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Cancer Trial 10853. J Clin Oncol 2001; 19: 2263–71. Silverstein M. The University of Southern Calofornia/Van Nuys prognostic index. In Silverstein M, ed. Ductal carcinoma in situ of the breast, 2nd edn. Philadelphia: Lippincott, Williams and Wilkins, 2002: 459–73.
PAHO fighting AIDS Sir—In your July 19 Editorial (p 179),1 you write: “. . . no international organisation has so far stepped forward to assume responsibility for controlling HIV at the country level.” This statement is incorrect. First, the statement ignores the history of the global fight against HIV/AIDS, led by the WHO Global Program on AIDS from 1987 to 1995, and by the Joint United Nations Programme on AIDS (UNAIDS) from 1996 to present. The Pan American Health Organization (PAHO), regional office of WHO for the Americas, has collaborated extensively with all countries and territories in Latin America and the Caribbean to develop national HIV/AIDS prevention and control plans and programmes. These efforts include training, establishing surveillance systems, transferring technology, disseminating information, and resource mobilisation, which have resulted in the creation of national programmes in practically every country in the region, some of which have received international commendation and recognition. PAHO has played a central part in the development of a response at the country level from the onset of the epidemic. Such a response was initially supported by resources from the former Global Programme on AIDS (GPA). With GPA’s support, PAHO fostered the development of national AIDS programmes in Latin America and the Caribbean. With GPA’s financial contribution public-health specialists and health educators were placed in various countries of Latin America and the Caribbean to provide continuous technical support to national programmes. Three clearing houses on AIDS were established to serve the needs of Spanish-speaking, Englishspeaking, and Portuguese-speaking countries. Besides providing direct technical cooperation to national AIDS programmes, PAHO also promotes technical cooperation between countries so that countries learn best practices from each other, such as between Bahamas and Belize, to control vertical transmission. This approach is also being applied in a project between
Brazil and Bolivia, in which the many strengths of the Brazilian national AIDS programme are being shared with the Bolivian one. Other PAHO projects, such as Safe Blood, greatly decrease the risk of acquiring HIV-1 through blood transfusions. PAHO puts its logistics system at the disposal of countries for the procurement of diagnostic tests that, in addition to opening a gate for clinical diagnosis, served to curb blood-borne transmission through screening of blood for transfusions. The PAHO procurement system was also available to all countries and territories for bulk purchase of affordable, top-quality condoms. The low prices were obtained by WHO/GPA. Additionally, PAHO has developed an overarching model of comprehensive care known as Building Blocks, in which comprehensive care interventions are undertaken at different levels, whether in the health system or in the community or home. Antiretroviral treatments is one component of Building Blocks and, to expand access to these treatments, PAHO has so far supported three successful negotiation rounds with pharmaceutical companies to reduce the costs of antiretroviral drugs in the Caribbean, Central America, and South America plus Mexico. Last, you imply that HIV/AIDS control at the country level is the responsibility of an international organisation. One of the main lessons of the epidemic is that without national leadership, participation, and long-term commitment, the spread of HIV cannot be controlled. PAHO long ago realised that the old-fashioned top-down paradigm is no longer viable. Mirta Roses Periago Pan American Health Organization, Regional Office for WHO, Washington, DC 20037, USA (e-mail:
[email protected]) 1
Editorial. WHO 2003–08: a programme of quiet thunder takes shape. Lancet 2003; 362: 179.
