RESUMO
The development of a vaccine for tuberculosis requires a combination of antigens and adjuvants capable of inducing appropriate and long-lasting T cell immunity. We evaluated Mtb72F formulated in AS02A in the cynomolgus monkey model. The vaccine was immunogenic and caused no adverse reactions. When monkeys were immunized with bacillus Calmette-Guérin (BCG) and then boosted with Mtb72F in AS02A, protection superior to that afforded by using BCG alone was achieved, as measured by clinical parameters, pathology, and survival. We observed long-term survival and evidence of reversal of disease progression in monkeys immunized with the prime-boost regimen. Antigen-specific responses from protected monkeys receiving BCG and Mtb72F/AS02A had a distinctive cytokine profile characterized by an increased ratio between 3 Th1 cytokines, IFN-gamma, TNF, and IL-2 and an innate cytokine, IL-6. To our knowledge, this is an initial report of a vaccine capable of inducing long-term protection against tuberculosis in a nonhuman primate model, as determined by protection against severe disease and death, and by other clinical and histopathological parameters.
Assuntos
Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Adjuvantes Imunológicos/química , Animais , Citocinas/metabolismo , Progressão da Doença , Haplorrinos , Sistema Imunitário , Interferon gama/metabolismo , Interleucina-6/metabolismo , Macaca fascicularis , Mycobacterium tuberculosis/metabolismo , Fatores de Tempo , Resultado do Tratamento , Tuberculose/microbiologia , Vacinas contra a Tuberculose/químicaRESUMO
The aim of this study was to describe the ocular conditions in multibacillary (MB) leprosy patients treated with 2 year WHO multiple drug therapy (MDT), consisting of dapsone, clofazimine and rifampin, a regimen expected to reduce ocular complications of leprosy. We conducted comprehensive eye examinations in 202 Filipino MB leprosy patients before, during, and after WHO 2 year MDT. Assessments were carried out for at least 5 years. Inflammatory "lepra" reactions occurred in 62% (reversal reaction, 52%; erythema nodosum leprosum, 10%); most were mild. Eye abnormalities consisted mostly of diminished corneal sensitivity before MDT (6%) and lagopthalmos (n = 7, 3.4%). Six of 7 lagopthalmos cases occurred in a subset of 132 patients with facial patches (5%). Visual acuity scores, intra-ocular pressures and pupil cycle times were unremarkable. Bacillary invasion, keratitis, episcleritis, iridocyclitis, ectropion, synechiae, glaucoma and cataract formation were not detected. Scleral clofazimine pigmentation was frequent, resolving in most within 3 years of treatment cessation. Facial patches at presentation may denote a higher risk for lagopthalmos. We propose the generally low rates of ocular problems reflected mild lepra reactions, due to anti-inflammatory properties of clofazimine, a relatively young cohort, and a readily accessible community-based clinic permitting earlier diagnosis and prompt treatment.
Assuntos
Oftalmopatias/epidemiologia , Hansenostáticos/uso terapêutico , Hanseníase Multibacilar/complicações , Hanseníase Multibacilar/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Clofazimina/efeitos adversos , Clofazimina/uso terapêutico , Dapsona/uso terapêutico , Quimioterapia Combinada , Oftalmopatias/microbiologia , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Filipinas/epidemiologia , Estudos Prospectivos , Rifampina/uso terapêutico , Adulto JovemRESUMO
OBJECTIVES: To compare the efficacy of a 4-week ofloxacin-containing regimen and the standard WHO-MDT regimen for PB leprosy, in terms of the rate and timing of relapse after treatment completion. DESIGN: 124 PB patients were enrolled in a randomised, double-blind trial. Of these, 66 received the standard 6-month WHO-MDT regimen, whereas 58 received 28 daily supervised doses of rifampicin 600mg + ofloxacin 400 mg, plus 5 months of placebo. Patients were regularly monitored for clinical response and for signs of relapse after treatment completion. RESULTS: Patients enrolled in the ofloxacin group had a mean follow-up of 10.8 years (628 patient-years) with 1 early relapse at 3 years after treatment completion. On relapse, this patient remained smear negative but was reclassified by current WHO criteria (> or =6 skin lesions) as multibacillary (MB). Patients on the WHO-MDT regimen had a mean follow-up of 11.3 years (749 patient-years) with two late relapses at 8 and 12 years, both still classified as PB on relapse. CONCLUSION: In conclusion, both regimens appeared generally efficacious, and, in particular, resulted in few relapses.
