# Therapeutic failure of multidrug therapy for leprosy: A retrospective case series in a hyperendemic Brazilian City

## TL;DR

A study in Brazil found that many leprosy patients still had active infection and worsening nerve damage after completing extended multidrug therapy, suggesting current treatment criteria are insufficient.

## Contribution

The study demonstrates that time-based multidrug therapy for leprosy may not ensure bacteriological clearance or prevent disability, advocating for post-treatment biological assessments.

## Key findings

- Half of patients had persistent M. leprae activity after 24-dose MDT, as shown by histopathology and molecular tests.
- 64% of mice inoculations confirmed viable bacilli post-treatment, indicating ongoing infection.
- Neurological disability increased from 53% to 87% in patients after completing MDT.

## Abstract

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.

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&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).

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.

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.

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae and its related species, M. lepromatosis. Untreated, it can lead to permanent nerve damage and disability. Globally, patients are considered “cured” after completing the World Health Organization’s multidrug therapy (MDT) regimen, yet many continue to experience inflammation.

Between 2016 and 2023, we evaluated 131 multibacillary patients who received twice the standard duration of MDT (24 monthly doses). At treatment completion, histopathology revealed persistent bacilli or inflammation in half of the biopsies (50%), in addition, two-thirds of the mice inoculations (64%) confirmed the presence of viable bacteria.

Molecular testing detected resistance mutations in only two patients (2.3%), suggesting that drug resistance does not account for the majority of treatment failures. Clinically, 68% of patients had no visible skin lesions at discharge; however, 87% presented with persistent or worsening nerve problems. The proportion with severe disability (grade 2) increased from 5% at diagnosis to 23% after treatment.

These findings show that time-based treatment alone may not clear hidden M. leprae or prevent disability. We recommend post-treatment follow-up with tissue-based and biological tests to detect persistence, guide retreatment, and reduce long-term nerve damage and stigma.