World Health Organization (WHO) antibiotic regimen against other regimens for the treatment of leprosy: a systematic review and meta-analysis.

BACKGROUND: To evaluate the effectiveness and safety of the World Health Organization antibiotic regimen for the treatment of paucibacillary (PB) and multibacillary (MB) leprosy compared to other available regimens. METHODS: We performed a search from 1982 to July 2018 without language restriction. We included randomized controlled trials, quasi-randomized trials, and comparative observational studies (cohorts and case-control studies) that enrolled patients of any age with PB or MB leprosy that were treated with any of the leprosy antibiotic regimens established by the WHO in 1982 and used any other antimicrobial regimen as a controller. Primary efficacy outcomes included: complete clinical cure, clinical improvement of the lesions, relapse rate, treatment failure. Data were pooled using a random effects model to estimate the treatment effects reported as relative risk (RR) with 95% confidence intervals (CI). RESULTS: We found 25 eligible studies, 11 evaluated patients with paucibacillary leprosy, while 13 evaluated patients with MB leprosy and 1 evaluated patients of both groups. Diverse regimen treatments and outcomes were studied. Complete cure at 6 months of multidrug therapy (MDT) in comparison to rifampin-ofloxacin-minocycline (ROM) found RR of 1.06 (95% CI 0.88-1.27) in five studies. Whereas six studies compare the same outcome at different follow up periods between 6 months and 5 years, according to the analysis ROM was not better than MDT (RR of 1.01 (95% CI 0.78-1.31)) in PB leprosy. CONCLUSION: Not better treatment than the implemented by the WHO was found. Diverse outcome and treatment regimens were studied, more statements to standardized the measurements of outcomes are needed.

Leprosy treatment during pregnancy and breastfeeding: A case report and brief review of literature.

Leprosy is a chronic disease which primarily affects the skin, mucous membranes and peripheral nerves due to Mycobacterium leprae. It is now infrequent in Europe and is rarely reported during pregnancy. Leprosy can be exacerbated during pregnancy, and without treatment it can permanently damage the skin, nerves, limbs and eyes. Therefore, it is important to treat leprosy during pregnancy. This article describes a patient with multibacillary lepromatous leprosy who was treated with multidrug therapy during pregnancy and breastfeeding. The patient delivered a healthy baby girl without perinatal complications, and the infant's growth and development were normal during the 1-year follow-up period. Multidrug therapy consisting of dapsone, rifampicine, and clofazimine is highly effective for people with leprosy and considered safe, both for the mother and the child. Antileprosy drugs are excreted into human milk but there is no report of adverse effects except for skin discoloration of the infant due to clofazimine. Multidrug therapy for leprosy patients should be continued unchanged during pregnancy and breastfeeding.

Bullous Erythema Nodosum Leprosum as the First Manifestation of Multibacillary Leprosy: A Rare Phenomenon.

Erythema nodosum leprosum (ENL) may uncommonly present before treatment in patients with multibacillary leprosy. Atypical manifestations are known in ENL and may be clinically misleading. Such wide variations in the clinical presentation of leprosy in reaction make histopathology an important tool for supporting clinical diagnosis. We report bullous ENL presenting as the first manifestation of leprosy in a 30-year-old Indian man diagnosed using histopathology.

Outcome of 6 months MBMDT in MB patients in Bangladesh- preliminary results.

Introduction: Duration of leprosy treatment remains long and difficult to complete in resource poor areas. Studies suggest that shortening duration of therapy for MB patients to 6 months may be possible. Methods: New MB patients in 2005 in two NGO projects in Bangladesh were treated with 6 months WHO MB MDT and the rate of relapse and fall in BI on slit skin smear during follow up to date were compared with a control group treated for 12 months the previous year. Results: 1612 patients were enrolled in the trial, and the average duration of follow up was over 7 years after diagnosis. During 11,425 PYAR of follow-up, no relapses were detected, by bacteriological or clinical criteria, in the 918 patients in the 6 months MB MDT group, nor in the 694 patients in the control group. Rate of decline of BI in those who were smear positive was not significantly different between groups. Conclusion: The data does not suggest that shortening duration of treatment from 2 months to 6 months MDT for MB leprosy patients leads to increased rates of relapse.

