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significantly more often than those without a response (loss of HBsAg, 52 percent vs. 9 percent; loss of HBV DNA, 70 percent vs. 30 percent). In addition, our results indicated that, after correction for baseline factors, a response to interferon alfa significantly increased the rate of survival and reduced the risk of hepatocellular carcinoma. Ganem and Prince also suggest that reducing the viral load with lamivudine therapy may allow the immune response to clear infected hepatocytes. Although a restored HBV-specific T-cell reactivity during treatment with lamivudine has been reported, hepatitis B core antigenspecific T-cell reactivity remained undetectable in another study.3,4 We found that an HBeAg response induced by lamivudine was significantly less durable than a response after therapy with interferon alfa.5 This difference with respect to relapse suggests a lack of efficient immune control after treatment with lamivudine. Both these arguments should encourage us to reconsider the rapid displacement of interferon from the roster of first-line therapies for HBV infection. Harry L.A. Janssen, M.D., Ph.D. Monika van Zonneveld, M.D. Solko W. Schalm, M.D., Ph.D.
Erasmus Medical Center 3015 GD Rotterdam, the Netherlands m.leeuwesteijn@erasmusmc.nl
1. Ganem D, Prince AM. Hepatitis B virus infection natural his-

to the editor: Ganem and Prince state that HBeAg-

negative chronic carriers with a viral load of less than 105 copies per milliliter and a normal alanine aminotransferase level have a low rate of disease progression and do not require treatment. Although HBV DNA levels of more than 105 copies per milliliter would exclude HBV carriers with inactive disease, nearly 30 percent of patients with chronic HBeAg-negative hepatitis B have an HBV DNA level that is persistently below this range.1 These patients have wide fluctuations in serum alanine aminotransferase levels, and 20 to 30 percent of patients with histologically documented chronic HBeAg-negative hepatitis B have normal serum alanine aminotransferase levels at the time of presentation.2 However, according to our experience (unpublished data), nearly all of them will have at least one episode of elevated alanine aminotransferase levels during two years of follow-up. Thus, a proportion of patients who are HBeAg-negative, have normal levels of alanine aminotransferase, and have HBV DNA levels below 105 copies per milliliter already have chronic HBeAg-negative disease and can be identified with frequent monitoring of alanine aminotransferase. Chronic HBeAg-negative hepatitis B is a severe and progressive liver disease with very rare spontaneous remissions and frequent development of cirrhosis if left untreated.2 Mehdi Mohamadnejad, M.D.
Iran University of Medical Sciences Tehran 15937, Iran

tory and clinical consequences. N Engl J Med 2004;350:1118-29.

2. van Zonneveld M, Honkoop P, Hansen BE, et al. Long-term fol-

low-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 2004;39:804-10. 3. Boni C, Bertoletti A, Penna A, et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 1998;102:968-75. 4. Marinos G, Naoumov NV, Williams R. Impact of complete inhibition of viral replication on the cellular immune response in chronic hepatitis B virus infection. Hepatology 1996;24:991-5. 5. van Nunen AB, Hansen BE, Suh DJ, et al. Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase. Gut 2003;52:420-4.

Reza Malekzadeh, M.D.

Tehran University of Medical Sciences Tehran 14114, Iran malek@ams.ac.ir
1. Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA lev-

els during different stages of chronic hepatitis B infection. Hepatology 2002;36:1408-15. 2. Papatheodoridis GV, Hadziyannis SJ. Current management of chronic hepatitis B. Aliment Pharmacol Ther 2004;19:25-37.

