TRANSACTIONS OF TKE ROYAL SOCIETY OF TROPICAI. MEDICINE
AND HYGIENE (1992) 86, 467-469
467
Royal Society of Tropical Medicine and Hygiene Meeting at Manson House, London, 16 January 1992 Aspects of tuberculosis 1. Tuberculosis
in Africa
in Africa in the AIDS era-the
role of chemoprophylaxis
J. D. H. Porter1>2 and K. P. W. J. McAdaml ‘Department of Clinical Sciences,London School of Hygiene and Tropical Medicine, Keppel Street, London, WClE 7HT, UK; 2Division of Field Services and Training, Public Health Laboratory Service Communicable Disease Surveillance Centre, London, UK Abstract
An estimated 2.8 million people in Africa have dual infections with tuberculosis and human immunodeficiency virus (HIV). Becauseof the increasing numbers of casesof tuberculosis as a consequenceof the HIV epidemic, chemoprophylaxis may become a cost effective tuberculosis control measure in high prevalence countries. Although isoniazid (INH) is the only drug evaluated in controlled trials of preventive tuberculosis therapy, studies are now under way to determine the efficacy of INH and other drugs, including rifarnpicin and pyrazinamide, in preventing tuberculosis reactivation in persons with HIV infection. If chemoprophylaxis is effective in persons with dual infection, further studies will be required to determine whether chemoprophylaxis is cost effective for tuberculosis prevention and control and whether it is feasible to introduce it asa~c&nmunity control measure, Introduction
Tuberculosis is estimated to affect one-fifth of the world’s population and 2-3 million people die of it each year (RODRIGUES & SMITH., 1990). The epidemic of human immunodeficiency vu-us (HIV) has altered the pattern of tuberculosis disease in many countries, but particularly in Africa where the prevalence of tuberculosis is high and where up to 50% of the population between 20 and 40 years of age have been infected with the disease(STYBLO, 1986; HARRIES, 1990) (Fig. 1). Dete-
In October 1990WHO estimated that 3.9% of all cases of tuberculosis worldwide were associatedwith HIV, but that in sub-Saharan Africa the figure was 17% (KOCHI, 1991b). Reported cases of tuberculosis have been increasing in all African countries affected by the HIV epidemic. In Zambia, the annual tuberculosis notification rate per 100 000 inhabitants has increased from 101 in 1985 to 216 in 1990 (Fig. 2). In Malawi the rate per
Botswana Zambia
Estimated population: 650 million 100,000 inhabitants Estimated
TB infected
population: 171 millIon Estimated population:
Estimated
HlVflB infected 2.8 million
HIV infected
population: 6 mullion
Fig. 1. Tuberculosis, human immunodeficiency virus and the acquired immune deficiency syndrome in Africa (source: WHO/Afro).
rioration in the immune system, which occurs with HIV infection, encourages reactivanon of tuberculous infection to produce tuberculosis disease (SUNDERAM et al., 1986). The character of tuberculosis in adults with HIV infection is also different, presenting more of the features usually seen in children; for example, miliary and extrapulmonary disease (THUER et al., 1990). In addition to the increase in numbers of persons presenting at chest clinics with reactivation of tuberculous infection, there are also people newly acquiring the diseasebecauseof the increase in circulation of Mycobacterium tuberculosis in communities and the increased susceptibility of persons with HIV infection (BARNES et al., 1991). The World Health Organization (WHO) estimatesthat approximately 8-10 million adults and 1 million children worldwide are presently infected with HIV. By the year 2000, 40 million persons may be infected, more than 90% of whom will live in countries in sub-Saharan Africa! south and south-east Asia, Latin America and the Caribbean (KOCHI, 1991a).
Fig. 2. Tuberculosis notification rates per 100 000 inhabitants in selected African countries, 1985-1990 (source: WHO/Afro).
