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Ribavirin for Chronic Hepatitis E Virus Infection To the Editor: Kamar et al. (March 20 issue)1 describe the successful use of ribavirin for the treatment of chronic hepatitis E virus (HEV) infection in 59 immunosuppressed recipients of solid-organ transplants. One wonders whether the results depended on the type of immunosuppressive therapy that the patients were receiving. The use of immunosuppressive medications has been proposed as a key factor in the development of chronic HEV infection among organ transplant recipients.2,3 Clinical evidence, however, suggests that various immunosuppressive regimens may differentially affect the infection course of HEV.2,3 The authors of a recent study2 suggested that glucocorticoids did not affect viral replication, and calcineurin inhibitors promoted HEV infection in vitro. Furthermore, in a retrospective report,4 tacrolimus therapy was the main risk factor for chronic HEV infection. Reductions in the dose of immunosuppressive therapy resulted in viral clearance in more than 30% of patients,3 an outcome that was due mainly to the reduction in therapytargeting T cells.3,4 Thus, it would be interesting to find out whether the antiviral response to ribavirin among patients in the study by Kamar et al. was associated with the immunosuppressive therapy they were receiving. this week’s letters 2446 Ribavirin for Chronic Hepatitis E Virus Infection 2448 Sirolimus in Severe Hyperinsulinemic Hypoglycemia 2449 Nutrition in the Acute Phase of Critical Illness 2451 Global Biomedical R&D Expenditures 2452 Emphysematous Aortitis after Endovascular Graft 2453 Physician Attitudes and Experience with Permit Applications for Concealed Weapons 2446

Hejer Harrabi, M.D. Ibn Al Jazzar Hospital Kairouan, Tunisia [email protected]

Imed Maaloul, M.D., Ph.D. University Hospital Hedi Chaker Sfax, Tunisia No potential conflict of interest relevant to this letter was reported. 1. Kamar N, Izopet J, Tripon S, et al. Ribavirin for chronic

hepatitis E virus infection in transplant recipients. N Engl J Med 2014;370:1111-20. 2. Wang Y, Zhou X, Debing Y, et al. Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E. Gastroenterology 2014 February 26 (Epub ahead of print). 3. Kamar N, Abravanel F, Selves J, et al. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation. Transplantation 2010;89:353-60. 4. Kamar N, Garrouste C, Haagsma EB, et al. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology 2011;140:1481-9. DOI: 10.1056/NEJMc1405191

To the Editor: In the study by Kamar et al., ribavirin was successfully used to treat chronic HEV infection. However, relapse occurred in 18% of the patients. It might be useful to compare viralload kinetics and plasma concentrations of ribavirin, since its pharmacokinetic activity varies a great deal among patients, with a weak relationship between dose per kilogram and plasma concentration,1 and depends on renal function.2 The effect of the immunosuppressive treatment is another key issue. Furthermore, 54% of the patients required erythropoietin, 12% received a blood transfusion, and mycophenolic acid was discontinued in five patients during ribavirin therapy. The results of an in vitro assay3 did not show any synergistic hemolytic effect between mycophenolic acid and ribavirin, although the two drugs are both inhibitors of inosine monophos-

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phate dehydrogenase. In these five patients, severe anemia was probably due to the additive central and peripheral effects of mycophenolic acid and ribavirin, respectively. We have shown that dehydroepiandrosterone (DHEA) could counteract the ribavirin-induced hemol­ ysis.4 Since the median age of patients was 51 years, DHEA supplementation might limit the hemolytic anemia associated with ribavirin. Etienne Brochot, Pharm.D., Ph.D. Gabriel Choukroun, M.D., Ph.D. Gilles Duverlie, Pharm.D., Ph.D. University of Picardy Jules Verne Amiens, France [email protected] No potential conflict of interest relevant to this letter was reported. 1. Brochot E, Castelain S, Duverlie G, Capron D, Nguyen-Khac E,

