Tuberculosis preventative treatment also prevented diarrhoea in HIV-infected patients in Zambia

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Persistent diarrhoea and tuberculosis are major causes of morbidity and mortality in HIV-infected patients. In spite of effective anti-tuberculosis treatment, mortality rates are high, reaching 50% by 18 months after treatment [1], often caused by HIV-related opportunistic infectious diseases including diarrhoea. Persistent diarrhoea in Zambian AIDS patients is associated with a high mortality rate, in one study reaching 16% in one month [2], and subsequent experience suggests that it is higher still. The prevention of both tuberculosis and diarrhoea may therefore substantially improve the longevity and quality of life of HIV-infected individuals in Africa. We performed a retrospective analysis of a previously published placebo controlled trial of tuberculosis preventative treatment in Zambia, and found that the combination of rifampicin and pyrazinamide was associated with a reduction of at least 57% in the incidence of diarrhoea. A total of 1053 HIV-positive patients were enrolled in a randomized controlled trial of tuberculosis preventative treatment given twice a week to three groups of patients. One group received a combination of rifampicin and pyrazinamide for 3 months, the second group received isoniazid for 6 months, and the third group received placebo for 6 months. The study patients were reviewed at monthly intervals for the first 6 months and every 3 months thereafter to the end of the study. During the routine reviews data were collected on evidence of progression of HIV disease, including episodes of diarrhoea. The study clinic had an open-door policy whereby the patients had immediate access to clinical care for any illness experienced between the reviews. During these extra visits, data were collected on the presenting clinical symptoms, and any treatment offered was recorded. In the initial analysis a total of 1053 patients were followed for 1631 person-years. The incidence of tuberculosis was lower in patients on preventative therapy although no difference in mortality rates was noted [3]. A comparison of the number of individuals who reported experiencing one or more episodes of diarrhoea between the two treatment arms and the placebo group over the first year of follow-up reveals a significantly lower rate of diarrhoea in patients on rifampicin and pyrazinamide during the 3 months of treatment compared with patients using isoniazid and placebo (Table 1). Thereafter, the rate of diarrhoea was similar to those in patients receiving placebo or isoniazid.Table 1: Individuals reporting episodes of diarrhoeal illness over 12 months of follow-up in adult patients receiving tuberculosis preventative therapy. Recent evidence suggested that another rifamycin, rifabutin, halved the incidence of cryptosporidiosis in HIV-infected Americans before highly active antiretroviral therapy was available [4]. Intestinal protozoa (Cryptosporidium parvum, Isospora belli, microsporidia) are the dominant cause of HIV-related diarrhoea in Zambia, so efficacy against one or more of these protozoa would have substantial benefits in HIV-infected individuals. Rifampicin may also have modest effects in suppressing clostridial infection, although we have not found Clostridium difficile in AIDS patients in Lusaka [5]. Little information is available on the possible role of mycobacteria in the pathogenesis of intestinal disease in Africans with AIDS. If this effect could be confirmed using data from other retrospective or prospective trials, rifampicin and pyrazinamide could be a significant addition to the range of prophylactic regimens available for HIV-infected Africans, although there will obviously be concern about the possibility of encouraging resistance to rifamycins in Mycobacterium tuberculosis. Such a dual benefit from one preventative therapy regimen would positively affect the cost–benefit analysis of this intervention. Our data may also indicate that tuberculosis treatment with 6 months of rifampicin and pyrazinamide should now be considered. Currently in Zambia, tuberculosis treatment uses rifampicin for the first 2 months of therapy only. There is clearly a need for a greater understanding of the role of mycobacterial infection in intestinal disease in African HIV-infected patients. There is also a need for clarification of the action, if any, of rifamycins against intestinal intracellular protozoa. Alwyn Mwingaa,b Maria Hospb Isaac Zulua,c Michael J. G. Farthingd Sylvia Mulambob Paul Kellya,c Acknowledgements The authors would like to thank Professor Bo Drasar, London School of Hygiene and Tropical Medicine, for valuable discussion, and Maria Quigley for statistical advice.

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