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Leprosy Relapse, Reinfection Detected in Proof-of-Principle Sequencing Study

NEW YORK (GenomeWeb) – New research suggests genomics may offer an avenue for following leprosy cases during treatment to pick up relapse or resistance as well as instances of re-infection with new strains of Mycobacterium leprae.

Researchers from Brazil, Switzerland, India, and Japan used whole-genome sequencing to assess samples from three individuals with recurrent leprosy who were treated through an open label, randomized, controlled clinical trial of multi-drug treatment program. Their findings, appearing online yesterday in PLOS Neglected Tropical Diseases, revealed genetic differences between the M. leprae strains at diagnosis and those involved in disease recurrence in one of the three cases — a pattern pointing to re-infection.

While the team did not see sequences associated with drugs such as rifampicin, dapsone, and ofloxacin when sifting through sequence data from the two remaining recurrent cases, the very subtle genetic differences between the initial and the recurrence samples were consistent with disease relapse.

From their results in this small sample set, the study's authors argued that genome sequencing "can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission."

Leprosy cases have dipped globally in the past few decades, following widespread adoption of multi-drug treatment strategies that employ specific antibiotics in combination over varied periods of time, the team noted. Even so, M. leprae infections still affect hundreds of thousands of people annually, it explained, and there are more recent concerns over leprosy relapse as investigators attempt to come up with standardized multi-drug treatment times.

"Although rare, recurrent clinical manifestations after [multi-drug treatment] can occur due to leprosy reactions, relapse by drug resistance, insufficient treatment, or reinfection," the authors wrote. "Relapse and reinfection cannot be differentiated clinically and molecular genotyping of a predefined set of loci have limited resolution due to exceptional M. leprae genome conservation and low sequence diversity between strains from the same geographical area."

Using Illumina's HiSeq 2500 instrument, the researchers did genome sequencing on original and relapse samples from three individuals with recurrent leprosy who were participating in a Brazilian trial of a uniform multi-drug treatment done for a set period of time compared with a more typical multi-drug treatment protocol that's used for a variable time period depending on a patient's skin lesion prevalence. That trial included more than 850 individuals with leprosy, they noted, and nearly 80 percent of those cases were classified as multibacilllary, with more than five skin lesions.

The three relapsing individuals experienced new leprosy symptoms some four to eight years after wrapping up multi-drug treatment. In one of these cases, the team identified nearly four dozen SNP differences between the initial strain and the relapse strain, along with a handful of small insertions or deletions and several variable number tandem repeats.

In contrast, just two SNPs and one variable number tandem repeat difference turned up when the researchers compared initial and relapse samples from another relapse case. And in the final relapse case, the M. leprae strains were genomically identical from the time the individual was first treated in 2007 to relapse in 2014, differing at a single variable number tandem repeat locus.

The study "provides a proof-of-concept and emphasizes the value of [whole-genome sequencing] in clinical follow up of leprosy," the authors wrote, noting that "shorter periods of monitoring would be unlikely to provide sufficient clinical evidence to suspect relapse or re-infection" due to M. leprae's slow growth and lengthy incubation.

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