High Prevalence of inhA Promoter Mutations among Patients with Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.
BACKGROUND
Drug-resistant tuberculosis (TB) remains extremely difficult to treat because there are often few remaining active medications and limited diagnostic options to detect resistance. Resistance to isoniazid is typically caused by mutations in either katG or the inhA promoter. inhA mutations confer low-level resistance to isoniazid and cross-resistance to ethionamide while katG mutations confer high-level isoniazid resistance and no cross-resistance. Line Probe Assays (LPAs) that detect mutations in katG and inhA are currently performed on all positive TB cultures in KwaZulu-Natal province, South Africa, but the frequency of inhA mutations in drug-resistant TB patients has not been examined.


METHODS
We sought to determine the proportion of patients who could potentially benefit from high-dose isoniazid and who may be resistant to ethionamide. We reviewed 994 LPA (Hain MTBDRplus) results at the TB reference laboratory in KwaZulu-Natal to determine the frequency of mutations in either katG or the inhA promoter. We stratified these results by drug-resistance category (i.e., MDR-TB, pre-XDR-TB, and XDR-TB) as determined by phenotypic drug-susceptibility testing.


RESULTS
Among MDR- and XDR-TB isolates, the prevalence of inhA mutations without a concurrent katG mutation was 14.8% and 10.3% respectively. The prevalence of inhA mutations with OR without a katG mutation was 30.3% and 82.8%, respectively.


CONCLUSIONS
More than 10% of patients with MDR- and XDR-TB may benefit from high-dose isoniazid. Although ethionamide is empirically included in all MDR- and XDR-TB regimens, nearly a third of MDR-TB patients and a majority of XDR-TB patients likely have resistance to ethionamide. Laboratories performing line probe assays should report specific band patterns so that clinicians may adjust treatment regimens accordingly.
Department of Medical Microbiology, National Health Laboratory Services and University of KwaZulu-Natal, Durban, South Africa.
Abraham J
AJ
Niehaus
Department of Medical Microbiology, National Health Laboratory Services and University of KwaZulu-Natal, Durban, South Africa.
Koleka
K
Mlisana
Departments of Epidemiology, Global Health, and Medicine, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.
Neel R
NR
Gandhi
Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York, United States of America.
Barun
B
Mathema
Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America.
James C M
JC
Brust
D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics*; D002374:Catalase / Q000235:genetics*; D005000:Ethionamide / Q000494:pharmacology / Q000627:therapeutic use; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D015995:Prevalence; D011401:Promoter Regions, Genetic; D013019:South Africa / Q000453:epidemiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; C085257:InhA protein, Mycobacterium; D005000:Ethionamide; D007538:Isoniazid