Long-term HIV remission of a perinatally infected individual, following a hematopoietic cell transplantation from a CCR5Δ32 homozygous donor for multiple myeloma: The kyiv patient

Abstract

Abstract Introduction: Antiretroviral therapy (ART) suppresses replication of HIV, though its inability to clear the latently infected reservoir represents the largest barrier to HIV cure. To date, 8 persons with HIV (PWH) have been cured utilizing an allogeneic hematopoietic cell transplantation (HCT) from donors homozygous for the CCR5Δ32 mutation, preventing CCR5 (R5) surface expression, thus conferring resistance to R5 tropic HIV (PMID:40638109). Only persons infected as adults have been cured to date, eradication of HIV from perinatally infected PWH has not been demonstrated and were still in doubt, considering the differences noted in their latent reservoirs and mechanism of infection (PMID:31999647). Here we present the first case of a perinatally infected male from Kyiv, Ukraine, who underwent HCT for multiple myeloma and has consistently suppressed HIV RNA 3 years off of ART. Methods: HIV viral load was monitored by quantitative HIV-1 PCR q week and immune reconstitution assays assessing CD4+/CD8+ T-cell count recovery were assessed from day -6 to day 70 and q 2 weeks to day 200 and q monthly to day 700, and q 3 months to date. T-cell and myeloid chimerism assessments were performed by standard means. Serum protein electrophoresis, immunofixation, and serum free light chains were monitored regularly in addition to positron emission tomography for disease assessment. Results: A child breastfed for 2 years presented with unusual recurrent infections after birth. After his father died of an HIV-associated opportunistic infection, the mother subsequently tested positive for HIV, as did the patient (Pt) at 9 years of age. At ART initiation CD4+T-cell counts were 751 cells/µl (30.1%) with HIV RNA of 41,196 copies/ml and had prompt suppression of viremia. He was well until a sinus plasmacytoma was diagnosed at 18 years of age. Complete remission (CR) was achieved after one cycle of melphalan/prednisone and local radiotherapy, but an abdominal relapse occurred six months later. Despite subsequent lines of therapy (bortezomib(bort)/lenalidomide(lena)/dexamethasone(dexa) and bendamustine/bort/dexa), the extramedullary multiple myeloma (MM) progressed. Remission was achieved after dexa/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide (DT-PACE) and an autologous HCT performed on 1/2021. Despite two more lines of therapy and a second autologous HCT the pt continued to relapse. The European Tumor Board of the Help for Ukrainian Hematology Patients (HUP) coordinated by the EBMT recommended an allogeneic HCT while in remission of his MM. He had remained on ART throughout chemotherapy, HIV RNA remained <40 copies/ml. Allogeneic HCT was performed in 8/2022 after fludarabine/melphalan conditioning and anti-thymocyte globulin from a CCR5-Δ32homozygous, unrelated HLA-matched donor; cyclosporine/methotrexate was utilized as graft-versus-host disease (GVHD) prophylaxis. Daily telemedicine consultations with WBMT representative (D.N.) were provided because of lack of experience in the Ukrainian transplant center. Neutrophil, CD4+ and platelet reconstitution was documented on days +12, +17 and +19, respectively, and full donor engraftment on day +28. Prophylactic immunosuppression was tapered off, but following grade II GVHD reintroduced on day +139. A Self-limited CMV reactivation occurred again on day +288.From day +339 on, normal protein electrophoresis, no M-protein and normal light chains were detected. ART was discontinued on day +6 after persistent negative viral PCR. On day 24, HIV RNA of 831 copies/ml was noted and normalized without therapy. ART was restarted on day +36 but permanently discontinued on day +69 due to renal toxicity. HIV RNA levels have been <40 copies/ml for 3 years and a negative HIV-1 ELISA is now present. The pt is now +1084 days after HCT without ART and in CR of his MM, consistently HIV RNA<40 c/ml with normal CD4+ counts and negative ELISA for HIV. Conclusion: To our knowledge, this represents the first report of ART-free HIV RNA suppression following allogeneic HCT with a CCR5Δ32homozygous donor in an individual perinatally infected with HIV. Despite the differences in the latent reservoir and the mechanism of perinatal infection, sustained HIV remission and potential cure is feasible in this population. Reduced-intensity conditioning regimen, with supervisory telemedicine support for centers with limited HCT experience can be successful, even in times of war.