100 000 has increased from 76 in 1985 to 140 in 1990. Of the 650 million estimated population of Africa, 171 million are estimated to be infected with tuberculosis. The estimated HIV infected population is 6 million and the present estimate of dual HIVituberculous infection is 2.8 million (KOCHI, 1991a). Present control methods
What are National Tuberculosis Control Programmes to do to try to limit this increasing rate of tuberculosis? There are 4 methods used at present for controlling tuberculosis worldwide: case finding and treatment, chemoprophylaxis, vaccination, and improvement of socio-economic conditions (PORTER, 1991). Casefinding and treatment is the method of control in African countries. However, with the changing pattern of tuberculosis induced by HIV infection, chemoprophylaxi? may becomean important part of tuberculosis control. Chemoprophylaxis
for control
Until now, becauseof the high prevalence of tuberculosis in Africa, it has not been cost effective to provide chemoprophylaxis for contacts (STYBLO, 1988). How-
468
ever, with the increasing numbers of tuberculosis cases and the increasing incidence of dual infection with HIV (NUNN et al., 19%; ELLIOTT et al., 1990), is chemoprophylaxis now appropriate in high-prevalence areasof Africa? Studies are needed to determine whether chemoprophylaxis prevents the reactivation of tuberculosis in HIV-positive individuals and, if it does, to determine which drug regimen is the most appropriate (most effective, solicits greatest compliance,and is least expensive) (ANONYMOUS, 1990). Chemonronhvlaxis mav have 2 benefits in addition to control of*tuberculosis* reactivation. First, it may prevent primary and secondary (reinfection) outbreaks of tuberculosis among the HIV negative and positive populations. Secondly,“chemoprophylaxis may slow the progression of HIV infection to the acauired immune deficiencv svndrome (EDWARDS& KILPATRICK, 1986). Chemoprophylaxis may therefore have benefits both for the individual and for the community. To consider using chemoprophylaxis in high prevalence African countries, drug regimens are needed which are efficaceous, which have a structure such that those taking the medication are compliant and, finally, which are cheap. Efficacy
What regimens are efficaceous? Until recently isoniazid (INH) was the onlv drug that had been evaluated in controlled trials of preventive therapy for tuberculosis (R. O’Brien. nersonal communication). The renorted efficacv of INH for the prevention of tuberculosis has ranged from 25% to 92% in a series of clinical trials (FEREBEE. 1969: COMSTOCK& WOOLPERT. 1984). These trials established that the maximum benefit from INH is obtained within 1 year and no increased benefit is derived from continuing the medication for a longer period. Although there has been no formal comparison, daily and twice weekly regimes appear equally effective (COMSTOCK,1975). Recently, other drug regimens have been studied. A Hong Kong silicosis study (HONG KONG CHESTSERVICEet al., 1992) provided evidence that rifampicin for 3 months is as good as INH for 6 months in preventing tuberculosis. There is no evidence of additional resistance in subjects given either INH or rifampicin alone. In addition, there were fewer abnormal liver function tests in patients given rifampicin alone than those given INH alone. What about the eflicaceousness of combined drug regimens? In therapy, INH rapidly kills most tubercle bacilli in the first few days. However, rifampicin and pyrazinamide subsequently provide for the final sterilization of tissues, killing the slowly and/or intermittently metabolizing bacilli (GROSSET,1978). Pyrazinamide has been shown to be most effective in the first 8 weeks of therapy, while rifampicin appears to have an important role throughout the entire course of therapy (HONG KONG CHESTSERVICEet al., 1984; EASTAFRICAN/BRITISH MEDICAL RESEARCHC&JNC~LS, 1981). Studies of INH and rifamnicin sueaest that rifamnicin has ereater sterilizing activ;y than rNH (DICKINSON & MIT&SON, 1980). Furthermore, resistance to rifampicin develops lessoften. Studies of the sterilizing properties of rifampicin, INH and pyrazinamide in a mouse model of chronic tuberculosis demonstrated the superiority of rifampicin and rifampicin combined with pyrazinamide (CARTEL et al., 1985). In this study, rifampicin alone for 3 months and rifampicin plus pyrazinamide for 2 months were more effective than INH alone for 6 months. Moreover, the addition of INH to the rifampicinipyrazinamide regimens anneared to have an inhibiting effect on sterilizine activiii. The 2 months regimen 0’: rifampicin plus pyurazinamide was the only regimen to result consistently in sterilization at the end of the treatment period. However, the tubercle bacilli in murine tuberculosis are essentially intracellular in macrophages,whereasin humans they are