Multibacillary leprosy mimicking systemic lupus erythematosus: case report and literature review.

Leprosy is an infectious chronic disease with a wide range of clinical and serological manifestations. We report a case of a woman presenting with a malar rash, painless oral ulcers, photosensitivity, arthritis, positive antinuclear antibodies test and leuko-lymphopenia. Our case illustrates an unusual presentation of leprosy initially diagnosed as systemic lupus erythematosus (SLE). After the confirmation of multibacillary leprosy and multidrug therapy recommended by the World Health Organization, a good clinical response was observed. Recognition of rheumatic manifestations in leprosy is important as they may be confused with SLE. A literature review is presented to encourage clinicians to consider leprosy as a differential diagnosis. Specifically in patients with unusual rheumatic manifestations and persistent skin lesions, and when neurological symptoms are present. Leprosy has not been eradicated, so misdiagnosis can be frequent. It is necessary to increase medical practitioner awareness in order start proper treatment.

TH17 cells, interleukin-17 and interferon-γ in patients and households contacts of leprosy with multibacillary and paucibacillary forms before and after the start of chemotherapy treatment.

BACKGROUND: Studies on the immunology of leprosy are fundamental to the understanding of the various forms of clinical manifestation of the disease. In some diseases, lymphocytes TH17 and one of its key cytokines, interleukin-17 has been shown to be essential in developing an effective immune response. In leprosy, involvement of lymphocyte TH17 and interleukin-17 remains understudied. OBJECTIVES: This study is the first investigation to examine the association between TH17 cells, interleukin-17 and interferon- γ in patients and households contacts of leprosy. METHODS: To document the participation of TH17 cells and interleukin-17 in the immunology of leprosy, to observe the behavior of interferon-γ in relation to interleukin-17 and to verify the differences found between individuals paucibacillary, multibacillary and household contacts, we analyzed samples peripheral blood to identify TH-17 cells, interleukin-17 and IFN-γ; establishing relationships between all the groups. RESULTS: There was a significant difference in the results found in the comparison between the paucibacillary and multibacillary groups of patients (P < 0.001), as well with the household contacts (P < 0.005). The polychemotherapeutic treatment modified the profile of immune response in multibacillary patients compared to what was observed before the start of treatment. CONCLUSION: The principal finding was that TH17 lymphocytes and interleukin-17 actively participating in the immune response of Hansen's disease as well these cells can stimulate the cellular immunity.

Ileofemoral Deep Vein Thrombosis (DVT) in Steroid Treated Lepra Type 2 Reaction Patient.

In 1998 a 57-year-old man having skin leisons of 6 months duration reported to Central Leprosy Teaching and Research Institute (CLTRI), Chengalpattu. It was diagnosed as a case of borderline lepromatous leprosy with a type 2 lepra reaction, was treated with multi bacillary-multi drug therapy (MBMDT) for a period of 12 months and the patient was released from treatment (RFT) in September 1999. For reactions the patient was treated with prednisolone for more than 10 months. After 14 years in April 2013 the same patient presented to CLTRI with complaints of weakness of both hands with loss of sensation for 4 months, so making a diagnosis suggestive of MB relapse with neuritis the patient was started with MB-MDT for period of 12 months with initial prednisolone 25 mg OD dose then increased to 40 mg for painful swollen leg and to follow the neuritis associated pain and swelling. Increased dose is not beneficial and the patient was investigated for other pathology. Doppler ultra-sound revealed a left ileofemoral deep vein thrombosis (DVT) in that patient with levels. Prednisolone was withdrawn and the patient was started with anticoagulant heparin followed by warfarin. During this period rifampicin was also withdrawn. After patient was in good condition he was put on MB-MDT regimen. Till the 6th pulse the patient continues to show improvement in functions without steroids and any tenderness, he is taking multivitamins; regular physiotherapy. This DVT appears to be due to prednisolone and such causative relationship though rare should be kept in mind when patient on long term treatment with steroids/and or immobilized or on prolonged bed rest report with such symptomatology.

