03296nas a2200289   4500000000100000008004100001260003700042653002200079653001900101653001200120100001800132700001200150700001600162700001400178700001900192700001500211700001500226700001600241700002300257700001000280245011900290856009900409300000900508490000700517520246800524022001402992       2025                            d  bPublic Library of Science (PLoS)10aMultidrug therapy10aHansen disease10aleprosy1 aFonseca AMFDA1 aRosa PS1 aBelone ADFF1 aSoares CT1 aBertoluci DDFF1 aDiório SM1 aFachin LRV1 ado Carmo RF1 ade Almeida Neto FB1 aXue F00aTherapeutic failure of multidrug therapy for leprosy: A retrospective case series in a hyperendemic Brazilian City  uhttps://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0013616&type=printable  a1-200 v193 a<p><strong>Background</strong></p>

<p>Leprosy remains endemic in many regions despite the global rollout of multidrug therapy (MDT). Clinical cure—defined by completion of a time-based MDT regimen—may not reflect proper bacteriological clearance, particularly in patients with persistent reactions or neurological symptoms. We aimed to assess subclinical disease activity in multibacillary patients who completed an extended 24-dose MDT course.</p>

<p><strong>Methods</strong></p>

<p>In this retrospective case series, between January 2016 and November 2023, 131 multibacillary patients treated at the Petrolina Infectious Diseases Service (SEINPE) underwent skin biopsy upon completing 24 monthly MDT doses. Disease activity was evaluated by histopathology (H&amp;E and Fite–Faraco staining; n = 123), slit-skin smear with bacilloscopic and morphological indices (BI, n = 126; MI, n = 74), qPCR for M. leprae (n = 101), and nude mice footpad inoculation (n = 45) at Instituto Lauro de Souza Lima, Bauru, Brazil. Drug-resistance mutations were detected by sequencing ( folP1, rpoB, gyrA ; n = 88). Neurological function was assessed using a Simplified Neurological Assessment (n = 117).</p>

<p><strong>Results</strong></p>

<p>Histopathology revealed active disease or bacillary persistence in 62/123 specimens (50.41%), while 29/45 inoculations (64.44%) yielded viable bacilli. qPCR detected M. leprae DNA in 96/101 patients (95.05%). Known resistance mutations were identified in 2/88 patients (2.27%). Clinically, 89/131 patients (67.94%) no longer exhibited skin lesions post-MDT; however, neurological impairment increased from 70/131 (53.44%) at diagnosis to 114/131 (87.02%) at discharge. The proportion with grade 2 disability increased from 5/100 (5.00%) to 27/117 (23.08%). Exact 95% CIs are reported in the manuscript.</p>

<p><strong>Conclusions</strong></p>

<p>More than half of patients treated with an extended 24-dose MDT regimen harbored persistent M. leprae activity despite apparent dermatological cure, and most experienced worsening neural function. Time-based discharge criteria alone are inadequate to confirm cure. We recommend integrating post-treatment histopathological, molecular, and inoculation assessments—particularly in patients with persistent reactions or neurological complaints—to identify therapeutic failure, guide retreatment, and prevent long-term disability.</p>
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