Two people with HIV who received stem cell transplants for
the treatment of lymphoma are now controlling HIV replication without
medication in the early weeks of treatment interruption, following the
discovery that both had experienced loss of detectable HIV DNA, researchers
from Boston reported on Wednesday at the 7th International AIDS
Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala
Although the treatment patterns of the two patients bear
some similarities to the 'Berlin patient' – who experienced a 'functional cure' of HIV infection
after aggressive chemotherapy, immunosuppressive treatment and a bone marrow
transplant from a donor with genetic resistance to HIV – the 'Boston patients'
also differ in several respects, which could provide important clues about how
remission from active HIV infection could be achieved in other people with
longstanding HIV infection.
"This is not a practical strategy that we can do for most people with HIV. Stem cell transplantation is dangerous." Dr Timothy Henrich
The findings were reported by Timothy Henrich of Brigham and
Women’s Hospital, Boston, who has led the team conducting extensive tests on
the patients. They concern a small group of people with HIV who were
evaluated after hematopoietic stem
cell transplants for lymphoma at hospitals in Boston (transfer of stem cells
that will replace all blood cells, derived the from genetically matched donors). Three patients were originally evaluated
but one died of recurrent Hodgkin's lymphoma six months after the transplant.
Both the surviving patients had been receiving prolonged
antiretroviral therapy and received stem cell transplants with a
reduced-intensity conditioning regimen of chemotherapy designed to eradicate
the cancer and eliminate the existing bone marrow. In the case of the two
patients under investigation, the conditioning regimen did not include
radiotherapy and it did not eliminate the residual lymphocyte population. In
contrast, the 'Berlin patient' received a much more aggressive regimen which
eliminated existing bone marrow cells.
The transplants also differed from the 'Berlin patient'
because they did not come from donors with genetic resistance to HIV infection
(a CCR5 delta 32 mutation), so the cells were susceptible to HIV infection.
Measurements of HIV DNA showed that, around 200 days after
transplant, HIV DNA levels had declined below 50 log copies per million PBMCs (peripheral blood mononuclear cells, part
of the immune system) in
one patient, while HIV DNA fell below this level around 280 days after
transplant in the other patient. In both cases, HIV DNA levels have continued to
decline after this point. After transplantation, the two patients have been
followed for 21 (patient A) and 42 months (patient B), respectively.
More sensitive HIV DNA testing using larger samples of blood
obtained by leukapheresis and rectal tissue biopsy showed that HIV DNA was
below the limit of detection in both patients. Patient A provided a sample of
25 million PBMCs, and testing with a limit of detection of 0.07 copies per
million PBMCs failed to detect HIV DNA. Patient B provided a sample of 50
million PBMCs, and testing with a limit of detection of 0.01 international units
per million PBMCs similarly failed to detect HIV DNA.
Viral co-culture from CD4 lymphocytes failed to detect HIV
in either patient. A rectal biopsy in patient B failed to detect HIV DNA in
rectal cells that would be expected to provide a reservoir for HIV (limit of
detection 2 copies per million cells).
After establishing that HIV DNA could not be detected, the
researchers conducted extensive discussions with the patients and healthcare
providers over a six-month period about the acceptability of an experimental
treatment interruption in order to test viral control off medication.
Both patients consented after review of the study protocol
by an internal review board. The patients are now being intensively monitored
with weekly viral load (RNA) tests and bi-weekly testing of HIV DNA in PBMCs
and, after six to eight weeks, the patients gave large volumes of blood for more sensitive
analysis of HIV DNA. Leukapheresis will be repeated every three months.
To date, Patient A has been off treatment for seven weeks and
Patient B for 15 weeks. Neither patient has yet shown any evidence of viral
replication by RNA testing or any evidence of HIV DNA in PBMCs. Week-six testing
of larger blood samples from Patient B has similarly failed to detect HIV.
Neither transplant recipient showed any evidence of HIV-specific
Timothy Henrich told reporters that the research group
believes the substantial reduction in the viral reservoir to be a consequence
of a post-transplant graft-versus-host reaction.
“This graft-versus-host effect clears out the residual host
cells,” he said. “For six to nine months after the reduced intensity
conditioning transplant, we see a mingling of the donor and host cells, and what
happens over time is that the donor cells clear out the host cells. The
peripheral blood lymphocytes that it clears out are a major reservoir for HIV.
What we think is happening is that there is a non-specific clearing by the
donor cells which recognise the host cells as being just a little bit different.”
Testing carried out around 200 days after the transplant
showed that in both patients host cells had been almost entirely replaced by
donor-derived PBMCs; only 0.00041-0.00081% of PBMCs were still host-derived in
one patient, and the distribution was almost identical in the other patient.
Donor cells seem to be protected “by the fact that we kept
them on antiretroviral therapy during and after transplantation while the
residual reservoir was decaying and the new donor cells were taking over”, said
The researchers are careful not to describe their findings
as a functional cure. Professor Dan Kuritzkes of Brigham and Women’s Hospital
and Harvard Medical School, also a member of the research group, commented that
previous studies of structured treatment interruption showed that the majority
of patients had experienced viral rebound within two to four weeks, virtually
everyone was viremic by week eight, and most reached a plateau in viral rebound by
weeks 12 to 16. “In each study one or two patients tend to lag behind the others,
so that’s why we’re being careful,” he said.
Researchers do not rule out the re-emergence of virus
replication after a year, which is why intensive sampling will continue for the
Henrich dismissed any suggestion that a future approach to either a functional or sterilising cure might involve stem cell transplants.
“This is not a
practical strategy that we can do for most people with HIV. Stem cell
transplantation is dangerous. There can be up to 20% mortality associated with
stem cell transfer in the first year after transplantation,” Dr Henrich told
The chief value of the study will be in what it tells
researchers about the reductions in HIV DNA that might need to be achieved in
order to control HIV off treatment, Timothy Henrich concluded.
“How low do we need to go – what level of reduction of the
reservoir do you need in order to achieve a lasting impact? We hope our study
will shed light on this important question.”