Can leprosy be eradicated with chemotherapy? An evaluation of the Malta Leprosy Eradication Project.

The Malta Leprosy Eradication Project (MLEP) was proposed in 1971 by Freerksen with the aim of eradicating leprosy in Malta. The project involved re-treatment of all known cases in Malta as of 1972 and all new cases thereafter with a regimen consisting of Isoprodian (a combination of dapsone, prothionamide and isoniazid) and rifampicin for varying intervals depending on the severity of their disease and their response to treatment. Overall the response to therapy was excellent with an extremely low relapse rate. During the 30 years of the project the incidence of leprosy steadily decreased continuing a decline that had started at least two decades earlier and Freerksen declared the disease eradicated from Malta in 2001. Although given the long incubation period of leprosy cases may still be occasionally detected in the future, the disease has been basically eradicated at this time and there are no patients currently receiving treatment. This work was done at the leprosy clinic, Boffa Hospital, Floriana, Malta.

Actualización en tratamiento de la lepra / no disponible

El tratamiento de la lepra ha variado, crecido y mejorado ostensiblemente en los últimos años y ello ha ayudado a eliminar esta enfermedad como problema de Salud Pública en muchos países. Sin embargo, son necesarios aún más estudios para el desarrollo de nuevos tratamientos. La llegada de nuevas drogas al arsenal terapéutico, como el ofloxacino o la minociclian, van sin dudas a reducir el tiempo de tratamiento, así como disminuir la aparición de efectos colaterales frecuentes en los esquemas hasta ahora recomendados. La talidomida, redescubierta en la actualidad como droga muy importante, no sólo para las leprorreacciones sino además para otras muchas patologías con importante componente inmunológico/inflamatorio, es objeto de numerosas investigaciones en la actualidad. Y, sobre todo, reconocer esta enfermedad que es la lepra como la expresión de una complicada – pero cada vez mejor conocida- cascada de acontecimientos inmunológicos, ha abierto un sinfín de nuevas posibilidades en el campo de la terapéutica, los inmunomoduladores, que también desempeñan un importante papel durante los episodios reacciónales, los cuales continúan siendo, a pesar de los avances actuales, el auténtico problema para el paciente bajo tratamiento. Como esta enfermedad infecciosa, la vacuna debe ser al final el objeto de todas las investigaciones, pues con la desaparición de la susceptibilidad de la población, el resto de los tratamientos, si no existen pacientes, poco han de aportar. Nuevas vacunas están haciendo su aparición en el abanico terapéutico de la lepra, de forma aislada o sumadas a los tratamientos por vía oral. Basado en las informaciones de textos de leprología actuales, así como en búsquedas en Internet acerca de investigaciones en curso sobre los nuevos tratamientos, este trabajo intenta mostrar un estudio cuidadoso de los esquemas terapéuticos en la actualidad y de las nuevas posibilidades que están surgiendo en los campos de la Farmacología y la Inmunología

The leprosy treatment has changed, grown and improved especially in the last few years, and this factor has helped to eliminate this disease as a Public Health problema inmany countries. Since the time the leprosy patients were espelled society until our days has improved very much. Although our country still has a big problem, and yet is necessary to do more research to develop new treatments. The introduction of new drugs to the therapeutic “arsenal”, as the ofloxacín or the minocicline, no doubt will reduce the time treatment, as to reduce the appearance of side-effect in the therapeutic plans recommended until now. The thalidomide, rediscovered nowadays as a drug very valued not only for the leprosy reactions as for the many other diseases with a very important immunological component/inflammatory is a target for many recent research. And for all, recognize this disease that is the leprosy as difficult expression but after all better known as an immunological cascade happening has opened many possibilities without an end in the therapeutically area, the immunomodulators, that develop a very important role during the reaction episodes, that continue to be, besides of the modern advances, the real treatment for the patients on treatment. As an infectious disease, the vaccine has to be the main objective of all the research, because with the with draw of the population susceptibility, the rest of the therapeutic if, doesn´t exist one sick, it won´t be necessary to add very much to it. New vaccines are appearing in the therapeutically leprosy cast, alone or together with the oral treatment. Based on the papers information about modern leprosy, as in research in the internet after information about new heading treatments, this paper is willing to show a new synthesized vision of the way followed in pharmacology for the leprosy treatment, studying carefully the therapeutically plans nowadays and showing new possibilities that are being evaluated in the pharmacology and immunology areas

A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy.