Assuntos
Dapsona/uso terapêutico , Hansenostáticos/uso terapêutico , Hanseníase Paucibacilar/tratamento farmacológico , Ofloxacino/uso terapêutico , Rifampina/uso terapêutico , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Pele/microbiologia , Fatores de Tempo , Resultado do Tratamento , Organização Mundial da SaúdeRESUMO
INTRODUCTION: Previously we reported a 2-month clinical trial of moxifloxacin therapy in eight patients with MB leprosy (7 LL and 1 BL), finding both rapid killing of M. leprae and clinical improvement, without serious side effects or toxicities. Here we report the outcomes in two patients treated with moxifloxacin. DESIGN: Two previously untreated LL patients were treated with a single 400 mg dose of moxifloxacin, no therapy for 7 days and then daily 400 mg moxifloxacin for 48 days. Clinical response, viability of M. leprae in the skin, and side effects/toxicities were carefully monitored. RESULTS: In both patients a single dose of moxifloxacin resulted in significant killing of M. leprae (P < 0.001%). In both patients no viable M. leprae were found after 15 doses of moxifloxacin. Improvement in skin lesions occurred again remarkably rapidly and no untoward effects were noted. CONCLUSION: Loss of viable M. leprae was quite rapid, similar to that found previously only for rifampicin, patients improved rapidly, and moxifloxacin was well tolerated.
Assuntos
Compostos Aza/uso terapêutico , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Viabilidade Microbiana/efeitos dos fármacos , Mycobacterium leprae/efeitos dos fármacos , Quinolinas/uso terapêutico , Adulto , Compostos Aza/administração & dosagem , Fluoroquinolonas , Humanos , Hansenostáticos/administração & dosagem , Hanseníase Virchowiana/microbiologia , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Mycobacterium leprae/isolamento & purificação , Quinolinas/administração & dosagem , Pele/microbiologia , Pele/patologia , Resultado do TratamentoRESUMO
In a clinical trial of moxifloxacin in eight multibacillary leprosy patients, moxifloxacin proved highly effective. In all trial patients, a single 400-mg dose of moxifloxacin resulted in significant killing (P Assuntos
Antibacterianos/uso terapêutico
, Compostos Aza/uso terapêutico
, Hanseníase/tratamento farmacológico
, Mycobacterium leprae/efeitos dos fármacos
, Quinolinas/uso terapêutico
, Adulto
, Animais
, Antibacterianos/administração & dosagem
, Antibacterianos/farmacologia
, Compostos Aza/administração & dosagem
, Compostos Aza/farmacologia
, Fluoroquinolonas
, Pé/microbiologia
, Humanos
, Hanseníase/microbiologia
, Hanseníase/patologia
, Masculino
, Camundongos
, Pessoa de Meia-Idade
, Moxifloxacina
, Mycobacterium leprae/crescimento & desenvolvimento
, Mycobacterium leprae/patogenicidade
, Quinolinas/administração & dosagem
, Quinolinas/farmacologia
, Pele/microbiologia
, Pele/patologia
, Resultado do Tratamento
RESUMO
The World Health Organization advocates 2 leprosy treatment regimens on the basis of disease classification (as multibacillary or paucibacillary) by skin lesion count. This method, which, in the Philippines, results in a high prevalence (78%) of patients with multibacillary leprosy, was directly compared with classification using standard histopathological and microbiological criteria in 264 currently untreated patients with leprosy. Of those whose leprosy was classified as paucibacillary, 38%-51% of patients had multibacillary leprosy according to classic criteria and were thus at risk of undertreatment according to World Health Organization recommendations.
