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obtaining faecal samples from 1000 patients before scheduled colonoscopy, as well as from those in a screening study on 5000 healthy persons above 45 years of age. *Markus R John, Heinrich SchmidtGayk, Andreas Sieg *Department of Internal Medicine I, Medizinische Klinik, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany; Laboratory Group, Heidelberg; and Internist and Gastroenterologist, Oestringen

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Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472–77. Kronborg O, Fenger C, Olsen J, et al. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 1996; 348: 1467–71. Gao P, John MR, Schmidt-Gayk H, et al. Solid-phase competitive luminescence immunoassay for lysozyme in faeces. Clin Chim Acta 1995; 239: 167–77. Schmidt-Gayk H. Immunoassay for fecal occult blood and early detection of colorectal cancer. In: Seitz HK, Simanowski UA, Wright NA, eds. Colorectal cancer: from pathogenesis to prevention? Berlin: Springer, 1989: 333–48. Lieberman DA. Cost-effectiveness model for colon cancer screening. Gastroenterology 1995; 109: 1781–90.

Author’s reply SIR—Your correspondents mistakenly assume that we were looking for a difference in all cause mortality as an endpoint of this trial. The purpose of showing all cause mortality was to demonstrate that the randomisation process had resulted in study and control groups of comparable health status. It would be impractical to attempt to show a significant reduction in all cause mortality because of the sample size that would be necessary. Colorectal cancer accounts for only 3% of all deaths; a 15% reduction in deaths from disease would thereafter be expected to reduce all cause mortality by only 0·5% which is included in the 95% CI of the observed risk. The same argument applies to all preventive interventions aimed at a single disease.1 Gøtzsche combines the results of the UK and Danish studies, although the risk difference for colorectal cancer is one death prevented per 1000 invited, not screened as he suggests. Our own combined analysis shows a relative risk of 0·84 (95% CI 0·75–0·94) in the group offered screening. He also raises the issue of psychological side-effects; this has been studied and we were pleased to find that a false-positive finding did not result in long-term psychiatric morbidity. Those data will be published shortly. John and colleagues are right that it is important to improve the

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performance of FOBT. However, improving test sensitivity may result in a reduction in specificity, thereby increasing costs, 1 this was demonstrated by our comparison of Hemoccult with a more sensitive immunological FOBT in population screening.2 J D Hardcastle Department of Surgery, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH, UK

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Laszlo Tabar, Gunnar Fagerberg, Stephen W Duffy, Nicholas E Day. J Epidemiol Comm Health 1989; 43: 107–14. Robinson MHE, Whynes DK, Marks CG, Farrands PA, Bostock K, Hardcastle JD. Eur J Surg Oncol 1995; 21: 261–64.

Author’s reply SIR—It has never been shown that an offer of screening turns the world’s healthy citizens into fearful patients-tobe”—on the contrary, there is no substantial evidence from other screening programmes to support Gøtzsche’s idea. Whether the benefits obtained justify the costs is a political matter. Long-term randomised studies including screening for many diseases have been done, and others are underway. Budenholzer is right that no reduction in overall mortality was documented in our study, but it was not our intention to identify such a effect. The slight reduction in mortality could mean a substantial reduction in number of patients dying from colorectal cancer, because of the high frequency of the disease compared with other cancers. Death from colorectal cancer is not sudden, and is usually combined with high morbidity from complications, making even a slight reduction attractive. We all have to die, and reducing the risk of dying from CRC does not mean that other causes of death will be less common. In reply Lijmer and Bossuyt, costeffectiveness analyses with the data from the Danish trial was underway, and the preliminary figures suggest that the cost per added year of life without dying from colorectal cancer will be somewhat less than that from mammography, and much less than that from cervical cancer screening. I agree with John and colleagues that it is important to improve performance of FOBTs, but so far, it has not been possible to achieve the same high specificity of Hemoccult-II with any other faecal test; the increase in sensitivity usually has to be paid for by a decrease in specificity. We certainly are looking forward to see the results of the combination test they suggest. Ole Kronborg Department of Surgery, Odense University Hospital, DK 5000 Odense, Denmark

