HIV-Associated Cryptococcal Meningitis: Bridging the Gap Between Developed and Resource-Limited Settings.

Cryptococcal meningitis is a major cause of HIV-associated morbidity and mortality worldwide. Most cases occur in low-income countries, where over half of patients die within 10 weeks of diagnosis compared to as few as 10 % of patients from developed countries. A host of factors, spanning the HIV care continuum, are responsible for this gap in treatment outcomes between developed and resource-limited settings. We explore factors responsible for this outcomes gap and describe low-cost, highly effective measures that can be implemented immediately to improve outcomes in resource-limited settings. We also explore health-system challenges that must be addressed to reduce mortality further, recent research in disease prevention, and novel short-course treatment regimens that, if efficacious, could be implemented in resource-limited settings where the cost of standard treatment regimens is currently prohibitive

Neurosyphilis in Africa: A systematic review.

INTRODUCTION: Neurological involvement is one of the most important clinical manifestations of syphilis and neurological disease occurs in both early and late syphilis. The impact of HIV co-infection on clinical neurosyphilis remains unclear. The highest prevalence of both syphilis and HIV is in Africa. Therefore it might be expected that neurosyphilis would be an important and not uncommon manifestation of syphilis in Africa and frequently occur in association with HIV co-infection; yet few data are available on neurosyphilis in Africa. The aim of this study is to review data on neurosyphilis in Africa since the onset of the HIV epidemic. METHODS: We searched the literature for references on neurosyphilis in Africa for studies published between the 1st of January 1990 and 15th February 2017. We included case reports, case series, and retrospective and prospective cohort and case-control studies. We did not limit inclusion based on the diagnostic criteria used for neurosyphilis. For retrospective and prospective cohorts, we calculated the proportion of study participants who were diagnosed with neurosyphilis according to the individual study criteria. Depending on the study, we assessed the proportion of patients with syphilis found to have neurosyphilis, and the proportion of patients with neurological syndromes who had neurosyphilis. Due to heterogeneity of data no formal pooling of the data or meta-analysis was undertaken. RESULTS: Amongst patients presenting with a neurological syndrome, three studies of patients with meningitis were identified; neurosyphilis was consistently reported to cause approximately 3% of all cases. Three studies on stroke reported mixed findings but were limited due to the small number of patients undergoing CSF examination, whilst neurosyphilis continued to be reported as a common cause of dementia in studies from North Africa. Ten studies reported on cases of neurosyphilis amongst patients known to have syphilis. Studies from both North and Southern Africa continue to report cases of late stage syphilis, including tabes dorsalis and neurosyphilis, in association with ocular disease. DISCUSSION: This is the first systematic review of the literature on neurosyphilis in Africa since the beginning of the HIV epidemic. Neurosyphilis continues to be reported as a manifestation of both early and late syphilis, but the methodological quality of the majority of the included studies was poor. Future well-designed prospective studies are needed to better delineate the incidence and clinical spectrum of neurosyphilis in Africa and to better define interactions with HIV in this setting

HIV-associated Cryptococcal Meningitis: a Review of Novel Short-Course and Oral Therapies

Abstract Purpose of review HIV-associated cryptococcal meningitis remains a significant public health problem in parts of Africa and Asia and a major cause of AIDS-related mortality, accounting for 15% of all AIDS-related deaths worldwide. Cryptococcal meningitis is uniformly fatal if untreated, and access to antifungal therapy in regions with the highest burden is often limited. Outcomes with fluconazole monotherapy are poor, and induction treatment with amphotericin B and high-dose fluconazole for 2 weeks is associated with significant drug-related toxicities and prolonged hospital admissions. This review focuses on the potential of novel short-course and oral combination therapies for cryptococcal meningitis. Recent findings Recent clinical trials have shown that shorter courses of amphotericin, if paired with oral flucytosine, rather than fluconazole, can achieve non-inferior mortality outcomes. In addition, an oral combination of fluconazole and flucytosine is a potential alternative. Liposomal amphotericin B may further simplify treatment; it is associated with fewer drug-related toxicities, and a recent phase II randomised controlled trial demonstrated that a single, high dose of liposomal amphotericin is non-inferior to 14 standard daily doses at clearing Cryptococcus from cerebrospinal fluid. This has been taken forward to an ongoing phase III, clinical endpoint study. Summary The incidence and mortality associated with cryptococcal meningitis is still unacceptably high. There is evidence supporting the use of short-course amphotericin B and oral combination antifungal treatment regimens for cryptococcal meningitis (CM). Ongoing research into short-course, high-dose treatment with liposomal amphotericin may also help reduce the impact of this devastating disease. </jats:sec

Preparation and ring-opening reactions of N-diphenylphosphinyl vinyl aziridines

Predominantly (E)-N-diphenylphosphinyl vinyl aziridines are prepared by a reaction of N-diphenylphosphinyl imines with α-bromoallyllithium in the presence of freshly fused ZnCl2. These aziridines undergo a ring-opening reaction with a variety of carbon and heteronucleophiles, in good yield, and generally with good regioselectivity

Symptomatic relapse of HIV-associated cryptococcal meningitis in South Africa: the role of inadequate secondary prophylaxis.

