Discussion

This is the first analysis of anti-TB drug intolerance and its relationship to non-completion of treatment in England, Wales and Northern Ireland derived from the ETS system, a whole population case register of TB patients.

Intolerance to anti-TB drugs was reported in 1.28% of notifications. This figure includes records in which drug intolerance had been indicated through free text comments, a threefold increase in reports compared with those made using the dedicated drug intolerance field only. This is partly because the drug intolerance field can only be completed for patients who are still on treatment at follow-up, and therefore omits those who experienced adverse events during their treatment but who, for example, completed treatment or were lost to follow-up.

Previous attempts to measure the incidence of drug intolerance in other settings have produced higher estimates, with 8.6% patients affected in a smaller single-centre cohort2 and 30% in a population-based study involving regular standardised collection of information regarding patients’ tolerance to the TB medications.3 This indicates that the number reports of intolerance to anti-TB drugs ascertained here are an underestimate of the true incidence of adverse events. A limitation of this method for identifying cases of drug intolerance that has contributed to this is the lack of standardisation in data entry: Drug intolerance information is not actively sought on ETS, there is no agreed system for grading side effects and completion of comments relies on retrospective recall by the case manager. It is therefore probable that only the most severe adverse events, or those that resulted in a change of treatment regimen, would prompt a case manager to comment.

Hepatotoxicity was the predominant reported adverse event caused by anti-TB drugs, and pyrazinamide was most frequently suggested as the cause. These results are consistent with previous understanding,2 ,3 although details of conditions and drugs were only available for approximately 30% of the reports of drug intolerance. Important risk factors associated with drug intolerance in this cohort were female sex, older age, later case report year and white ethnicity. Other studies2 have found similar relationships with sex and age, but it is probable that the association with year reflects a change in the way that the comments section has been used over time, rather than a real increase in incidence. There may also be residual confounding for factors that could not be controlled for in this study; notably HIV status,2 which is not included in TB surveillance data in the UK, and alcoholism, homelessness and drug use, which have only been collected in ETS since 2009.

This study provided evidence that drug intolerance is associated with an approximate fivefold increased odds of treatment non-completion. Although this is a logical association, few attempts have previously been made to quantify it. Adverse events were associated with a twofold higher rate of unsuccessful treatment outcomes at 6 months in one study, but this was a smaller analysis of patients at a single tertiary care hospital.4

The crude relationship between drug intolerance and non-completion of treatment was partially confounded by a number of covariates that were included in the adjusted analysis, but, again, there may have been residual confounding from unmeasured covariates such as alcohol dependence, homelessness and refugee status.5 The precision of our estimate of the effect of drug intolerance on treatment failure may also have been implicated by the likely underestimation of intolerance in the cohort and by the restriction of the categorical drug intolerance option on ETS to patients who are still on treatment at follow-up. This restriction would tend to increase the effect on treatment non-completion, although these reports made up a minority of the overall number of reports of drug intolerance that were ascertained.

The observed relationship between drug intolerance and treatment non-completion has consequences for the management of TB in patients with these symptoms. Such patients are more likely to have their treatment extended due to changes in drug regimens, are less likely to comply with treatment and are more likely to become lost to follow-up. As a result, they are prone to have longer disease duration, increasing their risk of death and the potential for the disease to spread. This highlights the importance of consultation with expert respiratory physicians where possible regarding management of patients with symptoms of drug intolerance and the crucial role of close case management by respiratory nurse specialists in the community so that issues can be detected early and dealt with accordingly. A more systematic way of recording instances of drug intolerance and classifying their severity would aid this, for example, by extending the dedicated drug intolerance field so that it can be completed for any case in ETS.

In conclusion, we provide evidence that intolerance to anti-TB drugs is significantly associated with failure to complete TB treatment regimens in the UK. A more accurate picture of the burden of these adverse events and the extent of the impact on treatment completion could be obtained through prospective systematic recording on ETS. Development of new, less toxic treatments should be given a high priority in order to reduce patient suffering, improve treatment completion rates and contribute to control of the disease.