Recent advances in AIDS-related cryptococcal meningitis treatment with an emphasis on resource limited settings.
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ABSTRACT:
SUBMITTER: Lofgren S
PROVIDER: S-EPMC5602588 | biostudies-literature | 2017 Apr
REPOSITORIES: biostudies-literature
Publications
Recent advances in AIDS-related cryptococcal meningitis treatment with an emphasis on resource limited settings.
Lofgren Sarah S Abassi Mahsa M Rhein Joshua J Boulware David R DR
Expert review of anti-infective therapy 20170209 4
<h4>Introduction</h4>Recent advances in the treatment and prevention of cryptococcal meningitis have the potential to decrease AIDS-related deaths. Areas covered: Targeted screening for asymptomatic cryptococcal antigenemia in persons with AIDS is a cost effective method for reducing early mortality in patients on antiretroviral therapy. For persons with symptomatic cryptococcal meningitis, optimal initial management with amphotericin and flucytosine improves survival compared to alternative the ...[more]
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Project description:BackgroundCryptococcal 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 findingsWe 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.ConclusionsShort-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.
| S-EPMC3463510 | biostudies-literature
Project description: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.
| S-EPMC4845086 | biostudies-literature
Project description:BackgroundAmphotericin B is the preferred treatment for cryptococcal meningitis, but it has cumulative severe side effects, including nephrotoxicity, hypokalemia, and hypomagnesemia. Amphotericin-induced severe hypokalemia may predispose the patient to cardiac arrhythmias and death, and there is very little data available regarding these toxicities in resource-limited settings. We hypothesized that standardized electrolyte management during amphotericin therapy is essential to minimize toxicity and optimize survival in sub-Saharan Africa.MethodsHuman immunodeficiency virus-infected, antiretroviral therapy naive adults with cryptococcal meningitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphotericin B deoxycholate induction treatment. Intravenous fluid use was intermittent in 2001-2002, and universal in 2006-2012. In 2001-2009, serum potassium (K(+)) was monitored on days 1, 7, and 14 of treatment with replacement (K(+), Mg(2+)) per clinician discretion. In 2011-2012, K(+) was measured on days 1, 5, and approximately every 48 hours thereafter with universal electrolyte (K(+), Mg(2+)) supplementation and standardized replacement. Clinical outcomes were retrospectively compared between fluid and electrolyte management strategies.ResultsWith limited intravenous fluids, the 14-day survival was 49% in 2001-2002. With universal intravenous fluids, the 30-day survival improved to 62% in 2006-2010 (P = .003). In 2011-2012, with universal supplementation of fluids and electrolytes, 30-day cumulative survival improved to 78% (P = .021 vs 2006-2010 cohort). The cumulative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011-2012 with universal supplementation (P < .001).ConclusionsImproved survival was seen in a resource-limited setting with proactive fluid and electrolyte management (K(+), Mg(2+)), as part of comprehensive amphotericin-based cryptococcal therapy.
| S-EPMC4281785 | biostudies-literature
Project description:BACKGROUND:Checklists can standardize patient care, reduce errors, and improve health outcomes. For meningitis in resource-limited settings, with high patient loads and limited financial resources, central nervous system diagnostic algorithms may be useful to guide diagnosis and treatment. However, the cost effectiveness of such algorithms is unknown. METHODS:We used decision analysis methodology to evaluate the costs, diagnostic yield, and cost effectiveness of diagnostic strategies for adults with suspected meningitis in resource-limited settings with moderate/high HIV prevalence. We considered 3 strategies: (1) comprehensive "shotgun" approach of utilizing all routine tests; (2) "stepwise" strategy with tests performed in a specific order with additional tuberculosis (TB) diagnostics; (3) "minimalist" strategy of sequential ordering of high-yield tests only. Each strategy resulted in 1 of 4 meningitis diagnoses: bacterial (4%), cryptococcal (59%), TB (8%), or other (aseptic) meningitis (29%). In model development, we utilized prevalence data from 2 Ugandan sites and published data on test performance. We validated the strategies with data from Malawi, South Africa, and Zimbabwe. RESULTS:The current comprehensive testing strategy resulted in 93.3% correct meningitis diagnoses costing $32.00 per patient. A stepwise strategy had 93.8% correct diagnoses costing an average of $9.72 per patient, and a minimalist strategy had 91.1% correct diagnoses costing an average of $6.17 per patient. The incremental cost-effectiveness ratio was $133 per additional correct diagnosis for the stepwise over minimalist strategy. CONCLUSIONS:Through strategically choosing the order and type of testing coupled with disease prevalence rates, algorithms can deliver more care more efficiently. The algorithms presented herein are generalizable to East Africa and Southern Africa.
