An allogeneic hematopoietic cell transplantation (alloHCT) intended to cure a patient’s refractory Hodgkin lymphoma (HL) may have also put his HIV virus into remission, according to a report published in Nature by researchers from the University of Cambridge.
The outcome of the alloHCT procedure was similar to that seen with the “Berlin patient,” the first patient whose HIV was functionally cured after he underwent two alloHCTs using cells from a homozygous CCR5Δ32 donor 12 years ago. His HIV has remained in remission since the procedure 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, including the [questionable] safety of gene editing and [the feasibility of] achieving 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 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.
“[Our report] offers hope that, in the future, we may be able to use gene therapy to knock out CCR5.“
—Ravindra K. Gupta, MD
In December 2012, he was diagnosed with stage IVB (nodular sclerosing) HL. The disease was refractory to firstline ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy 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, meaning the donor had two copies of a mutation in the CCR5 gene. “This 32-base pair deletion prevents CCR5 expression, rendering these cells resistant to infection with HIV variants [through] the CCR5 coreceptor,” the authors explained.
ART was interrupted one week before transplant. The patient experienced “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 conditioning with lomustine, cyclophosphamide, cytarabine, and etoposide, followed by infusion with 3.6×106 CD34-positive cells/kg. ART continued 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 developed fever, gastrointestinal symptoms, and Epstein-Barr virus and cytomegalovirus reactivation, but all resolved.
At six months and one year following 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 expression 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 experiences: The Berlin patient received total body irradiation plus cyclophosphamide as a conditioning regimen; the London patient underwent a reduced-intensity conditioning regimen 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.
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]