Diagnosis and Management of Cryptococcal Disease in Resource-Limited Settings

Cryptococcal meningitis is one of the most important fungal infections in the developing world, where deaths related to this disease are numerous. In resource-limited settings, mortality is high in large part because of difficulties in the diagnosis and management of this infection. This paper outlines many of the realities in many resource-limited settings, and describes priorities for public health action and research.     

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.     

Diagnostics in Ebola Virus Disease in Resource-Rich and Resource-Limited Settings

The Ebola virus disease (EVD) outbreak in West Africa was unprecedented in scale and location. Limited access to both diagnostic and supportive pathology assays in both resource-rich and resource-limited settings had a detrimental effect on the identification and isolation of cases as well as individual patient management. Limited access to such assays in resource-rich settings resulted in delays in differentiating EVD from other illnesses in returning travellers, in turn utilising valuable resources until a diagnosis could be made. This had a much greater impact in West Africa, where it contributed to the initial failure to contain the outbreak. This review explores diagnostic assays of use in EVD in both resource-rich and resource-limited settings, including their respective limitations, and some novel assays and approaches that may be of use in future outbreaks.     

A Clinical Prediction Score in Addition to WHO Criteria for Anti-Retroviral Treatment Failure in Resource-Limited Settings - Experience from Lesotho

Objective

To assess the positive predictive value (PPV) of a clinical score for viral failure among patients fulfilling the WHO-criteria for anti-retroviral treatment (ART) failure in rural Lesotho.

Methods

Patients fulfilling clinical and/or immunological WHO failure-criteria were enrolled. The score includes the following predictors: Prior ART exposure (1 point), CD4-count below baseline (1), 25% and 50% drop from peak CD4-count (1 and 2), hemoglobin drop≥1 g/dL (1), CD4 count<100/µl after 12 months (1), new onset papular pruritic eruption (1), and adherence<95% (3). A nurse assessed the score the day blood was drawn for viral load (VL). Reported confidence intervals (CI) were calculated using Wilsons method.

Results

Among 1''131 patients on ART≥6 months, 134 (11.8%) had immunological and/or clinical failure, 104 (78%) had blood drawn (13 died, 10 lost to follow-up, 7 did not show up). From 92 (88%) a result could be obtained (2 samples hemolysed, 10 lost). Out of these 92 patients 47 (51%) had viral failure (≥5000 copies), 27 (29%) viral suppression (<40) and 18 (20%) intermediate viremia (40–4999). Overall, 20 (22%) had a score≥5. A score≥5 had a PPV of 100% to detect a VL>40 copies (95%CI: 84–100), and of 90% to detect a VL≥5000 copies (70–97). Within the score, adherence<95%, CD4-count<100/µl and papular pruritic eruption were the strongest single predictors. Among 47 patients failing, 8 (17%) died before or within 4 weeks after being switched. Overall mortality was 4 (20%) among those with score≥5 and 4 (5%) if score<5 (OR 4.3; 95%CI: 0.96–18.84, p = 0.057).

Conclusion

A score≥5 among patients fulfilling WHO-criteria had a PPV of 100% for a detectable VL and 90% for viral failure. In settings without regular access to VL-testing, this PPV may be considered high enough to switch this patient-group to second-line treatment without confirmatory VL-test.     

Offering an American Graduate Medical HIV Course to Health Care Workers in Resource-Limited Settings via the Internet

Background

Western accredited medical universities can offer graduate-level academic courses to health care workers (HCWs) in resource-limited settings through the internet. It is not known whether HCWs are interested in these online courses, whether they can perform as well as matriculated students, or whether such courses are educationally or practically relevant.

Methods and Findings

In 2011, the University of Washington (UW) Schools of Medicine and Nursing offered the graduate course, “Clinical Management of HIV”, to HCWs that included a demographic survey, knowledge assessment, and course evaluation. UW faculty delivered HIV clinical topics through ten 2-hour weekly sessions from the perspectives of practicing HIV medicine in developed and developing settings. HCWs viewed lectures through Adobe Acrobat Connect Pro (Adobe Systems, San Jose, CA), and completed online homework on HIV Web Study (http://depts.washington.edu/hivaids/) and online quizzes. HCWs, who met the same passing requirements as UW students by attending 80% lectures, completing ≥90% homework, and achieving a cumulative ≥70% grade on quizzes, were awarded a certificate. 369 HCWs at 33 sites in 21 countries joined the course in 2011, a >15-fold increase since the course was first offered in 2007. The majority of HCWs came from Africa (72%), and most were physicians (41%), nurses (22%), or midlevel practitioners (20%). 298 HCWs (81%) passed all requirements and earned a certificate. In a paired analysis of pre- and post-course HIV knowledge assessments, 56% of HCWs improved their post-course score (p<0.0001) with 27% improving by at least 30%. In the course evaluation, most HCWs rated the course as excellent (53%) or very good (39%).

