Results

Between 1 October 1987 and 31 December 1992, 141 physicians from England, Scotland and Wales, Denmark, Finland, Norway and Sweden entered 223 patients, 106 with disease caused by M malmoense (52 RE, 54 REH), 75 with MAC (37 RE, 38 REH), and 42 with M xenopi (22 RE, 20 REH). The RE and REH groups were not appreciably different in any of the following characteristics: mean age, sex distribution, exposure to dust, previous lung diseases, conditions likely to impair immune response, previous BCG vaccination, sputum smear positivity, radiological extent of disease, cavitation and other pulmonary diseases evident on the chest radiograph (table 1).

In 49 patients (24 RE and 25 REH; table 2) the protocol was not followed: 12 received treatment different from that allocated because of unwanted effects from E, six because of unwanted effects from H, four because of unwanted effects from R; in the remaining 27 patients treatment varied from that allocated or was discontinued prematurely by the physician or GP (none because of HIV/AIDS) or the patient defaulted from follow up. In all of these respects there were no differences between the RE and REH groups neither within species nor overall.

For each species of opportunist mycobacteria there were no statistically significant differences between the RE and REH regimens in the number of deaths during the study (table 2). Overall there were 74 deaths (32 RE and 42 REH), a difference which was not significant at the 5% level (χ² =1.8, p=0.18, odds ratio (OR)=0.66, 95% CI 0.36 to 1.20). Of the 64 patients who died from causes other than mycobacterial disease, 20 died of respiratory failure, 13 of lung cancer, nine of pneumonia, eight of ischaemic heart disease, one of cor pulmonale, and seven of other causes (none due to AIDS or drug toxicity). In six patients the cause of death was uncertain.

Within each species the number of patients who died because of mycobacterial disease did not differ significantly between treatment groups, but when the three species were combined there were significantly fewer deaths resulting from mycobacterial disease in the RE group than in the REH group: 1% v 8% (Fisher's exact test, p=0.018, OR=0.10, exact 95% CI 0.00 to 0.76).

For M malmoense the numbers classified as failures of treatment and as relapses did not differ appreciably between the RE and REH groups, but in patients with MAC there were fewer failures of treatment/relapses in the REH group (χ²=4.5; p=0.033). For M xenopi there was a trend in favour of REH but this did not reach statistical significance (p=0.41). When all RE failures/relapses (22%) were compared with all REH failures/relapses (11%), a significant difference emerged in favour of REH (χ²= 4.5; p=0.033). The differences between those classified as alive and cured were not significant at the 5% level, neither within species nor for RE versus REH overall.

Pretreatment susceptibility results were available for R in 174, E in 174, and for H in 84 strains. There was no correlation between failure of treatment/relapse and in vitro resistance nor between cure and in vitro sensitivity (table 3).

Clinical progress, weight gain, and radiological improvement did not differ between RE and REH groups for any of the three species, nor when the three species were combined. Records of clinical progress were available from 1707 clinical encounters during and after treatment: in 88% these records indicated satisfactory clinical progress. Unsatisfactory progress was recorded on 12% of occasions but only a third of these were attributed to the opportunist mycobacterial lung disease. Mean (SD) weight gain to 5 years was 1.16 (6.96) kg by which time 25% of those with a complete series of chest radiographs showed closure of cavities and/or reduction in the extent of disease.

In order to provide overall outcome data for each species, the two treatment groups were combined within each species (table 4). Disease caused by M xenopi was associated with the highest 5 year mortality. MAC was more difficult to eradicate than the other two species. More patients with M malmoense were alive and cured at the end of 5 years than with the other two species.

Discussion

This is the first randomised trial of the treatment of pulmonary disease caused by opportunist mycobacteria. It is unique, not only in this respect, but also as the first large long term prospective survey of these conditions. It has demonstrated that a simple, relatively non-toxic, regimen can achieve results as good as any previously described with regimens which contained five or six drugs and were not well tolerated.