Bias in chlamydia prevalence surveys Sir—Louise McKay and colleagues (May 24, p 1792)1 note that 9·8% (78 of 798) of military recruits aged 16 years and older have chlamydia. Both they and the popular media2 infer from this finding that chlamydia is around five times more prevalent in the general population than suggested by the results of previous surveys. Since they had a 100% participation rate, McKay and colleagues suggest that the
population-based surveys underestimated chlamydia prevalence due to selection bias, arising from low participation rates. However, they ignore the selection bias that arises on entry to the army. There is overall a higher prevalence of chlamydia in military recruits than in the general population,3 a fact that might indicate differences in either behavioural or sociodemographic factors. Although infected men in McKay and colleagues’ study reported similar average numbers of sexual partners as men with chlamydia at a local genitourinary clinic, their sexual behaviour was not necessarily similar to that of men in the general population, since clinic attendees are themselves a selected group. Furthermore, McKay and colleagues did not measure condom use, concurrent partnerships, paid sexual encounters, and chlamydia prevalence within sexual networks that could have increased the risk of chlamydia in the study population. Recruits might also differ from the general population in other respects. Although neither individual4 nor ecological5 measures of social position are strongly associated with chlamydia prevalence in UK population-based surveys, there could be unmeasured factors associated with the disease that are more common in military recruits. Survey results based on military recruits are, therefore, subject to selection biases that could overestimate chlamydia prevalence. One finding of high chlamydia prevalence in a selected subgroup of the population does not mean that surveys of the general population have underestimated the prevalence. We agree that men should be included in such studies, however, and the Chlamydia Screening Studies project is investigating epidemiological, laboratory, economic, and qualitative features of homebased screening in more than 4500 men and women aged 16–39 years in Bristol and Birmingham, UK (http://www.chlamydia.ac.uk). The prevalence estimates needed to inform future screening programmes for chlamydia should come from true general population samples, and not be inferred from data derived from atypical groups. *Nicola Low, John Macleod, Chris Salisbury, Matthias Egger for the Chlamydia Screening Studies (ClaSS) group *Department of Social Medicine (NL, ME) and Division of Primary Care (CS), University of Bristol, Bristol BS8 2PR, UK; Department of General Practice and Primary Care, University of Birmingham, Birmingham, UK (JM) (e-mail:
[email protected])
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McKay L, Clery H, Carrick-Anderson K, Hollis S, Scott G. Genital Chlamydia trachomatis infection in a subgroup of young men in the UK. Lancet 2003; 361: 1792. Meikle J. Fertility threat to women. http://www.guardian.co.uk/uk_news/story/0, 3604,961845,00.html (accessed Sept 8, 2003). Sena AC, Miller WC, Hoffman IF, et al. Trends of gonorrhea and chlamydial infection during 1985–1996 among activeduty soldiers at a United States Army installation. Clin Infect Dis 2000; 30: 742–48. Fenton KA, Korovessis C, Johnson AM, et al. Sexual behaviour in Britain: reported sexually transmitted infections and prevalent genital Chlamydia trachomatis infection. Lancet 2001; 358: 1851–54. Macleod J, Salisbury C for the ClaSS study group. Prevalence of genital Chlamydia trachomatis infection in an UK general population sample. MSSVD/IUSTI Spring meeting, Leeds, June 12–14, 2003.
Treatment of SARS with human interferons Sir—We agree with J Cinatl and colleagues (July 26, p 293)1 that effective antiviral agents are urgently needed to treat severe acute respiratory syndrome (SARS). On the basis of their results, the authors state that interferons inhibit replication of SARS-associated coronavirus (SARS-CoV) in vitro, with interferon beta being the most potent of those interferons tested. However, we are concerned that shortcomings in the methods used to calculate and interpret their results could have led to misleading conclusions. First, when comparing the antiviral action of different preparations of interferons, the use of antiviral units of measurement, including international units (IU), might be inappropriate. Different preparations can have different specific activities—ie, IU/mg protein—as in the case of interferon beta (32⫻106 IU/mg protein) and interferon alfa (2·0–2·4⫻108 IU/mg protein). Therefore, for instance, the inhibitor concentration (EC50) value in Vero cells of interferon beta is not 62—ie, 6500/105 IU—times higher than the EC50 of interferon alfa, as stated,1 but only nine times—ie, 29·5/3·2 ng; this difference could be clinically relevant in pharmacokinetic and pharmacodynamic terms. Second, Cinatl and colleagues calculated the selectivity index, a parameter of fundamental importance from a therapeutic viewpoint, without knowing the cytotoxic concentration (CC50) values of the interferons used. In their calculation, a value of more than 10 000 was assumed. However,