Conclusions

This online HIV course demonstrated that opening a Western graduate medical and nursing curriculum to HCWs in resource-limited settings is feasible, popular, and valuable, and may address logistic and economic barriers to the provision of high quality education in these settings.     

Using the Lives Saved Tool (LiST) to Model mHealth Impact on Neonatal Survival in Resource-Limited Settings

While the importance of mHealth scale-up has been broadly emphasized in the mHealth community, it is necessary to guide scale up efforts and investment in ways to help achieve the mortality reduction targets set by global calls to action such as the Millennium Development Goals, not merely to expand programs. We used the Lives Saved Tool (LiST)–an evidence-based modeling software–to identify priority areas for maternal and neonatal health services, by formulating six individual and combined interventions scenarios for two countries, Bangladesh and Uganda. Our findings show that skilled birth attendance and increased facility delivery as targets for mHealth strategies are likely to provide the biggest mortality impact relative to other intervention scenarios. Although further validation of this model is desirable, tools such as LiST can help us leverage the benefit of mHealth by articulating the most appropriate delivery points in the continuum of care to save lives.     

The Cost-Effectiveness of Monitoring Strategies for Antiretroviral Therapy of HIV Infected Patients in Resource-Limited Settings: Software Tool

Background

The cost-effectiveness of routine viral load (VL) monitoring of HIV-infected patients on antiretroviral therapy (ART) depends on various factors that differ between settings and across time. Low-cost point-of-care (POC) tests for VL are in development and may make routine VL monitoring affordable in resource-limited settings. We developed a software tool to study the cost-effectiveness of switching to second-line ART with different monitoring strategies, and focused on POC-VL monitoring.

Methods

We used a mathematical model to simulate cohorts of patients from start of ART until death. We modeled 13 strategies (no 2^nd-line, clinical, CD4 (with or without targeted VL), POC-VL, and laboratory-based VL monitoring, with different frequencies). We included a scenario with identical failure rates across strategies, and one in which routine VL monitoring reduces the risk of failure. We compared lifetime costs and averted disability-adjusted life-years (DALYs). We calculated incremental cost-effectiveness ratios (ICER). We developed an Excel tool to update the results of the model for varying unit costs and cohort characteristics, and conducted several sensitivity analyses varying the input costs.

Results

Introducing 2^nd-line ART had an ICER of US$1651-1766/DALY averted. Compared with clinical monitoring, the ICER of CD4 monitoring was US$1896-US$5488/DALY averted and VL monitoring US$951-US$5813/DALY averted. We found no difference between POC- and laboratory-based VL monitoring, except for the highest measurement frequency (every 6 months), where laboratory-based testing was more effective. Targeted VL monitoring was on the cost-effectiveness frontier only if the difference between 1^st- and 2^nd-line costs remained large, and if we assumed that routine VL monitoring does not prevent failure.

Conclusion

Compared with the less expensive strategies, the cost-effectiveness of routine VL monitoring essentially depends on the cost of 2^nd-line ART. Our Excel tool is useful for determining optimal monitoring strategies for specific settings, with specific sex-and age-distributions and unit costs.     

Evaluation in Cameroon of a Novel,Simplified Methodology to Assist Molecular Microbiological Analysis of V. cholerae in Resource-Limited Settings

BackgroundVibrio cholerae is endemic in South Asia and Africa where outbreaks of cholera occur widely and are particularly associated with poverty and poor sanitation. Knowledge of the genetic diversity of toxigenic V. cholerae isolates, particularly in Africa, remains scarce. The constraints in improving this understanding is not only the lack of regular cholera disease surveillance, but also the lack of laboratory capabilities in endemic countries to preserve, store and ship isolates in a timely manner. We evaluated the use of simplified sample preservation methods for molecular characterization using multi-locus variable-number tandem-repeat analysis (MLVA) for differentiation of Vibrio cholerae genotypes.ConclusionsCollecting V. cholerae using simplified laboratory methods in remote and low-resource settings allows for subsequent advanced molecular characterization of V. cholerae O1. These simplified DNA preservation methods identify V. cholerae and make possible timely information regarding the genetic diversity of V. cholerae; our results set the stage for continued molecular epidemiological research to better understand the transmission and dissemination of V. cholerae in Africa and elsewhere worldwide.     