extracellular. If bacilli in human lesions persist inside macrophages, chemoprophylaxis with pyrazinamide would be expected to work, but if they are outside macrophages pyrazinamide would not sterilize. At present it is not-known whether persistent bacilli are intracellular or extracellular (MITCHISON. 1990). Further studies are therefore needed. Nevertheless, there is evidence that combining drugs with killing and sterilizing properties for chemoprophylaxis may produce regimens -which are more effcaceous than INH alone. The chemoprophylactic efficacy of other tuberculosis drugs needs to be tested: for example, long acting rifamycin derivatives and isoniazid derivatives. Rifapentine, a semi-synthetic rifamycin with a long elimination halflife and with an antibiotic spectrum similar to rifampicin (ARIOLI et al., 1981), has an elimination half life about 5 times longer than that of rifampicin, with a trend towards increased values if the dose is increased. It may therefore be given once a week. Until now, all chemoprophylaxis studies have been conducted on people not infected with HIV. For individuals infected with HIV there are few data available on the effect of preventive therapy. However, preliminary data from an INH prophylaxis study in Lusaka showed that this regimen reduced the incidence of M. tuberculosis in personswith dual infection (WADHAVANet al., 1990). Compliance
Motivating people to comply with a preventive regimen for 6 months is difficult. but studies have shown that compliance increased as the prescribed length of therapy decreased (INTERNATIONAL UNION AGAINST TUBERCULOSIS
COMMITTEE
ON PROPHYLAXIS,
1982).
The importance of compliance was demonstrated in a study by NOLAN et al. (1986), which showed that rioncompliance was associatedwith a 6 times higher risk of subseauent INH-suscentible tuberculosis. An advantage of a shorter course of-preventive therapy (i.e., 2 or-3 months rather than 6 months) is the expected increase in compliance. Chemotherapy for tuberculosis has been successfully shortened to 6 months using regimens including INH, rifampicin and pyrazinamide (SNIDER et al., 1984; SINGAPORE TUBERCULOSIS SERVICE & BRITISH MEDICAL RESEARCH COUNCIL, 1988; MITCHISON,
1985). In many of these studies, drugs were administered on an intermittent basis, either throughout the entire treatment period or following an initial period of daily therapy (SINGAPORE TUBERCULOSIS SERVICE & BRITISH MEDICAL RESEARCH COUNCIL, 1988). Tuberculosis preventive therapy employing several drugs with potent sterilizing properties, given for periods as short as 2 months, may be as effective as single drug therapy given for longer periods (DICKINSON & MITCHISON, 1980). Shortening drug regimens is one of the keys to improving compliance. cost In order for chemoprophylaxis to be cost effective, medications must be cheap and affordable for African tuberculosis control nrogrammes. INH is the cheanestof the drugs mentioned. Use of long acting drugs, hke rifapentine with its single weekly dose regimen, is likely to improve compliance and may reduce costs. Rifampicin and pyrazinamide are both expensive, but if they are efficaceousand the combination of the drugs can shorten the duration and improve compliance, they too may become cost effective. Present chemoprophylaxis
studies
Chemoprophylaxis studies are presently under way in several countries. The London School of Hygiene and Tropical Medicine is conducting collaborative studies in Kenya and Zambia. The Kenyan study is being conducted to determine the efficacy of 6 months of INH in the prevention of tuberculous reactivation in the Pumwani cohort of prostitutes in Nairobi. In Zambia, a pilot
