Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis

Background

Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.

Methods and Findings:

We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.

Conclusions

Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease. Please see later in the article for the Editors'' Summary.     

Long Term 5-Year Survival of Persons with Cryptococcal Meningitis or Asymptomatic Subclinical Antigenemia in Uganda

Data presented previously as an abstract at the 2011 CUGH Global Health Conference in Montreal, Canada on 15 Nov 2011. The long-term survival of HIV-infected persons with symptomatic cryptococcal meningitis and asymptomatic, subclinical cryptococcal antigenemia (CRAG+) is unknown. We prospectively enrolled 25 asymptomatic, antiretroviral therapy (ART)-naïve CRAG+ Ugandans with CD4<100 cells/mcL who received pre-emptive fluconazole treatment (CRAG+ cohort) and 189 ART-naïve Ugandans with symptomatic cryptococcal meningitis treated with amphotericin (CM cohort). The 10-week survival was 84% (95%CI: 70–98%) in the CRAG+ cohort and 57% (95%CI: 50%–64%) in the CM cohort. The CRAG+ cohort had improved five-year survival of 76% (95%CI: 59%–93%) compared to 42% (95%CI: 35%–50%) in the CM cohort (P = 0.001). The two cohorts had similar immunosuppression pre-ART with median CD4 counts of 15 vs. 21 CD4/mcL in the CRAG+ and CM cohorts, respectively (P = 0.45). Despite substantial early mortality, subsequent 5-year survival of persons surviving 6-months was excellent (>88%), demonstrating that long term survival is possible in resource-limited settings. Pre-ART CRAG screening with preemptive fluconazole treatment and improved CM treatment(s) are needed to reduce AIDS-attributable mortality due to cryptococcosis which remains 20–25% in sub-Saharan Africa.     

Performance of Cryptococcal Antigen Lateral Flow Assay Using Saliva in Ugandans with CD4 <100

Background

Cryptococcal meningitis can best be diagnosed by cerebrospinal fluid India ink microscopy, cryptococcal antigen detection, or culture. These require invasive lumbar punctures. The utility of cryptococcal antigen detection in saliva is unknown. We evaluated the diagnostic performance of the point-of-care cryptococcal antigen lateral flow assay (CrAg LFA) in saliva.

Methods

We screened HIV-infected, antiretroviral therapy naïve persons with symptomatic meningitis (n = 130) and asymptomatic persons with CD4+<100 cells/µL entering into HIV care (n = 399) in Kampala, Uganda. The diagnostic performance of testing saliva was compared to serum/plasma cryptococcal antigen as the reference standard.

Results

The saliva lateral flow assay performance was overall more sensitive in symptomatic patients (88%) than in asymptomatic patients (27%). The specificity of saliva lateral flow assay was excellent at 97.8% in the symptomatic patients and 100% in asymptomatic patients. The degree of accuracy of saliva in diagnosing cryptococcosis and the level of agreement between the two sample types was better in symptomatic patients (C-statistic 92.9, κ-0.82) than in asymptomatic patients (C-statistic 63.5, κ-0.41). Persons with false negative salvia CrAg tests had lower levels of peripheral blood CrAg titers (P<0.001).

Conclusion

There was poor diagnostic performance in testing saliva for cryptococcal antigen, particularly among asymptomatic persons screened for preemptive treatment of cryptococcosis.     

The ecology of the hippopotamus in Liwonde National Park,Malawi: implications for management

The hippopotamus population in Liwonde National Park, Malawi was studied from December 2002 to June 2003. Motorboat censuses along the River Shire counted 640 animals, but because of the large number of hippos in temporary water sources at the time, the true number is probably closer to 950. Marked shifts in hippo distribution from the Shire into temporary water sources occurred as the wet season advanced. Because of the Shire’s year‐round water supply, the hippo population is not regulated by the availability of aquatic refuges, but by food availability. By following feeding tracks, dry season grazing range was estimated to extend 5 km east and 1 km west of the river. Grazing intensity transects and visual estimates indicated only a small portion of this area is suitable for hippo grazing, leading to over‐grazing in suitable areas. Coupled with low primary productivity levels in Liwonde, this means that dry season food competition between hippos and other herbivores is probably high. Recent proposals to raise the Shire’s dry season water level should be considered very carefully, as this will flood late dry season grazing grounds, thereby intensifying grazing competition and increasing grazing pressure in remaining grazing areas, having potentially serious impacts on the animal community.     

