38 research outputs found
Antiretroviral therapy in the management of HIV/AIDS
Antiretroviral therapy is the standard of care for the treatment of human immunodeficiency virus (HIV) infection and current guidelines recommend the use of a combination of antiretroviral drugs (combination antiretroviral therapy, cART). This thesis describes clinical research that examined aspects of HIV disease progression during use of cART, immunological responses to long-term treatment with cART, and interventions for poor immunological responses during virologically successful cART.
The body of work commences with an exploration of literature on HIV natural history, pathogenesis and antiretroviral therapy. Chapter three summarises predictors of HIV-1 disease progression in patients initiating cART with advanced disease in a South-East Asian cohort. The evolution of CD4+ T-cell counts in patients on long-term suppressive cART is described in chapter four. More than 50% of patients exhibited a constant rate of CD4+ T-cell increase even after six years of cART. CD4+ T-cell percentage at the start of cART was a predictor of time to a CD4+ T-cell set-point. In chapter five, associations between exposure to individual nucleoside analogue reverse transcriptase inhibitors (NRTIs) as part of cART regimen and CD4+ T-cell outcomes for individuals on long-term suppressive cART were investigated in a retrospective cohort study. Long-term exposure to NRTIs did not significantly affect recovery of CD4+ T-cell counts, even in patients initiating therapy with advanced disease.
Chapter six is a review of literature on chronic inflammation and immune activation in HIV-1. These two features of HIV-1 infection have been well defined for many years but only recently a putative connection between these observations and a direct role in the immunopathogenesis of HIV disease has been proposed. Chapter seven describes the design, execution and findings from a randomised double-blind, placebo-controlled study that examined two therapeutic interventions in patients with sub-optimal CD4+ T-cell recovery despite sustained virologic suppressive cART. Neither raltegravir intensification nor addition of hyperimmune bovine colostrum to a cART regimen resulted in significant increases in CD4+ T-cell count or demonstrable changes in plasma microbial translocation markers, plasma HIV-RNA levels or T-cell activation. Finally, a summary of findings, general discussion and conclusions are presented in chapter eight
Service delivery challenges in HIV care during the first year of the COVID-19 pandemic: results from a site assessment survey across the global IeDEA consortium.
INTRODUCTION
Interruptions in treatment pose risks for people with HIV (PWH) and threaten progress in ending the HIV epidemic; however, the COVID-19 pandemic's impact on HIV service delivery across diverse settings is not broadly documented.
METHODS
From September 2020 to March 2021, the International epidemiology Databases to Evaluate AIDS (IeDEA) research consortium surveyed 238 HIV care sites across seven geographic regions to document constraints in HIV service delivery during the first year of the pandemic and strategies for ensuring care continuity for PWH. Descriptive statistics were stratified by national HIV prevalence (<1%, 1-4.9% and ≥5%) and country income levels.
RESULTS
Questions about pandemic-related consequences for HIV care were completed by 225 (95%) sites in 42 countries with low (n = 82), medium (n = 86) and high (n = 57) HIV prevalence, including low- (n = 57), lower-middle (n = 79), upper-middle (n = 39) and high- (n = 50) income countries. Most sites reported being subject to pandemic-related restrictions on travel, service provision or other operations (75%), and experiencing negative impacts (76%) on clinic operations, including decreased hours/days, reduced provider availability, clinic reconfiguration for COVID-19 services, record-keeping interruptions and suspension of partner support. Almost all sites in low-prevalence and high-income countries reported increased use of telemedicine (85% and 100%, respectively), compared with less than half of sites in high-prevalence and lower-income settings. Few sites in high-prevalence settings (2%) reported suspending antiretroviral therapy (ART) clinic services, and many reported adopting mitigation strategies to support adherence, including multi-month dispensing of ART (95%) and designating community ART pick-up points (44%). While few sites (5%) reported stockouts of first-line ART regimens, 10-11% reported stockouts of second- and third-line regimens, respectively, primarily in high-prevalence and lower-income settings. Interruptions in HIV viral load (VL) testing included suspension of testing (22%), longer turnaround times (41%) and supply/reagent stockouts (22%), but did not differ across settings.
CONCLUSIONS
While many sites in high HIV prevalence settings and lower-income countries reported introducing or expanding measures to support treatment adherence and continuity of care, the COVID-19 pandemic resulted in disruptions to VL testing and ART supply chains that may negatively affect the quality of HIV care in these settings
The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy.
The Kynurenine Pathway of Tryptophan Catabolism, CD4+ T-Cell Recovery, and Mortality Among HIV-Infected Ugandans Initiating Antiretroviral Therapy
Association Between Immunoglobulin E Levels and Kaposi Sarcoma in African Adults With Human Immunodeficiency Virus Infection.