Assuntos
Hanseníase/classificação , Pele/patologia , Classificação/métodos , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Hanseníase/patologia , Organização Mundial da SaúdeRESUMO
Buruli ulcer, caused by Mycobacterium ulcerans, is a destructive infection that most commonly affects the skin. Animal models for Buruli ulcer include guinea pigs, rats, mice, and armadillos, but each is limited in replicating the spectrum of human disease. Here, a cynomolgus monkey was infected with two concentrations of M. ulcerans (1.0 and 2.2 x 10(8)) by intradermal inoculation, 3 months apart. All injection sites developed papules that progressed to ulcers with undermined borders within 2-4 weeks. The rate of progression and size of the ulcers were proportional to the numbers of organisms inoculated. Biopsies from ulcer edges showed ulceration, robust inflammatory cell infiltrates, granulomatous-like responses, mild edema, and extracellular acid-fast bacilli. The ulcers healed spontaneously between Weeks 8 and 12, with no signs of systemic infection. This report, the first to describe a non-human primate experimentally infected with M. ulcerans, suggests that cynomolgus monkeys are modestly susceptible and develop some of the clinical and histologic features of Buruli ulcer.
Assuntos
Macaca fascicularis/microbiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Infecções por Mycobacterium não Tuberculosas/patologia , Mycobacterium ulcerans , Dermatopatias Bacterianas/microbiologia , Dermatopatias Bacterianas/patologia , Animais , Injeções Intradérmicas , MasculinoRESUMO
Cynomolgus monkeys, as animal models of scrub typhus, are typically infected with Orientia tsutsugamushi by intradermal inoculation. However, the clinical and histological features at the O. tsutsugamushi inoculation sites, akin to "eschars" at chigger inoculation sites in humans, have not been fully characterized. We intradermally inoculated one medial thigh of six cynomolgus monkeys with semi-purified O. tsutsugamushi (Karp). Within 7 days, two animals developed scrub typhus-like eschars and four had dusky plaques, accompanied by inguinal lymphadenopathy. Biopsies of eschars and an enlarged regional lymph node resembled human disease and stained positively for O. tsutsugamushi by Giemsa, anti-Karp fluorescent antibody, or streptavidin alkaline phosphatase. O. tsutsugamushi-specific IgM and IgG antibody levels measured in both of two monkeys rose steadily after infection. This pilot study shows that cynomolgus intradermally inoculated with O. tsutsugamushi replicate the localized cutaneous pathogenesis of human scrub typhus infections, strengthening the value of this animal model.
Assuntos
Macaca fascicularis/microbiologia , Doenças dos Macacos/patologia , Orientia tsutsugamushi/fisiologia , Tifo por Ácaros/patologia , Pele/patologia , Animais , Anticorpos Antibacterianos/sangue , Modelos Animais de Doenças , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Injeções Intradérmicas , Linfonodos/microbiologia , Doenças Linfáticas/etiologia , Doenças Linfáticas/microbiologia , Doenças Linfáticas/patologia , Masculino , Projetos Piloto , Tifo por Ácaros/complicações , Tifo por Ácaros/imunologiaRESUMO
In 1982-1984 we conducted a six-month clinical trial in 50 previously untreated lepromatous leprosy patients randomly assigned to directly observed monotherapy with one of two thioamides, ethionamide or prothionamide, each given six times a week at doses of either 250 mg or 500 mg. The findings of this study have only recently been analyzed, and the potential for the use of these thioamides in leprosy patients placed in perspective. However, because of the small number of patients included in this study, the results must be interpreted with some caution. Clinical improvement was noted in 74% of the patients treated with ethionamide and in 83% of those treated with prothionamide. Therapy was well tolerated and drug-related hepatotoxicity did not require discontinuation of therapy. The 500-mg dose of both ethionamide and prothionamide resulted in loss in Mycobacterium leprae viability more rapidly than did the 250-mg dose, and prothionamide at both dose levels was superior to the equivalent dose of ethionamide. Overall killing of M. leprae in this study was found to be similar to that obtained previously with dapsone and clofazimine, but less than was obtained with rifampin, minocycline, clarithromycin, pefloxacin, and ofloxacin.
