Treatment of HIV-associated cryptococcal meningitis in South Africa: The case for amphotericin B over conventional dose fluconazole for initial therapy

Cryptococcal meningitis is a major cause of morbidity and mortality in African AIDS patients, accounting for between 13% and 17% of deaths in Ugandan HIV-infected individuals(1,2) and 44% of deaths in a cohort of HIV-seropositive South African miners.(3) This burden of disease is a result of high incidence, especially in southern and East Africa, and high acute mortality.(4,6) In much of Africa, fluconazole rather than amphotericin B was, and still is, widely used as initial therapy, for a variety of reasons. These include the availability of fluconazole through free access programmes and in generic form, and the attractiveness of an easy to. use, safe oral regimen over a difficult to administer intravenous drug with significant side-effects, requiring inpatient admission and close laboratory monitoring. In addition, in the absence of antiretroviral therapy, treatment of cryptococcal meningitis has in the recent past been palliative rather than curative, reducing the rationale for more aggressive therapy, if this is associated with increased side-effects. However, what data there are suggest that outcomes with fluconazole at conventional dosage (up to 400 mg/d) as initial therapy are poor. In addition, the cost of amphotericin B, previously considerable in South Africa, has been reduced! More importantly, increasing access to antiretroviral therapy (ART) now means that the long-term prognosis of patients with cryptococcal meningitis is good, provided they survive the acute infection.(8) We summarise the evidence that a factor contributing to high acute mortality in cryptococcal meningitis is the inadequacy of fluconazole at up to 400 mg/d as an induction regimen, and present the case for initial treatment with amphotericin B in South Africa, where feasible

Treatment of HIV-associated cryptococcal meningitis in South Africa: The case for amphotericin B over conventional dose fluconazole for initial therapy

Cryptococcal meningitis is a major cause of morbidity and mortality in African AIDS patients, accounting for between 13% and 17% of deaths in Ugandan HIV-infected individuals1,2 and 44% of deaths in a cohort of HIV-seropositive South African miners.3 This burden of disease is a result of high incidence, especially in southern and East Africa, and high acute mortality.4-6 In much of Africa, fluconazole rather than amphotericin B was, and still is, widely used as initial therapy, for a variety of reasons. These include the availability of fluconazole through free access programmes and in generic form, and the attractiveness of an easy to use, safe oral regimen over a difficult to administer intravenous drug with significant side-effects, requiring inpatient admission and close laboratory monitoring. In addition, in the absence of antiretroviral therapy, treatment of cryptococcal meningitis has in the recent past been palliative rather than curative, reducing the rationale for more aggressive therapy, if this is associated with increased side-effects. However, what data there are suggest that outcomes with fluconazole at conventional dosage (up to 400 mg/d) as initial therapy are poor. In addition, the cost of amphotericin B, previously considerable in South Africa, has been reduced.7 More importantly, increasing access to antiretroviral therapy (ART) now means that the long-term prognosis of patients with cryptococcal meningitis is good, provided they survive the acute infection.8 We summarise the evidence that a factor contributing to high acute mortality in cryptococcal meningitis is the inadequacy of fluconazole at up to 400 mg/d as an induction regimen, and present the case for initial treatment with amphotericin B in South Africa, where feasible. Southern African Journal of HIV Medicine Vol. 8 (3) 2007: pp. 36-3

Recent advances in managing HIV-associated cryptococcal meningitis

The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in cryptococcal meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated cryptococcal meningitis

A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi

Introduction: Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data. Methods: From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. Results: Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score ,14 of 15), moderate/severe neurological disability (modified Rankin Score .3 of 5) and confusion (Abbreviated Mental Test Score ,8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. Conclusions: Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit

Impact of routine cryptococcal antigen screening and targeted pre-emptive fluconazole therapy in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL: a systematic review and meta-analysis.

Cryptococcal antigen (CrAg) screening and targeted pre-emptive fluconazole in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL seems promising to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg-positivity (31 studies; 35,644 participants) and asymptomatic CM in CrAg-positives, incidence of CM and all-cause mortality in screened participants. Pooled prevalence of blood CrAg-positivity was 6% (95%CI: 5 - 7) and asymptomatic CM in CrAg-positives was 33% (95%CI: 21 - 45). Incidence of CM without pre-emptive fluconazole was 21.4% (95%CI: 11.6 - 34.4) and 5.7% (95%CI: 3.0 - 9.7) with pre-emptive fluconazole initiated at 800 mg/day. In CrAg-positives, post-screening lumbar puncture prior to initiating pre-emptive fluconazole at 800 mg/day further reduced incidence of CM to null and showed some survival benefits. However, all-cause mortality remained significantly higher in CrAg-positives than CrAg-negatives: RR: 2.2 (95%CI: 1.7 - 2.9, p<0.001)

Equity in clinical trials for HIV-associated cryptococcal meningitis: A systematic review of global representation and inclusion of patients and researchers.