Effect of Steroid Prophylaxis on Nerve Function Impairment in Multi-bacillary Leprosy Patients on MDT-MB.

The effects of corticosteroids in varying doses and duration for the treatment of reaction and nerve function impairment (NFI) in leprosy have been studied extensively. However, an optimal dose and duration of steroid when used as a prophylactic agent for NFI is yet to be established. This study was aimed to determine whether addition of low dose steroid for the initial 8 months of multi drug therapy (MDT) can prevent further deterioration of nerve function (DON) in multibacillary leprosy patients. Sixty multibacillary leprosy patients were randomized into two groups and B consisting of 30 patients each. Group A received MDT-MB for 12 months with prednisolone 20 mg/day from the beginning of treatment for 6 months followed by tapering by 5 mg/2 weeks in 7th and 8th month. Group B received MDT-MB alone for 12 months. Nerve function assessment (NFA) using various modalities was done at the beginning (0 month), at the end of 8 months and at the completion of MDT (12 months). The proportion of patients showing DON was significantly higher in group B, while proportion of patients showing improvement was more in group A. This study thus shows all MB cases with or without NFI at registration should receive prophylactic steroid at least for 8 months. Since preventing deformities using; prophylactic steroids in leprosy is an important issue larger randomized control trials using longer duration of low dose steroid witha longer follow up period should be conducted.

Dapsone and body mass index in subjects with multibacillary leprosy.

BACKGROUND: The physiological changes in obese subjects can modify the pharmacokinetic profiles of drugs influencing the therapeutic efficacy. METHODS: In this study, the authors compare plasma dapsone trough levels of multibacillary leprosy subjects stratified by body mass index (BMI) to evaluate if obesity plays a significant role on drug levels. The relationship between drug levels and BMI was also determined. Dapsone was measured by high-performance liquid chromatography and BMI based on World Health Organization criteria. RESULTS: At steady state, the median plasma dapsone trough level was significantly lower in obesity class 2 group, when compared with other groups, but they were similar between normal weight and preobesity groups. A weak association between drug levels and BMI was observed. CONCLUSIONS: Obesity promotes a significant reduction in plasma dapsone trough levels of subjects with multibacillary leprosy with a weak association between drug levels and BMI.

Cardiovascular events associated with thalidomide and prednisone in leprosy type 2 reaction.

BACKGROUND: Thalidomide is the drug of choice for the treatment of type 2 leprosy reactions and is often associated with corticosteroids. The use of these drugs in multiple myeloma is associated with the risk of cardiovascular events, but there have been few studies assessing this risk in leprosy patients. OBJECTIVE: To evaluate the occurrence of cardiovascular events in patients with multibacillary leprosy and their correlation with the use of thalidomide and prednisone. METHODS: Analytical cross-sectional study of all patients diagnosed with multibacillary leprosy treated at the Dermatology Service between 2012 and 2022, using electronic medical records. Thromboembolic vascular events, both arterial and venous, including acute myocardial infarction, were considered. The main independent variable was the concomitant use of thalidomide and prednisone during follow-up. RESULTS: A total of 89 patients were included, of which 19 used thalidomide and prednisone concomitantly. There were five cardiovascular events (26.3%), three of which of deep venous thrombosis. The combined use of medications was associated with the events (PR=6.46 [3.92 to 10.65]; p<0.01). STUDY LIMITATIONS: Small number of events, single-center retrospective study. CONCLUSION: The hypothesis of an association between cardiovascular events and the concomitant use of thalidomide and prednisone is supported, but more robust prospective studies are required for a better assessment.

Late relapses in leprosy patients in Brazil: 10-year post-trial of uniform multidrug therapy (U-MDT/CT-BR).

