SEATTLE — A second patient has achieved sustained HIV remission following allogeneic hematopoietic stem-cell transplantation (allo-HSCT) with a less intensive conditioning regimen, a researcher said here.
Almost two decades after the original “Berlin patient,” a second patient has achieved sustained HIV remission, this time for 18 months after interruption in antiretroviral therapy, following an allogeneic hematopoietic stem-cell transplantation procedure, reported Ravindra K. Gupta, PhD, of University College London in England, and colleagues.
They noted several similarities between the two patients, including that both had cases of CCR5-tropic HIV infection and receipt of a CCR5Δ32/Δ32 transplant, both had minor graft versus host disease, which may have contributed to the loss of HIV-infected cells, and that both achieved “full donor chimerism in peripheral blood that may have contributed to reduced reservoir size.”
These findings are being presented in a late-breaking presentation at the Conference on Retroviruses and Opportunistic Infections (CROI), and were published in a research letter in Nature.
Paul Volberding, MD, director of the University of California San Francisco’s AIDS Research Institute, who was not involved with the research, characterized this as more of a research finding than a clinical one — but definitely encouraging.
“On one hand, it’s not surprising, because it’s not the first time this has happened,” Volberding told MedPage Today. “And I think 18 months is getting to the point where it’s already notable. Not as long as Timothy Ray Brown [the Berlin patient], of course, but absolutely worth watching.”
But Gupta and colleagues also commented on several differences between the two patients, most notably that the second patient received “a reduced intensity chemotherapy regimen,” which consisted of “chemotherapy agents with known activity against lymphoma,” while the Berlin patient received total body irradiation and cyclophosphamide as the conditioning agent, the authors said.
Volberding noted the difference in the second patient’s procedure, stating, “I think the encouraging thing is the conditioning appeared less rigorous and less fearful, so I think it opens more people up to possibly attempting this.”
Other differences included that the second patient achieved remission after a single allogeneic hematopoietic stem-cell transplantation, while the Berlin patient had a relapse of acute myeloid leukemia and “received chemotherapy with an anti-CD33 monoclonal conjugate” before a second allo-HSCT procedure.
The new patient, who was not identified even by sex, was diagnosed with HIV in 2003, and with stage IVB Hodgkin’s lymphoma in 2012. Following the lymphoma diagnosis, the patient was switched to an antiretroviral therapy regimen of rilpivirine (RPV), lamivudine (3TC) and dolutegravir (DTG) and achieved viral suppression, Gupta’s group said. But “mobilization of autologous peripheral blood stem cells failed despite the use of CXCR4 agonists,” they wrote. The patient then underwent allogeneic hematopoietic stem-cell transplantation procedures using cells with a homozygous mutation coreceptor CCR5 (CCR5Δ32/Δ32).
The donor was from an international registry, and the authors noted that the patient’s regimen of antiretroviral therapy was maintained throughout. They characterized the allogeneic hematopoietic stem cell transplantation as “relatively uncomplicated,” as the patient was discharged on day 31.
“Full-donor chimerism was achieved in the whole leukocyte and in CD3+ T cell fractions from day +30 and maintained in both cell fractions throughout,” Gupta and colleagues wrote, adding that the host genotype was CCR5wt/wt prior to the procedure and was CCR5Δ32/Δ32 afterwards.
Importantly, antiretroviral therapy was interrupted in the second patient 16 months after transplantation. Weekly plasma viral load was performed for the first 3 months and then monthly thereafter the authors said, but HIV viral load remained “undetectable” (limit of detection <1 copy RNA/ml), along with undetectable HIV DNA in peripheral CD4 T lymphocytes.
To confirm that post-transplant CD4 cells were resistant to HIV infection, researchers challenged CD4 T cells from the patient in vitro with CCR5-tropic viruses. But in contrast to a negative donor, they found “post-transplant cells from the study patient” could not be infected with this type of virus, though they could be infected with the CXCR-4-tropic HIV.
‘It’s Not For Everyone’
Timothy Henrich, MD, also of the University of California San Francisco, and a reviewer of the paper, told MedPage Today that this approach won’t be broadly applicable, at least for now. Finding someone who not only needs a transplant, but for whom this exact type of genetic match can be found, would be difficult, he said.
“Transplant has a lot of morbidity and mortality, and it’s not for everyone,” Henrich said. “It’s not for the majority of transplant patients with HIV.”
But Henrich still saw some longer term implications of this research, citing the example of potentially doing cord blood bank screening for CCR5.
Volberding agreed that bone marrow transplant would never be a “scalable approach” for treating HIV patients, but said that it underscored the role of CCR5 deletions.
“It certainly helps support attempts at gene editing, which at this point isn’t scalable, but I think is more likely to be scalable than transplants, per se,” he said.
This study was supported by a Wellcome Trust Senior Fellowship in Clinical Science, research capability funding from UCLH BRC, Oxford and Cambridge Biomedical Research Centres, amfAR, the MRC, a NIHR Clinical Lectureship and support from the NIHR and Imperial Biomedical Research Centre.
The authors disclosed no conflicts of interest.