| S-EPMC3683123 | biostudies-literature
Project description:Cryptococcal meningitis is a leading cause of mortality among HIV-infected individuals in sub-Saharan Africa but little is known about its treatment and outcomes in decentralised HIV outpatient settings. We assessed adherence to treatment guidelines and determined predictors of survival.A computerised laboratory database identified HIV-infected adults with cryptococcal meningitis at Family AIDS Care and Education Services in Nyanza Province, Kenya, between 2005-2009. Medical records were reviewed. Kaplan-Meier survival curves were generated. Bivariate and multivariate Cox proportional hazards models were used to determine associations between key clinical characteristics and survival.Medical records were located for 79% (71/90). Mortality was 38% (27/71) over a median follow-up period of 201 days (IQR: 10-705 days). Adherence to local guidelines for treatment of cryptococcal meningitis was 48% (34/71). Higher body mass index was associated with improved survival (HR: 0.82, 95% CI (0.68 to 0.99)) even after controlling for factors such as age, CD4 cell count, receipt of highly active anti-retroviral therapy, and treatment with any anti-fungal therapy.Cryptococcal meningitis diagnosed in routine HIV outpatient settings is largely treated as an outpatient and adherence to treatment guidelines is poor. Body mass index is a critical independent predictor of outcome. Additional research to determine the most effective strategies to reduce premature mortality is urgently needed.
| S-EPMC3722584 | biostudies-literature
Project description:BackgroundWe present an innovative approach to healthcare worker (HCW) training using mobile phones as a personal learning environment.Twenty physicians used individual Smartphones (Nokia N95 and iPhone), each equipped with a portable solar charger. Doctors worked in urban and peri-urban HIV/AIDS clinics in Peru, where almost 70% of the nation's HIV patients in need are on treatment. A set of 3D learning scenarios simulating interactive clinical cases was developed and adapted to the Smartphones for a continuing medical education program lasting 3 months. A mobile educational platform supporting learning events tracked participant learning progress. A discussion forum accessible via mobile connected participants to a group of HIV specialists available for back-up of the medical information. Learning outcomes were verified through mobile quizzes using multiple choice questions at the end of each module.MethodsIn December 2009, a mid-term evaluation was conducted, targeting both technical feasibility and user satisfaction. It also highlighted user perception of the program and the technical challenges encountered using mobile devices for lifelong learning.ResultsWith a response rate of 90% (18/20 questionnaires returned), the overall satisfaction of using mobile tools was generally greater for the iPhone. Access to Skype and Facebook, screen/keyboard size, and image quality were cited as more troublesome for the Nokia N95 compared to the iPhone.ConclusionsTraining, supervision and clinical mentoring of health workers are the cornerstone of the scaling up process of HIV/AIDS care in resource-limited settings (RLSs). Educational modules on mobile phones can give flexibility to HCWs for accessing learning content anywhere. However lack of softwares interoperability and the high investment cost for the Smartphones' purchase could represent a limitation to the wide spread use of such kind mLearning programs in RLSs.
| S-EPMC2942790 | biostudies-literature
Project description:IntroductionLipodystrophy is a term used to describe a metabolic complication of fat loss, fat gain, or a combination of fat loss and gain, which is associated with some antiretroviral (ARV) therapies given to HIV-infected individuals. There is limited research on lipodystrophy in low- and middle-income countries, despite accounting for more than 95% of the burden of HIV/AIDS. The objective of this review was to evaluate the prevalence, pathogenesis and prognosis of HIV-related lipoatrophy, lipohypertrophy and mixed syndrome, to inform clinical management in resource-limited settings.MethodsWe conducted a structured literature search using MEDLINE electronic databases. Relevant MeSH terms were used to identify published human studies on HIV and lipoatrophy, lipohypertrophy, or mixed syndrome in low-, low-middle- and upper-middle-income countries through 31 March 2014. The search resulted in 5296 articles; after 1599 studies were excluded (958 reviews, 641 non-human), 3697 studies were extracted for further review. After excluding studies conducted in high-income settings (n=2808), and studies that did not meet inclusion criteria (n = 799), 90 studies were included in this review.Results and discussionOf the 90 studies included in this review, only six were from low-income countries and eight were from lower middle-income economies. These studies focused on lipodystrophy prevalence, risk factors and side effects of antiretroviral therapy (ART). In most studies, lipodystrophy developed after the first six months of therapy, particularly with the use of stavudine. Lipodystrophy is associated with increased risk of cardiometabolic complications. This is disconcerting and anticipated to increase, given the rapid scale-up of ART worldwide, the increasing number and lifespan of HIV-infected patients on long-term therapy, and the emergence of obesity and non-communicable diseases in settings with extensive HIV burden.ConclusionsLipodystrophy is common in resource-limited settings, and has considerable implications for risk of metabolic diseases, quality of life and adherence. Comprehensive evidence-based interventions are urgently needed to reduce the burden of HIV and lipodystrophy, and inform clinical management in resource-limited settings.