BACKGROUND: Leprosy is a neglected dermato-neurologic, infectious disease caused by Mycobacterium leprae or M. lepromatosis. Leprosy is treatable and curable by multidrug therapy/MDT, consisting of 12 months rifampicin, dapsone and clofazimine for multibacillary/MB patients and for 6 months for paucibacillary/PB patients. The relapse rate is considered a crucial treatment outcome. A randomized Controlled Clinical Trial (U-MDT/CT-BR) conducted from 2007‒2012 compared clinical outcomes in MB patients after 12 months regular MDT/R-MDT and 6 months uniform MDT/U-MDT in two highly endemic Brazilian areas. OBJECTIVES: To estimate the 10 years relapse rate of MB patients treated with 6 months U-MDT. METHODS: The statistical analyses treated the data as a case-control study, sampled from the cohort generated for the randomized trial. Analyses estimated univariate odds ratio and applied logistic regression for multivariate analysis, controlling the confounding variables. RESULTS: The overall relapse rate was 4.08 %: 4.95 % (16 out of 323) in the U-MDT group and 3.10 % (9 out of 290) in the regular/R-MDT group. The difference in relapse proportion between U-MDT and R-MDT groups was 1.85 %, not statistically significant (Odds Ratio = 1.63, 95 % CI 0.71 to 3.74). However, misdiagnosis of relapses, may have introduced bias, underestimating the force of the association represented by the odds ratio. CONCLUSIONS: The relapse estimate of 10 years follow-up study of the first randomized, controlled study on U-MDT/CT-BR was similar to the R-MDT group, supporting strong evidence that 6 months U-MDT for MB patients is an acceptable option to be adopted by leprosy endemic countries worldwide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00669643.

Case Report: Borderline Lepromatous Leprosy Therapy Complicated by Type 1 Leprosy Reaction and Adverse Reactions with Dapsone and Clofazimine.

Leprosy is a global health issue, causing long-term functional morbidity and stigma. Rapid diagnosis and appropriate treatment are important; however, early diagnosis is often challenging, especially in nonendemic areas. Here, we report a case of borderline lepromatous leprosy accompanied by dapsone-induced (neutropenia, anemia, and methemoglobinemia) and clofazimine-induced (skin discoloration and ichthyosis) side effects and type 1 leprosy reactions during administration of the multidrug therapy. The patient completely recovered without developing any deformities or visual impairment. To ensure early diagnosis and a favorable outcome, clinicians should be aware of the diminished sensation of skin lesions as a key physical finding and manage the drug toxicities and leprosy reactions appropriately in patients on multidrug therapy.

Progression of leprosy disability after discharge: is multidrug therapy enough?

OBJECTIVE: To evaluate the risk factors related to worsening of physical disabilities after treatment discharge among patients with leprosy administered 12 consecutive monthly doses of multidrug therapy (MDT/WHO). METHODS: Cohort study was carried out at the Leprosy Laboratory in Rio de Janeiro, Brazil. We evaluated patients with multibacillary leprosy treated (MDT/WHO) between 1997 and 2007. The Cox proportional hazards model was used to estimate the relationship between the onset of physical disabilities after release from treatment and epidemiological and clinical characteristics. RESULTS: The total observation time period for the 368 patients was 1 570 person-years (PY), averaging 4.3 years per patient. The overall incidence rate of worsening of disability was 6.5/100 PY. Among those who began treatment with no disability, the incidence rate of physical disability was 4.5/100 PY. Among those who started treatment with Grade 1 or 2 disabilities, the incidence rate of deterioration was 10.5/100 PY. The survival analysis evidenced that when disability grade was 1, the risk was 1.61 (95% CI: 1.02-2.56), when disability was 2, the risk was 2.37 (95% CI 1.35-4.16), and when the number of skin lesions was 15 or more, an HR = 1.97 (95% CI: 1.07-3.63). Patients with neuritis showed a 65% increased risk of worsening of disability (HR = 1.65 [95% CI: 1.08-2.52]). CONCLUSION: Impairment at diagnosis was the main risk factor for neurological worsening after treatment/MDT. Early diagnosis and prompt treatment of reactional episodes remain the main means of preventing physical disabilities.

Clinical characteristics and outcome in multibacillary (MB) leprosy patients treated with 12 months WHO MDT-MBR: a retrospective analysis of 730 patients from a leprosy clinic at a tertiary care hospital of Northern India.

