Nathan Geffen, TAC

A prospective study of workers with TB in a South African gold mine that was published in Emerging Infectious Diseases provides useful data on the emergence of drug resistant TB. Calver and colleagues found that drug resistant TB was developing in this setting despite stringent treatment adherence. Much of this resistance was probably nosocomial, but also occurred in the work and living environments. The authors found that diagnosis delay and inappropriate therapy facilitated disease transmission and drug resistance. [1]

An over two-fold increase in drug-resistant TB cases at the mine was noted in 2003. The study was carried out at the mine from January 2003 to November 2005. Mine employees as well as any of their dependents who were diagnosed during the study period with drug-resistant TB were included in the study. The researchers found that 3,003 patients were diagnosed and notified with TB. Of these, 1,443 (48%) had new pulmonary TB cases, 755 (25%) were retreated for pulmonary TB and 805 (27%) patients had extrapulmonary TB.

Patients were identified either via an active screening programming that included biannual chest radiographic screening (30%) or because they sought care because they had TB symptoms (70%). The cure rate was high, 87%, and 12% of patients died. The remainder (less than 2%) defaulted or had an unsuccessful treatment outcome. Adherence was high, in the region of 95 to 98%.

Drug resistance

Drug-resistant TB was diagnosed in 128 mine workers, of whom 124 were male. All had worked at the mine for at least 6 months (median 15 years) and had passed a pre-employment physical examination that ruled out active TB. Of these 13 (10.2%) had isoniazid-resistance, 7 (5.6%) had poly–drug-resistant TB and 108 (84.4%) had MDR TB. Among patients with MDR TB, 26 had pre-XDR TB (ie resistance to either ofloxacin or kanamycin but not both) and 5 had XDR TB. HIV status was know for 91 drug-resistant patients, of whom 84 were HIV-positive and 7 were HIV-negative. 57 patients, including three with unknown HIV status, had CD4 counts below 200 cells/mm3.  Most patients, 95 (74%) were smear-positive. This was 70% for HIV-positive patients, approximately consistent with other findings of 65%. Seven patients started ART before TB diagnosis and 22 after. Median time to initiation for the latter was 172 days (range 41 to 1,425 days).

Outcomes for drug-resistant patients were poor: 40 completed treatment or were cured; one patient failed treatment; 45 died; 32 were transferred out and 10 were lost to follow up. Median time to death was 5 months (range 1-24 months).

Clustering of drug-resistant isolates

The researchers conducted genetic clustering analysis of the drug-resistant TB isolates to try to determine patterns of infection. They analysed isolates from 124 of the 128 patients. Of these, 74 were clustered into 11 clusters ranging in size from 2 to 42. At least 63 isolates had primary drug resistance. Among the 50 unclustered isolates, 25 were from first-time TB patients at this facility, also suggesting primary infection. Clustering was more frequent amongst MDR than mono or poly-resistant TB strains (adjusted OR 14.13, p = 0.002 – unadjusted rate was almost identical). The same was true for XDR isolates compared to mono and poly-resistant ones (unadjusted OR 27.42, p<0.001). The pre-XDR and XDR isolates were strongly clustered with the MDR ones (24 of the 30 isolates were in MDR clusters). 59% of clustered patients had a previously documented TB episode.

The researchers analysed the types of contacts patients in the largest cluster had. They found most patients had multiple different contacts that put them at risk:  32 of the 42 had a non–MDR TB hospitalization at the same time another patient in the cluster was admitted for MDR TB, 39 worked in a shaft in which another MDR TB patient in the cluster had worked and 36 resided in the same residential unit where another MDR TB patient had lived.