Assessing and Enhancing the Research Consent Capacity of Children and Youth

This study examined the capacity of 291 4th, 7th, and 10th graders, as well as college students, to understand their rights in research and the extent to which this capacity can be enhanced following exposure to The Research Participants' Bill of Rights. Comprehension of the research procedures, risks and benefits, voluntary nature of participation, and confidentiality protections improved in all grades following exposure to the Bill of Rights. Fourth graders performed poorer than older respondents when asked to match rights definitions, identify true and false statements about specific research rights, and label and recognize rights violations in hypothetical research vignettes. Data suggest that 7th graders, when compared to older participants, are still struggling to understand their veto power over adult permission, their right to be protected from harm, and to be informed about research procedures and results. Overall, 10th graders' responses did not differ from adults'. Implications of the findings for informed consent procedures are discussed.     

Change in Vitamin D Levels Occurs Early after Antiretroviral Therapy Initiation and Depends on Treatment Regimen in Resource-Limited Settings

Study Background

Vitamin D has wide-ranging effects on the immune system, and studies suggest that low serum vitamin D levels are associated with worse clinical outcomes in HIV. Recent studies have identified an interaction between antiretrovirals used to treat HIV and reduced serum vitamin D levels, but these studies have been done in North American and European populations.

Methods

Using a prospective cohort study design nested in a multinational clinical trial, we examined the effect of three combination antiretroviral (cART) regimens on serum vitamin D levels in 270 cART-naïve, HIV-infected adults in nine diverse countries, (Brazil, Haiti, Peru, Thailand, India, Malawi, South Africa, Zimbabwe and the United States). We evaluated the change between baseline serum vitamin D levels and vitamin D levels 24 and 48 weeks after cART initiation.

Results

Serum vitamin D levels decreased significantly from baseline to 24 weeks among those randomized to efavirenz/lamivudine/zidovudine (mean change: −7.94 [95% Confidence Interval (CI) −10.42, −5.54] ng/ml) and efavirenz/emtricitabine/tenofovir-DF (mean change: −6.66 [95% CI −9.40, −3.92] ng/ml) when compared to those randomized to atazanavir/emtricitabine/didanosine-EC (mean change: −2.29 [95% CI –4.83, 0.25] ng/ml). Vitamin D levels did not change significantly between week 24 and 48. Other factors that significantly affected serum vitamin D change included country (p<0.001), season (p<0.001) and baseline vitamin D level (p<0.001).

Conclusion

Efavirenz-containing cART regimens adversely affected vitamin D levels in patients from economically, geographically and racially diverse resource-limited settings. This effect was most pronounced early after cART initiation. Research is needed to define the role of Vitamin D supplementation in HIV care.     

干细胞用于乳腺癌治疗的研究进展

乳腺癌是女性最常见的恶性肿瘤之一,是一种严重影响女性身心健康甚至危及生命的恶性肿瘤,男性乳腺癌罕见.目前,乳腺癌的治疗仍以外科治疗为主.随着干细胞生物学的发展,人们发现造血干细胞移植在恶性肿瘤大剂量放、化疗后的造血重建和免疫重建中有着重要作用,而间充质干细胞可以作为基因栽体而抑制肿瘤细胞的生长.这些研究为乳腺癌的治疗提供了全新的思路.分析目前人们应用干细胞治疗乳腺癌的研究现状,同时统计分析了中国临床试验注册中心数据库和美国clinicaltrials 数据库中用干细胞治疗乳腺癌的临床试验的最新数据,并且指出了干细胞用于乳腺癌治疗的研究趋势,目的是为后续开展的用干细胞治疗乳腺癌的研究提供一定的参考.     

EUCAST and CLSI: Working Together Towards a Harmonized Method for Antifungal Susceptibility Testing

The U.S. Clinical and Laboratory Standards Institute (CLSI) and the European Committee of Antimicrobial Susceptibility Testing (AFST-EUCAST) have developed broth microdilution methodologies for testing yeasts and filamentous fungi (molds). The mission of these methodologies is to identify in vitro antifungal resistance, which is accomplished by the use of either clinical breakpoints (CBPs), or to a lesser degree, epidemiologic cutoff values (ECVs). The newly adjusted and species-specific CLSI CBPs for Candida spp. versus fluconazole and voriconazole have ameliorated some of the differences between the two methodologies. In the absence of CBPs for mold testing, CLSI ECVs are available for six Aspergillus species versus the triazoles, caspofungin and amphotericin B. Recently, breakpoints were developed by the EUCAST for certain Aspergillus spp. versus amphotercin B, itraconazole and posaconazole, which to some extent are comparable to ECVs. We summarize these latest accomplishments, which have made possible the harmonization of some susceptibility cutoffs, if not methodologies for some agent/species combinations.