study is looking at 2 different chemoprophylactic regimens: 6 months of INH and 3 months of rifamoiciniova.~~ razinamide. There are other drug regimens which n&d to be studied, including rifampicin alone and the long acting rifamycins like rifapentine. Conclusion The interaction between tuberculosis and HIV infection has meant that new approachesto tuberculosis control are necessarv. Preliminarv data from Zambia indicate that isoniazid chemoprophylaxis is effcaceous (WADHAVAN et al., 1990), but information from other current studies will supply further information and allow a balanced decision to be taken whether chemoprophylaxis is efficaceous in persons with HIV infection. The next stage is to determine whether chemoprophylaxis
can
be introduced on a large scale, by comparing the cost effectiveness of chemoprophylaxis with that of casefinding and treatment control methods. In addition, feasibility studies are needed to determine if it is possible to introduce chemoprophylaxis for community control. Provisional information from Kenyan studies indicates that recurrencies occur within 6 months of treatment among the HIV infected nooulation (NUNN et al.. 1991). If chemoprophylaxis tin prevent reactivation in’persohs with dual infection it may be a cheaper method for controlling the disease than waiting for patients to present with tuberculosis and then treating them, with a subsequent high risk
of recurrence. References
Anonymous (1990). Africa’s tuberculosis burden and chemoprouhvlaxis. Lancet. 335.1249-1250. Ahofi, V., Berti,‘M.,‘Carniti,, G., Randisi, E. & Rossi, T. (1981). Antibacterial rifamycm derivatives. Journal of Antibiotics,34, 1026. Barnes, P. F., Bloch, A. B., Davidson, P. T. & Snider, D. E (1991). Tuberculosis in patients with human immunodeficiency virus infection. New EnglandJournal of Medicine, 324, 1644-1650. Cartel, J., Naudillon, Y., Arthus, J. & Grosset,J. (1985). Hepatotoxicity of the daily combination of 5 mgikg prothionamide ,+ 10 mgikg rifampicin. International Journal of Leprosy, 53, 15-18. Comstock, G. W. (1975). Frost revisited: the modern epidemioloev of tuberculosis. American ?‘ournal of” E6idemioloev. . I, 101., 38-382. Comstock, G. W. & Woolpert, S. F. (1984). Preventive therapy. In: The Mycobacteria: A SourceBook, part B, Kubica, G. P. & Wayne, L. G. (editors). New York: Marcel Dekker. Dickinson, J, M. & Mitchison, D. A. (1980). Experimental models to explain the high sterilizing activity of rifampicin in the chemotherapy of tuberculosis. AmericanReview of Respiratorv Diseases. 121.939-947.
East~LifricaniBritish ‘Medical ResearchCouncils (1981). Controlled clinical trial of five short-course (4 month) chemotherapy regimens in pulmonary tuberculosis. American Review of Respiratoy Diseases?123, 165-170. Edwards, D. & Kirkpatrick, C. (1986). The immunology of mycobacterial diseases.American Review of Respiratory Diseases, 134,1062-1071. Elliott, A. M., Luo, N., Tembo, G., Halwiindi, B. & McAdam, K. P. W. J. (1990). Impact of HIV on tuberculosis in Zambia: a cross sectional study. British MedicalJournal, 301, 412415. Ferebee, S. H. (1969). Controlled chemoprophylaxis trials in tuberculosis. A general review. Advances in Tuberculosis Research, 17,28-1016.
Grosset, J. (1978). The sterilizing value of rifampicin and pyrazinamide in experimental short course chemotherapy. Tubercle, 59,287-297.
Harries, A. D. (1990). Tuberculosis and human immunodefi-
ciency virus infection in developing countries. Lancet, 335, 387-390. Hong Kong Chest Service, Tuberculosis Research Centre, Madras and British Medical Research Council (1984). A controlled trial of 2 months, 3 months and 12 months regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis: results at 60 months. American Review of Respiratoy Diseases, 130,23-28.
Hong Kong Chest Service, Tuberculosis Research Centre, Madras and British Medical Research Council (1992). A double blind placebo controlled clinical trial of three antituberculosis chemourouhvlaxis regimens in oatients with silicosis in Hona Kong.-Aieriian Rev& ofResp&atoy Diseases, 145,36-41. International Union Against Tuberculosis Committee on Prophylaxis (1982). Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in ;~5~~6~T trial. Bulletin of the World Health Organization, 60, Kochi, A. (1991a). The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle, 72, 1-6.