BACKGROUND: Shortened (12 months) multidrug multibacillary regimen (MDT MBR) was implemented in India in 1998, however there is yet a paucity of crucial data on its long-term outcome. OBJECTIVE: To assess the efficacy of 12 months MDT MBR in multibacillary (MB) patients at our centre. DESIGN: This was a retrospective study undertaken analysing the clinic records of 1210 patients registered at the leprosy clinic of our institute from 1999 to 2010. RESULTS: 730 MB patients were treated with 12 months MDT MBR over this period. High bacillary index (BI) > or = 3 + was observed in 313 patients at the time of registration. Four hundred and one (54.9%) patients experienced lepra reactions. Recurrent ENL was observed in only 14 patients which manifested even after 5 years of stopping treatment. Clinico-histological correlation was noted in 361 (49.5%) patients. During follow up period ranging from 9 months to 10 years, nearly all patients had clearance of skin lesions including histopathological/bacteriological improvement. Only 13 (1.7%) patients relapsed. CONCLUSIONS: All patients responded well with 12 months MDT MBR without significant side effects. The overall relapse rate was only 1.7%. Thus, the recommendation for 12 months MDT MBR for all MB patients is robust and operationally practical, a decision which seems logical.

Twelve months fixed duration WHO multidrug therapy for multibacillary leprosy: incidence of relapses in Agra field based cohort study.

BACKGROUND & OBJECTIVES: The reported low relapse rates after 24 months multidrug therapy (MDT) for multibacillary leprosy (MB) led to the recommendation of reducing duration of therapy to 12 months. However, only a few reports exist on long term follow up data after 12 months fixed duration therapy (FDT). The present study was done to assess the incidence of relapse in MB leprosy patients after 12 months treatment. METHODS: The leprosy patients detected in field surveys during 2001-2006 in Agra district, Uttar Pradesh, India, were put on WHO-MDT and followed up for treatment completion, relapse, reactions and development of disability. The assessment was done clinically by following up the patients until January 2011. Data collected were analyzed for risk and survival analysis. RESULTS: The incidence of relapse was found to be 1.97/100 person years of follow up. The incidence of relapse by age (34 yr vs >34 yr), sex (male vs female), delay in detection (<36 months vs >36 months) and smear status (smear +ve vs -ve) was not found to be significantly different but patients with no nerve involvement were observed to have significantly higher relapses than those with three or more nerve involvement (P<0.05). Similarly, borderline-borderline and BB with reaction (BB/BBR) patients were observed to have significantly high relapses than among those with borderline tuberculoid or BT with reaction (BT/BTR) or borderline lipromatous/lepromatous/neuritic (BL/LL/N) type of leprosy (P<0.01). INTERPRETATION & CONCLUSION: From the observations in the study, it can be suggested that relapses occur in 12 months FDT and almost as much as reported in 24 months FDT for MB leprosy. Although, early relapses may be due to insufficient treatment, late relapses may be due to persistent dormant mycobacteria. However, a study relating to immunological response of treatment and change in immunological profile relating to the occurrence of relapses and its clinical correlates may suggest better information on causes of relapses.

Comparison between lymecycline with multidrug therapy and standard multidrug regimen (WHO-MDT) in the treatment of multibacillary leprosy patients: a retrospective cohort study.

BACKGROUND: Hansen's disease or leprosy is a chronic, infectious disease that has locally and globally afflicted all populations. Despite standard treatment with multidrug therapy (WHO-MDT), the incidence of drug resistance has been an increasingly prevalent global problem in leprosy management. This study compared the effectiveness between lymecycline with WHO-MDT and standard WHO-MDT in leprosy treatment. METHODS: The research is a retrospective cohort study at a tertiary hospital from January 2011 to July 2021. Pre- and post-treatment bacillary index, presence of new lesions, nerve function impairment, and leprosy reactions were obtained through chart review. RESULTS: The results showed a significant difference in bacteriological index (BI) in both groups at the end of the treatment. However, a higher reduction in BI was noted for the lymecycline group. For the group that took WHO-MDT alone, BI decreased by 0.7 (P < 0.001) whereas patients who took lymecycline and WHO-MDT had a BI difference of 3 (P < 0.001) upon completion of treatment. A significant decrease in the recurrence of lesions (P = 0.006) and nerve function impairment (P = 0.038) was also noted in the lymecycline group whereas there was no significant difference in leprosy reactions between the two groups. CONCLUSION: Lymecycline 600 mg daily for 3 months can be used as an adjunct in cases of leprosy resistance and treatment failure among multibacillary patients. Lymecycline significantly reduced bacillary index, recurrence of skin lesions, and nerve function impairment through its possible immunomodulatory, antiapoptotic, and neuroprotective effects.