Evolution of Cryptococcal Antigen Testing: What Is New?

Over the last decade, an upsurge in both the frequency and severity of fungal infections due to the HIV/AIDS epidemic and the use of immunosuppressive therapy has occurred. Even diagnostic methods like culture and microscopy, which have low sensitivity and longer turnaround times, are not widely available, leading to delays in timely antifungal therapy and detrimental patient outcomes. The evolution of cryptococcal antigen (CrAg) testing to develop inexpensive and more sensitive methods to detect cryptococcal antigen is significant. These newer tests employ immunoassays as part of point-of-care platforms, which do not require complex laboratory infrastructure, and they have the potential to detect early disease and reduce time to diagnosis of cryptococcal infection. Advocacy for widely available and efficacious life-saving antifungal treatment should be the only remaining challenge.     

Severe Sepsis in Two Ugandan Hospitals: a Prospective Observational Study of Management and Outcomes in a Predominantly HIV-1 Infected Population

Background

Sepsis likely contributes to the high burden of infectious disease morbidity and mortality in low income countries. Data regarding sepsis management in sub-Saharan Africa are limited. We conducted a prospective observational study reporting the management and outcomes of severely septic patients in two Ugandan hospitals. We describe their epidemiology, management, and clinical correlates for mortality.

Methodology/Results

Three-hundred eighty-two patients fulfilled enrollment criteria for a severe sepsis syndrome. Vital signs, management and laboratory results were recorded. Outcomes measured included in-hospital and post-discharge mortality.Most patients were HIV-infected (320/377, 84.9%) with a median CD4+ T cell (CD4) count of 52 cells/mm³ (IQR, 16–131 cells/mm³). Overall mortality was 43.0%, with 23.7% in-hospital mortality (90/380) and 22.3% post-discharge mortality (55/247). Significant predictors of in-hospital mortality included admission Glasgow Coma Scale and Karnofsky Performance Scale (KPS), tachypnea, leukocytosis and thrombocytopenia. Discharge KPS and early fluid resuscitation were significant predictors of post-discharge mortality. Among HIV-infected patients, CD4 count was a significant predictor of post-discharge mortality.Median volume of fluid resuscitation within the first 6 hours of presentation was 500 mLs (IQR 250–1000 mls). Fifty-two different empiric antibacterial regimens were used during the study. Bacteremic patients were more likely to die in hospital than non-bacteremic patients (OR 1.83, 95% CI = 1.01–3.33). Patients with Mycobacterium tuberculosis (MTB) bacteremia (25/249) had higher in-hospital mortality (OR 1.97, 95% CI = 1.19–327) and lower median CD4 counts (p = 0.001) than patients without MTB bacteremia.

Conclusion

Patients presenting with sepsis syndromes to two Ugandan hospitals had late stage HIV infection and high mortality. Bacteremia, especially from MTB, was associated with increased in-hospital mortality. Most clinical predictors of in-hospital mortality were easily measurable and can be used for triaging patients in resource-constrained settings. Procurement of low cost and high impact treatments like intravenous fluids and empiric antibiotics may help decrease sepsis-associated mortality in resource-constrained settings.     

Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study

Background

Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.

Methods and Findings

We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1–5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7–25.6, p<0.001).

Conclusions

Pre-ART increases in Th₁₇ and Th₂ responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions. Please see later in the article for the Editors'' Summary