--
Kochi, A. (1991b). Government intervention programs in HIVltuberculous infection. Bulletin of the International Union against Tuberculosis and Lung Disease, 66,33-36.
Mitchison. D. A. (1985). The action of anti-tuberculosis drugs ” in shortIcourse chemdtherapy. Tubercle,,66,219-225. Mitchison, D. A. (1990). Pyrazinamide m the chemoprophylaxis of tuberculosis. American Review of Respiratory Diseases, 142,1467.
Nolan, C. M., Aitken, M. L., Elarth, A. M., Anderson, K. M. & Miller, W. T. (1986). Active tuberculosis after isoniazid chemoprophylaxis of South-eastAsian refugees. American Review ofRe&ratorv
Diseases. 133.431-436.
Nunn, P., Odhiambo, J. & Elliott, A. (1990). Tuberculosis and HIV infection. Lance!, 335, 1044. Nunn, I’., Porter, J., Glthui, W. & Odhiambo, J. (1991). Treating tuberculosis in HIV positive Africans. Lancet, 338, 1141. Porter, I. D. H. 11991).Tuberculosis in develooine countries. Con&nicable
&seas; Report, 1, R135-139.
-
-
Rodrigues, L. C. & Smith, I’. G. (1990). Tuberculosis in developing countries and methods for its control. Transactions of th.h4?qal Society of Tropical Medicine and Hygiene, 84, 739-
Singapore Tuberculosis Service and British Medical Research Council (1988). Five Year follow-UD of a clinical trial of three 6-month‘ regimens of chemotherapy given intermittently in the continuation phase in the treatment of pulmonary tuberculosis. American Review of Respiratory Diseases,137, 11471150. Snider, D. E., Graczyk, J., Bek, E. & Rogowski, J. (1984). Supervised 6 months treatment of newly diagnosed pulmonary tuberculosis using isoniazid, rifampicin, and pyrazinamide with and without streptomvcin. American Review of Respiratory Diseases,130, 109i-1093. Stvblo. Ki (1986‘1.Tuberculosis control and surveillance. In: decent A&a&s in Respiratoy Medicine,, Fleny, D. C. & ~;~l;ydsT.L. (editors). Edinburgh: Church111Livingstone, pp. Styblo, K. (1988). The potential impact of AIDSon the tuberculosis situation in developed and developing countries. Bulletin of the International ease, 63,25-28.
Union against Tuberculosis and Lung Dis-
Sunderam, G., McDonals, R. J., Maniatis, T., Oleske, J., Kapila, R. & Reichman, L. B. (1986). Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (AIDS).Journal of the American Medical Association, 256, 362366. Thuer, C. P., Hopewell, P. C., Elias, D., Schecter, G. F., Rutherford, G. W. & Chaisson, R. E. (1990). Human immunodeficiency virus infection in tuberculosis patients. Journal of Infectious Diseases, 162, S-12. Wadhavan. D.. Hira. S.. Mwansa. N.. Tembo. G. & Perine. P. L. (1990) Isbniazih piophylaxis am&g patients with HIfinfection. Sixth International Conference on AIDS, San Francisco, abstract Th B 510.
