Drug-associated adverse events and their relationship with outcomes in patients receiving treatment for extensively drug-resistant tuberculosis in South Africa

BACKGROUND: Treatment-related outcomes in patients with extensively drug-resistant tuberculosis (XDR-TB) are poor. However, data about the type, frequency and severity of presumed drug-associated adverse events (AEs) and their association with treatment-related outcomes in patients with XDR-TB are scarce. METHODS: Case records of 115 South-African XDR-TB patients were retrospectively reviewed by a trained researcher. AEs were estimated and graded according to severity [grade 0 = none; grade 1-2 = mild to moderate; and grade 3-5 = severe (drug stopped, life-threatening or death)]. FINDINGS: 161 AEs were experienced by 67/115(58%) patients: 23/67(34%) required modification of treatment, the offending drug was discontinued in 19/67(28%), reactions were life-threatening in 2/67(3.0%), and 6/67(9.0%) died. ∼50% of the patients were still on treatment at the time of data capture. Sputum culture-conversion was less likely in those with severe (grade 3-5) vs. grade 0-2 AEs [2/27(7%) vs. 24/88(27%); p = 0.02]. The type, frequency and severity of AEs was similar in HIV-infected and uninfected patients. Capreomycin, which was empirically administered in most cases, was withdrawn in 14/104(14%) patients, implicated in (14/34) 41% of the total drug withdrawals, and was associated with all 6 deaths in the severe AE group (renal failure in five patients and hypokalemia in one patient). CONCLUSION: Drug-associated AEs occur commonly with XDR-TB treatment, are often severe, frequently interrupt therapy, and negatively impact on culture conversion outcomes. These preliminary data inform on the need for standardised strategies (including pre-treatment counselling, early detection, monitoring, and follow-up) and less toxic drugs to optimally manage patients with XDR-TB

Type of adverse event that occurred (n = 161) and total number of patients experiencing these adverse events (n = 115) in patients from the Western Cape, Northern Cape and Gauteng provinces who initiated treatment for XDR-TB.

<p>Type of adverse event that occurred (n = 161) and total number of patients experiencing these adverse events (n = 115) in patients from the Western Cape, Northern Cape and Gauteng provinces who initiated treatment for XDR-TB.</p

Definitions used to grade, identify and classify adverse events.

1<p>These were graded according to the modified American National Institute of Health common terminology criteria for adverse events [CTCAE].</p

Socio-demographic and treatment related clinical characteristics of 115 patients who initiated treatment for extensively drug-resistant tuberculosis (XDR-TB).

*<p>The only other ethnic group in the cohort was Black. Grade 0–2 AE 42(47.7%). Grade 3–5 13(48.1%).</p

Effect of TB strain type on AEs stratified by Beijing and non-Beijing strain type.

*<p>p = 0.03 (severe vs. mild to moderate AEs).</p>**<p>p = 0.0001 (total Beijing versus non-Beijing).</p

Univariate and multivariate analysis of factors associated with mortality in 115 patients with XDR-TB.

<p>Univariate and multivariate analysis of factors associated with mortality in 115 patients with XDR-TB.</p

Study plan stratified according to treatment site, HIV status and severity of adverse drug reactions.

<p>Study plan stratified according to treatment site, HIV status and severity of adverse drug reactions.</p

Kaplan-Meier probabilities of XDR-TB culture-conversion in: (A) The whole cohort of patients who experienced AEs stratified by severity score i.e. none or mild to moderate (grade 0, 1 and 2; dashed line) versus severe (grade 3 to 5; solid line); (B) HIV-infected patients whom experienced AEs stratified by stratified by severity score; (C) HIV-uninfected patients who experienced AEs stratified by stratified by severity score, and Kaplan-Meier probabilities of death: (D) The whole cohort of patients from the date of treatment-initiation, (E) HIV-infected patients who experienced AEs stratified by severity score, and (F) HIV-uninfected patients who experienced AEs stratified by severity categories.

<p>Kaplan-Meier probabilities of XDR-TB culture-conversion in: (A) The whole cohort of patients who experienced AEs stratified by severity score i.e. none or mild to moderate (grade 0, 1 and 2; dashed line) versus severe (grade 3 to 5; solid line); (B) HIV-infected patients whom experienced AEs stratified by stratified by severity score; (C) HIV-uninfected patients who experienced AEs stratified by stratified by severity score, and Kaplan-Meier probabilities of death: (D) The whole cohort of patients from the date of treatment-initiation, (E) HIV-infected patients who experienced AEs stratified by severity score, and (F) HIV-uninfected patients who experienced AEs stratified by severity categories.</p