Cryptococcal Antigen Screening for Patients Initiating Antiretroviral Therapy: Time for Action

Clinical Infectious Diseases, Dec 2010

Jarvis, Joseph N., Lawn, Stephen D., Wood, Robin, Harrison, Thomas S.

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Cryptococcal Antigen Screening for Patients Initiating Antiretroviral Therapy: Time for Action

Clinical Infectious Diseases 0 Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Faculty of Health Sciences , Anzio Rd, Observatory 7925, Cape Town , South Africa To the Editor-I am delighted to begin to see published studies on specific connectors, such as Dr. Maki's article [1]. I agree that “there is an urgent need to develop new technologies” [1, p.1581] to prevent catheter-related infections. Beginning with in vitro studies is appropriate, and I hope to see further research on connector technology and outcomes. There are several issues I would like to be considered by all who develop, implement, and evaluate research studies on connectors. 1. Awareness of potential bias and ethical issues regarding research implemented by the manufacturers of products. A better methodology would be research performed by independent laboratories and/ or research groups. 2. Awareness that simulation research is not a substitute for clinical trials and should not be used to fully change care, policy, or procedures. 3. Actual clinical study designs should include withdrawal of blood through the connector as part of actual clinical practice, and designs should not be implemented under strict sterile conditions, because handling or heavy manipulation under sterile conditions will lead to sterile results, which are not very useful for clinical reality. 4. Controls are needed, and any negative difference between the number of colony-forming units in the inoculated media and the number of colony-forming units retrieved needs to be explained and verified as actual killing of the organisms or actual passage of the organisms into the patient. 5. Products need to be clearly defined. For example, in the article by Maki [1], the luer-activated ClearLink (a connector Cryptococcal Antigen Screening for Patients Initiating Antiretroviral Therapy; Time for Action - type with large reflux and priming volume, both of which are variables that lend to intraluminal bacterial growth) had an add-on production effect of a coating with silver, and the revised product was named V-Link (both manufactured by Baxter Healthcare). The major question is, Does the add-on create positive outcomes, meet safety guidelines, and increase clinical effectiveness? 6. Methodological questions should include the following: Does the drying process itself lend to bacterial kill? Does silver coating, at some point in time, act as a docking station for biofilm? Does the actual infusion of fluids, as well as a 25 C temperature, simulate a clinical environment? 7. As in all technologies, design is a significant factor and affects outcomes. For connectors, the major question is, How do positive, negative, and zero fluid displacement designs and silver-coated versus silver-impregnated products affect outcomes? I hope we can consider these points in connector research, because the goal is saving lives, and as professionals, we first do no harm. Again, thank you for publishing this initial study on such a needed topic. Acknowledgments Potential conflicts of interest. C.C.: no conflicts. Cynthia Chernecky Department of Physiological and Technological Nursing, Medical College of Georgia, Augusta 1. Maki DG. In vitro studies of a novel antimicrobial luer-activated needleless connector for prevention of catheter-related bloodstream infection. Clin Infect Dis 2010; 50:1580–1587. 1 5 D E C E M B E R To the Editor—We agree strongly with the conclusions of Meya and colleagues [ 1 ] that serum cryptococcal antigen (CRAG) screening in patients with CD4 cell counts 100 cells/mL should be integrated into national antiretroviral treatment (ART) programs in sub-Saharan Africa, to decrease the high ongoing human and economic costs of cryptococcal meningitis [ 1, 2 ]. In South Africa, cryptococcal meningitis is now the most common cause of adult meningitis, accounting for 63% of laboratory-confirmed cases [ 3 ]. As access to ART expands, an increasing proportion of cryptococcal meningitis cases develop in patients who have recently started ART. In Cape Town, 1 in 5 cases develop while a patient is receiving ART (after a median of 41 days) and have high