Assuntos
Etionamida/uso terapêutico , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Mycobacterium leprae/crescimento & desenvolvimento , Protionamida/uso terapêutico , Adolescente , Adulto , Animais , Biópsia , Criança , Relação Dose-Resposta a Droga , Etionamida/efeitos adversos , Feminino , Humanos , Hansenostáticos/efeitos adversos , Masculino , Camundongos , Pessoa de Meia-Idade , Protionamida/efeitos adversosRESUMO
The search for new and improved tuberculosis (TB) vaccines has focused on IFN-γ both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-γ in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31® adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-γ-responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-γ production did not correlate with or predict disease outcome. This study's main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB.
Assuntos
Adjuvantes Imunológicos/farmacologia , Vacina BCG/imunologia , Imunização Secundária/métodos , Macaca fascicularis , Proteínas Recombinantes de Fusão/imunologia , Tuberculose/prevenção & controle , Animais , Modelos Animais de Doenças , Interferon gama/metabolismo , Análise de Sobrevida , Tuberculose/metabolismoRESUMO
In a randomized, double-blind, double-dummy controlled study, 22 men with erythema nodosum leprosum (ENL) received six capsules containing either 100 mg (group A, n = 12) or 300 mg (group B, n = 10) of thalidomide daily for one week. A six-week, four capsules per day taper followed, in which group A received 50 mg/day of thalidomide in weeks 2 and 3, then dummy capsules in weeks 4 through 7, while group B had gradual decrements every two weeks. Both regimens caused comparable improvement in 19 patients at day 7 (group A [12 of 12] versus group B [7 of 10]; P = 0.08), but slower tapering in group B showed less re-emergence of ENL through week 7 (P = 0.02, versus group A). Most patients developed new lesions soon after stopping treatment. Slower tapering from a higher initial thalidomide dose may improve clinical ENL responses, but high recurrence rates after discontinuation indicates further assessment is needed to identify better tapering regimens.
Assuntos
Eritema Nodoso/tratamento farmacológico , Hansenostáticos/administração & dosagem , Hanseníase Virchowiana/tratamento farmacológico , Talidomida/administração & dosagem , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Interleucina-6/sangue , Hansenostáticos/efeitos adversos , Linfócitos , Masculino , Pessoa de Meia-Idade , Neopterina/urina , Talidomida/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Monthly doses of rifampin, ofloxacin, and minocycline (ROM) are expected to be effective treatment for multi-bacillary leprosy. Patients with MB leprosy received ROM (n = 10) or World Health Organization multi-drug therapy (MDT) (n = 11). Treatment with ROM was given as 24 consecutive monthly observed doses of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg). Treatment with MDT was given as 24 consecutive monthly observed doses of rifampin (600 mg) and clofazimine (300 mg), and unobserved daily dapsone (100 mg) and clofazimine (50 mg). Twenty patients completed the 24-month regimens with > 99% compliance. Treatments with ROM and MDT were safe, tolerable, and caused similar improvements in lesions, bacterial indices, and histology. All MDT recipients developed clofazimine-induced pigmentation. Six ROM and nine MDT recipients assessed at five or more years after completion of treatment had no evidence of relapse. Twenty-four months of treatment with ROM is a safe, well-tolerated, and convenient regimen that may provide an alternate therapy to MDT for MB leprosy. Larger trials with sufficient follow-up would better define the role of ROM.