OBJECTIVES: Cryptococcal meningitis is the commonest cause of adult meningitis in Southern Africa. A sizeable proportion of this disease burden is thought to be due to symptomatic relapse of previously treated infection. We carried out a study to examine 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 categorized into 1) patients not taking fluconazole prophylaxis, 2) immune reconstitution inflammatory syndrome (IRIS) and 3) 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 taking fluconazole prophylaxis, 45%(31) were due to IRIS and 12%(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% (14) had not been prescribed secondary prophylaxis by their healthcare providers. Importantly, we documented no relapses due to fluconazole resistance in this cohort of patients who has received amphotericin B as initial therapy. CONCLUSIONS: Large numbers of relapses of cryptococcal meningitis are due to failed prescription, dispensing, referral for or adherence to secondary fluconazole prophylaxis. Interventions to improve the use of secondary fluconazole prophylaxis are essential

Symptomatic relapse of HIV-associated cryptococcal meningitis in South Africa: The role of inadequate secondary prophylaxis

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

Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial.

BACKGROUND: Interferon-gamma (IFNγ) is of key importance in the immune response to Cryptococcus neoformans. Mortality related to cryptococcal meningitis remains high, and novel treatment strategies are needed. We performed a randomized controlled trial to determine whether addition of IFNγ to standard therapy increased the rate of clearance of cryptococcal infection in HIV-associated cryptococcal meningitis. METHODS: Patients were randomized to amphotericin B 1 mg/kg per day and 5FC 100 mg/kg per day for 2 weeks (standard therapy), standard therapy and IFNγ1b 100 μg days 1 and 3 (IFNγ two doses), or standard therapy and IFNγ1b 100 μg days 1, 3, 5, 8, 10 and 12 (IFNγ six doses). Primary outcome was rate of clearance of cryptococcus from the cerebrospinal fluid (CSF) (early fungicidal activity, EFA) calculated from serial quantitative cultures, previously shown to be independently associated with survival. RESULTS: Rate of fungal clearance was significantly faster in IFNγ containing groups than with standard treatment. Mean EFA [log colony forming unit (CFU)/ml per day] was -0.49 with standard treatment, -0.64 with IFNγ two doses, and -0.64 with IFNγ six doses. Difference in EFA was -0.15 [confidence interval (95% CI) -0.02 to -0.27, P=0.02] between standard treatment and IFNγ two doses, and -0.15 (95% CI -0.05 to -0.26, P=0.006) between standard treatment and IFNγ six doses. Mortality was 16% (14/88) at 2 weeks and 31% (27/87) at 10 weeks, with no significant difference between groups. All treatments were well tolerated. CONCLUSION: Addition of short-course IFNγ to standard treatment significantly increased the rate of clearance of cryptococcal infection from the CSF, and was not associated with any increase in adverse events. Two doses of IFNγ are as effective as six doses

Increase in CD5+ B Cells in Juvenile Rheumatoid Arthritis

Objective. To investigate the association between CD5+ B cell expression and IgM rheumatoid factor (IgM-RF) in juvenile rheumatoid arthritis (JRA). Methods. CD5+ B cell levels analyzed by flow cytometry and IgM-RF expression determined by enzymelinked immunosorbent assay were compared in children with JRA, children with other collagen vascular diseases, and healthy controls. Results. Children with polyarticular JRA had expanded populations of CD5+ B cells, and expansion of CD5+ B cells and IgM-RF both correlated with disease activity. Conclusion. The results indicate that an expanded CD5+ B cell population leads to IgM-RF production in patients with polyarticular JRA, as well as patients with RA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37790/1/1780350213_ftp.pd

CD4 Cell Count Threshold for Cryptococcal Antigen Screening of HIV-Infected Individuals: A Systematic Review and Meta-analysis.

Background: Current guidelines recommend screening all people living with human immunodeficiency virus (PLHIV) who have a CD4 count ≤100 cells/µL for cryptococcal antigen (CrAg) to identify those patients who could benefit from preemptive fluconazole treatment prior to the onset of meningitis. We conducted a systematic review to assess the prevalence of CrAg positivity at different CD4 cell counts. Methods: We searched 4 databases and abstracts from 3 conferences up to 1 September 2017 for studies reporting prevalence of CrAg positivity according to CD4 cell count strata. Prevalence estimates were pooled using random effects models. Results: Sixty studies met our inclusion criteria. The pooled prevalence of cryptococcal antigenemia was 6.5% (95% confidence interval [CI], 5.7%-7.3%; 54 studies) among patients with CD4 count ≤100 cells/µL and 2.0% (95% CI, 1.2%-2.7%; 21 studies) among patients with CD4 count 101-200 cells/µL. Twenty-one studies provided sufficient information to compare CrAg prevalence per strata; overall, 18.6% (95% CI, 15.4%-22.2%) of the CrAg-positive cases identified at ≤200 cells/µL (n = 11823) were identified among individuals with a CD4 count 101-200 cells/µL. CrAg prevalence was higher among inpatients (9.8% [95% CI, 4.0%-15.5%]) compared with outpatients (6.3% [95% CI, 5.3%-7.4%]). Conclusions: The findings of this review support current recommendations to screen all PLHIV who have a CD4 count ≤100 cells/µL for CrAg and suggest that screening may be considered at CD4 cell count ≤200 cells/µL