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Impact of Systemic Cytotoxic Chemotherapy for Malignancies on HIV-1 Reservoir Persistence
Timothy J. Henrich, Emily Hanhauser, Jonathan Z. Li, Andrea Heisey, Jeremy S. Abramson, Ayad Hamdan, Philippe Armand, Ann S. LaCasce, Daniel R. Kuritzkes *Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, United States, Brigham and Women’s Hospital, Cambridge, MA, United States, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
Background: The effects of cytotoxic chemotherapeutic agents on viral reservoir size are not well understood. Therefore, we studied the longitudinal effect of combination chemotherapy for hematologic malignancies and single-agent chemotherapy for Kaposi Sarcoma (KS) on HIV-1 reservoir size.
Methodology: HIV-infected individuals with a diagnosis of malignancy, including hematologic malignancies, KS and Multicentric Castleman’s Disease (MCD) requiring systemic chemotherapy were enrolled. Large volume peripheral blood collections were performed at time points before, during, and postchemotherapy. Flow cytometric characterizations of T lymphocyte subsets were performed and viral DNA and RNA were extracted and quantified from purified CD4+ T cells using sensitive real-time PCR assays. Residual plasma viremia was also quantified using a single-copy RNA assay.
Results: We obtained 28 samples from 15 patients (KS/MCD = 4, Hodgkin = 2, non-Hodgkin lymphoma = 9). In an analysis of all participants, a nonsignificant decrease in CD4+ T cell-associated HIV-1 DNA was observed between the pre- or earliest on chemotherapy time-points and the first postchemotherapy time-point (median 576 and 228 copies/10^6 CD4+ T cells, P=0.26 from paired analysis; see Figure). A non-significant decrease in DNA was also observed in a subset of patients on stable antiretroviral therapy with all viral loads <1000 copies/mL (N=13, median 523 and 213 copies/10^6 CD4+ cells, P=0.39). No significant changes in CD4+ T cell-associated RNA were observed, and the frequency and amplitude of residual viremia were similar across time-points. One patient with both angioblastic T-cell lymphoma and B-cell lymphoma had undetectable HIV-1 DNA and RNA from purified CD4 T cells and no detectable viremia by Cobas Taqman PCR viral load assay after 8 cycles of salvage chemotherapy with brentuximab and high-dose methotrexate. The patient died from recurrent CNS disease pending allogeneic stem cell transplantation.
Conclusions: Peripheral blood HIV-1 reservoirs persist after cytotoxic chemotherapy, although one patient had undetectable cell-associated DNA and RNA on salvage chemotherapy for T cell lymphoma. These findings suggest that cytotoxic chemotherapy may have an impact on viral reservoir size, but this effect may vary depending on specific oncologic, chemotherapeutic and viral disease factors. Further investigation of immune function, inflammation and activation in this cohort is warranted.