Efficacy of fixed duration multidrug therapy for the treatment of multibacillary leprosy: A prospective observational study from Northern India.

BACKGROUND: In endemic regions of several countries, the prevalence of leprosy has not come down to the level of elimination. On the contrary, new cases are being detected in large numbers. Clinically, it is frequently noted that despite completion of multibacillary multidrug therapy for 12 months, the lesions remain active, especially in cases with high bacteriological indices. AIM: The present study focused on finding out the viable number of Mycobacterium leprae during the 12-month regimen of multibacillary multidrug therapy, at six and 12 months intervals and, attempting to determine their role in disease transmission. METHODS: Seventy eight cases of multibacillary leprosy cases were recruited from leprosy patients registered at The Leprosy Mission hospitals at Shahdara (Delhi), Naini (Uttar Pradesh) and Champa (Chhattisgarh), respectively. Slit skin smears were collected from these patients which were transported to the laboratory for further processing. Ribonucleic acid was extracted by TRIzol method. Total Ribonucleic acid was used for real-time reverse transcription-polymerase chain reaction (two-step reactions). A standard sample with a known copy number was run along with unknown samples for a reverse transcription-polymerase chain reaction. Patients were further assessed for their clinical and molecular parameters during 6th month and 12th month of therapy. RESULTS: All 78 new cases showed the presence of a viable load of bacilli at the time of recruitment, but we were able to follow up only on 36 of these patients for one year. Among these, using three different genes, 20/36 for esxA, 22/36 for hsp18 and 24/36 for 16S rRNA cases showed viability of M. leprae at the time of completion of 12 months of multidrug therapy treatment. All these positive patients were histopathologically active and had bacillary indexes ranging between 3+ and 4+. Patients with a high copy number of the Mycobacterium leprae gene, even after completion of treatment as per WHO recommended fixed-dose multidrug therapy, indicated the presence of live bacilli. LIMITATIONS: Follow up for one year was difficult, especially in Delhi because of the migratory nature of the population. Patients who defaulted for scheduled sampling were not included in the study. CONCLUSION: The presence of a viable load of bacilli even after completion of therapy may be one of the reasons for relapse and continued transmission of leprosy in the community.

Seventy years of evidence on the efficacy and safety of drugs for treating leprosy: a network meta-analysis.

OBJECTIVE: The World Health Organization (WHO) recommends multidrug therapy (MDT) with rifampicin, dapsone, and clofazimine for treating leprosy, which is based on very low-quality evidence. Here, we performed a network meta-analysis (NMA) to produce quantitative evidence to strengthen current WHO recommendations. METHOD: All studies were obtained from Embase and PubMed from the date of establishment to October 9, 2021. Data were synthesized with frequentist random-effects network meta-analyses. Outcomes were assessed using odds ratios (ORs), 95% confidence intervals (95% CIs), and P score. RESULTS: Sixty controlled clinical trials and 9256 patients were included. MDT was effective (range of OR: 1.06-1255584.25) for treating leprosy and multibacillary leprosy. Six treatments (Range of OR: 1.199-4.50) were more effective than MDT. Clofazimine (P score=0.9141) and dapsone+rifampicin (P score=0.8785) were effective for treating type 2 leprosy reaction. There were no significant differences in the safety of any of the tested drug regimens. CONCLUSIONS: The WHO MDT is effective for treating leprosy and multibacillary leprosy, but it may not be effective enough. Pefloxacin and ofloxacin may be good adjunct drugs for increasing MDT efficacy. Clofazimine and dapsone+rifampicin can be used in the treatment of a type 2 leprosy reaction. Single-drug regimens are not efficient enough to treat leprosy, multibacillary leprosy, or a type 2 leprosy reaction. AVAILABILITY OF DATA AND MATERIALS: All data generated or analyzed during this study are included in this published article [and its supplementary information files].