Assuntos
Hansenostáticos/administração & dosagem , Hanseníase/tratamento farmacológico , Minociclina/administração & dosagem , Ofloxacino/administração & dosagem , Rifampina/administração & dosagem , Adolescente , Adulto , Clofazimina/administração & dosagem , Dapsona/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Some mycobacterial infections, such as tuberculosis, are characterized by apoptosis of infected or by-stander mononuclear immune cells. For localized (paucibacillary, PB) and disseminated (multibacillary, MB) leprosy, characterized by polarized Th1-like vs. Th2-like immune responses, respectively, little is known about lesional apoptosis. We analyzed sections of paraffin-embedded, untreated leprosy lesions from 21 patients by an indirect immunofluorescent terminal deoxynucleotide-transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay. Some TUNEL (+) PB sections were then reacted with phycoerythrin-conjugated (red) antibodies against T cells, monocytes, or antigen-presenting (Langerhans) cells. TUNEL (+) bodies were detected in 9 of 16 PB lesions (56%) and in 1 of 5 MB lesions (20%). Some TUNEL (+) bodies in PB disease were CD3+ (T cell), as well as CD4+ (T-helper) or CD8+ (T-cytotoxic). Apoptosis characterizes PB and MB leprosy lesions and may be more frequent in PB disease. In PB disease, some TUNEL (+) bodies may derive from T cells.
Assuntos
Apoptose , Imunofenotipagem/métodos , Marcação In Situ das Extremidades Cortadas/métodos , Hanseníase/imunologia , Humanos , Hanseníase/microbiologia , Mycobacterium leprae/patogenicidade , Linfócitos T/imunologia , Linfócitos T/fisiologiaRESUMO
A 2-month clinical trial of pefloxacin and ofloxacin in previously untreated multibacillary patients was conducted at the Leonard Wood Memorial Leprosy Research Center, Cebu, the Philippines. Treatment with either pefloxacin or ofloxacin resulted in rapid clinical improvement, in this regard pefloxacin appearing somewhat superior. Reactions and side effects were minimal. Single doses of either agent did not result in significant killing of Mycobacterium leprae, but significant bactericidal activity was observed for all fluoroquinolone-treated patients by one week of daily therapy (n = 21), and either agent independently by 3 weeks of daily therapy. At the completion of therapy only two of 10 pefloxacin-treated patients and 0 of 11 ofloxacin-treated patients harboured any detectable viable M. leprae from active lesions, confirming previous work that these fluoroquinolones exhibit bactericidal activity in leprosy patients and more than that found previously for dapsone and clofazimine.
Assuntos
Hanseníase Virchowiana/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Ofloxacino/administração & dosagem , Pefloxacina/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hanseníase Virchowiana/diagnóstico , Masculino , Filipinas , Probabilidade , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress-induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56.
Assuntos
Vacina BCG/administração & dosagem , Macaca fascicularis/imunologia , Oligodesoxirribonucleotídeos/administração & dosagem , Oligopeptídeos/administração & dosagem , Vacinas contra a Tuberculose/administração & dosagem , Tuberculose/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Bactérias/genética , Modelos Animais de Doenças , Combinação de Medicamentos , Genes Bacterianos , Humanos , Imunização Secundária , Interferon gama/biossíntese , Tuberculose Latente/imunologia , Tuberculose Latente/prevenção & controle , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologiaRESUMO
Cynomolgus monkeys are a useful model for human tuberculosis, but susceptibility to M. leprae is unknown. A cynomolgus model of leprosy could increase understanding of pathogenesis-importantly, neuritis and nerve-damaging reactions. We administered viable Mycobacterium leprae to 24 cynomolgus monkeys by three routes, with a median follow-up period of 6 years (range = 1-19 years) involving biopsies, nasal smears, antiphenolic glycolipid-1 (PGL-1) antibody serology, and lepromin skin testing. Most developed evanescent papules at intradermal M. leprae inoculation sites that, on biopsy, showed a robust cellular immune response akin to a lepromin skin test reaction; many produced PGL-1 antibodies. At necropsy, four monkeys, without cutaneous or gross neurological signs of leprosy but with elevated PGL-1 antibodies, including three with nasal smears (+) for acid fast bacilli (AFB), showed histological features, including AFB, suggestive of leprosy at several sites. Overall, however, cynomolgus monkeys seem minimally susceptible to leprosy after experimental M. leprae administration.
