Elsevier

The Lancet

Volume 368, Issue 9547, 4–10 November 2006, Pages 1575-1580
The Lancet

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Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa

https://doi.org/10.1016/S0140-6736(06)69573-1Get rights and content

Summary

Background

The epidemics of HIV-1 and tuberculosis in South Africa are closely related. High mortality rates in co-infected patients have improved with antiretroviral therapy, but drug-resistant tuberculosis has emerged as a major cause of death. We assessed the prevalence and consequences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in a rural area in KwaZulu Natal, South Africa.

Methods

We undertook enhanced surveillance for drug-resistant tuberculosis with sputum culture and drug susceptibility testing in patients with known or suspected tuberculosis. Genotyping was done for isolates resistant to first-line and second-line drugs.

Results

From January, 2005, to March, 2006, sputum was obtained from 1539 patients. We detected MDR tuberculosis in 221 patients, of whom 53 had XDR tuberculosis. Prevalence among 475 patients with culture-confirmed tuberculosis was 39% (185 patients) for MDR and 6% (30) for XDR tuberculosis. Only 55% (26 of 47) of patients with XDR tuberculosis had never been previously treated for tuberculosis; 67% (28 of 42) had a recent hospital admission. All 44 patients with XDR tuberculosis who were tested for HIV were co-infected. 52 of 53 patients with XDR tuberculosis died, with median survival of 16 days from time of diagnosis (IQR 6–37) among the 42 patients with confirmed dates of death. Genotyping of isolates showed that 39 of 46 (85%, 95% CI 74–95) patients with XDR tuberculosis had similar strains.

Conclusions

MDR tuberculosis is more prevalent than previously realised in this setting. XDR tuberculosis has been transmitted to HIV co-infected patients and is associated with high mortality. These observations warrant urgent intervention and threaten the success of treatment programmes for tuberculosis and HIV.

Introduction

Tuberculosis is the most common cause of morbidity and mortality in individuals with HIV-1 infection in sub-Saharan Africa.1 HIV greatly increases the risk of active tuberculosis disease2 and about 80% of patients presenting with active tuberculosis in the province of KwaZulu Natal, South Africa, are co-infected with HIV. Mortality rates of up to 40% per year have been reported in patients co-infected with tuberculosis and HIV who are receiving treatment for tuberculosis, but not for HIV.3 Although antiretroviral therapy is likely to reduce HIV-associated morbidity and mortality as it becomes more widely available, any reduction is likely to be blunted if efforts are not taken to improve tuberculosis programmes concurrently.4, 5, 6

The number of tuberculosis cases in sub-Saharan Africa has increased substantially in the past decade, fuelled by the HIV epidemic,7 making it difficult for tuberculosis programmes to improve outcomes.8 In South Africa, the national DOTS treatment success rate has been reported to be only 67%,9 well below the WHO standard of 85%.10 Low rates of treatment completion place patients at risk for relapse of tuberculosis disease as well as for development of drug-resistance.

Rates of multidrug-resistant (MDR) tuberculosis among new cases of tuberculosis in sub-Saharan Africa have been low in the past, ranging from 0·8% to 2·6% in the last global drug resistance survey (1999–2002), compared with 7·8–14·2% in countries with the highest rates.11 However, the prevalence of drug resistance in the region seems to have risen since the last global drug resistance survey.12, 13 In KwaZulu Natal, South Africa, the rate of MDR tuberculosis in new patients was reported at 1·7% between 2000 and 2002;14 the rate was 9% in a study integrating treatment for tuberculosis and HIV that we undertook from 2003 to 2006 in the same region.15

Resistance to second-line treatment for tuberculosis is another concern that has recently been raised in a study by Shah and colleagues.16 The investigators found emerging resistance not only to isoniazid and rifampicin (MDR tuberculosis), but also to at least three classes of second-line drugs, which they termed extensively drug-resistant (XDR) tuberculosis. 347 patients with the disease were described worldwide,16 but data from Africa were few and data about HIV co-infection were not available. In our tuberculosis-HIV integration study in KwaZulu Natal, six of 119 (5%) patients co-infected with both diseases met the revised criteria for XDR tuberculosis,17 defined as resistance to at least isoniazid, rifampicin, fluoroquinolones, and either aminoglycosides (amikacin, kanamycin) or capreomycin, or both. This finding raised the concern that not only MDR tuberculosis, but also XDR tuberculosis, was emerging in this region with high HIV prevalence.15

We therefore undertook a study to assess the extent of MDR tuberculosis and XDR tuberculosis in this rural area in South Africa. We also aimed to describe characteristics and treatment histories of individuals with XDR tuberculosis in this setting.

Section snippets

Setting and study population

We did this study in the Msinga sub-district of KwaZulu Natal, South Africa, a 2000 km2 rural area, which is home to 300 000 traditional Zulu people. A provincial government district hospital of 355 beds is the focus of health care for this population. 40% of inpatient beds in this hospital are occupied by patients infected with HIV, and the prevalence of HIV infection in women presenting to the maternity ward is 20%. A government-sponsored tuberculosis treatment programme, using the WHO DOTS

Results

We sent 2203 sputum specimens from 1539 individual patients for mycobacterial culture between Jan 1, 2005, and March 31, 2006. 542 patients had at least one culture that was positive for M tuberculosis. Table 1 shows the distribution of these patients and the classification of resistance over the three groups. In total, 221 cases of MDR tuberculosis were identified. Of these, 53 patients had XDR tuberculosis, with resistance to isoniazid, rifampicin, ethambutol, streptomycin, aminoglycosides,

Discussion

We undertook enhanced surveillance for drug-resistant tuberculosis by instituting routine mycobacterial culture and drug susceptibility testing on patients with suspected or diagnosed tuberculosis in a rural resource-limited setting, with a high prevalence of HIV, in South Africa. We found a substantially higher prevalence of XDR tuberculosis and MDR tuberculosis than previously reported.14 All patients with XDR tuberculosis who had previously been tested for HIV were co-infected with the

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