Browsing by Author "Harrison, Thomas S"

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    Cerebrospinal Fluid Cytokine Profiles Predict Risk of Early Mortality and Immune Reconstitution Inflammatory Syndrome in HIV-Associated Cryptococcal Meningitis
    (Public Library of Science, 2015) Jarvis, Joseph N; Meintjes, Graeme; Bicanic, Tihana; Buffa, Viviana; Hogan, Louise; Mo, Stephanie; Tomlinson, Gillian; Kropf, Pascale; Noursadeghi, Mahdad; Harrison, Thomas S
    Author Summary Cryptococcal meningitis is a severe opportunistic infection, estimated to kill several hundred thousand HIV-infected individuals each year. One of the factors contributing to this high death toll is the inadequacy of antifungal treatments. As few novel antifungal drugs are being developed, several groups have started to investigate the potential of immune modulation, with treatments designed to change the patient's immune response to infection. However, our understanding of the immune response to cryptococcal infection in HIV-infected patients, and how these responses impact on clinical outcomes, is limited. In this study, we took advantage of the fact that we can sample cerebrospinal fluid (CSF) from the site of the infection in patients when they develop cryptococcal meningitis. We undertook a detailed analysis measuring levels of immune response parameters in the CSF of these patients, and demonstrated that there were several distinct components of the immune response. Variations in these responses were associated with both the rate at which patients cleared their infection during treatment, and with mortality. Our results provide a basis for the development of future immunomodulatory therapies, and may allow identification of patients most at risk of dying, enabling more intensive treatments to be given to those at highest risk.
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    Correction to: AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial
    (2019-01-14) Lawrence, David S; Youssouf, Nabila; Molloy, Síle F; Alanio, Alexandre; Alufandika, Melanie; Boulware, David R; Boyer-Chammard, Timothée; Chen, Tao; Dromer, Francoise; Hlupeni, Admire; Hope, William; Hosseinipour, Mina C; Kanyama, Cecilia; Lortholary, Oliver; Loyse, Angela; Meya, David B; Mosepele, Mosepele; Muzoora, Conrad; Mwandumba, Henry C; Ndhlovu, Chiratidzo E; Niessen, Louis; Schutz, Charlotte; Stott, Katharine E; Wang, Duolao; Lalloo, David G; Meintjes, Graeme; Jaffar, Shabbar; Harrison, Thomas S; Jarvis, Joseph N
    Following publication of the original article [1], we have been notified that one of the author names was listed incorrectly. Both incorrect and correct author names are presented below. The original publication has been corrected.
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    Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa
    (Public Library of Science, 2013) Jarvis, Joseph N; Harrison, Thomas S; Lawn, Stephen D; Meintjes, Graeme; Wood, Robin; Cleary, Susan
    Objectives Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM. Design Cost-effectiveness analysis. METHODS: Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts <100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART. RESULTS: The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence ≥0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US$158 versus US$51per person year; incremental cost effectiveness ratio(ICER) US$889,267 per life year gained). Both CRAG screening strategies are less costly and more clinically effective than current practice. Primary prophylaxis is more effective than current practice, but relatively cost-ineffective (ICER US$20,495). CONCLUSIONS: CRAG screening would be a cost-effective strategy to prevent CM-related mortality among patients initiating ART in South Africa. These findings provide further justification for programmatic implementation of CRAG screening.
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    Genotypic diversity is associated with clinical outcome and phenotype in cryptococcal meningitis across Southern Africa
    (Public Library of Science, 2015) Beale, Mathew A; Sabiiti, Wilber; Robertson, Emma J; Fuentes-Cabrejo, Karen M; O'Hanlon, Simon J; Jarvis, Joseph N; Loyse, Angela; Meintjes, Graeme; Harrison, Thomas S; May, Robin C
    Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn) isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven 'high frequency' sequence types. Spatial analysis of patients' cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival) performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic diversity is structured across African environments, allowing assessment of the risks different ecotypes pose to infection.
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    Routine cryptococcal antigen screening for HIV-infected patients with low CD4+ T-lymphocyte counts - time to implement in South Africa?
    (2011) Jarvis, Joseph N; Harrison, Thomas S; Govender, Nelesh; Lawn, Stephen D; Longley, Nicky; Bicanic, Tihana; Maartens, Gary; Venter, Francois; Bekker, Linda-Gail; Wood, Robin; Meintjes, Graeme
    Cryptococcal meningitis (CM) is a major cause of death among HIV-infected individuals. It causes an estimated 957 900 cases and 624 700 deaths worldwide annually, the vast majority of them in sub-Saharan Africa.1 In Cape Town, CM is now the most common cause of adult meningitis (63% of all microbiologically confirmed cases2), and acute outcomes are poor.3 Even with optimal treatment in study settings, 10-week mortality rates are between 24% and 37%.4,5 In 2009, in a routine care setting at an urban hospital in Johannesburg, 67% of patients had died or were lost to follow-up at 3 months (N Govender et al., unpublished data). Unfortunately almost half of South African patients still receive sub-optimal initial treatment with oral fluconazole rather than intravenous amphotericin B.3,6 Clearly, given the substantial mortality and morbidity associated with CM, preventive interventions should be prioritised.
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    Symptomatic relapse of HIV-associated cryptococcal meningitis in South Africa: The role of inadequate secondary prophylaxis
    (2010) Jarvis, Joseph N; Meintjes, Graeme; Williams, Zomzi; Rebe, Kevin; Harrison, Thomas S
    Objectives. Cryptococcal meningitis is the most common cause of adult meningitis in southern Africa. Much of this disease burden is thought to be due to symptomatic relapse of previously treated infection. We studied the contribution of inadequate secondary fluconazole prophylaxis to symptomatic relapses of cryptococcal meningitis. Design. A prospective observational study of patients presenting with laboratory-confirmed symptomatic relapse of HIV-associated cryptococcal meningitis between January 2007 and December 2008 at GF Jooste Hospital, a public sector adult referral hospital in Cape Town. Outcome measures. Relapse episodes were categorised into: (i) patients not taking fluconazole prophylaxis; (ii) immune reconstitution inflammatory syndrome (IRIS); and (iii) relapses occurring prior to ART in patients taking fluconazole. In-hospital mortality was recorded. Results. There were 69 relapse episodes, accounting for 23% of all cases of cryptococcal meningitis; 43% (N=30) of relapse episodes were in patients not receiving fluconazole prophylaxis, 45% (N=31) were due to IRIS, and 12% (N=8) were in patients pre-ART taking fluconazole. Patients developing relapse due to inadequate secondary prophylaxis had severe disease and high in-hospital mortality (33%). Of the 30 patients not taking fluconazole, 47% (N=14) had not been prescribed secondary prophylaxis by their health care providers. We documented no relapses due to fluconazole resistance in these patients who received amphotericin B as initial therapy. Conclusions. A large number of relapses of cryptococcal meningitis are due to failed prescription, dispensing and referral for or adherence to secondary fluconazole prophylaxis. Interventions to improve the use of secondary fluconazole prophylaxis are essential.