AND HYGIENE (1992) 86, 467-469
467
Royal Society of Tropical Medicine and Hygiene Meeting at Manson House, London, 16 January 1992 Aspects of tuberculosis 1. Tuberculosis
in Africa
in Africa in the AIDS era-the
role of chemoprophylaxis
J. D. H. Porter1>2 and K. P. W. J. McAdaml ‘Department of Clinical Sciences,London School of Hygiene and Tropical Medicine, Keppel Street, London, WClE 7HT, UK; 2Division of Field Services and Training, Public Health Laboratory Service Communicable Disease Surveillance Centre, London, UK Abstract
An estimated 2.8 million people in Africa have dual infections with tuberculosis and human immunodeficiency virus (HIV). Becauseof the increasing numbers of casesof tuberculosis as a consequenceof the HIV epidemic, chemoprophylaxis may become a cost effective tuberculosis control measure in high prevalence countries. Although isoniazid (INH) is the only drug evaluated in controlled trials of preventive tuberculosis therapy, studies are now under way to determine the efficacy of INH and other drugs, including rifarnpicin and pyrazinamide, in preventing tuberculosis reactivation in persons with HIV infection. If chemoprophylaxis is effective in persons with dual infection, further studies will be required to determine whether chemoprophylaxis is cost effective for tuberculosis prevention and control and whether it is feasible to introduce it asa~c&nmunity control measure, Introduction
Tuberculosis is estimated to affect one-fifth of the world’s population and 2-3 million people die of it each year (RODRIGUES & SMITH., 1990). The epidemic of human immunodeficiency vu-us (HIV) has altered the pattern of tuberculosis disease in many countries, but particularly in Africa where the prevalence of tuberculosis is high and where up to 50% of the population between 20 and 40 years of age have been infected with the disease(STYBLO, 1986; HARRIES, 1990) (Fig. 1). Dete-
In October 1990WHO estimated that 3.9% of all cases of tuberculosis worldwide were associatedwith HIV, but that in sub-Saharan Africa the figure was 17% (KOCHI, 1991b). Reported cases of tuberculosis have been increasing in all African countries affected by the HIV epidemic. In Zambia, the annual tuberculosis notification rate per 100 000 inhabitants has increased from 101 in 1985 to 216 in 1990 (Fig. 2). In Malawi the rate per
Botswana Zambia
Estimated population: 650 million 100,000 inhabitants Estimated
TB infected
population: 171 millIon Estimated population:
Estimated
HlVflB infected 2.8 million
HIV infected
population: 6 mullion
Fig. 1. Tuberculosis, human immunodeficiency virus and the acquired immune deficiency syndrome in Africa (source: WHO/Afro).
rioration in the immune system, which occurs with HIV infection, encourages reactivanon of tuberculous infection to produce tuberculosis disease (SUNDERAM et al., 1986). The character of tuberculosis in adults with HIV infection is also different, presenting more of the features usually seen in children; for example, miliary and extrapulmonary disease (THUER et al., 1990). In addition to the increase in numbers of persons presenting at chest clinics with reactivation of tuberculous infection, there are also people newly acquiring the diseasebecauseof the increase in circulation of Mycobacterium tuberculosis in communities and the increased susceptibility of persons with HIV infection (BARNES et al., 1991). The World Health Organization (WHO) estimatesthat approximately 8-10 million adults and 1 million children worldwide are presently infected with HIV. By the year 2000, 40 million persons may be infected, more than 90% of whom will live in countries in sub-Saharan Africa! south and south-east Asia, Latin America and the Caribbean (KOCHI, 1991a).
Fig. 2. Tuberculosis notification rates per 100 000 inhabitants in selected African countries, 1985-1990 (source: WHO/Afro).
