A London man has no remaining detectable HIV a year and a half after
undergoing a bone marrow stem cell transplant to treat lymphoma, researchers
are reporting this week at the Conference on Retroviruses and Opportunistic
Infections (CROI 2019)
in Seattle.

Ravindra Gupta, now at the University
of Cambridge, will present the case on Tuesday, but after a premature embargo break
many media outlets reported the findings in advance, with some suggesting that
the case represents a second HIV cure, similar to that of Timothy Ray Brown,
known as the ‘Berlin patient’.

Brown – the
first and so far only person known to have been cured of HIV
– received two stem cell transplants to treat leukaemia in 2006. The donor had double
copies of an uncommon gene mutation known as CCR5-delta-32 that results in
missing CCR5 co-receptors on T cells, the gateway most types of HIV use to
infect cells. He underwent intensive conditioning chemotherapy and whole-body
radiation to kill off his cancerous immune cells, allowing the donor stem cells
to rebuild a new HIV-resistant immune system.

As described at the 2007 CROI, Brown stopped antiretroviral
therapy at the time of his first transplant but his viral load did not rebound.
Researchers extensively tested his blood, gut, brain and other tissues, finding
no evidence of replication-competent HIV anywhere in his body. This week Brown
celebrated 12 years free of HIV at a community cure workshop prior to the
conference.

Other attempts to discontinue antiretroviral therapy in
HIV-positive bone marrow transplant recipients have been less successful.
Timothy Henrich, now at the University of California at San Francisco, and
colleagues attempted to reproduce Brown’s cure in two cancer patients in Boston,
but in those cases the donors had normal or ‘wild-type’ stem cells that remained
susceptible to HIV, they received less intensive chemotherapy and they stayed
on antiretroviral therapy.

After no HIV could be detected in their blood and tissues for years, the
men underwent closely monitored treatment interruptions. Although their HIV
remained in remission longer than expected – for three and eight months – eventually
their virus returned
, showing that the stem cell transplant process
itself is not enough to eradicate HIV. More recently, researchers reported that
a bone marrow transplant recipient in Minnesota had viral remission lasting
nearly 10 months after an analytic treatment interruption, but he
too ultimately experienced viral rebound
.

The so-called ‘London patient’, who remains anonymous, underwent stem cell
transplantation to treat Hodgkin lymphoma in May 2016. Like Brown, his donor
had a double CCR5-delta-32 mutation.

The man continued on his antiretroviral regimen of dolutegravir (Tivicay), rilpivirine (Edurant) and lamivudine. He also received
less aggressive conditioning chemotherapy (lomustine, cyclophosphamide,
cytarabine and etoposide), alemtuzumab (Campath,
a monoclonal antibody that targets CD52 on malignant B and T cells), and cyclosporine-A
and methotrexate, immunosuppressive drugs used to prevent graft-versus-host
disease (when transplanted immune cells attack the recipient’s body).

The transplant led to complete lymphoma remission and testing
showed that the man’s CD4 T cells now lack CCR5 receptors. Extensive testing of
blood plasma and T cells revealed undetectable HIV and his HIV-specific
antibody level also dropped. About 10 weeks post-transplant he developed mild
graft-versus-host disease, which resolved on its own. He also experienced
reactivation of pre-existing Epstein-Barr virus (EBV) and cytomegalovirus (CMV)
infection, which were treated.

The man stopped antiretroviral therapy in an analytic treatment
interruption 17 months after the transplant. His blood viral load remains
undetectable 18 months later, no HIV DNA can be found in peripheral CD4 cells using
a sensitive assay with a 1 copy/ml limit and tests showed no “reactivatable”
virus in 24 million resting T cells. One blood sample revealed bits of viral
genetic material, which may reflect laboratory contamination or defective virus
that is unable to replicate. Unlike Brown, the London patient has not yet
undergone testing for residual HIV in his gut and other tissues.

These findings demonstrate that “the Berlin patient was not
an anomaly,” the researchers said. What’s more, this current case shows
that remission can happen without harsh conditioning chemotherapy or radiation.
While this appears to be the second longest adult HIV remission yet observed, they acknowledge that “it is premature to
conclude that this patient has been cured.”

A poster presented at CROI described another case of long-term HIV
remission after a stem cell transplant from a donor with a double CCR5-delta-32
mutation. This patient, treated in Dusseldorf, underwent the procedure in
February 2013 to treat acute myeloid leukemia. The man remained on
antiretroviral therapy with undetectable viral load until November 2018.
Extensive testing showed no viral DNA in his bone marrow, gut tissue samples
rectal tissue samples or lymph nodes. The Dusseldorf patient stopped antiretroviral
therapy in November 2018, still has undetectable HIV and is undergoing
continued monitoring.

Experts
caution that even if CCR5-delta-32 stem cell transplantation can lead to a
functional cure of HIV, this high-risk procedure will not be an option for most
people. Stem cell transplantation is life-threatening – Brown nearly died
during the process and was left with lasting side-effects. However, this new
case adds to the evidence that using gene therapy to delete CCR5 receptors from
T cells may be a feasible approach.

“This is
not a treatment appropriate for people with HIV who do not have cancer,”
the Treatment Action Group said in a statement. “The hope is that lessons
can be learned to help develop more widely applicable therapeutic approaches
for attaining HIV remissions or cures.”