François C. Ribavirin monitoring in chronic hepatitis C therapy: anaemia versus efficacy. Antivir Ther 2010;15:687-95. 2. Kamar N, Chatelut E, Manolis E, Lafont T, Izopet J, Rostaing L. Ribavirin pharmacokinetics in renal and liver transplant patients: evidence that it depends on renal function. Am J Kidney Dis 2004;43:140-6. 3. Brochot E, François C, Castelain S, et al. A new tool to study ribavirin-induced haemolysis. Antivir Ther 2012;17:1311-7. 4. Brochot E, Bodeau S, Nguyen-Khac E, Duverlie G. DHEA and progesterone have a protective effect on ribavirin-induced hemolysis. J Hepatol 2014;60:897-8. DOI: 10.1056/NEJMc1405191

To the Editor: Given the threat of chronic HEV infection,1 preventing such infection in high-risk populations is important. To achieve this aim, HEV vaccination, similar to vaccination against hepatitis A virus infection,2 could be an important strategy. In a phase 3 study involving 112,604 healthy Chinese adults in a region in which genotypes 1 and 4 of HEV are predominant, a recombinant HEV vaccine, HEV 239, was effective in preventing HEV infection.3 More clinical trials are warranted to evaluate the efficacy of the vaccine in patients with genotype 3 infection and the safety of the vaccine in high-risk populations. Kuan-Yeh Lee, M.D. National Taiwan University Hospital Hsinchu Branch Hsinchu, Taiwan

Chien-Ching Hung, M.D., Ph.D. National Taiwan University Hospital Taipei, Taiwan [email protected] No potential conflict of interest relevant to this letter was reported. 1. Kamar N, Selves J, Mansuy JM, et al. Hepatitis E virus and

chronic hepatitis in organ-transplant recipients. N Engl J Med 2008;358:811-7. 2. Danziger-Isakov L, Kumar D. Vaccination in solid organ transplantation. Am J Transplant 2013;13:Suppl 4:311-7.

3. Zhu FC, Zhang J, Zhang XF, et al. Efficacy and safety of a

recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet 2010;376:895-902.

DOI: 10.1056/NEJMc1405191

The authors reply: Several of the correspondents question the effect of the immunosuppression regimen on the virologic response, a very important point. In our study, the proportions of patients receiving calcineurin inhibitors, mycophenolic acid, glucocorticoids, and tacrolimus were 80%, 76%, 75%, and 71%, respectively. However, because of the small number of patients who were included in the study, we could not fully assess the effect of the various immunosuppressive regimens on virologic response. A larger study is required to answer this question. The main adverse event that we observed was anemia, which required the use of erythropoietin in 54% of the patients and blood transfusions in 12%. Although a relatively high proportion of patients presented with anemia, the degree of anemia was mild — in other words, the required doses of erythropoietin were low, and no lifethreatening anemia occurred. Improved adjustment of the dose of ribavirin with respect to kidney function and monitoring of ribavirin trough levels, especially in patients receiving mycophenolic acid, may improve ribavirin tolerance. On the basis of in vitro studies, Brochot and colleagues speculate that the use of DHEA may prevent ribavirin-induced hemolytic anemia.1 However, the proposed protective effect of DHEA has not been proved in a clinical setting, particularly among transplant recipients in whom several factors can contribute to the development of anemia, including impaired kidney function, the concomitant use of mycophenolic acid or inhibitors of the mammalian target of rapamycin, the use of angiotensin-converting–enzyme inhibitors, and possible concomitant viral infections.2 In addition, the levels of DHEA in transplant recipients, as well as the target levels to prevent ribavirin-induced anemia in a clinical setting, are unknown. Hence, rigorous clinical studies that include a large number of patients are required to decrease the effects of confounding factors and to assess the possible efficacy of DHEA in such patients. Finally, we fully agree that the HEV vaccine should be evaluated in patients with genotype 3 HEV infection, not only because of the risk of chronic hepatitis in immunosuppressed patients

