ABSTRACT
Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal demyelinating disease of the central nervous system caused by reactivation of the JC virus in the context of immune suppression such as HIV, malignancy, and certain immunomodulatory medications. PML has been reported only rarely in multiple myeloma patients, and its presenting features and natural history in this population are not well known. We describe six cases of PML among multiple myeloma patients treated at our institution between 2013 and 2022, including two that developed on or shortly after treatment with recently developed BCMA-directed immunotherapies.
Subject(s)
JC Virus , Leukoencephalopathy, Progressive Multifocal , Multiple Myeloma , Humans , Leukoencephalopathy, Progressive Multifocal/diagnosis , Leukoencephalopathy, Progressive Multifocal/etiology , Multiple Myeloma/complications , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , JC Virus/physiology , Central Nervous System/pathology , Immunosuppression Therapy/adverse effectsABSTRACT
BACKGROUND: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 µg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , HIV Infections/drug therapy , HIV/isolation & purification , Viremia/prevention & control , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Neutralizing/adverse effects , Broadly Neutralizing Antibodies , Female , HIV/genetics , HIV Antibodies , HIV Infections/virology , Historically Controlled Study , Humans , Male , Middle Aged , Phylogeny , RNA, Viral/blood , Viral LoadABSTRACT
PURPOSE: To evaluate United States Public Health Service (USPHS) guidelines for discontinuing anticytomegalovirus (CMV) therapy in patients with AIDS who have immune recovery and quiescent retinitis after initiating highly active antiretroviral therapy. DESIGN: Cohort study of patients with CMV retinitis (Longitudinal Study of Ocular Complications of AIDS). METHODS: Participants had CMV retinitis and CD4+ T-cell counts of 50 cells/µL or fewer enrolled from 1998 through 2009 who demonstrated sustained immune recovery (2 consecutive CD4+ T-cell counts of 100 cells/µL or more at least 6 months apart) and inactive retinitis. Participants were classified into 2 groups according to anti-CMV treatment after immune recover: (1) continued anti-CMV therapy and (2) discontinued therapy. We evaluated survival, visual acuity, and CMV retinitis activity; we used propensity scores to adjust for confounding factors for these analyses. RESULTS: Of 152 participants reviewed, 71 demonstrated immune recovery, 37 of whom discontinued therapy and 34 of whom continued therapy. At immune recovery, participants continuing therapy tended to be older (44 vs 40 years; P = .09), have bilateral retinitis (53% vs 32%; P = .10), and have lower CD4+ T-cell counts (148 vs 207 cells/µL; P < .001). There were no statistical differences in any of the clinical outcomes (death, retinitis progress, visual acuity, or incidence of bilateral retinitis). Both groups lost visual acuity during follow-up, on average 1.2 letters per year (P < .01). CONCLUSIONS: Discontinuation of anti-CMV therapy after immune recovery did not increase the risk of poor outcomes. These results support the current guidelines for discontinuation of anti-CMV therapy after achievement of sustained immune recovery.
