Biological treatment usage in patients with HIV and rheumatic disease, 2003-2021: long-term safety and follow-up.

OBJECTIVE: This study examined the safety and efficacy of biological agents, especially tumour necrosis factor (TNF) inhibitors, for HIV-positive rheumatology patients refractory to standard therapy. METHODS: This study is a retrospective case series including patients derived from a community HIV clinic as well as from two academic centres. Initial visit data collected included: sociodemographic characteristics, CD4 counts, HIV viral load and medication use. Patients with persistent disease activity despite standard conservative therapy were begun on biological agents.The main outcomes were patient and physician global assessment of treatment response and medication side effects in patients with rheumatological disorders treated with biological medications over time. RESULTS: Seventeen patients were seen from 2003 to 2021, including eight from our previous cohort published in 2008 and nine seen since then, five of whom taking TNF blockers for more than 10 years. Three (17.7%) had rheumatoid arthritis, five (29.4%) psoriatic arthritis, four (23.5%) axial spondyloarthritis and the rest (29.4%) peripheral spondyloarthritis. Antiretroviral therapy had been used in 15. All but one had at least a partial response to biological therapy. There were no major infectious episodes necessitating the discontinuation of medications with only one patient discontinuing treatment due to rising HIV viral load. Patients not on antiretroviral therapy reported no adverse side effects from biological therapy. Four patients were switched to ustekinumab, secukinumab, tocilizumab or upadacitinib from anti-TNF therapy without complications. CONCLUSIONS: These data suggest that biological therapy, especially anti-TNF agents are safe and well tolerated in HIV positive individuals even over several years.

Systemic lupus erythematosus in the setting of HIV-1 infection: a longitudinal analysis.

Patients with concomitant HIV-1 infection and systemic lupus erythematosus (SLE) followed longitudinally at an HIV outpatient clinic from 1994 to 2019 were examined. Patients met 1982 and 1997 ACR classification criteria for SLE at the Thomas Street clinic from 1994 to 2019. Clinical and demographic comparisons were made with a non HIV-SLE patient cohort, the Lupus in Minorities Studies, Nature versus Nurture (LUMINA) study. Twenty-two patients with concomitant HIV-1 infection and SLE were identified, including 18 females, 3 males, and 1 male to female transgender. Overall, 81.8% of SLE-HIV patients were African-American compared to 55.3% of the 5856 patients seen at the HIV clinic from 2016 to 2017 (p = 0.02, OR = 3.6). There were 12 patients that developed HIV-1 in the setting of SLE and 10 patients that developed SLE in the setting HIV-1. This demographic distribution was significant when compared with the 1604 unique patients in the HIV rheumatology clinic from 1994 to 2019 (p = 0.03, OR = 5.9) and also significant when compared with the 5856 patients attending the county HIV clinic overall in 2016-2017 (p = 0.008, OR = 7.2). When comparing with the non-HIV SLE cohort, anti-dsDNA antibodies were noted less frequently in all HIV-SLE patients (p = 0.0002) including all sub-cohorts of our patients. Skin/mucosal involvement (p = 0.0003) and cytopenias (p = 0.0001) occurred less frequently in the patients that were diagnosed with HIV after their SLE diagnosis compared to non-HIV SLE patients. In a large county HIV clinic setting, the prevalence of SLE was significantly higher in African American women. Anti-dsDNA antibodies were less frequent in HIV-1 positive SLE patients.Key Points• This paper presents clinical and laboratory data on the largest cohort of SLE patients with HIV-1 infection reported to date.• The prevalence of SLE in a large outpatient HIV-1 clinic was larger than reported in HIV negative population studies.• The prevalence of SLE was particularly high in black HIV-1 infected women.• Skin/mucosal involvement and anti-ds DNA antibodies were less common in patients with HIV-1 and SLE compared to patients with SLE without SLE>.

Polymicrobial bloodstream infection in pediatric patients: risk factors, microbiology, and antimicrobial management.

BACKGROUND: Few studies focus on polymicrobial bloodstream infections (PBSIs) in children. In previous reports, children with PBSI frequently had complex underlying medical conditions and a high incidence of specific microorganisms, but systematic evaluation with controls was not performed. We postulated that specific clinical risk factors are associated with an increased risk of PBSI, and that illness may be more severe with these infections. Additionally, we suspected that routine empiric antimicrobial therapy may frequently be inadequate to treat the variety of pathogens in PBSI. METHODS: Positive blood cultures from 1998 to 2004 were reviewed. Patients whose cultures grew >1 organism were age-matched with monomicrobial bloodstream infection controls. Records were reviewed to compare their underlying medical conditions, organisms isolated, adequacy of therapy, and clinical characteristics of illness. RESULTS: Twenty-nine episodes of PBSI were identified in 18 subjects. PBSI patients were more likely to have chronic medical conditions, chronic gastrointestinal pathology, central venous catheters, and to be receiving parenteral nutrition than controls. Pathogens found more commonly in PBSI episodes included Enterococcus spp., coagulase-negative staphylococci, and Candida spp. Empiric antimicrobial therapy was less likely to be adequate in patients with PBSI. PBSI patients were hospitalized longer, required longer intensive care and had prolonged bloodstream infection. Subjects with PBSI had prolonged duration of fever and had higher degrees of sepsis than controls. CONCLUSIONS: Chronic medical conditions, particularly gastrointestinal disease, are risk factors for PBSIs. Because clinical illness may be more severe, alteration of the empiric antimicrobial regimen should be considered in some of these patients.

Infection and musculoskeletal conditions: Rheumatologic complications of HIV infection.

