Extensively Drug-Resistant TB Threatens Treatment

Veronica Hackethal, MD

August 06, 2014

Extensively drug-resistant TB (XDR-TB) develops in almost 9% of patients with multidrug-resistant tuberculosis (MDR-TB) and without baseline resistance to certain second-line drugs (SLD) during treatment, according to a study published online July 23 in Clinical Infectious Diseases.

"Treatment of MDRTB involves substantial risk of acquired resistance to SLD, increasing as baseline drug resistance increases," write J. Peter Cegielski, MD, MPH, from the Centers for Disease Control and Prevention, Atlanta, Georgia, and colleagues. "The risk was significantly lower in programs documented by the [international Green Light Committee (GLC)] to meet specific standards."

In 2000, the World Health Organization established the GLC to assist tuberculosis control programs with MDR-TB management strategies aimed at increasing access to second-line MDR-TB drugs while preventing acquired resistance. GLC criteria for project approval included strong directly observed treatment programs, drugs made under strict regulatory requirements, and World Health Organization–recommended regimens. Approved projects receive quality-assured SLDs and assistance from MDR-TB experts.

The international prospective cohort study, the Preserving Effective TB Treatment Study (PETTS), looked at the effect of GLC on preventing resistance to SLDs in GLC-approved programs compared with nonapproved ones. Researchers followed-up adults with pulmonary MDR-TB through the full course of treatment between January 1, 2005, and December 31, 2008. Tests included monthly sputum cultures, drug susceptibility testing, and mycobacterium genotyping. Among 9 countries that volunteered for the study, 5 met GLC criteria and 4 did not apply to the GLC.

The analysis included 832 patients. Among those without baseline resistance to certain SLDs, 68 (8.9%) acquired XDR-TB, 79 (11.2%) developed fluoroquinolone resistance, and 56 (7.8%) developed resistance to second-line injectables.

Compared with non-GLC sites, GLC-approved sites had a 73% lower relative risk (RR) of developing XDR-TB (RR, 0.27; 95% confidence interval [CI], 0.16 - 0.47; P < .0001) and a 72% lower RR of developing fluoroquinolone resistance (RR, 0.28; 95% CI, 0.17 - 0.45; P < .0001). They also had lower RR of developing resistance to 3 second-line injectables: kanamycin (RR, 0.60; 95% CI, 0.34 - 1.05; P = .07), amikacin (RR, 0.15; 95% CI, 0.06 - 0.39; P < .0001), and capreomycin (RR, 0.24; 95% CI, 0.16 - 0.47; P = .002).

"The strongest, most consistent risk factor [for acquiring resistance] was pre-treatment (baseline) resistance to other drugs, i.e., having fewer effective drugs available," the authors write.

Non-GLC programs were more affected as baseline resistance increased. In GLC programs, the risk for acquired XDR-TB increased from 1.4% to 15.9% with increasing baseline drug resistance; this risk jumped from 3.4% to 60.9% in non-GLC programs.

Limitations included lack of a control group and possible sampling bias resulting from omission of nonconsenting patients.

"[P]rograms should first treat patients with the lowest risk of developing further resistance...treating new patients [without additional drug resistance] generally led to successful outcomes, while treating the previously treated patients...led to acquired drug resistance," the authors conclude.

"[I]n settings where drug-resistant TB has already become endemic, and rapid molecular tests are used selectively due to cost constraints, then new patients should be prioritized for rapid screening with these tests."

In an accompanying editorial, Charles Daley, MD, from National Jewish Health in Denver, Colorado, and C. Robert Horsburgh, Jr, MD, from Boston University School of Public Health in Massachusetts, disagreed with the researchers' recommendation.

"All drug resistant cases should be diagnosed and once MDR-TB is detected, begun on appropriate treatment as soon as possible," Dr. Daley and Dr. Horsburgh assert. "Undiagnosed cases of MDR-TB will continue to transmit drug-resistant [Mycobacterium Tuberculosis] to others and delays in therapy will result in additional individual morbidity and death. Instead of limiting diagnosis of MDR-TB we should...do more, not less testing."

Dr. Daley and Dr. Horsburgh also emphasized investing in basic TB control and MDR-TB management programs, as well as introducing new drugs and treatment regimens.

"[We should] roll out new drugs and regimens with caution, but roll them out expeditiously, as people are dying," Dr. Daley and Dr. Horsburgh conclude. "Failure to take these steps means drug resistant TB will get even worse."

The authors and editorialists have disclosed no relevant financial relationships.

Clin Infect Dis. Published online July 23, 2014. Article abstract, Editorial extract

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