correspondence

Bethanie Wilkinson, Ph.D. Sriram Krishnaswami, Ph.D. Pfizer Groton, CT [email protected]

Ronald F. van Vollenhoven, M.D. Karolinska Institute Stockholm, Sweden Since publication of their article, the authors report no further potential conflict of interest. 1. Isaacs JD, Zuckerman A, Krishnaswami S, et al. Changes in

serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials. Arthritis Res Ther 2014;16:R158. 2. Kremer J, Kivitz AJ, Simon-Campos JA, et al. Evaluation of the effect of tofacitinib on measured glomerular filtration rate

in patients with active rheumatoid arthritis. Ann Rheum Dis 2014;73:Suppl 2:222. abstract. 3. Kahn C, Cohen S, Bradley JD, et al. Tofacitinib for rheumatoid arthritis. Presented at the Tofacitinib Arthritis Advisory Committee Meeting, Silver Spring, MD, May 9, 2012 (http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/ArthritisAdvisoryCommittee/UCM304200.pdf). 4. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009;60:1895-905. [Erratum, Arthritis Rheum 2012; 64:1487.] 5. Winthrop KL, Racewicz A, Lee EB, et al. Evaluation of influenza and pneumococcal vaccine responses in rheumatoid arthritis patients using tofacitinib. Arthritis Rheum 2012;64:Suppl: S550. abstract. DOI: 10.1056/NEJMc1408607

Antiretroviral Therapy after Cryptococcal Meningitis To the Editor: Boulware et al. (June 26 issue)1 address the timing of initiation of antiretroviral therapy (ART) for human immunodeficiency virus–associated cryptococcal meningitis, and they conclude that excess mortality in association with “earlier ART” was probably due to the immune reconstitution inflammatory syndrome (IRIS). However, they reported no significant difference in the incidence of IRIS between the two groups (P = 0.32). Another explanation could be that more participants had elevated intracranial pressure at diagnosis in the earlier-ART group than in the deferred-ART group (58% vs. 51%). If the 24 participants in whom intracranial pressure was not measured at diagnosis are included in the analysis, this association could have been significant (P = 0.01 with the use of Fisher’s exact test). Furthermore, differences in intracranial pressure during the 2 weeks of induction of amphotericin-based therapy were not reported. In our experience, aggressive management of intracranial pressure during the induction phase is a major determinant of patient outcomes.2,3 It would be helpful if the authors could comment on whether the measurement, levels, or management of intracranial pressure differed between the two groups after diagnosis. This study highlights the need for operational studies of the rapid point-of-care assay to detect circulating antigens before the onset of meningitis.4,5

Paul K. Drain, M.D., M.P.H. Harvard Medical School Boston, MA [email protected]

Yunus Moosa, M.B., Ch.B., Ph.D. University of KwaZulu-Natal Durban, South Africa

William G. Powderly, M.D. Washington University School of Medicine St. Louis, MO No potential conflict of interest relevant to this letter was reported. 1. Boulware DR, Meya DB, Muzoora C, et al. Timing of anti-

retroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014;370:2487-98. 2. Meda J, Kalluvya S, Downs JA, et al. Cryptococcal meningitis management in Tanzania with strict schedule of serial lumber punctures using intravenous tubing sets: an operational research study. J Acquir Immune Defic Syndr 2014;66(2):e31-e36. 3. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 1997;337:15-21. 4. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Geneva: World Health Organization, 2011. 5. Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011;53:1019-23. DOI: 10.1056/NEJMc1409052

To the Editor: Boulware and colleagues found that deferring combination ART for 5 weeks after

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the diagnosis of cryptococcal meningitis was associated with improved survival. In the subgroup analysis, mortality was lower with deferred ART among patients with a pathogen burden of more than 100,000 colony-forming units per milliliter at diagnosis (hazard ratio, 2.44) and those with a cerebrospinal fluid (CSF) white-cell count of less than 5 cells per cubic millimeter at randomization (hazard ratio, 3.87). Although this study addresses an important gap in the use of ART, we wish to draw attention to two points. First, the benefit of deferred ART was almost exclusively apparent in patients with a CSF white-cell count of less than 5 cells per cubic millimeter (Fig. 2C of the article). However, patients with a CSF white-cell count of 5 or more cells per cubic millimeter who received deferred ART fared just as poorly as those who received early ART (Fig. 2B of the article). Second, deferring ART in patients with low CD4 counts increases the risk of other opportunistic diseases,1 including tuberculosis and cryptococcal meningitis relapse. Thus, although deferring ART in patients with cryptococcal meningitis seems appropriate for those with a CSF white-cell count of less than 5 cells per cubic millimeter and no other opportunistic conditions, early ART may still be considered in patients with a CSF white-cell count of 5 or more cells per cubic millimeter, possibly together with glucocorticoids.2,3 Hans H. Hirsch, M.D. Elisabeth Wehrle-Wieland, M.D. Manuel Battegay, M.D. University Hospital Basel Basel, Switzerland [email protected] No potential conflict of interest relevant to this letter was reported. 1. Chêne G, Sterne JA, May M, et al. Prognostic importance of

initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet 2003;362:679-86. 2. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconstitution in HIV-infected patients. Clin Infect Dis 2004;38: 1159-66. 3. Khanna N, Nüesch R, Buitrago-Tellez C, Battegay M, Hirsch HH. Hearing loss after discontinuing secondary prophylaxis for cryptococcal meningitis: relapse or immune reconstitution? Infection 2006;34:163-8. DOI: 10.1056/NEJMc1409052

