Global challenge of tuberculosis

Letters to the Editor

Global

challenge of tuberculosis

SiR-We disagree strongly with your editorial (July 30) opinion that the relation between HIV infection and tuberculosis in Africa has been challenged by a paper describing false-positive tests for HIV antibodies in patients infected with Mycobacterium leprae and M tuberculosis.’ Objections to Kashala and colleagues’ work are detailed elsewhere2 but, most importantly, patients reported upon in this paper had leprosy not tuberculosis; Kashala et al generalised their questionable conclusions to tuberculosis. 1

Several lines of evidence incriminate HIV infection as the strongest risk factor for tuberculosis to have been identified. These include: (1) increased rates of tuberculosis among HIV-positive persons dying in Africa; (2) increased rates of HIV infection among tuberculosis patients in Europe, North America, and Africa; (3) increased tuberculosis incidence in HIV-infected persons in Europe, North America, and Africa; (4) overlap between tuberculosis and HIV disease in North America and Africa in terms of time, place, and persons affected; and (5) an association within Africa between the severity of the epidemic of HIV infection and the magnitude of tuberculosis. The impact of HIV infection on the course of tuberculosis is clearly demonstrated by the more aggressive disease and high mortality rates in HIV-positive persons with tuberculosis; the highest mortality rates are concentrated among those who are most immunosuppressed. The public health impact of the association between HIV infection and tuberculosis is most severe in countries where rates with both infections are high, such as in sub-Saharan Africa. We agree that a global approach is required and that support is needed for increased biomedical research. You fail to question, however, whether public health benefit is more likely to result from new knowledge or from better application of what we already know. Providing developing countries with molecular methods of diagnosis is exactly the sort of approach that will not enhance tuberculosis control. The control of tuberculosis requires identification and treatment of patients with smear-positive pulmonary tuberculosis within adequately funded, well-managed programmes.

Weakness of public health infrastructure, underfunding of programmes, insecure supplies of drugs, and HIV infection are the major reasons for the disastrous tuberculosis situation in many African countries. If we are to consider tuberculosis as a global problem, we should adopt optimal treatment regimens on a global basis and not accept the many different and inferior regimens used in many poorer countries. Tuberculosis control requires the disease to be made a priority by governments and donor agencies that until now have not considered it as such. Lack of public health leadership, lack of resources, and lack of commitment are more important causes of today’s dismal situation than purely technical issues. One technical and operational

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that does wait to be resolved, and which was not discussed in your editorial, is the exact role of and best regimen for preventive therapy for tuberculosis in HIVinfected people in resource-poor areas.

question

Kevin M De Cock, Sebastian B Lucas Clinical Sciences, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; and Department of Histopathology, University College London Medical School

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2

Kashala O, Marlink RG,

Ilunga M, et al. Infection with human immunodeficiency virus type 1 (HIV-1) and human T cell lymphotropic viruses among leprosy patients and contacts: correlation between HIV-1 cross-reactivity and antibodies to lipoarabinomannan. J Infect Dis 1994; 169: 296-304. Lucas SB, Fine PEM, Sterne JAC, et al. Infection with HIV-1 among leprosy patients in Zaire. J Infect Dis (in press).

SiR-Your intention to set tuberculosis in its global context is welcome. The Tuberculosis Programme at WHO has worked since 1990 to form a worldwide coalition of member national tuberculosis states, programme managers, international agencies, such as the World Bank, nongovernmental agencies, and foundations, in the recognition that tuberculosis will not be eradicated in industrialised countries without considerable reductions in the disease in their less-industrialised neighbours.I WHO’s updated estimates of the numbers of new cases and the attendant mortality due to tuberculosis have emphasised the previously unrecognised scale of the tuberculosis epidemic.2 Targets have been set for the world: cure of at least 85% of all new smear-positive cases presenting for treatment by the year 2000 and identification of at least 70% of all such cases. To mobilise international action and reach these targets, there are three prerequisites: an economically persuasive strategy for treatment; political acceptance of tuberculosis as a problem requiring attention in all countries; and a focused attack on the heaviest tuberculosis burdens in the largest countries. WHO has provided global direction by playing a leading part in each of these three areas. Collaboration with the International Union against Tuberculosis and Lung Disease (IUATLD) showed the striking costeffectiveness of anti-tuberculosis treatment for smear-positive patients. WHO has published new guidelines for treatment, a comprehensive framework for modern tuberculosis control programmes, and several policy statements on controversial aspects of tuberculosis. Often with the World Bank, WHO provides essential assistance to several countries revitalising their tuberculosis programmes, including the countries of the ex-Soviet bloc (Burns and colleagues, June 11, p 1445). Experience shows clearly that tuberculosis control need to be evaluated and reviewed programmes The built-in information systematically. system for individual registration, monitoring, and evaluation of outcome of every patient is a key component of WHO’s