BACKGROUND: It is essential that clinical trial participants are representative of the population under investigation. Using HIV-associated cryptococcal meningitis (CM) as a case study, we conducted a systematic review of clinical trials to determine how inclusive and representative they were both in terms of the affected population and the involvement of local investigators. METHODS: We searched Medline, EMBASE, Cochrane, Africa-Wide, CINAHL Plus, and Web of Science. Data were extracted for 5 domains: study location and design, screening, participants, researchers, and funders. Data were summarised and compared over 3 time periods: pre-antiretroviral therapy (ART) (pre-2000), early ART (2000 to 2009), and established ART (post-2010) using chi-squared and chi-squared for trend. Comparisons were made with global disease burden estimates and a composite reference derived from observational studies. RESULTS: Thirty-nine trials published between 1990 and 2019 were included. Earlier studies were predominantly conducted in high-income countries (HICs) and recent studies in low- and middle-income countries (LMICs). Most recent studies occurred in high CM incidence countries, but some highly affected countries have not hosted trials. The sex and ART status of participants matched those of the general CM population. Patients with reduced consciousness and those suffering a CM relapse were underrepresented. Authorship had poor representation of women (29% of all authors), particularly as first and final authors. Compared to trials conducted in HICs, trials conducted in LMICs were more likely to include female authors (32% versus 20% p = 0.014) but less likely to have authors resident in (75% versus 100%, p < 0.001) or nationals (61% versus 93%, p < 0.001) of the trial location. CONCLUSIONS: There has been a marked shift in CM trials over the course of the HIV epidemic. Trials are primarily performed in locations and populations that reflect the burden of disease, but severe and relapse cases are underrepresented. Most CM trials now take place in LMICs, but the research is primarily funded and led by individuals and institutions from HICs

Commentary – ordering lab tests for suspected rheumatic disease

One of the least-appreciated advances in pediatric rheumatology over the past 25 years has been the delineation of the many ways in which children with rheumatic disease differ from adults with the same illnesses. Furthermore, we are now learning that paradigms that are useful in evaluating adults with musculoskeletal complaints have limited utility in children. Nowhere is that more true than in the use of commonly used laboratory tests, particularly antinuclear antibody (ANA) and rheumatoid factor (RF) assays. This short review will provide the practitioner with the evidence base that supports a more limited use of ANA and RF testing in children

Ischemic stroke as a complication of cryptococcal meningitis and immune reconstitution inflammatory syndrome: a case report.

BACKGROUND: Cryptococcal meningitis remains the leading cause of adult meningitis in Sub-Saharan Africa. Immune Reconstitution Inflammatory Syndrome (IRIS) following anti-retroviral therapy (ART) initiation is an important complication. Here we report the first documented case of a IRIS reaction presenting as an ischemic stroke. CASE PRESENTATION: A 38 year old newly diagnosed HIV-infected, ART naive Malawian male presented to a tertiary referral hospital in Blantyre, Malawi with a 2 week history of headache. A diagnosis of cryptococcal meningitis was made and the patient was started on 1200 mg fluconazole once daily and flucytosine 25 mg/kg four times daily as part of the Advancing Cryptococcal Treatment for Africa (ACTA) clinical trial. There was an initial clinical and microbiological response to anti-fungal treatment and anti-retroviral therapy was started at week 4. The patient re-presented 16 days later with recurrence of headache, fever, and a sudden onset of left sided weakness in the context of rapid immune reconstitution; peripheral CD4 count had increased from a baseline of 29 cells/μl to 198 cells/μl. Recurrence of cryptococcal meningitis was excluded through CSF examination and fungal culture. Magnetic Resonance Imaging (MRI) of the brain demonstrated multi-focal DWI (diffusion weighted imaging) positive lesions consistent with an ischemic stroke. Given the temporal relationship to ART initiation, these MRI findings in the context of sterile CSF with raised CSF protein and a rapid immune reconstitution, following an earlier favorable response to treatment is most consistent with a paradoxical Immune Reconstitution Inflammatory Syndrome. CONCLUSIONS: Stroke is an increasing cause of morbidity and mortality amongst HIV infected persons. Ischemic stroke is a recognized complication of cryptococcal meningitis in the acute phase and is thought to be mediated by an infectious vasculitis. This is the first time an ischemic stroke has been described as part of a paradoxical IRIS reaction. This report adds to the spectrum of clinical IRIS presentations recognized and highlights to clinicians the potential complications encountered at ART initiation in severely immunocompromised patients