donor bone marrow cells. Only
one of them received cells with the CCR5-32 double-delete mutation, the other two
received wild type. The two matched-donor cell recipients, one with CCR5-32 double-delete,
one with wild-type cells, have undetectable HIV DNA in all samples.
however, none so far has been taken off antiretroviral therapy (ART). As with another
study presented at the Cure Symposium of women treated in 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 at all.
hope for another Timothy Ray Brown, and it would be even more exciting if the wild-type
recipient stayed undetectable after treatment interruption, but researchers have
not yet set criteria or a date for stopping.