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Summary: Leprosy is effectively treated with multi-drug therapy (MDT), a regimen containing three antibiotic drugs, including dapsone - a sulfone drug associated with potentially life-threatening adverse drug reactions. Specifically, dapsone hypersensitivity syndrome (DHS), linked to HLA-B∗13:01 polymorphism, and hemolytic anemia associated with glucose-6-phosphate dehydrogenase deficiency (G6PDd).Both of these pharmacogenetic polymorphisms can be prevented through diagnostic screening before MDT initiation averting potential complications. However, in leprosy-endemic areas like Indonesia, access to these tests often remains inaccessible due to high costs and limited laboratory capacity. Additionally, alternative dapsone-sparing treatment regimens are usually unavailable or unaffordable, restraining individuals onto suboptimal dual-therapy with rifampicin and clofazimine, which has uncertain efficacy. We raise concerns regarding the safety of dapsone-containing MDT without routine pharmacogenetic screening and the unavailability of alternative regimens. We call for action to address persisting global health inequities in care delivery, ensuring all individuals receive the safest and most effective leprosy treatment options.

Background The clinical management of leprosy is complicated by leprosy reactions (LR) causing irreversible nerve damage and disabilities. LR often require long-term use of corticosteroids causing serious side effects. Adjunct host-directed therapy (HDT) is a potentially attractive strategy in leprosy to prevent LR and associated immunopathology, modulate immunological memory that protects against recurrence, and thereby reduce nerve damage, disability and corticosteroid-associated morbidities. Metformin, a well-tolerated, safe and cheap anti-hyperglycaemic drug, is repurposed as HDT in auto-immune and infectious diseases, like tuberculosis (TB). Metformin use in people with diabetes is associated with reduced risks of TB-infection, progression to active TB, treatment failure and TB-mortality. Given the similarities both mycobacteria share, we hypothesize that among persons with multibacillary (MB) leprosy, adjunctive metformin may prevent/mitigate LR. Methods We will perform a double-blind controlled proof-of-concept trial in which people with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin hydrochloride 1000mg extended release once daily versus placebo for 24 weeks in addition to standard-of-care WHO MB multidrug therapy (MDT) during 48 weeks. We aim to enrol 166 participants aged between 18 and 65 years, across five clinical sites in two leprosy endemic areas in Indonesia. Primary outcomes are the proportion of participants experiencing a LR and the frequency of (serious) adverse events. Secondary outcomes are the severity and time to first LR, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks. Discussion LR signify the most important cause of irreversible nerve damage leading to anatomical deformities and disabilities, imposing a social and financial burden on those affected. Our study aims to evaluate the efficacy, tolerability and safety of adjunct metformin added to MDT in persons with multibacillary leprosy, and explore its effects on clinical and immunological outcomes. ClinicalTrials.gov registration NCT05243654 (17/02/2022)

Neglected tropical diseases (NTD) refer to a group of 21 diseases that disproportionally affect impoverished communities in low- and middle-income countries (LMIC) [1]. NTD collectively impact 1.7 billion people, which is about 20% of the world's population [1]. Each year, NTD account for more than 200,000 deaths, with millions left disabled and disfigured due to insufficient access to care and affordable treatment, often leading to social exclusion, stigmatization and discrimination. Although the term NTD has successfully directed funding and resources towards these conditions and encouraged global partnerships and high-level policy initiatives, the term may also have unintended negative consequences. In this paper, we aim to explore the term NTD and stimulate a dialogue that re-evaluates its meaning into more inclusive and equitable language.

Chromoblastomycosis, an implantation mycosis, is a neglected tropical disease that causes decreased quality of life, stigma, and disability. The global burden of disease is unknown and data on disease epidemiology and outcomes are severely limited by a lack of access to needed diagnostic tools and therapeutics. The World Health Organization outlined targets for chromoblastomycosis in the Road Map for Neglected Tropical Diseases 2021-2030, but little progress has been made in initiating and implementing an effective control program globally. This lack of guiding policy and progress led to the recent formation of a Global Chromoblastomycosis Working Group which has developed a global chromoblastomycosis strategy. We describe this strategy, which outlines specific steps needed to improve technical progress, strategy and service delivery, and enablers. Clinicians, researchers, public and government officials, patients, and policy makers can align their time, expertise, and resources to improve the lives of communities affected by chromoblastomycosis through this strategy.

Previous studies indicate that human immunodeficiency virus (HIV)-infection and combination antiretroviral therapy (cART) can affect bone turnover. Furthermore, HIV-infected patients have lower bone mineral density (BMD) compared to a healthy reference population.To evaluate the longitudinal effect of HIV-infection and cART on bone turnover markers (BTMs) and BMD in men with primary HIV-infection (PHI).Thirty-five PHI-men were divided into two groups, those that received cART for the first time (n = 26) versus no-cART (n = 9). Dual-energy X-ray absorptiometry (DXA) was performed on femoral neck (FN), total hip (TH) and lumbar spine (LS) and BTMs (P1NP, alkaline phosphatase, osteocalcin, ICTP and CTX) were measured at baseline and follow-up.At baseline, the median CD4+ T-cell count was 455 cells/mm3 (IQR 320-620) and plasma viral load 5.4 log10 copies/mL (IQR 4.7-6.0) in the cART treated group, compared to 630 (IQR 590-910) and 4.8 (IQR 4.2-5.1) in the untreated group. The median follow-up time was 60.7 weeks (IQR 24.7-96.0). All BTMs, except ICTP, showed a significant increase during cART versus no changes of BTMs in the untreated group. FN and TH BMD showed a significant decrease in both groups. LS BMD did not change in both groups.Bone turnover increased in PHI-men treated with cART which was accompanied by a decrease in FN and TH BMD. No increase of bone turnover was seen in untreated PHI-men. Our study suggests that cART results in increased bone turnover and decreased BMD of the hip in PHI-men.

BACKGROUND:Neutralizing antibodies develop in natural HIV-1 infection. Their development often takes several years and may rely on chronic virus exposure. At the same time recent studies show that treatment early in infection may provide opportunities for immune preservation. However, it is unknown how intermittent treatment in early infection affects development of the humoral immune response over time. We investigate the effect of cART in early HIV infection on the properties of the memory B cell compartment following 6 months of cART or in the absence of treatment. The patients included participated in the Primo-SHM trial where patients with an early HIV-1 infection were randomized to no treatment or treatment for 24 or 60 weeks. METHODS:Primo-SHM trial patients selected for the present study were untreated (n = 23) or treated for 24 weeks (n = 24). Here we investigate memory B cell properties at viral set-point and at a late time point (respectively median 54 and 73 weeks) before (re)-initiation of treatment. RESULTS:At viral set-point, the memory B cell compartment in treated patients demonstrated significantly lower fractions of antigen-primed, activated, memory B cells (p = 0.006). In contrast to untreated patients, in treated patients the humoral HIV-specific response reached a set point over time. At a transcriptional level, sets of genes that showed enhanced expression in memory B cells at viral setpoint in untreated patients, conversely showed rapid increase of expression of the same genes in treated patients at the late time point. CONCLUSION:These data suggest that, although the memory B cell compartment is phenotypically preserved until viral setpoint after treatment interruption, the development of the HIV-specific antibody response may benefit from exposure to HIV. The effect of viral exposure on B cell properties is also reflected by longitudinal changes in transcriptional profile in memory B cells over time in early treated patients.