The pandemic caused by the human immunodeficiency virus (HIV) has entered its second quarter-century, with 40 million people now affected worldwide - particularly in Africa, where the impact has been most devastating. A complex array of rheumatic disease manifestations has been described, including diseases specific to HIV infection such as HIV-associated arthritis and the diffuse infiltrative lymphocytosis syndrome; other conditions which occur prominently in HIV-positive individuals include vasculitis, reactive and psoriatic arthritis and HIV-associated polymyositis, opportunistic musculoskeletal infections, and finally disorders that were originally ameliorated by HIV infection, such as rheumatoid arthritis and lupus. Effective antiretroviral treatment ameliorates many of these disorders; however, the introduction of highly active antiretroviral treatment (HAART) has introduced a new spectrum of disorders and new challenges confronting the clinician, including osteonecrosis, rhabdomyolysis, and, with immune reconstitution, the appearance de novo of a variety of autoimmune disorders and phenomena.

An investigation into the spectral analysis of dielectric aging in ferroelectrics.

Aging and degradation indicate the time-dependent change of physical and electrical properties. Most studies neglect to report the effects of aging on the electromechanical properties of an electroactive material and subsequent deterioration of performance. Recent work has shown that the strain and polarization response of an electroactive device can be transformed into its harmonic spectrum (transformation from the time domain to the frequency domain) through the implementation of Fourier analysis. The ability to create this harmonic spectrum provides a new way to characterize the effects of aging by revealing subtle changes in the fundamental components that comprise the response. This study shows how Fourier analysis can be applied to an aged PMN-PT-BT composition to characterize and quantify the effects of aging. The average weak-field permittivity is measured as a function of time, temperature, and frequency. A typical "saddle" in the permittivity and dielectric loss is apparent, and the magnitude decays logarithmically with time. Harmonic analysis of the strain response reveals a slight time-dependent amplitude variation and logarithmic dependence of the phase of the 6th order harmonic. Similar analysis of the polarization response, as a function of time, fully characterizes the development of constriction or wasting seen in a typical aged electrostrictive material. Variations in the amplitudes of the 5th and higher order harmonics of polarization, logarithmic in nature, and the phase of the 5th order harmonic combine to define aging on the harmonic level.

Adenovirus 5-vectored P. falciparum vaccine expressing CSP and AMA1. Part A: safety and immunogenicity in seronegative adults.

BACKGROUND: Models of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers. METHODOLOGY/PRINCIPAL FINDINGS: The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7-10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites. SIGNIFICANCE: As found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses. TRIAL REGISTRATION: ClinicalTrials.govNCT00392015.

Changing spectrum of the diffuse infiltrative lymphocytosis syndrome.

OBJECTIVE: To describe the changing clinical spectrum of patients with diffuse infiltrative lymphocytosis syndrome (DILS) after the introduction of highly active antiretroviral treatment (HAART), and to carry out HLA class II oligotyping in these patients. METHODS: A retrospective chart review of patients with DILS who were referred to an outpatient facility for human immunodeficiency virus (HIV)-positive individuals between 1994 and 2003 was performed. DILS was diagnosed as suggested by previous criteria. Demographic features and relevant clinical, laboratory, and radiologic data were recorded and results analyzed. RESULTS: A total of 129 patients with DILS were identified. Of them, 56 (43%) were African American, 41 (32%) were white, and 32 (25%) were Hispanic. Parotid gland swelling appeared to be the sine qua non of DILS. Twenty-seven percent of patients had opportunistic infections. The status of 103 patients was available as of December 2003: 26 (25%) had died, of which only 6 (6%) succumbed to opportunistic infections. The prevalence of DILS had significantly decreased in the post-HAART era (1998 onwards) compared with that of the pre-HAART period (P < 0.000001). The prevalence of lymphocytic interstitial pneumonitis had also dropped significantly following introduction of HAART therapy (P = 0.015). A higher frequency of certain HLA class II alleles (DRB1) was found in African Americans with DILS compared with those with HIV without DILS (P = 0.006). CONCLUSION: The epidemiology, clinical presentation, and certain extraglandular manifestations of DILS have changed, concomitant with the introduction of HAART, further suggesting that DILS is an antigen (viral)-driven response and the primary treatment for it is anti-HIV therapy.

Human immunodeficiency virus-associated polymyositis: a longitudinal study of outcome.

OBJECTIVE: To determine the clinical course and optimum treatment of human immunodeficiency virus (HIV)-associated myositis. METHODS: Sixty-four patients attending a county outpatient HIV/acquired immunodeficiency syndrome facility were referred for the presence of elevated creatine kinase (CK) levels or muscle weakness. Patients underwent neurologic and rheumatologic evaluation, electromyography, and muscle biopsy after exclusion for recreational drug or alcohol use, metabolic/endocrine disorders, zidovudine therapy, and other infections. RESULTS: Thirteen patients (20%) had biopsy-proven myositis. The median duration of HIV infection prior to diagnosis of myositis was 4.3 years (range 0-11 years). Six patients had concomitant diffuse infiltrative lymphocytosis syndrome. There was no correlation of severity of weakness, stage of HIV infection, or retroviral treatment with the CK level at diagnosis. Eight patients received prednisone (60 mg/day) with 5 attaining complete resolution of myositis. The remaining 3 patients received immunosuppressive therapy (azathioprine or methotrexate and intravenous immunoglobulin) and had normalization of strength and CK. Four patients had spontaneous resolution of their myositis without treatment. CONCLUSION: HIV-associated myositis occurs at any stage of HIV infection, has a relatively good prognosis, responds well to immunosuppressive therapy, and has little evidence of adverse outcome on the HIV infection.