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but also because HEV infection has recently been Jacques Izopet, Pharm.D., Ph.D. associated with several neurologic symptoms, CHU Purpan such as Guillain–Barré syndrome and neuralgic Toulouse, France Since publication of their article, the authors report no furamyotrophy, in immunocompetent patients.3 ther potential conflict of interest. However, the concentration of anti-HEV antibody 1. Brochot E, Bodeau S, Nguyen-Khac E, Duverlie G. DHEA and that can protect immunocompromised patients progesterone have a protective effect on ribavirin-induced hemolysis. J Hepatol 2014;60:897-8. against infection remains to be determined.4 2. Vanrenterghem Y, Ponticelli C, Morales JM, et al. Prevalence

Nassim Kamar, M.D., Ph.D. Centre Hospitalier Universitaire (CHU) Rangueil Toulouse, France [email protected]

Vincent Mallet, M.D., Ph.D. Institut Cochin Paris, France

and management of anemia in renal transplant recipients: a European survey. Am J Transplant 2003;3:835-45. 3. Kamar N, Dalton HR, Abravanel F, Izopet J. Hepatitis E virus infection. Clin Microbiol Rev 2014;27:116-38. 4. Abravanel F, Lhomme S, Chapuy-Regaud S, et al. Hepatitis E virus reinfections in solid-organ-transplant recipients can evolve into chronic infections. J Infect Dis 2014 March 11 (Epub ahead of print). DOI: 10.1056/NEJMc1405191

Sirolimus in Severe Hyperinsulinemic Hypoglycemia To the Editor: The study by Senniappan et al. (March 20 issue)1 shows that four infants with severe hyperinsulinemic hypoglycemia had a clear glycemic response to sirolimus, and there were no major adverse events during 1 year of followup. Toxic effects on the lung have been recognized as an underlying complication with sirolimus therapy, particularly in persons with immunodeficiency.2 In the study by Senniappan et al., the monitoring of adverse events associated with sirolimus therapy did not include monitoring of lung function. In addition, because sirolimus is an immunosuppressive agent, its longterm use will probably induce certain adverse effects of immunosuppression. Consequently, 1 year of follow-up seems insufficient to us. Song Mao, M.D., Ph.D. Aihua Zhang, M.D., Ph.D. Songming Huang, M.D., Ph.D. Nanjing Children’s Hospital Nanjing, China No potential conflict of interest relevant to this letter was reported. 1. Senniappan S, Alexandrescu S, Tatevian N, et al. Sirolimus

therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014;370:1131-7. 2. Molinari L, Rosenbaum T, Aruj P, et al. Sirolimus-associated interstitial pneumonia in four renal transplant recipients. Chest 2014;145:630A. abstract. DOI: 10.1056/NEJMc1404716

children undergoing renal transplantation, and to our knowledge there have been no reports of increased toxic effects on the lung in these children. The risk of toxic effects on the lung with mTOR inhibitors is increased among elderly patients with impaired pretreatment pulmonary function or a history of lung disease.1 Monitoring of pulmonary function is recommended in patients with underlying lung disease who are receiving mTOR inhibitors.2 In our study, we closely monitored patients for respiratory symptoms, and no adverse effect on respiratory function has so far been observed. Because sirolimus can induce immunosuppression, we continue to monitor the patients in our study very closely, which includes measurement of neutrophil and lymphocyte counts. To date we have not observed any abnormalities in these levels or any adverse events resulting from immunosuppression. We agree that long-term follow-up will be essential to identify potential risks. We aim to taper and ultimately discontinue treatment with sirolimus, since the natural history of the disease indicates that most forms of hyperinsulinism become milder over time. Senthil Senniappan, M.D., Ph.D. University College London Institute of Child Health London, United Kingdom

Robert E. Brown, M.D. The Authors Reply: The mammalian target of rapamycin (mTOR) inhibitors are widely used in 2448

University of Texas Medical School Houston, TX

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Ribavirin for chronic hepatitis E virus infection.

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