Tuberculosis: where are we going?

losis (TB) as, ‘the captain of all these men of death’. In the late 20th century the World Health Organization (WHO) pronounced it a ‘global emergency’. Whether described by poetry or prose, TB has been the leading global infectious cause of morbidity and mortality for more than 500 years. New directions are required to combat the disease but we need to remember where we have come from before we decide how to progress. Sixty years ago there was no effective treatment for TB. In 1946, 51,289 cases were reported in the UK: 42,173 (82.2%) with pulmonary disease and 9,116 (17.8%) with extra-pulmonary disease.1 Those with advanced pulmonary disease had a 50% five-year survival rate,2 although a rapid death was inevitable if miliary, pericardial or meningeal disease intervened. Many retreated to Alpine sanatoria to find a cure, which inspired some (notably Thomas Mann, who wrote The magic mountain (1924) after his experiences in a sanatorium in Davos, Switzerland), but cured no one. Then, in the mid-1940s, came the simultaneous but independent discoveries of two compounds active against Mycobacterium tuberculosis – streptomycin and para-aminosalicylic acid (PAS). The assessment of these two drugs for the treatment of tuberculosis was a defining moment in medicine. The need for a rapid, authoritative, unbiased assessment was paramount and the chosen methodology, the random assignment of control and experimental treatment regimens, would become a cornerstone of clinical research. The British Medical Research Council (MRC) performed the first trials, comparing streptomycin with bed rest for acute progressive bilateral pulmonary tuberculosis2 and showed that streptomycin reduced six-month mortality and improved bacteriological and radiological cure rates. Resistance to streptomycin developed, however, in 35/41 patients and after five years the number of deaths in the streptomycin group (53%) was only slightly less than in the controls (63%). Urgent strategies were required to overcome the problem of resistance and in 1948 the MRC started a trial comparing streptomycin alone, PAS alone and the two in combination. It demonstrated unequivocally that combined therapy reduced the risk of developing a resistance.3 Consistent and complete cures only became a reality in 1952 with the addition of isoniazid to these two drugs, although a treatment programme of at least 12 months was required. Ethambutol replaced PAS (which caused frequent side effects) and led to a better-tolerated regimen.4 But reductions in treatment length only became possible with the addition of rifampicin, when the term ‘short-course chemotherapy’ was coined.5 A remarkable series of trials performed by the MRC Units in East and Central Africa defined the limits of short-course chemotherapy and demonstrated that complete cure could be achieved following six-months treatment.6 They discovered that pyrazinamide (a drug that was initially discarded due to fears of hepatic toxicity) in combination with rifampicin and isoniazid was a key component of the regimen. Further trials in Hong Kong, Singapore, Madras and Algeria showed that the best results were achieved after an ‘intensive’ phase of two months of rifampicin, isoniazid and pyrazinamide followed by a ‘continuation’ phase of four months rifampicin and isoniazid. By the late 1970s the best drug combinations and the duration of the treatment had been worked out. In the 1980s the total number of notified TB cases in the UK fell to just over 5,000 a year,1 one tenth of the figure 40 years earlier. Optimism was rampant and there was even talk of sending TB the way of smallpox and banishing it to the history books.7 Amid this collective glow of satisfaction, however, the seeds of our current problems with TB were sown. In 1986, the MRC tuberculosis trial units closed. In 40 years they had delineated the measures necessary for successful TB control, the optimal drug regimens and the importance of directly observed therapy (DOT). Two subsequent events suggest the closure of these units was premature. The first was predictable – the increasing prevalence of drug resistance and resulting treatment failures. The second, the arrival of HIV, was not predictable, although by 1986 it was already clear that TB and HIV had a special relationship.8 For a decade the developed world lost focus on the challenges presented by TB; systems of disease control and prevention were disbanded, clinicians lost basic skills in diagnosing and treating the disease and research into novel diagnostic and therapeutic approaches fell away. Our backs turned, tuberculosis continued to plague the poorest people on the planet and crept back into the life of the developed world. Have we turned this problem around in time? Patients with multi-drug resistant tuberculosis (defined as resistance to at least rifampicin and isoniazid) are considered incurable with conventional EDITORIALS