Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study

Summary

Background

Long-term treatment-related outcomes in patients with extensively drug-resistant (XDR) tuberculosis are unknown. We followed up a cohort of patients to address knowledge gaps.

Methods

Between March, 2008, and August, 2012, we prospectively followed up a cohort of 107 patients from three provinces in South Africa, who had been diagnosed with XDR tuberculosis between August 2002, and February, 2008. Available isolates from 56 patients were genotyped to establish strain type and used for extended susceptibility testing.

Findings

All patients were treated empirically as inpatients with a median of eight drugs (IQR six to ten). 44 patients (41%) had HIV. 36 (64%) of 56 isolates were resistant to at least eight drugs, and resistance to an increasing number of drugs was associated with the Beijing genotype (p=0·01). After 24 months of follow-up, 17 patients (16%) had a favourable outcome (ie, treatment cure or completion), 49 (46%) had died, seven (7%) had defaulted (interruption of treatment for at least 2 consecutive months), and 25 (23%) had failed treatment. At 60 months, 12 patients (11%) had a favourable outcome, 78 (73%) had died, four (4%) had defaulted, and 11 (10%) had failed treatment. 45 patients were discharged from hospital, of whom 26 (58%) had achieved sputum culture conversion and 19 (42%) had failed treatment. Median survival of patients who had failed treatment from time of discharge was 19·84 months (IQR 4·16–26·04). Clustering of cases and transmission within families containing a patient who had failed treatment and been discharged were shown with genotypic methods. Net sputum culture conversion occurred in 22 patients (21%) and median time to net culture conversion was 8·7 months (IQR 5·6–26·4). Independent predictors of probability of net culture conversion were no history of multidrug-resistant tuberculosis (p=0·0007) and use of clofazamine (p=0·0069). Independent overall predictors of survival were net culture conversion (p<0·0001) and treatment with clofazamine (p=0·021). Antiretroviral therapy was also a predictor of survival in patients with HIV (p=0·003).

Interpretation

In South Africa, long-term outcomes in patients with XDR tuberculosis are poor, irrespective of HIV status. Because appropriate long-stay or palliative care facilities are scarce, substantial numbers of patients with XDR tuberculosis who have failed treatment and have positive sputum cultures are being discharged from hospital and are likely to transmit disease into the wider community. Testing of new combined regimens is needed urgently and policy makers should implement interventions to minimise disease spread by patients who fail treatment.

Funding

European and Developing Countries Clinical Trials Partnership, South African National Research Foundation (SARChI), and the South African Medical Research Council.

Introduction

Tuberculosis remains a major global problem: the estimated number of new cases in 2011 was almost 9 million.¹ Sustained control is undermined by the growing threat of drug-resistant tuberculosis. Of 12 million cases of tuberculosis worldwide in 2010, 650 000 (5·4%) were estimated to be of multidrug-resistant disease.² 5–10% of the cases of multidrug-resistant tuberculosis are thought to be extensively drug-resistant (XDR) disease—defined as multidrug-resistant disease with resistance to a fluoroquinolone and either capreomycin, amikacin, or kanamycin.³

In South Africa—where the incidence of tuberculosis is 948 per 100 000 individuals per year¹—surveys indicated that the percentage of tuberculosis cases that were multidrug-resistant disease increased in the country from 3·1% in 2002, to 9·6% in 2008.4, 5, 6 In 2011, more than 8000 culture-confirmed cases of multidrug-resistant tuberculosis were identified, of which about 500 were culture-confirmed XDR disease.1, 7 According to South African guidelines,⁸ patients with XDR tuberculosis should be admitted to designated treatment facilities and empirically treated with a para-aminosalicylic acid and capreomycin-based regimen (until 2010, capreomycin resistance profiling was not available in the public sector).

The issue of drug-resistant tuberculosis is important because it predominantly affects economically productive young adults and is associated with a high mortality.⁹ Additionally, the high treatment-related costs are unsustainable in the low-income and middle-income countries where it is most prevalent. For example, in 2010, despite drug-resistant tuberculosis being officially responsible for less than 3% of the total case load in South Africa, it consumed almost 45% of the national tuberculosis budget of about US$280 million.¹⁰ Such disproportionate and prohibitive costs threaten to destabilise tuberculosis control programmes in South Africa and other countries with similar resource constraints. Cogent intervention strategies and public policies are needed to control XDR tuberculosis, but rational planning of interventions and allocation of public health resources are hampered by the scarcity of long-term outcome data relating to mortality, cure, and treatment failure.

In view of the long treatment duration and scarcity of outcome data, how treatment failure should be defined is also unknown. The present practice, by which patients who do not achieve culture conversion after 12 months are deemed to have failed treatment, is not well supported by robust evidence. Few data are available for the proportion of patients with XDR tuberculosis who fail treatment, their outcomes after treatment failure, and their long-term potential for disease transmission. Therefore, long-term outcomes of XDR tuberculosis and the fate of patients with treatment failure, and how these outcomes differ by HIV status, remain unknown. To address these knowledge gaps, and particularly those from a high burden African setting, we prospectively followed up a cohort of patients, and now report the long-term treatment outcomes.