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when the therapeutic efficacy of different drugs is compared, this assumption might be incorrect: higher than 10 000 might mean 10 001 IU, for example, for interferon beta and 100 000 IU, for example, for interferon alfa. Although such wide variations in the values are highly unlikely, they would imply indirectly that interferon alfa, which has a lower antiviral activity, is more interesting from a therapeutic viewpoint than interferon beta because the selectivity index for interferon alfa is higher. Finally, the antiviral action of interferons against a specific virus is usually, historically, measured by back titration of the viral yields when the interferon is added some 18–24 h before virus adsorption. The addition of interferon before and after virus infection does not allow a direct comparison of the sensitivity of SARSCoV with that of other animal viruses, including human coronaviruses. Cinatl and colleagues have undoubted merit in having addressed promptly the issue of antiviral action of interferons against SARS-CoV. We consider, however, that their calculations could have been made and their general conclusion—that only interferon beta can be used as an antiviral agent after infection—might have been drawn with undue haste, which has led to errors. *Guido Antonelli, Carolina Scagnolari, Elisa Vicenzi, Massimo Clementi *Department of Experimental Medicine and Pathology, Virology Section, University “La Sapienza”, Viale di Porta Tiburtina 28, 00185 Rome, Italy (GA, CS); AIDS Immunopathogenesis Unit, San Raffaele Scientific Institute, Milan (EV); and Laboratory of Microbiology and Virology, San Raffaele Scientific Institute and University “Vita-Salute” San Raffaele, Milan (MC) (e-mail:
[email protected]) 1
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Treatment of SARS with human interferons. Lancet 2003; 362: 293–94.
Authors’ reply Sir—Guido Antonelli and colleagues are right to point out that different interferon preparations, including those we used, can have different specific activities (IU/mg protein). In clinical practice this difference can be important in pharmacokinetic and pharmacodynamic terms, since interferons with high specific activity can be used at low protein concentrations relative to interferons with low specific activity. However, our data based on the use of IU/mL suggest that even in the case of application of same protein concentrations interferon beta (specific
activity 3·2⫻107 IU/mg) would be better than interferon alfa (2–2·4⫻108 IU/mg) in terms of antiviral activity. To directly address this point we tested different preparations of interferon alfa and interferon beta in Vero cells infected with SARS-CoV. The results (not presented in our research letter) showed higher antiviral potency for interferon beta than for interferon alfa independent of specific activity—ie, interferon beta-1a has a specific activity (2⫻108 IU/mg) similar to interferon alfa-2b, but its antiviral activity was about 40 times higher. The differences in antiviral activity of both type 1 interferons could result from their ability to differentially influence expression of cellular genes important for antiviral activity. For example, when the human fibrosarcoma cell line HT1080 is treated with 1000 IU/mL of type 1 interferons, more than 20 genes, including double-stranded RNAactivated protein kinase, are induced by interferon beta but not by interferon alfa.1 Antonelli and colleagues also argue that selectivity index as a parameter for therapeutic efficacy cannot be ascertained without knowing cytotoxic concentrations (CC50) of the interferon used. 10 000 IU/mL was the maximum concentration we tested, since higher concentrations of interferons are probably not achievable in the infected cells of patients. CC50 value higher than 10 000 simply means that antiviral effects in our culture system are not due to non-specific toxic effects. Our initial experiments were undertaken with a range of concentrations that are commonly used in in-vitro investigations. In additional experiments done by us, interferon concentrations up to were used without 106 IU/mL increased toxicity of interferon beta versus interferon alfa in confluent layers of Vero cells. In conclusion, these results do not lend support to the notion that increased antiviral activity of interferon beta is associated with increased toxicity and thus decreasing of therapeutic index relative to interferon alfa as suggested by Antonelli and colleagues. Treatment of patients who have SARS with interferon alfa and restricted use of steroids did not improve clinical symptoms and signs.2 This finding could be explained at least partly by our observations, indicating an inability of interferon alfa to inhibit SARS-CoV replication when added to cultured cells after virus infection. Therefore, the selective antiviral activity of interferon beta
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