In the reports of some of the retrospective studies attention has been drawn to the fact that the in vivo response did not appear to be related to the results of in vitro susceptibility tests in the way that it is for M tuberculosis.4-6 ,8 ,9 ,13 ,14 This prospective, relatively large, study has confirmed that the results of such tests, using single antimycobacterial drugs and performed by the standard modal resistance technique,18 ,19 do not predict the clinical and bacteriological response. Until levels of in vitro resistance that correlate with clinical outcome are defined, giving in vitro susceptibility results to clinicians is likely to confuse treatment rather than aid it. Laboratories may well wish to rethink not only how they report the results to the clinicians, but also how they perform the tests.

Although for each species the difference between the RE and REH regimens in respect of deaths caused by the opportunist mycobacteria, favouring the RE group, did not reach statistical significance, when all three species were combined RE emerged as the superior regimen on this criterion. However, this difference must be interpreted with caution: attributing the cause of death was a matter of judgement between the coordinating physician, the patient's physician and/or GP, none of whom was blind to the treatment received by the patient when deciding cause of death. Precise decisions about cause of death are not always easy and in some instances there will be an element of subjective judgement. When the regimens were compared according to the more objective outcome measure “failure of treatment/relapse”, the overall difference went the other way, favouring the REH group rather than the RE group (p=0.033). This emerged particularly for the patients with MAC in whom REH was significantly superior to RE, whereas in those with M xenopi or M malmoense the differences were not statistically significant. The results of this trial indicate that isoniazid has little or no place in the treatment of M xenopi orM malmoense. It is of use in MAC but, in view of the possibility that it might be associated with a higher death rate, perhaps it should only be added if RE is failing to render the sputum negative on culture.

The results of treatment compared favourably with those reported in the retrospective studies in the literature,1-11 ,13 ,14 ,20although neither regimen produced high cure rates. The relatively high death rates and failure/relapse rates we have found may be partially explained by the age of the patients and the high prevalence of pre-existing clinical and/or radiological lung disease, all factors which might reduce the patient's response to the infection. Relatively few patients were unable to tolerate treatment because of unwanted effects of the drugs, in contrast to the high intolerance rates reported in studies where second line or third line antimycobacterial drugs had been used because of the results of in vitro susceptibility tests.4 ,5 ,10 ,20 Failure/relapse rates for MAC were less than those observed by Huang et al 20 and were also less than those reported by Dutt and Stead who used five drugs ± surgery.3 Hunteret al, reporting results of regimens containing REH or streptomycin, PAS and H, obtained results much like ours.4 For M malmoense the results were little different from those reported by Bankset al 5 and by Franceet al 6 for regimens containing ER, but were better than the results they found with second or third line drugs. M xenopi infection was associated with high overall mortality in this trial as it was in the previous reports, although only 7% of deaths were attributed to the organism compared with 10–20% in the earlier series.9 ,10

While the trial was in progress the macrolide and quinolone agents clarithromycin and ciprofloxacin were shown to have in vitro activity against opportunist mycobacteria.21-23 There have been reports of their efficacy in vivo,21 ,24-28 but randomised clinical trials which demonstrate efficacy have only been reported for MAC disease in HIV positive patients.29-31The Research Committee of the BTS is currently conducting a further multicentre randomised trial to assess the value of clarithromycin and of ciprofloxacin in the treatment of pulmonary disease in HIV negative patients; a regimen of 2 years of rifampicin, ethambutol, and clarithromycin is being compared with 2 years of rifampicin, ethambutol, and ciprofloxacin. In addition, there is an optional arm where patients can be further randomised to receive immunotherapy withM vaccae (SRL 172) or to no immunotherapy. That study, as the one reported here, will use the hard end points of death, failure of treatment, and relapse rather than the surrogate measures of outcome reported in recent uncontrolled studies.27 ,28 It is hoped that these new regimens will improve cure rates but, in the meantime, the evidence from this study indicates that a regimen of RE for 2 years offers a better chance of successful outcome in patients with M malmoenseor M xenopi than REH for 2 years. For those with MAC the addition of H will reduce failure/relapse rates but this three drug regimen may possibly be associated with an increased death rate. The final results of this randomised controlled trial will allow the Joint Tuberculosis Committee to reclassify the relevant recommendations in the 1999 guidelines on management of opportunist mycobacterial infections from grade B to grade A.32