100 000 has increased from 76 in 1985 to 140 in 1990. Of the 650 million estimated population of Africa, 171 million are estimated to be infected with tuberculosis. The estimated HIV infected population is 6 million and the present estimate of dual HIVituberculous infection is 2.8 million (KOCHI, 1991a). Present control methods
What are National Tuberculosis Control Programmes to do to try to limit this increasing rate of tuberculosis? There are 4 methods used at present for controlling tuberculosis worldwide: case finding and treatment, chemoprophylaxis, vaccination, and improvement of socio-economic conditions (PORTER, 1991). Casefinding and treatment is the method of control in African countries. However, with the changing pattern of tuberculosis induced by HIV infection, chemoprophylaxi? may becomean important part of tuberculosis control. Chemoprophylaxis
for control
Until now, becauseof the high prevalence of tuberculosis in Africa, it has not been cost effective to provide chemoprophylaxis for contacts (STYBLO, 1988). How-
468
ever, with the increasing numbers of tuberculosis cases and the increasing incidence of dual infection with HIV (NUNN et al., 19%; ELLIOTT et al., 1990), is chemoprophylaxis now appropriate in high-prevalence areasof Africa? Studies are needed to determine whether chemoprophylaxis prevents the reactivation of tuberculosis in HIV-positive individuals and, if it does, to determine which drug regimen is the most appropriate (most effective, solicits greatest compliance,and is least expensive) (ANONYMOUS, 1990). Chemonronhvlaxis mav have 2 benefits in addition to control of*tuberculosis* reactivation. First, it may prevent primary and secondary (reinfection) outbreaks of tuberculosis among the HIV negative and positive populations. Secondly,“chemoprophylaxis may slow the progression of HIV infection to the acauired immune deficiencv svndrome (EDWARDS& KILPATRICK, 1986). Chemoprophylaxis may therefore have benefits both for the individual and for the community. To consider using chemoprophylaxis in high prevalence African countries, drug regimens are needed which are efficaceous, which have a structure such that those taking the medication are compliant and, finally, which are cheap. Efficacy
What regimens are efficaceous? Until recently isoniazid (INH) was the onlv drug that had been evaluated in controlled trials of preventive therapy for tuberculosis (R. O’Brien. nersonal communication). The renorted efficacv of INH for the prevention of tuberculosis has ranged from 25% to 92% in a series of clinical trials (FEREBEE. 1969: COMSTOCK& WOOLPERT. 1984). These trials established that the maximum benefit from INH is obtained within 1 year and no increased benefit is derived from continuing the medication for a longer period. Although there has been no formal comparison, daily and twice weekly regimes appear equally effective (COMSTOCK,1975). Recently, other drug regimens have been studied. A Hong Kong silicosis study (HONG KONG CHESTSERVICEet al., 1992) provided evidence that rifampicin for 3 months is as good as INH for 6 months in preventing tuberculosis. There is no evidence of additional resistance in subjects given either INH or rifampicin alone. In addition, there were fewer abnormal liver function tests in patients given rifampicin alone than those given INH alone. What about the eflicaceousness of combined drug regimens? In therapy, INH rapidly kills most tubercle bacilli in the first few days. However, rifampicin and pyrazinamide subsequently provide for the final sterilization of tissues, killing the slowly and/or intermittently metabolizing bacilli (GROSSET,1978). Pyrazinamide has been shown to be most effective in the first 8 weeks of therapy, while rifampicin appears to have an important role throughout the entire course of therapy (HONG KONG CHESTSERVICEet al., 1984; EASTAFRICAN/BRITISH MEDICAL RESEARCHC&JNC~LS, 1981). Studies of INH and rifamnicin sueaest that rifamnicin has ereater sterilizing activ;y than rNH (DICKINSON & MIT&SON, 1980). Furthermore, resistance to rifampicin develops lessoften. Studies of the sterilizing properties of rifampicin, INH and pyrazinamide in a mouse model of chronic tuberculosis demonstrated the superiority of rifampicin and rifampicin combined with pyrazinamide (CARTEL et al., 1985). In this study, rifampicin alone for 3 months and rifampicin plus pyrazinamide for 2 months were more effective than INH alone for 6 months. Moreover, the addition of INH to the rifampicinipyrazinamide regimens anneared to have an inhibiting effect on sterilizine activiii. The 2 months regimen 0’: rifampicin plus pyurazinamide was the only regimen to result consistently in sterilization at the end of the treatment period. However, the tubercle bacilli in murine tuberculosis are essentially intracellular in macrophages,whereasin humans they are
extracellular. If bacilli in human lesions persist inside macrophages, chemoprophylaxis with pyrazinamide would be expected to work, but if they are outside macrophages pyrazinamide would not sterilize. At present it is not-known whether persistent bacilli are intracellular or extracellular (MITCHISON. 1990). Further studies are therefore needed. Nevertheless, there is evidence that combining drugs with killing and sterilizing properties for chemoprophylaxis may produce regimens -which are more effcaceous than INH alone. The chemoprophylactic efficacy of other tuberculosis drugs needs to be tested: for example, long acting rifamycin derivatives and isoniazid derivatives. Rifapentine, a semi-synthetic rifamycin with a long elimination halflife and with an antibiotic spectrum similar to rifampicin (ARIOLI et al., 1981), has an elimination half life about 5 times longer than that of rifampicin, with a trend towards increased values if the dose is increased. It may therefore be given once a week. Until now, all chemoprophylaxis studies have been conducted on people not infected with HIV. For individuals infected with HIV there are few data available on the effect of preventive therapy. However, preliminary data from an INH prophylaxis study in Lusaka showed that this regimen reduced the incidence of M. tuberculosis in personswith dual infection (WADHAVANet al., 1990). Compliance
Motivating people to comply with a preventive regimen for 6 months is difficult. but studies have shown that compliance increased as the prescribed length of therapy decreased (INTERNATIONAL UNION AGAINST TUBERCULOSIS
COMMITTEE
ON PROPHYLAXIS,
1982).