in-hospital mortality (29%) [ 4 ]. We have previously demonstrated that nearly all such cases could be identified by CRAG screening at entry into ART programs [ 5 ]. The incidence of cryptococcal meningitis rapidly decreases with effective ART (Figure 1), and shortterm “preemptive treatment” followed by secondary prophylaxis in patients with a positive result of CRAG screening could potentially prevent most, if not all, cryptococcal meningitis cases that occur after ART [ 5 ]. Importantly, in addition to the 20% of patients with cryptococcal meningitis who present after ART initiation, an additional 58% of our patients who present with cryptococcal meningitis have already received a human immunodeficiency virus (HIV) diagnosis, made a median of 4 months prior to development of cryptococcal meningitis, but have yet to start ART [ 6 ]. CRAG screening at the time of HIV diagnosis may also identify these patients, allowing for preemptive therapy and fast-tracking of ART—an issue of particular priority where delays in ART initiation following diagnosis are common [ 7 ]. The analysis of the Ugandan cohort reported by Meya and colleagues [ 1 ] presents a compelling case for the cost-effectiveness of CRAG screening. However, this may underestimate the true cost-effectiveness, because of both the high cost of the CRAG test used in their analysis, and the potential for large cost reductions to be realized by prevention of expensive hospital admissions. The high price currently paid per test in Uganda ($16.75) would likely decrease to a more reasonable $5.61, as paid in South Africa, with bulk testing. Moreover, at a total health care cost of $2883 per patient admitted with cryptococcal meningitis in South Africa [ 8 ], each admission prevented would represent a cost saving equating to 172 CRAG tests, even at current Ugandan prices—a factor not considered in the analysis of Meya et al—which clearly needs to be weighed against CRAG testing costs. Further evidence of the potential cost savings can be extrapolated from data showing that 31% of all inpatient days in the initial 32 weeks of ART in a South African cohort were the result of cryptococcal meningitis [ 9 ]. Such a favorable cost-benefit ratio, particularly in view of the generally unfavorable cost-effectiveness analyses of the alternative prevention strategy of primary prophylaxis [ 10–13 ], is rightly leading to widespread interest in introducing CRAG screening policies. As the case for CRAG screening grows, so does the need to define the optimal management of asymptomatic, CRAG-positive patients. Natural history data from Cape Town suggest that up to 56% of patients will have clearance of antigenemia with ART alone—clearly not enough. But as Meya and colleagues [1] demonstrate, standard-dose fluconazole in short courses is also inadequate; 3 (14%) of 21 treated patients developed cryptococcal meningitis. It remains unclear whether asymptomatic antigenemic patients require lumbar puncture to rule 1464 • CID 2010:51 (15 December) • CORRESPONDENCE out involvement of the central nervous system, whether CRAG titers can be used to guide treatment decisions, and whether high-dose fluconazole alone will be sufficient to prevent disease in all patients. Optimal timing of ART also needs to be defined for such patients. Studies are underway to answer these questions in South Africa. In the meantime, any programmatic screening intervention must be closely monitored, and data should be reported to help formulate optimal strategies for this important intervention. Acknowledgments Financial support. Wellcome Trust, London (WT081794 and WT081667 to J.N.J. and S.D.L.). Potential conflicts of interest. All authors: no conflicts. Joseph N. Jarvis,1,2,3,4 Stephen D. Lawn,1,2,5 Robin Wood,1 and Thomas S. Harrison1,4 Preexisting Antibodies against Pandemic 2009 Influenza A (H1N1) Virus in Taiwan To the Editor—In April 2009, a new swine-origin influenza A (H1N1) virus, the pandemic 2009 influenza A (H1N1) virus, that efficiently transmitted among humans emerged in Mexico and the United States [ 1, 2 ] and spread worldwide. This new 2009 H1N1 virus was probably a “quadruple” reassortant containing the HA (H1) gene of classical swine virus origin [ 3 ]. Most individuals were expected to lack immunity to this new virus. However, an early study in the United States revealed that the 2009 influenza A (H1N1) virus caused less morbidity and mortality from severe pneumonia in patients aged 60 years [ 4 ]. Serological