TB in Persons with HIV in South Africa Increasingly Rifampicin-Resistant

Persons living with HIV (PLWH) are not only more susceptible to contracting tuberculosis, but were found at increased risk for rifampicin-resistant strains, in an epidemiology study in South Africa that encompassed molecular identification of tuberculosis isolates.

Helen Cox, MPH, PhD, Institute of Infectious Diseases and Molecular Medicine, Wellcome Centre for Infectious Diseases Research (CIDRI-Africa), University of Cape Town, Cape Town, South Africa and colleagues sought to determine whether observed increases in rifampicin mono-resistant (RMR) tuberculosis, and in PLWH in particular, are due to increased resistance acquisition or increased transmission of resistant strains.

Cox and colleagues estimate that globally, half a million individuals develop rifampicin-resistant tuberculosis annually; with approximately 82% of these having multidrug-resistant (MDR) TB, and the approximate 18% remainder with RMR TB.

They note that South Africa is among the countries with the highest burden of MDR and RMR TB; and that their comparison of data from 2001-02 and 2012-14 reveals that MDR has remained at approximately 3% of cases, while RMR has increased from 0.5 to 1.8%, and now comprises 38% of all rifampicin-resistant tuberculosis.

"Although HIV has undoubtedly driven the broader tuberculosis epidemic, systematic reviews also suggest an independent association between HIV and MDR or rifampicin-resistant tuberculosis," Cox and colleagues indicate."This association could be due to either increased resistance acquisition or increased transmission of resistant strains among people living with HIV."

To distinguish between the two possibilities, the investigators conducted a retrospective cohort study to identify MDR or RMR among all individuals routinely diagnosed and treated for TB in one township of Cape Town between January 1, 2008 and December 31, 2017. Data were derived from two prospectively maintained databases; and resistance acquisition versus transmission was inferred from whole-genome sequencing (WGS) of M tuberculosis isolates prospectively maintained in a regional biobank.

"As the risk of developing rifampicin-resistant TB is likely to be very low for each patient, using this unique data set allowed us to work backwards using data from patients who already had rifampicin-resistant TB," Cox explained, in a statement released by the CIDRI-Africa.

Their cohort included 2041 patients, with 1169 having available WGS evidence of MDR or RMR tuberculosis.HIV positivity during previous TB treatment versus HIV negativity (adjusted odds ratio [OR] 2.07, 95% CI 1.35-3.18), and 3 or more previous tuberculosis treatment episodes versus 1 (1.96, 1.21-3.17) were associated with RMR tuberculosis.

RMR TB versus MDR TB (adjusted OR 4.96, 3.40-7.23), HIV positivity during previous TB treatment (1.71, 1.03-2.84), and diagnosis in 2013-17 versus 2008-12 were associated with isolates having WGS uniqueness.

With the five-fold risk of genomic uniqueness in the M tuberculosis isolates obtained from PLWH versus those without HIV, Cox and colleagues posited, "These data suggest HIV infection during first-line tuberculosis treatment might be responsible for an increased risk of acquired rifampicin resistance, in turn leading to increased risk of subsequent RMR tuberculosis."

The investigators found no association with incomplete adherence to tuberculosis treatment, as has previously been suggested for increases in acquired drug resistance.Instead, they suggest that pharmacokinetic variability between individuals is a more likely mechanism.

"In contrast, data suggest that HIV, compounded by advanced immunosuppression and ART (antiretroviral therapy), might lead to lower concentrations of tuberculosis drugs and variable pharmacokinetics," the investigators suggest.

Cox and colleagues will now endeavor to quantify the increased risk, with further analyses of the databases, according to the CIDRI-Africa release.

"In the meantime, studies are underway that may result in increased doses of rifampicin being used to treat TB," Cox indicated."This could be one way of reducing the risk of resistance being acquired during TB treatment."