HIV Drug Resistance

to the editor: Clavel and Hance (March 4 issue)1 countries. However, the fact that the expected viro-

review resistance to drugs used for the treatment of human immunodeficiency virus infection. Few data are available concerning patterns of antiretroviral-drug resistance among patients in developing

logic success rates of commonly used regimens containing nucleoside reverse-transcriptase inhibitors is approximately 65 percent at 48 weeks is cause for alarm.2

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correspondence

Access to second-line regimens is restricted by Alexandra Calmy, M.D. their cost, which is currently 10 to 20 times that of Fernando Pascual, Pharm.D. first-line regimens. For example, the second-line Doctors without Borders regimen of tenofovir, didanosine, and either rito- 1211 Geneva, Switzerland navir or lopinavir, recommended by the World alexandra.calmy@geneva.msf.org Health Organization, costs up to $6,000 (U.S. dol- Nathan Ford, B.Sc. lars) per patient per year.3,4 In the past four years, Doctors without Borders generic competition has brought the price of first- London EC1N 8QX, United Kingdom line drugs down from $10,000 to less than $300 1. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med 2004;350: (U.S. dollars) per person per year.5 A similar mar- 1023-35. ket situation must be encouraged for second-line 2. Van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, medicines. efavirenz, or both drugs, plus stavudine and lamivudine: a randomMoreover, the diagnosis of virologic failure ised open-label trial, the 2NN Study. Lancet 2004;363:1253-63. (based on clinical data or the CD4 cell count) is of- 3. Scaling up antiretroviral therapy in resource-limited settings: ten delayed owing to a lack of affordable and easy- treatment guidelines for a public health approach. Geneva: World Health Organization, December 2003. to-use viral-load monitoring. New tools must also 4. Untangling the web of price reductions: a pricing guide for the be developed to diagnose early virologic failure to purchase of ARVs for developing countries. 5th ed. Geneva: Mdcontrol viral replication more efficiently, to im- ecins Sans Frontires, December 2003. 5. von Schoen Angerer T, Wilson D, Ford N, Kasper T. Access and prove the clinical outcome, and to prevent the de- activism: the ethics of providing antiretroviral therapy in developing velopment of resistance to second-line medicines. countries. AIDS 2001;15:Suppl 5:S81-S90.

The Danger Within

to the editor: Jerome and Corey (Jan. 22 issue)1 reactive oxygen species, rather than the uric acid,

comment on the identification of urate crystals as an immunologic danger signal released from apoptotic cells in mice, as shown in part by the ability of purified urate crystals to induce maturation of dendritic cells in vitro (when cultured in 10 percent fetal-calf serum).2 Inconsistent with this proposed signal is the finding that humans lacking xanthine oxidase, and hence urate, have no known immunologic disorder.3 Because mice and cattle (but not humans) express urate oxidase (uricase), we wondered whether the hydrogen peroxide produced by uricase in fetal-calf serum might be responsible for effects attributed to urate crystals. Urate crystals induced maturation of dendritic cells that were cultured in fetal-calf serum, but not those cultured in human serum. Incubating dendritic cells with urate crystals in fetal-calf serum, but not in human serum, resulted in the production of reactive oxygen species. Adding hydrogen peroxide alone or urate crystals and uricase in combination (but neither alone) induced maturation of dendritic cells in human serum. In humans lacking uricase, the mitochondria of apoptotic cells produce abundant reactive oxygen species. Our results suggest that the

may be the ultimate danger signal. Yiing Gu, Ph.D.

Hospital for Sick Children Toronto, ON M5G 1X8, Canada ac@sickkids.ca

Michael S. Hershfield, M.D.

Duke University Medical Center Durham, NC 27710

Amos Cohen, Ph.D.

Hospital for Sick Children Toronto, ON M5G 1X8, Canada
1. Jerome KR, Corey L. The danger within. N Engl J Med 2004;350:

411-2.
2. Shi Y, Evans JE, Rock KL. Molecular identification of a danger

signal that alerts the immune system to dying cells. Nature 2003; 425:516-21. 3. Ichida K, Amaya Y, Kamatani N, Nishino T, Hosoya T, Sakai O. Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J Clin Invest 1997; 99:2391-7.

the authors reply: The study by Shi et al.1 left open the question of how urate crystals are recognized by dendritic cells. The data presented by Gu et al. suggest that it is not the urate crystals themselves

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