Phylogenetic analysis indicated that resistant pyraziamide resistance occurred on two separate occasions. Then ethambutol resistance evolved independently. Ofloxacin resistance later evolved on six separate occasions, of which one of these isolates evolved into XDR causing disease in a single patient. The authors state that the “evolution of resistance to ethambutol and pyrazinamide represents the further amplification of drug resistance in the context of patients with undiagnosed MDR TB initially being given standard therapy”. They further explain that, “an MDR TB case-patient with a strain resistant to isoniazid, rifampin, ethambutol, and pyrazinamide could then spread disease to persons who were cohospitalised for drug-susceptible TB or illnesses other than TB.  Disease may develop in these persons, and they can then spread MDR TB to their contacts at their place of work or residence, thereby unintentionally perpetuating the drug- resistant TB outbreak. We believe that this observation is not unique to this setting.”

The authors claim that although the mine’s TB control programme was effective at preventing acquisition of resistance to first-line drugs, it was unable to prevent transmission of pre-existing MDR TB. Their study also confirms other findings that a prior TB episode increases the risk of a later episode through reinfection.

The authors concluded with several recommendations: integration of DOTS and HIV management programmes to ensure wider ARV availability, public awareness raising of TB symptoms to encourage earlier diagnosis, active screening of all patients making contact with the public health system, aggressive case finding, more frequent sputum smear examinations, more frequent culture-based diagnoses to identify cases before they become infectious, development and implementation of rapid drug susceptibility testing diagnostics, studies to optimise drug regimens and dosages and more rigorous control measures in health facilities to reduce nosocomial transmission.

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This excellent study provides data that can be used for better modelling the development and spread of drug-resistant TB, at least within high-risk mine settings. Two other studies in community settings referenced by the authors are worth noting. In a 1999 study by van Rie and colleagues they used genetic analysis to determine that two patients treated for drug-susceptible TB contracted MDR TB outside hospital, leading the researchers on that study to state that transmission of MDR TB is not limited to HIV-positive patients in institutional settings. [2] More recently, a 2007 study by Victor and colleagues found a cluster of 64 patients –out of 450 with drug-resistant TB– that shared a rare mutation, indicating the spread of this drug-resistant strain within the cluster. They concluded that factors leading to the “development and spread of this drug-resistant genotype were inappropriate chemotherapy, poor adherence to treatment and prolonged periods of infectiousness due to delays in susceptibility testing.” [3]

The conclusions and recommendations of Calver and colleagues must be supported. In particular, that 12 patients with drug-resistant TB died while receiving first-line therapy indicates the need for investigating how to optimise the process of diagnosing drug-resistant TB, including analysis of the National Health Laboratory Service’s systems. Methods to reduce delays in health-seeking behaviour by people with symptoms of TB also need investigation. To implement all of Calver and colleagues’ recommendations will require a massive investment of state, corporate and donor funds into TB. This is clearly necessary.

The authors also state that the “incidence of drug-susceptible TB has continued to rise, an increase that reflects both the rising HIV prevalence in this community and the occupational risks specific to the mine setting such as silicosis, congregate living, and working conditions.” Pressure should be put on mining companies both by unions, civil society organisations and government to address these unacceptable living and working conditions in order to reduce the spread of TB, especially drug-resistant strains.

Much of the Department of Health’s messaging aimed at promoting the reduction of drug-resistant TB emphasises patient adherence. This study adds to the body of evidence showing that this is only one part of the problems. Despite excellent adherence, drug-resistant TB continued to emerge because of poor technology and sub-optimal systems as well as working and living conditions conducive to the spread of TB.

References

1. Calver et al. 2010. Emergence of increased resistance and extensively drug-resistant tuberculosis despite treatment adherence, South Africa. Emerging Infectious Diseases Vol. 16, No. 2, February 2010.

http://www.cdc.gov/eid/content/16/2/264.htm

2. Van Rie A et al. Transmission of a multidrug-resistant Mycobacterium tuberculosis strain resembling “strain W” among noninstitutionalized, human immunodeficiency virus-seronegative patients. J Infect Dis. 1999;180:1608–15. DOI: 10.1086/315054

http://www.jstor.org/pss/30110459

3. Victor TC et al. Spread of an emerging Mycobacterium tuberculosis drug-resistant strain in the western Cape of South Africa. Int J Tuberc Lung Dis. 2007;11:195–201.

http://www.ncbi.nlm.nih.gov/pubmed/17263291