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Researchers report case of bone marrow transplant patient off ART for 288 days without HIV rebound
Liz Highleyman, 2017-03-06 07:50:00
An HIV-positive bone marrow
transplant recipient at the Mayo Clinic experienced prolonged viral remission
lasting nearly 10 months – longer than the so-called Boston patients – after
interrupting antiretroviral therapy (ART), according to a report at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) last
month in Seattle. Although his viral load eventually rebounded, his HIV
reservoirs appeared to be reduced.
The only person known to be cured of HIV – Timothy Ray Brown, known as the 'Berlin Patient' – stopped ART when he received a
bone marrow transplant to treat leukaemia and has not had detectable virus for ten
years. Brown received a transplant from a donor with a double CCR5-delta-32
mutation, meaning they lack the CCR5 co-receptors most types of HIV use to
enter T-cells. It is unclear whether his sustained
remission is attributable to the donor's CCR5 mutation, the strong chemotherapy
conditioning regimen used to kill off cancerous blood cells, a
graft-versus-host reaction or multiple factors.
Bone marrow transplantation is apparently not
sufficient to eradicate HIV. A few years ago, Timothy Henrich reported on two HIV-positive bone marrow transplant patients in
Boston who got stem cells from 'wild-type' donors
without the CCR5-delta-32 mutation, received a milder conditioning regimen and
experienced acute graft-versus-host disease (GVHD).
Both men maintained undetectable viral load longer than expected after
interrupting ART, but eventually they experienced viral rebound at three and eight
months after stopping HIV treatment.
The latest case, presented by Nathan Cummins of the
Mayo Clinic in Rochester, Minnesota, and colleagues, involved a 55-year-old man who
was diagnosed with HIV in 1990
and started combination ART in 1999 with a CD4 T-cell count of 300 cells/mm3.
He stopped treatment between 2004 and 2009 for unexplained reasons, then
restarted ART consisting of ritonavir-boosted atazanavir (Prezista) plus tenofovir disoproxil fumarate (DF) and emtricitabine (the drugs in Truvada).
In April 2013 the man was diagnosed with B-cell acute lymphoblastic leukaemia.
In anticipation of chemotherapy, his ART regimen was switched to raltegravir (Isentress), etravirine (Intelence), and tenofovir
DF/emtricitabine. In October 2013 he underwent reduced intensity conditioning
followed by an allogeneic stem cell transplant from a CCR5 'wild-type' donor.
At the time of transplantation the man had an HIV viral load of 25
copies/ml and a CD4 count of 288 cells/mm3, and he stayed on ART
without interruption. After the transplant he developed opportunistic
infections (E. coli septicaemia and pneumocystis pneumonia) and experienced GVHD
at four months post-transplant.
The man continued on ART for more than two years after
transplantation, mostly with detectable plasma viral load levels. HIV RNA was
also undetectable in gut biopsy samples. HIV DNA in his peripheral blood cells
became undetectable by day 56, and
repeated leukapheresis procedures showed significant reductions in HIV RNA and
DNA reservoir size.
In addition, that man's HIV antibody levels decreased, as indicated by
weaker Western blot bands. However, single genome sequencing and phylogenetic
analysis identified identical HIV clones at day 142, possibly due to
homeostatic proliferation, or replication of latently infected cells, while he
After having such low HIV levels for a prolonged period, the man
underwent an analytic treatment interruption, or carefully monitored discontinuation
of ART. His plasma HIV RNA levels were tested every two weeks for the first 12
weeks of ART interruption, then every four weeks.
At day 288 – 9.6 months after stopping ART – he was found to have
low-level viral rebound to 60 copies/ml. This rose to 1640 copies/ml by day
293, requiring that he restart HIV treatment. The man had no evidence of drug
resistance and his viral load was re-suppressed within a month.
"Allogeneic peripheral blood stem cell transplantation in the
setting of HIV is associated with significant reductions in HIV reservoir size
by multiple measures, including prolonged combination ART-free remission,"
the researchers concluded.
They added that stem cell transplantation in the setting of suppressed
viral replication may be associated with loss of HIV-specific immunity, and
hypothesised that "immune activation in the setting of GVHD without
anti-HIV specific immunity may cause homeostatic proliferation of latently
infected cells, decreasing the chance of HIV eradication."