The Delta trial SIR—In his reply to my letter (Nov 2, p 1237),1 Sherer attacks my clarification of his commentary2 as a “disservice to clinicians making clinical decisions”. However, the data from the completed Delta 22 and ACTG 1754,5 trials and his own commentary support my view: neither trial shows significant benefit in terms of relative risk of disease or death from two-drug combination anti-HIV therapy for experienced zidovudine users. The overall summary of the Delta 2 trial, presented in table 5 (p 288),3 indicates no significant reduction of risk in any of the four categories of death, disease progression, or their combinations for those receiving either two-drug combination therapy, zidovudine and didanosine or zidovudine and zalitabine, compared with those receiving only zidovudine, when analysed separately or in aggregate. The Delta 2 trial result for the treatment effect of zidovudine and didanosine in experienced zidovudine users presented in figure 1 and given in the text (p 287),3 cited by Sherer, is one of multiple comparisons, and, therefore, with p=0·05 is of doubtful statistical significance. The complete results of the ACTG 175 trial,4,5 published on Oct 10, 1996, were not available when I submitted my letter. The data of the ACTG 175 trial for individuals with CD4 cell counts of 200–500 per µL presented in table 4 (p 1085),4 indicates a modest effect from zidovudine and didanosine compared with zidovudine alone for experienced zidovudine users, and similarly for the endpoint of death alone. However, the modest effect is questionable. Multiple comparisons raise the question of its statistical significance, and, as Sherer noted, “unlike Delta and Nucombo, ACTG 175 had a high lost-to-follow-up rate and few events, so its findings should be interpreted cautiously”.2 The ACTG 175 trial finding4 indicated no significant benefit from zidovudine and zalitabine therapy compared with zidovudine alone for experienced zidovudine users in terms of progression to AIDS or death. ACTG 175 report on effects of combination therapy on individuals with AIDS or CD4 cell counts less than 200 per µL indicates no benefit from combination therapy with either zidovudine and didanosine or zidovudine plus zalitabine compared with zidovudine alone in terms of disease progression or death for those with more than 12 months of previous zidovudine treatment (table 4, p 1104).5 For those with such experience of less than or equal to 12 months duration, a slight benefit in terms of disease progression or death resulted from

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treatment with zidovudine and zalitabine, compared with zidovudine alone (p<0·05), which, because there are multiple comparisons, cannot be regarded as statistically significant. No benefit in terms of disease progression or death resulted from treatment with zidovudine and didanosine for the group with less than or equal to 12 months of previous zidovudine treatment, and no benefit in terms of death resulted from either combination of drugs for both those with greater than and less than 12 months of previous exposure to zidovudine. The history of anti-HIV therapy suggests caution in reporting and interpretation of the results of clinical trials that indicate the benefit of antiHIV therapy are clinically modest and not statistically significant. A careful examination of the complete reports of the Delta and ACTG 175 trials uphold my previous conclusion, which I reiterate here.

replication. In this setting, three new drugs, including a protease inhibitor (ie, ritonavir or indinavir), are best. In patients in whom maximum suppression will be unsuccessful or not feasible because of toxicities, drug interactions, non-adherence to medications, or other causes—ie, patients for whom partial suppression of viral replication is the goal of therapy—there are many treatment alternatives, including combination nucleoside therapy. For combination therapy to offer its potentially greatest benefit, by contrast with the treatment strategy used in Delta 2 and ACTG 175, two new drugs should be initiated together when combination nucleoside therapy is offered. Renslow Sherer HIV Center, Division of Infectious Disease, Cook County Hospital, Rush Medical College, Chicago, IL 60612, USA

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Malcolm D Z aretsky Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA

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Sherer R. The Delta trial. Lancet 1996; 348: 1237–38. Sherer R. Delta in the real world. Lancet 1996; 348: 278–79. Delta Coordinating Committee. Delta: a randomized double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283–91. Hammer S, Katzenstein D, Hughes M, et al, for the ACTG Study Team. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996; 335: 1081–90. Saravolatz L, Collins G, Hodges J, et al. Zidovudine alone or in combination with didanosine or zalitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Engl J Med 1996; 335: 1099–106.