Assuntos
Hanseníase/imunologia , Macaca fascicularis , Doenças dos Macacos/microbiologia , Mycobacterium leprae/imunologia , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Biópsia/veterinária , Modelos Animais de Doenças , Feminino , Glicolipídeos/imunologia , Histocitoquímica/veterinária , Antígeno de Mitsuda , Hanseníase/microbiologia , Masculino , Doenças dos Macacos/imunologiaRESUMO
We evaluated the incidence, severity, and duration of reactional states in 139 multibacillary (MB) leprosy patients in the first 2 years after the completion of the 1 year regimen of multidrug therapy (MDT) currently recommended by the World Health Organization (WHO) and compared those findings with 295 MB leprosy patients treated with the same regimen previously recommended for 2 years. During the first year after the completion of 1 year MDT, patients experienced 1 or more reactional states 27% of the time, the vast majority being lepra type 1 reactions (reversal reactions, RR), whereas patients who received 2 year MDT experienced a reactional state during that time period only 8% of the time (P < 0.001). Furthermore, during the first year after the completion of therapy, and during the first 2 years, both the number of reactional states and reversal reactions were significantly (P < or = 0.004) more frequent, severe, of longer duration, and more commonly associated with neuritis.
Assuntos
Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Adolescente , Adulto , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Hansenostáticos/administração & dosagem , Hansenostáticos/uso terapêutico , Masculino , Adulto JovemRESUMO
From 1987 to 1994, we enrolled 500 subjects completing 2-year WHO multiple drug therapy (MDT) for multibacillary leprosy in a prospective relapse study. Relapse was defined as new skin lesions and an increase in the bacterial index (BI) > or = 2+ (> or = 100x) at any single slit-skin smear site. At the study end in 2006, follow-up was 6,401 subject-years, a mean of 12.8 years/subject. We observed 23 relapses, 6-16 years after MDT (mean, 10.5 years; 95% confidence interval [CI], 9.2-11.8), peaking in Years 11-12 (> 1%/year). The cumulative risk was 6.6% (95% CI, 5.0-8.2%). In a subset of 181 subjects with pre-MDT average BI > or = 4+, 11 relapses occurred (cumulative risk, 10.1%). In mouse footpad assays, Mycobacterium leprae from relapsed subjects were rifampin and clofazimine sensitive. Taken together, the data suggest relapses are related to activation of dormant organisms (persisters) not killed by MDT rather than new infection.
Assuntos
Hansenostáticos/administração & dosagem , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Farmacorresistência Bacteriana , Quimioterapia Combinada , Humanos , Pessoa de Meia-Idade , Mycobacterium leprae/efeitos dos fármacos , Filipinas/epidemiologia , Recidiva , Fatores de Tempo , Adulto JovemRESUMO
As a participant in a multicenter trial, we evaluated the relapse rate in 189 multibacillary (MB) leprosy patients treated with four different regimens and followed-up for as many as 12 years after the initiation of treatment. Treatment regimens included 1 year of WHO MDT (a regimen including dapsone, clofazimine, and rifampin), 2 years of WHO MDT, 1 month of daily rifampin and daily ofloxacin, and 1 year of WHO MDT plus an initial 1 month of daily rifampin and daily ofloxacin. Relapse rates after 9 and 12 years from the initiation of therapy in the three regimens that included WHO MDT were 0-3%, whereas relapses occurred in those treated with the 1-month regimen alone at a significantly greater rate (P < 0.05): 11% at 9 years and 25% at 12 years. Relapses occurred late, beginning at 5 years after the initiation of therapy, and were confined to those patients histopathologically borderline lepromatous and polar lepromatous having a high bacterial burden. Prospects for an alternative effective short-course therapy of leprosy are presented.