Breakthrough for treating XDR-TB and ameliorating TB-IRIS

24 April 2017. Related: Conference reports, Coinfections and complications, TB coinfection, CROI 24 (Retrovirus) 2017.

Richard Jefferys, TAG

Several important TB studies were presented as late breaker oral presentations at CROI 2017, on treatment for extensively drug-resistant TB (XDR-TB) and on TB-IRIS.

Highly promising results from the Nix-TB study were presented by Francesca Conradie of the University of the Witwatersrand in Johannesburg, on a breakthrough in treating XDR-TB, a condition normally requiring the use of debilitating, toxic injectable drugs. [1]

This small study uses a new combination of three oral drugs (bedaquiline, pretomanid, and linezolid). Of the 72 participants (39 men and 33 women) enrolled so far, 31/72 have reached the primary endpoint of being culture negative after 6 months follow-up. Of these, only two cases of relapse/reinfection were reported (still to be determined, but suspected reinfections), and only one case with XDR-TB. However, four participants died, all within the first eight weeks: 3/4 due to multi-organ TB (on autopsy) and 1 due to gastrointestinal bleed relating to erosive oesophagitis.

Tolerability was good with most side effects (peripheral neuropathy and myelosuppression relating to linezolid) being manageable, even with short dose interruptions.

This greatly shortened all-oral combination therefore provided extremely encouraging results both for safety and efficacy.

A short report by Jon Cohen in Science, included a comment that the combination would have likely efficacy for MDR-TB, whether Nix-TB data would be sufficient for pretomanid to become approved and the issues of cost and access. [2]

Immune reconstitution inflammatory syndrome (IRIS) is a potentially life-threatening consequence of the restoration of immune responses to opportunistic pathogens in people who initiate ART at low CD4 T cell counts.

Evidence suggests that immune responses can become exaggerated and overly inflammatory as a deficient, dysregulated immune system begins to recover due to ART-mediated HIV suppression. In some cases opportunistic infections can get worse before improving, a problem termed paradoxical IRIS. This is a particularly significant concern in tuberculosis (TB), with a reported mortality rate of around 3%. [3]

In an effort to reduce morbidity and mortality from paradoxical TB-IRIS, Graeme Meintjes and colleagues conducted a randomised trial evaluating a four-week course of the corticosteroid prednisone in individuals at risk. The encouraging results were debuted as a late-breaker at CROI, with Meintjes reporting a significant 30% reduction in the incidence of paradoxical TB-IRIS and a trend toward decreased hospitalisations in the prednisone arm. [4]

No evidence of an increase in cancer risk – which had been raised as a potential issue with prednisone – was observed. The evidence from the trial suggests that the approach should be adopted as the standard of care for individuals at risk for paradoxical TB-IRIS.

References:

1. Conradie C et al. The NIX-TB trial of pretomanid, bedaquiline and linezolid to treat XDR-TB. Conference on Retroviruses and Opportunistic Infections (CROI 2017), 13-16 February 2017, Seattle. Late breaker oral abstract 80LB.
   http://www.croiconference.org/sessions/nix-tb-trial-pretomanid-bedaquiline-and-linezolid-treat-xdr-tb (abstract)
   http://www.croiwebcasts.org/console/player/33483 (webcast)
2. Cohen J et al. Simpler, safer treatment hailed as ‘breakthrough’ against drug-resistant TB. Science. Feb. 15, 2017. doi: 10.1126/science.aal0769.
   http://www.sciencemag.org/news/2017/02/simpler-safer-treatment-hailed-breakthrough-against-drug-resistant-tb
3. Lanzafame M et al. Tuberculosis-immune reconstitution inflammatory syndrome. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases 2016:(3);6-9. doi: http://dx.doi.org/10.1016/j.jctube.2016.03.002.
   http://www.clinicaltuberculosisjournal.com/article/S2405-5794(15)30009-7/fulltext
4. Meintjes G et al. Randomized controlled trial of prednisone for prevention of paradoxical TB-IRIS. Conference on Retroviruses and Opportunistic Infections (CROI 2017), 13-16 February 2017, Seattle. Late breaker oral abstract 81LB.
   http://www.croiconference.org/sessions/randomized-controlled-trial-prednisone-prevention-paradoxical-tb-iris (abstract)
   http://www.croiwebcasts.org/console/player/33484 (webcast)