Research Article: Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study

Date Published: November 28, 2017

Publisher: Public Library of Science

Author(s): Nathan W. Cummins, Stacey Rizza, Mark R. Litzow, Stephane Hua, Guinevere Q. Lee, Kevin Einkauf, Tae-Wook Chun, Frank Rhame, Jason V. Baker, Michael P. Busch, Nicolas Chomont, Patrick G. Dean, Rémi Fromentin, Ashley T. Haase, Dylan Hampton, Sheila M. Keating, Steven M. Lada, Tzong-Hae Lee, Sekar Natesampillai, Douglas D. Richman, Timothy W. Schacker, Stephen Wietgrefe, Xu G. Yu, Joseph D. Yao, John Zeuli, Mathias Lichterfeld, Andrew D. Badley, Sharon R. Lewin

Abstract: BackgroundNotwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia.Methods and findingsWe prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures—including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue—the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case.Conclusionsallo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs.

Partial Text: Since identification of the human immunodeficiency virus (HIV-1) as the causative agent for acquired immunodeficiency syndrome (AIDS), more than 70 million people have been infected, and an estimated 36 million people live with HIV-1 today [1]. Basic science advances in the understanding of HIV-1 have occurred at an unprecedented pace, allowing the development of numerous antiretroviral (ARV) agents, and advances in clinical science have determined optimal ways of using these drugs to reduce the morbidity and mortality associated with HIV-1 infection. Notwithstanding these impressive successes in the management of HIV-1, individuals who receive effective ARV therapy nonetheless have excess mortality compared to HIV-1 negative populations, due to the effects of inflammation and accelerated aging, manifested as increased risk of cardiovascular, metabolic, and malignant diseases [2]. Thus, a cure for HIV-1 infection is needed [3].

In June 2013, a 55-year-old HIV-1 positive man was referred to Mayo Clinic for evaluation of B-lineage acute lymphoblastic leukemia. Pre-transplant HIV-1 history is described in Table 1. Briefly, he had been first diagnosed with HIV-1 infection in 1990 and believed his infection occurred in 1982. At the time of diagnosis, his CD4 count was >500 cells/μl (reference range 365–1,437), his plasma HIV-1 RNA viral load was approximately 400 copies/ml, and he did not receive ARV therapy. In 1999, when his CD4 count had declined to approximately 300 cells/μl and his HIV-1 viral load had increased to 10,000 copies/ml, he was started on ritonavir-boosted indinavir and zidovudine/lamivudine. In 2004, he took a drug holiday. When his HIV-1 viral load had increased to approximately 10,000 copies/ml in 2009, he initiated ritonavir-boosted atazanavir and tenofovir/emtricitabine. His regimen was changed to raltegravir and tenofovir/emtricitabine in April 2013 to avoid potential drug–drug interactions with anticipated chemotherapy (as noted below). He tolerated these medications with excellent adherence, and at the time of presentation for leukemia evaluation, his anti-HIV-1 Western blot was positive, with a plasma HIV-1 viral load of 107 copies/ml and a CD4 count of 293 cells/μl (37% of CD3+ cells).

To date, the only described cure of an adult with HIV-1 is the Berlin patient, who was cured of HIV-1 following treatment for acute myeloid leukemia that included induction chemotherapy and anti-thymoglobulin treatment, followed by 2 allo-SCTs from a donor with a homozygous CCR5 Δ32 mutation [4]. Two Harvard patients who underwent reduced intensity conditioning and allo-SCT, and had significant reductions in the latent viral reservoir, eventually had virologic rebound off ART; these cases are cautionary examples that near eradication of the reservoir may not be sufficient to achieve even a functional cure [6]. We present extensive host and virologic studies on an additional HIV-1 positive individual who underwent allo-SCT. Table 3 compares clinical features between these 4 cases of prolonged ARV-free HIV-1 remission after allo-SCT. Results from our patient confirm that HIV-1 burden (as measured by total HIV-1 DNA and integrated HIV-1 DNA) can decline significantly after allo-SCT, but this is not necessarily accompanied by cure of HIV-1 infection.



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