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New and noteworthy research from the
medical literature landscape
Patient With HIV and Hodgkin Lymphoma Is
Virus-Free Following Transplant
An allogeneic hematopoietic cell trans-
plantation (alloHCT) intended to cure
a patient’s refractory Hodgkin lym-
phoma (HL) may have also put his HIV
virus into remission, according to a
report published in Nature by research-
ers from the University of Cambridge.
The outcome of the alloHCT pro-
cedure was similar to that seen with
the “Berlin patient,” the first patient
whose HIV was functionally cured af-
ter he underwent two alloHCTs using
cells from a homozygous CCR5Δ32
donor 12 years ago. His HIV has
remained in remission since the pro-
cedure and he was able to stop taking
antiretroviral therapy (ART).
The report that a second patient
whose disease may have been put in
remission with this type of transplant
“offers hope that, in the future, we may
be able to use gene therapy to knock
out CCR5,” lead author Ravindra K.
Gupta, MD, of the University College
London, told ASH Clinical News.
“There are a number of barriers to
making this scalable, however, includ-
ing the [questionable] safety of gene
editing and [the feasibility of] achiev-
ing high proportions of modified cells.
Another is the degree of immune
suppression needed.”
The so-called “London patient” in
the Nature paper had been diagnosed
with HIV in 2003, after presenting with
ASHClinicalNews.org
a baseline HIV-1 plasma viral load
(pVL) of 180,000 copies/mL. In 2012,
he began ART with tenofovir disoproxil
fumarate, emtricitabine, and efavirenz.
In December 2012, he was diag-
nosed with stage IVB (nodular scleros-
ing) HL. The disease was refractory to
firstline ABVD (doxorubicin, bleomycin,
vinblastine, dacarbazine) chemother-
apy and subsequent salvage regimens,
including ESHAP (etoposide, methyl-
prednisolone, cytarabine with or without
cisplatin), brentuximab, and the mini-
LEAM (lomustine, etoposide, cytarabine,
melphalan) chemotherapy regimen.
He was selected to undergo an
alloHCT after stem cell mobilization
produced insufficient results for an
autologous procedure. The transplant
team identified an unrelated, 9/10
human leukocyte antigen–matched,
homozygous CCR5Δ32 donor, mean-
ing the donor had two copies of a
mutation in the CCR5 gene. “This
32-base pair deletion prevents CCR5
expression, rendering these cells re-
sistant to infection with HIV variants
[through] the CCR5 coreceptor,” the
authors explained.
ART was interrupted one week
before transplant. The patient experi-
enced “a rapid viral rebound” of HIV-1
pVL – owing to resistance mutations
in K65R and M184V. Viral suppression
was achieved after ART regimen was
adjusted; ART continued throughout
the procedure and follow-up.
The patient then underwent con-
ditioning with lomustine, cyclophos-
phamide, cytarabine, and etoposide,
followed by infusion with 3.6×10 6
CD34-positive cells/kg. ART contin-
ued post-alloHCT.
The researchers reported that
this was “a relatively uncomplicated”
procedure: Full donor chimerism was
achieved from day 30 post-alloHCT,
and the patient was discharged at 31
days post-alloHCT. Later, he devel-
oped fever, gastrointestinal symptoms,
and Epstein-Barr virus and cytomega-
lovirus reactivation, but all resolved.
At six months and one year fol-
lowing transplant, CT/PET scans
confirmed that the patient’s HL was
in complete remission.
To monitor HIV burden, the
transplant team measured HIV-1 pVL
monthly. During the first three months
and then each month thereafter, the
HIV-1 pVL was undetectable, with a
limit of detection of <1 copy RNA/mL.
The total peripheral blood mononuclear
cell–associated HIV-1 DNA also fell
under the logarithm of the odds.
By day 876 post-alloHCT, the
total DNA in CD4-positive T cells
was undetectable in all replicates,
per quantitative polymerase chain
reaction testing (<0.65 HIV long term
repeats copies/million cells and <0.69
HIV-1 group-specific antigen copies/
million cells).
They next challenged the patient’s
T cells in vitro with the CCR5-tropic
viruses to determine if the post-
transplant CD4 cells lacked expres-
sion of CCR5 and were resistant to
HIV-1 infection. “In contrast to an
HIV-negative donor, post-transplant
cells from the study patient could not
be infected with either CCR5 tropic
virus,” they reported. “Likewise, HIV-1-
specific antibodies and avidities fell to
levels comparable to those in the Berlin
patient following transplantation.”
Per treatment protocol, ART was
interrupted 16 months after alloHCT,
after viral load was consistently <50
copies/mL. The patient has remained
off ART for 18 months as of the
report’s publication.
The findings are similar to those
of the “Berlin patient,” but Dr. Gupta
pointed out a key difference in the ex-
periences: The Berlin patient received
total body irradiation plus cyclophos-
phamide as a conditioning regimen;
the London patient underwent a
reduced-intensity conditioning regi-
men with only chemotherapy agents
that targeted lymphoma.
“[Our report] further supports
the development of HIV remission
strategies based on preventing CCR5
expression,” the authors concluded.
The authors also noted that the
transplant in this instance was intended
to treat the patient’s HL – not HIV.
So, while these findings offer hope,
Dr. Gupta reiterated that patients with
HIV have an effective treatment option
available: lifelong ART.
However, he added, “achieving
remission was a pleasant surprise,
given the patient’s significant HIV
reservoir prior to transplant and the
viral rebound that occurred in the
year before transplant with associated
drug resistance.” Longer-term follow-
up is needed before the HIV in this
patient can be considered “cured.”
The authors report no conflicts of
interest.
REFERENCE
Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV-1 remission
following CCR5Δ32/Δ32 haematopoietic stem-cell
transplantation. Nature. 2019 March 5. [Epub ahead of print]
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