Toxicity associated with tuberculosis chemotherapy in the REMoxTB study

Combination therapy for drug-susceptible tuberculosis (TB) using isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) has been the standard of care for several decades. While there is recognised toxicity associated with some of the individual drugs (for example hepatotoxicity [1], peripheral neuropathy [2], and gastrointestinal upset [3]) there are few prospective studies of regimen-related toxicity [4–7]. Consequently, clinicians treating tuberculosis largely rely on retrospective or anecdotal evidence to guide their choices when patients experience adverse events.

Previous reports include female gender, alcohol use, human immunodeficiency virus (HIV) infection and certain ethnic groups [3–5, 8–11] as risk factors for experiencing adverse events during therapy. Accurate definition of the risk is confounded by the varying definitions of adverse events or drug-related toxicity, and uncertainty of the recording mechanism or its completeness. For example, ethambutol related impairment of visual acuity rates vary from 0.02% [12] and 9.4% [13] despite the importance of the complication and the simplicity of its measurement.

To overcome the difficulties of biased reporting we used the consistent adverse event reporting system used in the REMoxTB trial [14] to investigate drug related toxicity, as we believe that this is the most comprehensive source of safety data for standard tuberculosis therapy currently available. The aim of the paper was to accurately characterise the patients at greatest risk, the incidence and nature of the toxicity related to standard TB therapy, and to investigate the impact of toxicity on treatment outcomes. Additionally, the paper aimed to compare the incidence of toxicity for standard TB therapy and the two experimental arms in REMoxTB.

In a study encompassing a large number of drug-sensitive TB patients from across the world there is evidence that almost a tenth of patients experienced serious side effects due to their TB medication. The existing literature quotes a rate of approximately 5–20% for significant toxicity from standard TB therapy [5, 9, 16–21] and hepatotoxicity is the most frequently detected [1, 22, 23]. The liver enzyme profile on treatment for standard TB therapy and the experimental arms in REMoxTB has been described in more detail elsewhere [24]. As the exclusion criteria removed those with severe disease or concomitant diseases, our estimate must be considered a minimum [14], however the follow-up period was comparable to two other recent large tuberculosis trials [25, 26].

We observed that most of the AEs in standard therapy occurred in the intensive phase. The explanation for this is uncertain, and could involve a degree of survivorship bias or increased tolerance of side effects, but may relate to the presence of pyrazinamide in all three regimens. Pyrazinamide is a drug with a well-recognised toxicity profile [11], while ethambutol (the other drug only present for the intensive phase) has few reported side effects [27]. Additionally, hepatotoxicity and arthralgia were among the most common events and these are frequently reported side effects of pyrazinamide [28, 29]. The sterilising activity of pyrazinamide makes it an essential component of standard therapy [30], but there is still some uncertainty surrounding its ideal dosing [31] and there is evidence of a dose-response relationship with toxicity [32]. There is a pressing need to direct more research to optimise the most effective and least toxic dose alongside the other components of the standard regimen [33].

It is perhaps significant there was little difference in the number of related AEs in months 5 and 6 between those receiving active treatment and those on placebo. This could emphasise the importance of TB induced pathology on the presence and reporting of significant medical events. Reducing toxicity associated with medication is one of the factors driving the development of shorter treatment regimens for TB [34], however this finding suggests that concerns about toxicity may not be as important as previously thought. While the experimental arms were less toxic, it should be noted that they were also less effective. It was notable that both experimental regimens were less toxic and both of these reduced the bacterial load more quickly than standard regimen [14]. Whether there is a causal relationship between these observations is not known. This means, perhaps, that the motivation for shortening treatment needs to focus around patient acceptability and logistical benefits of few doses, visits to clinics and enhanced adherence.

We found female patients and HIV-positive patients to be at significantly higher risk of toxicity. Existing guidelines acknowledge the issues surrounding TB-HIV co-infection [35, 36], but these do not reference female gender as a risk factor for a more complicated treatment course (outside of pregnancy). It is unclear if reporting bias has played a role in AE recording for the trial, as there have been discrepancies noted between the genders in regards to healthcare-seeking behaviour previously [37, 38]. Nonetheless, clinicians should consider closer monitoring of both HIV-positive and female patients taking HRZE, especially in the intensive phase of treatment.

Those patients reporting one or more related grade 3/4 AE were more likely to fail to achieve sustained sputum culture negative status. This is an important observation and emphasises the need to detect toxicity early and manage it properly. The reasons for this difference in outcome is uncertain and would merit further investigation in prospective studies. It may be that better management of drug toxicity in tuberculosis treatment could deliver better outcomes.

It is notable that the majority of deaths occurred after completing treatment and were unrelated to trial medication, emphasising the importance of social context of TB infection. It may be that this is due to other underlying conditions that also contribute to a poor outcome or that experiencing toxicity reduces adherence to therapy. This relationship may explain why the cure rate with standard therapy for drug-sensitive disease can be as low as 80% in real-world settings [39].

This study is limited by innate reporting bias and reliance on a subjective assessment of severity in many cases (for example, pain scores). An example of this is the reporting activity at one site in the trial. After a trial pause this site reported almost one third of its total grade 3/4 AEs, and assessed 75% of them as being related to treatment in a 30 week period. Attributing causality to AEs has been shown to produce unreliable and subjective data [40] and caution has been advised when using trial data to evaluate drug safety profiles [41]. Given the proximity of the recent pause in trial recruitment it could be that there was concern over the safety of the experimental regimens and that in a double-blind trial this translated into a lower threshold to both report events and to attribute causality to the drugs.

While there is still merit in using AEs to investigate drug safety profiles, the often subjective nature of the reporting is a limitation. We are also aware of the potential dangers of drawing conclusions based on relatedness assessments for AEs [40, 42] and to this end have presented both total and related AEs in the analysis. Overall, the careful and consistent way in which data were recorded for this large number of patients does mean, however, that we are able to generate important observations and suggest future research.

In this paper we have shown that most adverse events occur in the intensive phase of treatment with female patients and those who are HIV positive constituting a demographic that should be closely monitored for toxicity. We have also found that those who experience clinically significant drug related-toxicity while taking standard TB therapy are at greater risk of failing treatment. From this we conclude that we need to improve our methods of detecting and managing patients experiencing toxicity, and that there is real need for novel drugs with more favourable toxicity profiles. Our data provide an evidence base to plan future research and to support improved treatment guidelines. Tuberculosis remains a global health threat, predominantly affecting a vulnerable and disadvantaged population, and this paper illustrates the need for clinicians to be quick to respond to side effects from treatment to ensure their patients have the best chance of achieving a cure.