recommended strategy. Widespread adoption of such systems would, incidentally, answer your call for an international system of monitoring treatment outcomes. You correctly raise the issues of drug resistance, new drug development, the application of new technology-based diagnostic tests, supervision of treatment, BCG, and the impact of HIV as concerns to be addressed by your conference. WHO has developed drug resistance surveillance guidelines, which are now being implemented. However, so far, all the evidence points towards drug resistance being mainly the consequence of poor programmes and bad policies and that it can be reduced by competent programme management working with the right policies. The urge to develop new drugs for tuberculosis is driven by the spectre of multidrug resistance (MDR), which may be confined to the USA. Logically, however, the impetus should come from the fact that a 6-month treatment regimen is unacceptably long wherever you are, so that even when MDR levels fall in the USA this work should continue. The scientific community and political leaders should commit themselves unreservedly to using already available anti-tuberculosis drugs which can save the lives of tens of millions of people in the next decade or two while the search for better drugs proceeds. It is certainly true that "conventional diagnostic methods are of limited value in extrapulmonary and childhood infections" but we urge restraint in the adaptation of newer technologies by non-industrialised nations until such techniques have been clearly shown to be as good or better than the conventional ones. Directly observed therapy (DOT) is of proven value, not only in improving rates of cure but also in limiting the development of resistance. The question is not so much whether DOT should be universally applied, but rather how to do it affordably and effectively in various cultures and conditions. After all this time, there is unlikely to be a meeting of the minds on the efficacy of BCG. Even if there were, it probably would alter current policy very little. It certainly would have little impact on the immense burden of death and disability from TB in the next decade. A focused debate on the best avenues to pursue for a new, more effective vaccine, without detracting from current resources for treatment, would be welcome. We agree that "the impact of the human immunodeficiency virus (HIV) on the incidence of tuberculosis has been catastrophic". However, you then refer to recent suggestions that antibodies to Mycobacterium leprae can cause widespread false-positive HIV tests, and that the same might occur in tuberculosis. This conclusion is premature, since the work in question3 refers only to leprosy patients. Our goal must be to reduce the burden of death and suffering caused by tuberculosis: over 500 million new infections, 88 million new cases, and 30 million deaths this decade from a single disease where a costeffective intervention already exists. This is surely a challenge to the global village to get its act together. We believe the evidence is clear that the WHO Tuberculosis Programme is leading the world’s response to this challenge and we welcome the contribution of The Lancet and its 1995 conference. A Kochi Tuberculosis Programme, World Health

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2 3

Organization, 1211

Geneva 27, Switzerland

Raviglione MC, Sudre P, Rieder HL, et al. Secular trends of tuberculosis in Western Europe. Bull World Health Organ 1993; 71: 297-306. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality. Bull World Health Organ 1994; 72: 213-20. Kashala O, Marlink R, Ilunga M, et al. Infection with Human Immunodeficiency Virus type 1 (HIV-1) and human T cell lymphotrophic viruses among leprosy patients and contacts: correlation between HIV-1 cross reactivity and antibodies to lipoarabinomannan. J Infect Dis 1994; 169: 296-304.

SIR-It is surprising that your editorial makes no reference the highly successful national tuberculosis control projects conducted with support from the International Union against Tuberculosis and Lung Disease (IUATLD) in some of the poorest countries. For instance in 1990 about 68 000 sputum-positive patients in African countries were treated by short-course chemotherapy with 75% sputum conversion (Tanzania 79%, Malawi 80%, Benin 73%, Mozambique 69%).’ On the basis of these programmes the World Bank reported in The Lancer that such projects rank as the most costeffective of all therapeutic programmes in terms of years of life saved. It was the success of these projects that stimulated WHO to launch its global programme, still grossly underfunded, to apply these methods world wide. In view of the incipient explosion of the HIV epidemic in Asian countries, many with already high tuberculosis rates, WHO is right in insisting that the HIV/tuberculosis threat is a to

global

emergency. In Tanzania the HIV epidemic has resulted in an increase of 70% of cases of tuberculosis between 1988 and 1993. Nevertheless, it is calculated that 70% of new cases are successfully detected and 80% are successfully treated. Moreover there seems to have been no increase in the overall prevalence of tuberculous infection as judged by tuberculin 1

surveys.’

