Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years.

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations. METHODS: We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality. RESULTS: After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher. CONCLUSIONS: Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.).

Mycobacterial Immune Reconstitution Inflammatory Syndrome in HIV is Associated With Protein-Altering Variants in Hemophagocytic Lymphohistiocytosis-Related Genes.

People with HIV (PWH) and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy. The pathophysiology of mycobacterial-IRIS overlaps with primary hemophagocytic lymphohistiocytosis (pHLH). To assess possible genetic predisposition to IRIS, protein-altering variants in genes associated with HLH were evaluated in 82 PWH and mycobacterial infections who developed IRIS (n = 56) or did not develop IRIS (n = 26). Protein-altering variants in cytotoxicity genes were found in 23.2% of IRIS patients compared to only 3.8% of those without IRIS. These findings suggest a possible genetic component in the risk of mycobacterial IRIS in PWH. Clinical Trials Registration. NCT00286767, NCT02147405.

Severe Mycobacterial Immune Reconstitution Inflammatory Syndrome (IRIS) in Advanced Human Immunodeficiency Virus (HIV) Has Features of Hemophagocytic Lymphohistiocytosis and Requires Prolonged Immune Suppression.

BACKGROUND: People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity. METHODS: HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell subsets were assessed at baseline and IRIS-equivalent time points. RESULTS: HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6-114.8) and for longer duration (21.2; 95%CI: 10.7-31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNγ-IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. CONCLUSIONS: Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS [FIRIS]). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS.

Polyfunctional Antigen Specific CD4+ T cell Responses in Patients With Human Immunodeficiency Virus/AIDS and Histoplasmosis Immune Reconstitution Inflammatory Syndrome.

In the combination antiretroviral era, there are limited data regarding the pathogenesis of histoplasmosis immune reconstitution inflammatory syndrome (IRIS) in people with human immunodeficiency virus (HIV). We immunologically characterized 10 cases of histoplasmosis, 4 of whom developed histoplasmosis IRIS. CD4+ T cells in histoplasmosis IRIS demonstrated a significant polyfunctional cytokine response to histoplasma antigen.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Disseminated Mycobacterium marinum in Human Immunodeficiency Virus Unmasked by Immune Reconstitution Inflammatory Syndrome.

Distinguishing disseminated Mycobacterium marinum from multifocal cutaneous disease in persons with human immunodeficiency virus/AIDS can present a diagnostic challenge, especially in the context of immune reconstitution inflammatory syndrome (IRIS). In this work, we demonstrate the utility of flow cytometry and whole genome sequencing (WGS) to diagnose disseminated M. marinum unmasked by IRIS following initiation of antiretroviral therapy. Flow cytometry demonstrated robust cytokine production by CD4 T cells in response to stimulation with M. marinum lysate. WGS of isolates from distinct lesions was consistent with clonal dissemination, supporting that preexisting disseminated M. marinum disease was uncovered by inflammatory manifestations, consistent with unmasking mycobacterial IRIS.

Eight-day Inpatient Directly Observed Therapy for Antiretroviral Therapy (ART) Failure: A Tool For Preventing Unnecessary ART Changes and Optimizing Adherence Support.

Eight-day inpatient directly observed therapy confirmed nonadherence as the major cause of virologic failure for 9 (45%) of 20 highly treatment-experienced persons with human immunodeficiency virus, extensive antiretroviral drug resistance, and high self-reported adherence rates, preventing unnecessary regimen changes.

Utilization of Direct Oral Anticoagulants in People Living with Human Immunodeficiency Virus: Observational Data from the District of Columbia Cohort.

BACKGROUND: Direct oral anticoagulants (DOACs) have become first-line treatment for venous thrombotic events. DOAC prescribing trends among people living with human immunodeficiency virus (PWH) are not well described. The coadministration of DOACs with the antiretroviral (ARV) pharmacokinetic boosters ritonavir (RTV) or cobicistat (COBI) may be complicated by pharmacokinetic interactions. METHODS: A longitudinal cohort study was conducted using the D.C. Cohort Database in Washington, D.C., from January 2011 to March 2017, to describe oral anticoagulant prescribing among PWH ≥ 18 years old and the prevalence of DOAC use with RTV or COBI. Data collection included demographic and clinical characteristics, ARV and anticoagulant prescriptions, and International Classification of Diseases Ninth and Tenth Edition diagnosis codes. RESULTS: Among 8315 PWH, there were 236 anticoagulant prescriptions (96 DOAC, 140 warfarin) for 206 persons. PWH prescribed anticoagulants were predominantly Black (82%) and male (82%), with a mean age at anticoagulant initiation of 56 years. DOAC use increased from 3% of total anticoagulant prescribing in 2011 to 43% in 2016, accounting for 64% of all newly recorded anticoagulant prescriptions by 2016. There were 19 bleeding events recorded among 16 individuals. Despite the Food and Drug Administration label recommendation to avoid rivaroxaban with boosted ARVs, 41% remained on boosted ARVs after rivaroxaban initiation. CONCLUSIONS: DOAC use increased substantially in PWH by 2016. Although rivaroxaban is not recommended with RTV or COBI, concomitant use was recorded in 41% of rivaroxaban recipients in this cohort. As DOAC usage increases, clinicians need to be aware of potential DOAC/ARV interactions in order to select the most appropriate oral anticoagulant and monitoring plan for PWH.

Multicenter Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapenem-Resistant Enterobacteriaceae Infections.

