Fourth HIV-positive patient shows prolonged remission after stem cell transplant for AML
Presenter: Jana K. Dickter, MD, City of Hope Comprehensive Cancer Center, Duarte, California
HIV-1 remission has been previously reported in 2 men and 1 woman following allogeneic hematopoietic stem cell transplantation (aHCT).1-6 City of Hope Comprehensive Cancer Center researchers reported on a fourth patient (66-year-old male), diagnosed with HIV in 1988 who after developing acute myelogenous leukemia (AML) and undergoing aHCT, is in prolonged HIV remission without antiretroviral therapy (ART), according to Jana K. Dickter, MD, associate clinical professor, City of Hope Comprehensive Cancer Center, Duarte, California.
No detectable HIV DNA was identifiable 17 months after analytic treatment interruption (ATI) off ART and 39 months after transplant from an unrelated donor who was homozygous for a CCR5-Δ32 mutation. The patient’s chemotherapy regimen intensity was reduced to fludarabine/melphalan and prophylaxis for graft-versus-host disease consisted of tacrolimus and sirolimus.
At the time of HIV diagnosis, the patient’s nadir CD4 count was < 100 cells/µL with no history of opportunistic infections. Prior to his diagnosis of AML, his HIV was well controlled with CD4 counts of 243 to 1,007 cells/µL and HIV viral loads that were undetectable for many years. The only genotype from 1999 showed some resistance to first-generation nucleoside/nucleotide and non-nucleoside/nucleotide reverse transcriptase inhibitors. The patient had positive hepatitis B virus (HBV) core and surface antibody and achieved remission of his AML with three courses of chemotherapy. Prior to starting chemotherapy, his ART regimen was changed to emtricitabine/tenofovir alafenamide plus dolutegravir to minimize drug-drug interactions.
The best available transplant donor was an HLA-matched unrelated donor who carried the CCR5-Δ32 homozygous mutation. Human leukocyte antigen A testing demonstrated that prior to transplant, he had wild type homozygous CCR5 receptors. Pretransplant, the patient’s HIV-1 coreceptor was majority R5 virus with possibly some X4 minority variants.
Following the 2019 transplant, his only infectious complication was probable invasive pulmonary aspergillosis. Systemic immunosuppression was discontinued at 16 months, after which he developed oral graft-versus-host disease. Ten months after transplant, he initiated an HBV vaccination series, after which his HBV surface antibody level was protective. He had slow CD4 reconstitution and reached pretransplant levels by 19 months after transplant.
Chimerase testing 100 days post-transplant remained at 100% donor cells. “After ATI, his CD4 count ranged from 356 to 1,271 cells/µL post-ATI and his HIV viral load remained undetectable at < 20 copies/mL both pre- and post-transplant and post-ATI,” Dickter noted.
Reservoir testing from peripheral blood mononuclear DNA samples conducted for 2 years post-transplant were mostly negative, “but there were sporadic low-level detectable cellular HIV in blood and gut tissue,” she said.
Interestingly, the donor was HBV core antibody-negative and the recipient pretransplant was HBV core antibody-positive. More than 3 years after transplant, his HBV core antibody remains positive possibly indicating persistence of recipient plasma cells secreting antibodies.
At 37 months post-transplant and 12 months into ATI, most T cells were CD8 cells with a ratio of 0.47. Analysis of memory T cell subsets showed that 70% of CD8 cells were terminal effector or effector memory cells. In contrast, 40% of the CD4 cells were naïve central memory or stem cell memory cells.
Studies to assess responsiveness of the patient’s T cells to CMV and HIV recall antigens showed that both CD4 and CD8 cells showed robust expression of activation-induced markers in response to CD3/CD28 beads. Importantly, stimulation was seen in peptide mix resulted in marked response in both CD4 and CD8 T cells, with > 2% CMV reactive T cells. In contrast, no responses were observed by stimulation with HIV peptide mix.
“These studies indicate that at 1 year ATI, T cells are responsive to mitogenic stimuli, and donor T cells have been exposed to CMV but not HIV,” said Dr. Dickter.
When challenged with X4 and dual HIV-1 strains, recipient cells developed detectable levels of HIV p24 antigen by day 7. However, when challenged by R5 virus, they had undetectable levels of p24 antigen, demonstrating that they could not be infected with R5 virus.
Disclosure
Dr. Dickter reported no conflicts of interest.
References
- Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009; 360(7):692-698. doi: 10.1056/NEJMoa0802905
- Hutter G, Thiel E. Allogeneic transplantation of CCR5-deficient progenitor cells in a patient with HIV infection: an update after 3 years and the search for patient no. 2. AIDS 2011; 25(2):273-274. doi:10.1097/QAD.0b013e328340fe28
- Gupta RK, Peppa D, Hill AL, et al. Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. Lancet HIV 2020; 7(5):e340-e347. doi:10.1016/S2352-3018(20)30069-2
- Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature. 2019; 568(7751):244-248. doi:10.1038/s41586-019-1027-4
- Yukl SA, Boritz E, Busch M, et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog 2013; 9(5):e1003347. doi:10.1371/journal.ppat.1003347
- Bryson Y et al. HIV-1 remission with CCR5∆32∆32 haplo-cord transplant in a US woman: IMPAACT P1107. CROI 2022, 12–16 and 22–24 February, virtual meeting. Oral abstract 65.