In the IUATLD-assisted

countries, where good

treatment

is provided through government services and little treatment is given by others, drug resistance is not a major problem. The situation is far more dangerous in some Asian countries where many factors, notably ignorant or unscrupulous treatment

by qualified

or

unqualified doctors,4 poses

a

major

threat. It is a good general rule that, apart from certain factors such as unreliable drugs in some countries, all drug resistance is due to bad doctoring and is therefore avoidableThe principles of tuberculosis control have been established for about forty years. It has now been shown that these can be effectively applied even in the poorest countries. The challenge is to see that they are. Britain, after being a world leader in this field, notably through the activities of the MRC tuberculosis unit, shamefully neglected it

subsequently. John Crofton Spylaw Bank Road, Colinton, Edinburgh

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3 4 5

EH13 OJW, UK

IUATLD. Tuberculosis Programme 1991-92. Activity report, 1992: section A. Murray CJ, De Jonghe E, Chum HJ, Nyangulu DS, Salomao A, Styblo K. Cost effectiveness of chemotherapy for pulmonary tuberculosis in three sub-Saharan African countries. Lancet 1991; 338: 1305-08. World Health Organization. The global tuberculosis situation. Geneva: WHO, July, 1993. Upelkar MW, Shepard DS. Treatment of tuberculosis by private practitioners in India. Tubercle 1991; 72: 284-90. Crofton J. The prevention and management of drug-resistant tuberculosis. Bull Int Union Tuberc Lung Dis 1987; 62: 6-11.

SiR-We welcome the attention that The Lancet is giving to tuberculosis but are concerned by the uncritical repetition in your editorial of two results that are not widely acceptednamely, an overall protective efficacy estimate for BCG and the supposed cross-reactivity between mycobacterial infection and HIV tests. There is no evidence that HIV tests are unreliable in the presence of Mycobacterium tuberculosis. As demonstrated in several studies, including the one cited,’ the variability in the efficacy of BCG observed in different trials and case-control studies vastly exceeds that which would be expected by chance. It is no more meaningful to calculate a single average efficacy when the efficacy is known to differ to this extent than it would be to

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calculate the average risk of being knocked over when crossing a road, knowing that this will hide the differences between Niger, Rio de Janeiro, and New York. The question in your call for abstracts for The Lancet’s 1995 conference ("Why can no-one agree about the value of BCG vaccine?") is therefore misleading. The important question is "What determines the variable protection afforded by BCG?". Your editorial begins by discussing the incidence of tuberculosis, seeming to blame national public health systems for the rise. While the relative importance of different risk factors will vary from place to place, a consensus would probably put the HIV pandemic and poverty at the top of the list (see Drucker and colleagues’ paper, for example2). We agree that close collaboration between researchers and international agencies is necessary to improve tuberculosis control, but scientists have to take the lead with a critical and balanced appraisal of data, and thereby set the research agenda. Judith R

Glynn, Jonathan A

C Sterne, Laura C

Department of Epidemiology and Population Sciences, Tropical Medicine, London WC1E 7HT, UK

Rodrigues

London School of

Hygiene and

Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA 1994; 271: 698-702. Drucker E, Alcabes P, Bosworth W, Sekell B. Childhood tuberculosis in the Bronx, New York. Lancet 1994; 343: 1482-85.