Ceftazidime-avibactam is a novel cephalosporin-beta-lactamase inhibitor combination that is active against many carbapenem-resistant Enterobacteriaceae (CRE). We describe a retrospective chart review for 60 patients who received ceftazidime-avibactam for a CRE infection. In-hospital mortality was 32%, 53% of patients had microbiological cure, and 65% had clinical success. In this severely ill population with CRE infections, ceftazidime-avibactam was an appropriate option.

Case-case-control study of patients with carbapenem-resistant and third-generation-cephalosporin-resistant Klebsiella pneumoniae bloodstream infections.

Strains of third-generation-cephalosporin-resistant Klebsiella pneumoniae (3GCRKP) and carbapenem-resistant K. pneumoniae (CRKP) are rapidly spreading. Evidence is needed to establish whether differences exist between patients at risk for 3GCRKP and those at risk for CRKP bloodstream infections (BSIs); thus, this retrospective case-case-control study was conducted to determine if the risk factors for these two infections differ. The inclusion criteria for cases were positive blood cultures for K. pneumoniae, first episode of BSI, age of ≥18 years, and susceptibility results indicating resistance to either third-generation cephalosporins (3GCRKP group) or carbapenems and cephalosporins (CRKP group). Controls were patients admitted for ≥72 h and were matched to cases by month/year and medical unit. Variables of interest were analyzed by univariate analysis, and those of significance were analyzed by logistic regression. In total, 111 patients with 3GCRKP BSIs and 43 patients with CRKP BSIs were matched to 154 controls. Multivariate analyses of 3GCRKP case and control groups demonstrated that a length of stay (LOS) of >40 days (odds ratio [OR], 17.7; 95% confidence interval [CI], 3.7 to 84.3), the use of antibiotics in the past 90 days (OR, 4.3; 95% CI, 1.5 to 11.9), and the presence of a central venous catheter (OR, 4.1; 95% CI, 1.3 to 13.4) were independent risk factors. Multivariate analyses of the CRKP case and control groups demonstrated that a LOS of >40 days (OR, 13.5; 95% CI, 2.9 to 62.8) and the use of antibiotics in the past 90 days (OR, 5.9; 95% CI, 1.3 to 26.5) were independent risk factors. Similar factors put patients at risk for these two types of K. pneumoniae BSIs.

Immune reconstitution inflammatory syndrome drives emergence of HIV drug resistance from multiple anatomic compartments in a person living with HIV.

Reservoirs of HIV maintained in anatomic compartments during antiretroviral therapy prevent HIV eradication. However, mechanisms driving their persistence and interventions to control them remain elusive. Here we report the presence of an inducible HIV reservoir within antigen-specific CD4+T cells in the central nervous system of a 59-year-old male with progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome (PML-IRIS). HIV production during PML-IRIS was suppressed by modulating inflammation with corticosteroids; selection of HIV drug resistance caused subsequent breakthrough viremia. Therefore, inflammation can influence the composition, distribution and induction of HIV reservoirs, warranting it as a key consideration for developing effective HIV remission strategies.

High-level dolutegravir resistance can emerge rapidly from few variants and spread by recombination: implications for integrase strand transfer inhibitor salvage therapy.

The integrase strand transfer inhibitor (INSTI) dolutegravir is commonly used in combination antiretroviral therapy regimens and retains strong potency even with primary resistance mutations to some other INSTIs. Acquisition of accessory mutations to primary mutations results in significant increases in dolutegravir resistance. Previously, we reported that addition of the secondary mutation T97A can result in rapid treatment failure in individuals with INSTI mutations at positions 140 and 148. Here, we conducted a detailed case study of one of these individuals and find that T97A-containing HIV emerged from a large replicating population from only a few (≤4) viral lineages. When combined with primary INSTI resistance mutations, T97A provides a strong selective advantage; the finding that T97A-containing variants spread by replication and recombination, and persisted for months after discontinuing dolutegravir, has important implications as dolutegravir is rolled out worldwide.

Rapid Development of High-Level Resistance to Dolutegravir With Emergence of T97A Mutation in 2 Treatment-Experienced Individuals With Baseline Partial Sensitivity to Dolutegravir.

HIV integrase mutation T97A emerges after suboptimal therapy with integrase strand transfer inhibitors (INSTIs), but the contribution of T97A to dolutegravir resistance remains uncertain. Here we report >10-fold increase in dolutegravir resistance after the single addition of T97A in 2 individuals with prior INSTI resistance receiving dolutegravir salvage therapy.

Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV-Infected Patient Following Oral and Jejunostomy-Tube Administration.

The use of enteral feeding tubes to administer antiretroviral medications is necessary in certain patients with human immunodeficiency virus (HIV) infection. However, adequacy of drug exposures after these administration routes are largely unknown, making dosing recommendations and the attainment of viral suppression challenging in this patient population. This report describes a patient with advanced HIV infection and a complicated medical history including long-term intractable nausea/vomiting necessitating antiretroviral medication administration via a Roux-en-Y jejunostomy (J)-tube. Pharmacokinetic assessments were performed to compare differences in antiretroviral drug absorption and plasma exposure following oral and J-tube administration of dolutegravir, tenofovir disoproxil fumarate, and emtricitabine. Results were also compared with published pharmacokinetic data in HIV-infected individuals. Exposure to dolutegravir and tenofovir were similar between J-tube and oral administration routes, whereas emtricitabine exposure was 38% lower when administered via J-tube. However, in comparison with reference data in HIV-infected individuals taking these medications orally, exposure to dolutegravir and tenofovir was 75-76% and 55-61% lower, respectively, following both routes of administration. Emtricitabine exposure was similar to and 71% higher than reference data following J-tube and oral administration, respectively. This report highlights the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral treatment success.