The Kynurenine Pathway of Tryptophan Catabolism and AIDS-associated Kaposi\u27s Sarcoma in Africa
Background—Other than Kaposi\u27s sarcoma (KS)-associated herpesvirus and CD4+ T cell lymphopenia, the mechanisms responsible for KS in the context of HIV are poorly understood. One recently explored pathway of HIV pathogenesis involves induction of the enzyme indoleamine 2,3 dioxygenase-1 (IDO), which catabolizes tryptophan into kynurenine and several other immunologically active metabolites that suppress T cell proliferation. We investigated the role of IDO in the development of KS in HIV disease.
Methods—In a case-control study among untreated HIV-infected Ugandans, cases were adults with KS and controls were without KS. IDO activity was assessed by the ratio of plasma kynurenine to tryptophan levels (KT ratio), measured by liquid chromatography tandem mass spectrometry.
Results—We studied 631 HIV-infected subjects: 222 KS cases and 409 controls. Non-KS controls had a higher median plasma KT ratio (130, IQR: 90 to190 nM/μM) than cases (110, IQR: 90 to 150 nM/μM) (p = 0.004). After adjustment for age, sex, CD4 count and plasma HIV RNA level, subjects with the highest (fourth quartile) plasma KT ratios had a 59% reduction (95% CI: 27% to 77%) in the odds of KS compared to those with the lowest (first quartile) levels. KS was also independently associated with lower CD4+ count, higher plasma HIV RNA, and men.
Conclusions—Among HIV-infected individuals, greater activity of the kynurenine pathway of tryptophan catabolism, as evidenced by higher levels of plasma KT ratio, was associated with lower occurrence of KS. Some consequences of immune activation in HIV infection might actually suppress certain cancers
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Point-of-care C-reactive protein testing to facilitate implementation of isoniazid preventive therapy for people living with HIV.
BACKGROUND: Symptom-based tuberculosis screening identifies less than one-third of eligible HIV-infected patients as candidates for isoniazid preventive therapy (IPT). We evaluated whether testing for C-reactive protein (CRP) improves patient selection for IPT. METHODS: We measured CRP levels (normal <10 mg/L) using a point-of-care (POC) assay on stored serum samples from HIV-infected Ugandan adults initiating antiretroviral therapy. We assessed diagnostic accuracy in reference to baseline tuberculosis status adjudicated by an expert committee and calculated net reclassification improvement to quantify the incremental discriminatory benefit of POC-CRP in determining IPT eligibility compared to the World Health Organization (WHO) symptom screen. RESULTS: Of 201 patients (median CD4 cell count, 137 cells/ÎĽL; interquartile range, 83-206), 5 (2.5%) had tuberculosis. Compared to the WHO symptom screen, POC-CRP had similar sensitivity (100% vs. 80%, P = 0.30) but greater specificity (21% vs. 87%, P < 0.0001) for tuberculosis. If based on the WHO symptom screen, no patients with tuberculosis but only 42 of 196 patients without tuberculosis would have been considered IPT eligible. If POC-CRP were used instead, 1 patient with tuberculosis (reclassification of cases, -20%; P = 0.32) and 129 patients without tuberculosis (reclassification of noncases, +66%; P < 0.001) would have been reclassified as IPT eligible, a net reclassification improvement of 46% (P = 0.03). In addition, POC-CRP testing would have reduced the proportion of patients without active tuberculosis requiring confirmatory tuberculosis testing (87% vs. 21%, P < 0.0001). CONCLUSIONS: POC-CRP testing increased more than 4-fold the proportion of HIV-infected adults immediately identified as IPT eligible and decreased the proportion of patients requiring referral for further tuberculosis diagnostic testing. POC-CRP testing could substantially improve implementation of tuberculosis screening guidelines
Evolution of CD4+ T cell count in HIV-1-infected adults receiving antiretroviral therapy with sustained long-term virological suppression
Association Between Immunoglobulin E Levels and Kaposi Sarcoma in African Adults With Human Immunodeficiency Virus Infection.
It has been demonstrated that activated mast cells (MCs) are enriched in Kaposi sarcoma (KS) tumors and contribute to the inflammatory microenvironment. Mechanisms driving MC activation, however, are incompletely understood. We sought to understand whether immunoglobulin E (IgE), a potent activator of MCs, was associated with KS incidence and severity. In a cross-sectional study of untreated human immunodeficiency virus (HIV)-infected adults with or without KS in Uganda, we found that patients with KS had higher plasma IgE levels than those without KS. After adjustment for age, sex, CD4+ T-cell count, and HIV RNA levels, there was a dose-response relationship between plasma IgE levels and the presence and severity of KS. Higher eosinophil counts were also associated with IgE levels, and plasma interleukin 33 concentrations were higher in individuals with KS. These findings suggest that IgE-driven atopic inflammation may contribute the pathogenesis of KS. Therapies targeting IgE-mediated MC activation thus might represent a novel approach for treatment or prevention of KS