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The Authors Reply: Drain and colleagues highlight an important neglected issue of management of increased intracranial pressure in patients with cryptococcal meningitis. We strongly concur that therapeutic lumbar punctures are of lifesaving importance. Among screened participants in the Cryptococcal Optimal ART Timing trial, those who underwent at least one additional therapeutic lumbar puncture in the first week after diagnosis were 69% less likely to die before trial randomization (when a scheduled lumbar puncture occurred) than participants who did not undergo an additional lumbar puncture in the first week.1 This survival benefit was irrespective of the presence of an initial elevated CSF opening pressure.1 At the time of trial randomization (median, 8 days), as we described in Table 1 of our article, the intracranial pressure did not differ between groups: 26 of 71 patients in the earlier-ART group (37%) and 25 of 65 patients in the deferred-ART group (38%) had elevated intracranial pressure of greater than 250 mm of water. At day 14 of amphotericin treatment, the mean (±SD) CSF opening pressures did not differ between the earlier-ART group and the deferredART group (217±109 vs. 222 ±130 mm of water; P = 0.67). Hirsch and colleagues’ dissection of the subgroup analysis raises a fundamental question of whether an intervention is “safe” versus “nonharmful.” Earlier ART was not beneficial in any subgroup, and our study did not show harm from deferring ART for 4 to 6 weeks in any group. The data and safety monitoring board unilaterally chose to halt the study earlier than the written a priori stopping guidelines. The smaller-than-planned sample size drastically limited the ability to provide customized guidance for individual patients. We would be highly cautious about public health guidance based on subgroup analyses, and we believe that the prevailing principle should remain: first, do no harm (primum non nocere). We did not study glucocorticoids and warn that extreme caution should be taken in populations with chronic Strongyloides stercoralis infection, in whom glucocorticoids could cause iatrogenic harm.2 In an ongoing trial (Current Controlled Trials number, ISRCTN59144167), Day and colleagues are studying the use of adjunctive glucocorticoids.

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correspondence

We concur that preventing of a cryptococcal disease with targeted pre-ART cryptococcal antigen screening in patients with CD4 cell counts lower than 100 per cubic millimeter is preferable to treating meningitis.3 Cryptococcal antigen screening is probably cost-saving.4,5 Our randomized clinical trial (ClinicalTrials.gov number, NCT01535469) in Uganda is testing broad implementation of World Health Organization recommendations for cryptococcal screening. David R. Boulware, M.D., M.P.H. University of Minnesota Minneapolis, MN [email protected]

David B. Meya, M.Med. Infectious Disease Institute Kampala, Uganda

Since publication of their article, the authors report no further potential conflict of interest. 1. Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of thera-

peutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014 July 23 (Epub ahead of print). 2. Boulware DR, Stauffer WM, Hendel-Paterson BR, et al. Maltreatment of Strongyloides infection: case series and worldwide physicians-in-training survey. Am J Med 2007;120:545.e1-545.e8. 3. Meya DB, Manabe YC, Castelnuovo B, et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count ≤100 cells/ μL who start HIV therapy in resource-limited settings. Clin Infect Dis 2010;51:448-55. 4. Rajasingham R, Meya DB, Boulware DR. Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care. J Acquir Immune Defic Syndr 2012;59(5):e85-e91. 5. Jarvis JN, Harrison TS, Lawn SD, Meintjes G, Wood R, Cleary S. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. PLoS One 2013;8(7):e69288. DOI: 10.1056/NEJMc1409052

Antidepressant Use in Pregnancy and the Risk of Cardiac Defects To the Editor: Congenital heart disease can have devastating consequences, even in patients with simple defects.1-3 Huybrechts et al. (June 19 issue)4 suggest that the risk of cardiac malformations in children of mothers receiving antidepressants is low. It is interesting that in the unadjusted analysis, the relative risk of cardiac malformations is increased by 25% among infants exposed to antidepressants. However, after adjustment for multiple factors, this association was lost. Thus, the key to applying these results to clinical practice is to understand the methods that were used. Such factors as misclassification resulting from the low adherence to antidepressant use and the lack of data on spontaneous or medical terminations have the potential to bias the results. Information on missing data is lacking, especially in measurements that were used to construct the propensity scores, and such missing data would automatically exclude patients from the analysis, introducing bias. Although we agree with the authors that a risk– benefit decision should be made in treating patients with severe depression, caution should be taken in overinterpreting the data and declaring antidepressants to be safe during pregnancy,

which may promote liberal use and perhaps an increase in malformations, both cardiac and noncardiac. Aleksander Kempny, M.D. Lorna Swan, M.B., Ch.B., M.D. Konstantinos Dimopoulos, M.D., Ph.D. Royal Brompton Hospital London, United Kingdom

[email protected] No potential conflict of interest relevant to this letter was reported. 1. Brickner ME, Hillis LD, Lange RA. Congenital heart disease

in adults: first of two parts. N Engl J Med 2000;342:256-63.

2. Brickner ME, Hillis LD, Lange RA. Congenital heart disease

in adults: second of two parts. N Engl J Med 2000;342:334-42.

3. Kempny A, Dimopoulos K, Uebing A, et al. Reference values

for exercise limitations among adults with congenital heart disease: relation to activities of daily life-single centre experience and review of published data. Eur Heart J 2012;33:1386-96. 4. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med 2014;370:2397-407. DOI: 10.1056/NEJMc1409203

To the Editor: The study by Huybrechts et al. raises several methodologic issues, which could explain the inconsistencies with other published studies. Cardiac defects were identified at 1 to

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Antiretroviral therapy after cryptococcal meningitis.

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