The importance of compliance was demonstrated in a study by NOLAN et al. (1986), which showed that rioncompliance was associatedwith a 6 times higher risk of subseauent INH-suscentible tuberculosis. An advantage of a shorter course of-preventive therapy (i.e., 2 or-3 months rather than 6 months) is the expected increase in compliance. Chemotherapy for tuberculosis has been successfully shortened to 6 months using regimens including INH, rifampicin and pyrazinamide (SNIDER et al., 1984; SINGAPORE TUBERCULOSIS SERVICE & BRITISH MEDICAL RESEARCH COUNCIL, 1988; MITCHISON,
1985). In many of these studies, drugs were administered on an intermittent basis, either throughout the entire treatment period or following an initial period of daily therapy (SINGAPORE TUBERCULOSIS SERVICE & BRITISH MEDICAL RESEARCH COUNCIL, 1988). Tuberculosis preventive therapy employing several drugs with potent sterilizing properties, given for periods as short as 2 months, may be as effective as single drug therapy given for longer periods (DICKINSON & MITCHISON, 1980). Shortening drug regimens is one of the keys to improving compliance. cost In order for chemoprophylaxis to be cost effective, medications must be cheap and affordable for African tuberculosis control nrogrammes. INH is the cheanestof the drugs mentioned. Use of long acting drugs, hke rifapentine with its single weekly dose regimen, is likely to improve compliance and may reduce costs. Rifampicin and pyrazinamide are both expensive, but if they are efficaceousand the combination of the drugs can shorten the duration and improve compliance, they too may become cost effective. Present chemoprophylaxis
studies
Chemoprophylaxis studies are presently under way in several countries. The London School of Hygiene and Tropical Medicine is conducting collaborative studies in Kenya and Zambia. The Kenyan study is being conducted to determine the efficacy of 6 months of INH in the prevention of tuberculous reactivation in the Pumwani cohort of prostitutes in Nairobi. In Zambia, a pilot
study is looking at 2 different chemoprophylactic regimens: 6 months of INH and 3 months of rifamoiciniova.~~ razinamide. There are other drug regimens which n&d to be studied, including rifampicin alone and the long acting rifamycins like rifapentine. Conclusion The interaction between tuberculosis and HIV infection has meant that new approachesto tuberculosis control are necessarv. Preliminarv data from Zambia indicate that isoniazid chemoprophylaxis is effcaceous (WADHAVAN et al., 1990), but information from other current studies will supply further information and allow a balanced decision to be taken whether chemoprophylaxis is efficaceous in persons with HIV infection. The next stage is to determine whether chemoprophylaxis
can
be introduced on a large scale, by comparing the cost effectiveness of chemoprophylaxis with that of casefinding and treatment control methods. In addition, feasibility studies are needed to determine if it is possible to introduce chemoprophylaxis for community control. Provisional information from Kenyan studies indicates that recurrencies occur within 6 months of treatment among the HIV infected nooulation (NUNN et al.. 1991). If chemoprophylaxis tin prevent reactivation in’persohs with dual infection it may be a cheaper method for controlling the disease than waiting for patients to present with tuberculosis and then treating them, with a subsequent high risk
of recurrence. References
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