HIV is a risk factor for acquired resistance to key second-line anti-TB drugs

“The present study provides the first comprehensive assessment of predictors of acquired resistance to two key classes of second-line antituberculosis drugs, fluoroquinolones and second-line injectable agents,” write the authors. “The proportion of acquired resistance was larger among MDR TB [multi-drug resistant TB] patients, patients with positive HIV status, and those with SLD [second-line drugs] in the initial treatment regimen.”

Resistance to anti-TB drugs is a growing public health problem. The World Health Organization (WHO) estimates that there were 650,000 cases of multidrug-resistant TB (defined as resistance to the first-line drugs isoniazid and rifampicin) in 2011.

There are also concerns around resistance to second-line anti-TB drugs. Resistance to an injectable second-line therapy and a drug in the fluoroquinolone class means that someone has extensively drug-resistant TB (XDR-TB). Treatment outcomes for people with XDR-TB are poor and mortality is high. XDR-TB has been reported in 77 countries, including the US.

Investigators wanted to determine the incidence and risk factors for the emergence of resistance to injectable drugs and fluoroquinolone in people taking TB therapy in the US.

They therefore analysed data from the US National TB Surveillance System between 1993 and 2008. People were eligible for inclusion in the study if the results of drug susceptibility tests conducted at the start and completion of TB therapy were available.

Of 2274 people without resistance to an injectable second-line agent at baseline, 49 (2.2%) acquired resistance during follow-up. Of the 1141 people who were initially susceptible to a fluoroquinolone, 32 (2.8%) developed resistance. A total of five people with MDR-TB at baseline acquired resistance to both an injectable drug and a fluoroquinolone “and thus developed XDR-TB.”

Encouragingly, resistance became less frequent after 1993. “The decrease in frequency of acquired resistance beginning in 1992 may be attributed to the public health response to the TB epidemic,” suggest the investigators. This included “greatly improved TB control activities and increased proportion of patients treated under directly observed therapy (DOT) in the US from that time.” However, they caution, “acquisition of resistance to SLD in the US continues to occur.”

Factors associated with the emergence of resistance to injectable second-line drugs were: age between 25 and 44 years (aOR = 2.7; 95% CI, 95% CI, 1.2-6.3); infection with HIV (aOR = 2.5; 95% CI, 1.3-4.7); treatment for MDR-TB at baseline (aOR = 5.5; 95% CI, 2.9-10.5); and therapy that included any second-line drug (aOR = 2.4; 95% CI, 1.2-4.7).

The authors note that the people aged between 25 and 44 who acquired resistance included a high proportion of people with HIV and injecting drug users.

Acquired resistance to fluoroquinolones was associated with baseline MDR-TB (aOR = 6.5; 95% CI, 2.9-14.6). The small number of people developing resistance to this type of drug limited the investigators’ ability to find other associations.

They conclude that people in groups with a high-risk of resistance “should be prioritized for fast-track DST [drug susceptibility testing] and rapid molecular tests for drug resistance and strictly follow supervised treatment based on the drug susceptibility test results. Earlier identification of patients at risk of developing XDR TB enables more diligent infection control measures, critical for preventing transmission of the disease.”