Author’s reply SIR—Zaretsky concedes that Delta 2 showed a significant treatment advantage of didanozine and zidovudine compared with zidovudine alone (p=0·05) in zidovudine experienced patients, whether or not this represents doubtful significance, and that ACTG 175 also showed a modest benefit.1 I agree that the clinical benefits, as well as degree of reductions in viral load (around 0·05 log), are modest at best.2,3 The important point for clinicians is that combination therapy in treatmentexperienced patients should not be limited to two nucleosides whenever possible, especially when the clinician and patient agree on a therapeutic goal of maximum suppression of viral

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Zaretsky MD. The Delta trial. Lancet 1996; 348: 123–27. Delta Coordinating Committee. Delta: a randomized double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283–91. Hammer S, |Katzenstein D, Hughes M, et al for the ACTG Study Team. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 counts from 200 to 500 per cubic millimeter. New Engl J Med 1996; 335: 1081–90.

Can tetanus boosting be rejected? SIR—Based on our experience since 1953 with combined vaccines to eradicate infectious diseases, and on the basis of nearly one million observations, we dispute some of the views advanced by Bowie (Nov 2, p 1185)1 who is not convinced that regular tetanus boosting throughout adult life is necessary. During immunisation of the young we never had problems with the protective efficacy of tetanus toxoid; however, protection of those older than 50 years could be ensured only with vaccines containing lipopolysaccharides in addition to the usual adjuvant: initial and repeat immunisation with monovalent vaccines, whereas the typhoid-tetanus product containing lipolysaccharides was 70% effective.2 Bowie indicates that 0·15 IU tetanus antitoxin per mL is too low to ensure protection, but the accepted threshold titre is 0·03 IU. If the plasma (3500 mL/70 kg body mass) contains 0·15 IU/mL, then the total circulating antitoxin is 525 IU, which we find to be protective. One IU tetanus antitoxin neutraliser 106–107 (mouse) LD100

tetanus toxin, while one human lethal dose (calculated per kg body mass) equals 30 (mouse) LD100—the minimum lethal dose for a 70 kg man equals 2100 (mouse) LD100. The human lethal dose of tetanus toxin was defined in 1950, during a disaster caused with an anti-pertussis human hyperimmune globilia contaminated with the toxin and given for prophylaxis or treatment of children.3 After vaccination with tetanus toxoid, immunological memory may persist for life, although an injury with potential infection necessitates a single boost of toxoid, which results in a 10-fold to 100-fold increase of circulating antitoxin within 24 h. Thus, boosting yields 5000–50 000 IU in the vaccinee. In sating that “immunisation policies in developed countries are based on the laboratory findings of reduced concentrations of antitoxin titres with age and the assumption of waning immunity”, Bowie appears to confuse the natural (time-dependent) decrease of immunity with the genetic reduction of immune activity. Circulating specific antibodies never hinder the activation of immune memory. Bowie states that regular decennial boosters may cause different allergictype side reactions. We have witnessed the sensitising property of toxoid in both animals and man but we have never encountered a fatal reaction among millions of vaccinees.5 Bowie further argues that “each additional booster reduces the sensitivity of response to tetanus antigen after three or four challenges”. Perhaps he confuses the antitetanus prevention by recall and the prevention with (xenogenous) animal serum. The latter acts as antigen, inducing production of antibodies which destroy the tetanus serum at repeated injections. Bowie believes that, apart from a sensible dirty wound policy “. . . the benefits of regular tetanus boosting throughout adult life are insufficient to justify the costs of the administration of the toxoid, the sensitivity reactions that may occur, and the dulling of the immune system by oversensitisation”. We investigated the recall activity of tetanus toxoid in 65 volunteers 30 years after first immunisation. Before the recall, no antibodies were found. Following a single booster, 62 of 65 persons (95%) had antitoxin titre above 0·1 IU/mL (ie, above the threshold of safe immunity). Three persons had titres of 0·03 IU/mL (ie, above the internationally accepted threshold). There is another but relevant dilemma—namely in women of reproductive age, mainly in developing countries, who have not received a complete tetanus immunisation series. If these women are not included in a boosting schedule, then the WHO’s

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