| S-EPMC4297925 | biostudies-literature
Project description:BackgroundAvailable information on the causes of death among people living with human immunodeficiency virus (PLHIV) in low- and middle-income countries (LMICs) remains scarce. We aimed to provide data on causes of death in PLHIV from two LMICs, Brazil and Mozambique, to assess the impact of clinical misdiagnosis on mortality rates and to evaluate the accuracy of minimally invasive tissue sampling (MITS) in determining the cause of death in PLHIV.MethodsWe performed coupled MITS and complete autopsy on 164 deceased PLHIV (18 children, 36 maternal deaths, and 110 adults). HIV antibody levels and HIV RNA viral loads were determined from postmortem serum samples.ResultsTuberculosis (22.7%), toxoplasmosis (13.9%), bacterial infections (13.9%), and cryptococcosis (10.9%) were the leading causes of death in adults. In maternal deaths, tuberculosis (13.9%), bacterial infections (13.9%), cryptococcosis (11.1%), and cerebral malaria (8.3%) were the most frequent infections, whereas viral infections, particularly cytomegalovirus (38.9%), bacterial infections (27.8%), pneumocystosis (11.1%), and HIV-associated malignant neoplasms (11.1%) were the leading cause among children. Agreement between the MITS and the complete autopsy was 100% in children, 91% in adults, and 78% in maternal deaths. The MITS correctly identified the microorganism causing death in 89% of cases.ConclusionsPostmortem studies provide highly granular data on the causes of death in PLHIV. The inaccuracy of clinical diagnosis may play a significant role in the high mortality rates observed among PLHIV in LMICs. MITS might be helpful in monitoring the causes of death in PLHIV and in highlighting the gaps in the management of the infections.
| S-EPMC8672756 | biostudies-literature
Project description:The vast majority of people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome reside in the developing world, in settings characterized by limited health budgets, critical shortages of doctors, limited laboratory monitoring, a substantial burden of HIV in children, and high rates of coinfection, in particular tuberculosis. Therefore, the extent to which new antiretrovirals will contribute to improvements in the management of HIV globally will depend to a large extent on their affordability, ease of use, low toxicity profile, availability as pediatric formulations, and compatibility with tuberculosis and other common drugs. We undertook a systematic review of the available evidence regarding drug interactions, and the efficacy and safety of rilpivirine (also known as TMC-278), and assessed our findings in view of the needs and constraints of resource-limited settings. The main pharmacokinetic interactions relevant to HIV management reported to date include reduced bioavailability of rilpivirine when coadministered with rifampicin, rifabutin or acid suppressing agents, and reduced bioavailability of ketoconazole. Potential recommendations for dose adjustment to compensate for these interactions have not been elaborated. Trials comparing rilpivirine and efavirenz found similar outcomes up to 96 weeks in intent-to-treat analysis; failure of rilpivirine was mainly virological, whereas failure among those exposed to efavirenz was mainly related to the occurrence of adverse events. Around half of the patients who fail rilpivirine develop non-nucleoside reverse transcriptase inhibitor resistance mutations. The incidence of Grade 2-4 events was lower for rilpivirine compared with efavirenz. Grade 3-4 adverse events potentially related to the drugs were infrequent and statistically similar for both drugs. No dose-response relationship was observed for efficacy or safety, and the lowest dose (25 mg) was selected for further clinical development. The potential low cost and dose of the active pharmaceutical ingredient means that rilpivirine can potentially be manufactured at a low price. Moreover, its long half-life suggests the potential for monthly dosing via nonoral routes, with promising early results from studies of a long-acting injectable formulation. These characteristics make rilpivirine an attractive drug for resource-limited settings. Future research should assess the potential to improve robustness and assess the clinical significance of interaction with antituberculosis drugs.
| S-EPMC3218710 | biostudies-literature
Project description:Latin America is the region with the third most AIDS-related cryptococcal meningitis infections globally. Highly active antiretroviral therapy (HAART) has reduced the number of infections; however, the number of deaths and the case-fatality rate continues to be unacceptable. In this review, we focus on the burden of AIDS-related cryptococcosis in Latin America and discuss potential strategies to reduce early mortality from Cryptococcus. In this review, we highlight the importance of: (1) earlier HIV diagnosis and HAART initiation with retention-in-care to avoid AIDS; (2) pre-HAART cryptococcal antigen (CRAG) screening with preemptive fluconazole treatment; (3) better diagnostics (e.g. CRAG testing); and (4) optimal treatment with aggressive management of intracranial pressure and induction therapy with antifungal combination. Implementation of these strategies can reduce cryptococcal-related deaths, improve care, and reduce healthcare costs.
| S-EPMC3747670 | biostudies-literature