studies from England and the United States also indicated that 23%–33% of older persons had moderate levels of cross-reactive antibodies to this virus [ 5, 6 ]. Therefore, individuals aged 65 years were not included in the initial target groups for 2009 H1N1 vaccination [7]. In contrast, recent data from China revealed that 0%–10% of serum samples from older individuals were positive for 2009 influenza A (H1N1) [ 8–10 ]. In Japan, preexisting antibodies were found only in individuals born before 1920 [ 11 ]. In Finland, the antibody prevalence was approximately 96% in individuals born during the period 1909–1919 but varied from 77% to 14% in those born during the period 1920–1944 [ 12 ]. This discrepancy in immune status may be attributed to geographic variability [ 13 ]. To evaluate the preexisting antibody titer to 2009 influenza A (H1N1) in the elderly and to formulate vaccination strategies for 2009 influenza A (H1N1), we measured the prevalence of preexisting antibodies to this virus in 79 persons aged 60 years in Taoyuan County, Taiwan, during the period February–March 2009, before the current pandemic. In addition, 169 health care workers aged 22–60 years at Chang Gung Memorial Hospital in Taoyuan, Taiwan, were evaluated during the period October–November 2009, after the first wave of infection in Taiwan, before they received monovalent vaccination against 2009 influenza A (H1N1). Reference serum samples collected from 20 patients 3–4 months after laboratory-confirmed 2009 influenza A (H1N1) infections were used as positive controls. Antibody responses to 2009 H1N1 (A/ Taiwan/126/09) and seasonal H1N1 (A/ Brisbane/59/07 [H1N1]–like) virus were detected by means of hemagglutination inhibition assay in accordance with standard methods [14]. CORRESPONDENCE • CID 2010:51 (15 December) • 1465 1. Meya DB , Manabe YC , Castelnuovo B , et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIVinfected persons with a CD4+ cell count 100 cells/mL who start HIV therapy in resourcelimited settings . Clin Infect Dis 2010 ; 51 : 448 - 455 . 2. Park BJ , Wannemuehler KA , Marston BJ , Govender N , Pappas PG , Chiller TM . Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS . AIDS 2009 ; 23 : 525 - 530 . 3. Jarvis JN , Meintjes G , Williams A , Brown Y , Crede T , Harrison TS . Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases . BMC Infect Dis 2010 ; 10 : 67 . 4. Jarvis JN , Meintjes G , Harrison TS . Outcomes of cryptococcal meningitis in antiretroviral naive and experienced patients in South Africa . J Infect 2010 ; 60 : 496 - 498 . 5. Jarvis JN , Lawn SD , Vogt M , Bangani N , Wood R , Harrison TS . Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa . Clin Infect Dis 2009 ; 48 : 856 - 862 . 6. Jarvis JN , Meintjes G , Wood R , Harrison TS . Testing but not treating: missed opportunities and lost lives in the South African antiretroviral therapy programme . AIDS 2010 ; 24 : 1233 - 1235 . 7. Lawn S , Harries A , Anglaret X , Myer L , Wood R . Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa . AIDS 2008 ; 22 : 1897 - 1908 . 8. Haile B , Maartens G , Wood R . Economic evaluation of cryptococcal meningitis and inpatient tuberculosis treatment for HIV-infected adults in South Africa [abstract 25431] . In: Program and abstracts of the 129th Annual Meeting of the American Public Health Association (Atlanta) . 2001 . 9. Harling G , Orrell C , Wood R . Healthcare utilization of patients accessing an African national treatment program . BMC Health Serv Res 2007 ; 7 : 80 . 10. John L , Nelson M. Primary prophylaxis for cryptococcal meningitis . HIV Med 2004 ; 5 : 131 - 132 . 11. Scharfstein JA , Paltiel AD , Freedberg KA . The cost-effectiveness of fluconazole prophylaxis against primary systemic fungal infections in AIDS patients . Med Decis Making 1997 ; 17 : 373 - 381 . 12. Yazdanpanah Y , Goldie SJ , Paltiel AD , et al. Prevention of human immunodeficiency virus-related opportunistic infections in France: a cost-effectiveness analysis . Clin Infect Dis 2003 ; 36 : 86 - 96 . 13. Freedberg KA , Scharfstein JA , Seage GR 3rd, et al. The cost-effectiveness of preventing AIDS-related opportunistic infections . JAMA 1998 ; 279 : 130 - 136 .


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Jarvis, Joseph N., Lawn, Stephen D., Wood, Robin, Harrison, Thomas S.. Cryptococcal Antigen Screening for Patients Initiating Antiretroviral Therapy: Time for Action, Clinical Infectious Diseases, 2010, 1463-1465, DOI: 10.1086/657405