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SiR-You refer to the fact that "fewer than half the patients with tuberculosis in developing countries are in contact with treatment services", but also suggest that new technologies of tuberculosis diagnosis "should be made available without delay to non-industrialised countries". These statements are not relevant to the problems of tuberculosis control in such countries. Successful tuberculosis control in developing (and former Eastern bloc) countries needs improved political commitment and funding to implement national tuberculosis control programmes along the lines recommended by the International Union against Tuberculosis and Lung Disease. The new WHO’ strategy to improve case detection and cure rates rests upon four cornerstones of a developing country’s national tuberculosis control programme: a reliable sputum-smear microscopy service, registration of all tuberculosis patients, a secure drug supply, and supervision of programme activities at all levels. New technologies are expensive and there is a danger that their introduction in developing countries would divert attention and money from the real issues. Since the vast majority of the world-wide estimated 8-10 million annual cases of tuberculosis and 3 million tuberculosis deaths are in developing countries, the global challenge of tuberculosis lies in the implementation of old, tried, and tested technologies. Dermot Maher University of Malawi, College of Medicine,

Private

Bag 360, Chichiri, Blantyre 3,

regimen patients

Kochi A. The global tuberculosis situtation and the new control strategy of the World Health Organization. Tubercle 1991; 72: 1-6.

F A Drobniewski, A H C Uttley Regional Tuberculosis Centre, Dulwich Hospital,

PHLS

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SiR-Lancet

correspondents (June 25,

p

260, 261)

two

Small PM, Hopewell PC, Singh SP, et al. The epidemiology of tuberculosis in San Francisco: population-based study using conventional and molecular methods. N Engl J Med 1994; 330: 1703-09. Alland D, Kalkut GE, Moss AR, et al. Transmission of tuberculosis in New York City: an analysis by DNA fingerprinting and conventional epidemiological methods. N Engl J Med 1994; 330: 1710-06. Jacobs WR Jr, Barletta RG, Udani R, et al. Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science 1993; 260: 819-22.

raise

overlapping requirements-namely, therapeutic

success

for the patient and the public goal of interruption of transmission. We agree with Nunn et al (June 25) that clinical and microbiological cure should be the criteria for success, especially where evidence for the efficacy of a 610

London SE22 8QF, UK

1640; July 23,

several issues about efficacy and of practicality supervised intermittent ambulatory treatment (SIAT) regimens. Any anti-tuberculosis regimen must satisfy p

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Tuberculosis treatment programmes

limited, and where sputum smear-positive

be rendered non-infectious before discharge from isolation to begin SIAT. Small et al’ in their epidemiological analysis of tuberculosis in San Francisco, describe one non-compliant individual who, as indicated by molecular typing, infected 6% of all identified cases despite the efforts of an excellent tuberculosis control programme which ensured that 95% of patients completed therapy during the study period. In their study and that of Alland et al,2 30-40% of clinical cases identified were due to infection within the previous 2 years, reflecting the importance of ensuring compliance and therapeutic success.’"* Once a regimen known to be effective against an individual’s strain of Mycobacterium tuberculosis has been started ambulatory care can be supervised by non-medical but carefully trained community health workers with ready access to doctors if side-effects develop. The alternative of bulk supplying drugs to untrained "supervisors" to cover the entire treatment period may open such a system to abuse, leading to partial and ultimately ineffective treatment, especially if the therapeutic outcome is not directly assessed. However, where testing is available validation of an individual patient’s regimen can be made and the treatment changed but that would be outside the scope of nurses or other non-medical staff. The use of two agents in the continuation phase, as Nunn et al argue, could proceed in the knowledge that both were effective. This would benefit poorer districts or states in Africa, Eastern Europe, or Asia where incomes are low, drug supplies insecure, and the cost of four agents for a period of 4 months is an unacceptable burden when incidence or prevalence of clinical disease is high. Without testing, as Wilkinson et al argue, maintenance of the four-drug regimen is essential where the prevalence of drug resistance is either not known or high. Present diagnostic methods do not usually permit drug susceptibility testing within the early period of clinical care. We therefore need molecular methods that can detect specific drug mutations or phenotypic systems detecting drug resistance such as those based on luciferase reporter phages3 within 2 weeks of clinical presentation. In kit form and with bulk production these methods could have worldwide application. As newer drugs are developed and older ones re-evaluated for direct or adjuvant activity against mycobacteria, the testing of drugs singly and in combination will permit the rational design of new therapeutic regimens. These systems would, with conventional testing, support the controlled trials of the SIAT regimen that Wilkinson et al describe.

Malawi

1

is

must

In-vitro fertilisation and family breast cancer

history of

SiR-We report a case of early-onset familial breast cancer after in-vitro fertilisation (IVF). Our patient had three cycles of IVF at age 36, involving administration of clomiphene citrate, human menopausal gonadotropin, and human