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.

[Chemotherapy-induced erythema nodosum leprosum: successful treatment with thalidomide]. / Erythema nodosum leprosum unter Chemotherapie. Erfolgreiche Behandlung mit Thalidomid.

The severity and outcome of a chronic granulomatous infection caused by M. leprae depend on the cell-mediated immunity towards the pathogen. The disease classification is based on the host's response to M. leprae ranging from high to low resistance (polar tuberculoid leprosy to polar lepromatous leprosy). The host's position in the spectrum is not stable; leprosy reactions reflecting changed immune status may occur spontaneously or during chemotherapy. The type II reaction or erythema nodosum leprosum can most often be seen in patients with lepromatous leprosy, a multiorgan disease characterized by an unrestricted bacillary replication. Clinically, this reaction is characterized by crops of painful bright pink, dermal and subcutaneous nodules arising in clinically normal skin, in association with fever, malaise, glomerulonephritis and arthralgias. Therefore, prompt institution of immunosuppressive therapy with corticosteroids or thalidomide is recommended. This case report describes the development of erythema nodosum leprosum during chemotherapy treated successfully with thalidomide. Furthermore, immunologic effects and potential side effects of this drug are discussed.

The Malta Project--a country freed itself of leprosy. A 27-year progress study (1972-1999) of the first successful eradication of leprosy.

The successful conclusion of the first leprosy eradication program carried out with combination therapy is reported. This program started in Malta in June 1972. It was based on extensive experimental and clinical studies and was formally concluded on 31 December 1999. No new infections occurred after the start of this 27-year progress report. The youngest patient was 16, and the eldest 83 years old. Of the total of 261 cases in the project, 201 had already received pretreatment [mainly with diaminodiphenylsulfone (DDS)] at the start. Sixty-one cases had no pretreatment. These were predominantly elderly patients who were late in deciding to have treatment. The very long follow-up period totaling 27 years was consistently maintained in order to be able to refute all potential objections empirically, e.g. with regard to relapses at a late stage. Besides the overall symptoms which are typical for the broad picture of leprosy, the involvement of the eyes was very striking (at least 50%). The therapeutic effect was of very rapid onset in these cases without surgery. Rifampicin (RMP) + isoniazid + prothionamide + DDS (trade name Isoprodian-RMP) was used as medication in a fixed combination. This fixed combination had already proved to be highly effective in the treatments during the course of the project, surprising therapy results (including lifesaving effects) were also noticed in other diseases.

A simple and rapid technique for the detection of rifampin resistance in Mycobacterium leprae.

The rifampin resistance of Mycobacterium leprae is due to missense mutations in the rpoB gene encoding the beta-subunit of the essential enzyme RNA polymerase. A rapid and very simple method has been developed to detect rifampin resistance in small numbers of M. leprae present in biopsies. It involves polymerase chain reaction amplification of a defined region of the rpoB gene followed by single-strand conformational polymorphism analysis (PCR-SSCP). The reliability of the method has been tested on a sample of known drug-resistant and susceptible isolates of M. leprae.

Effects of chemotherapy on antibody levels directed against PGL-I and 85A and 85B protein antigens in lepromatous patients.

IgG antibodies against antigens 85A and 85B from Mycobacterium bovis BCG, IgM antibodies against phenolic glycolipid-I (PGL-I) and circulating PGL-I antigen were measured in the serum of 11 patients with lepromatous leprosy receiving multidrug therapy (MDT). Before treatment, 6 patients were reactive to antigen 85A, 10 patients to antigen 85B, and 11 patients to PGL-I; circulating PGL-I was detected in the sera of all of them. After 2 years of MDT PGL-I antigen could no longer be detected in all of the patients, except for two who were not compliant with treatment. IgG antibodies directed against the 85A and 85B antigens and IgM antibodies against the PGL-I antigen also decreased significantly during treatment but more slowly. The determination of circulating PGL-I antigen remains the most appropriate tool for monitoring lepromatous leprosy under MDT.

A case of relapse with drug-susceptible M. leprae after multidrug therapy.

A male born in 1930 was diagnosed as smear-positive borderline leprosy in 1971, and was treated with dapsone and/or sulfamethoxypyridazine from 1972 to 1980 with clinical improvement. However, new skin lesions with smears strongly positive appeared in August 1980, and he was diagnosed as having downgraded to lepromatous (LL) leprosy, but the bacilli recovered from the skin biopsy were fully susceptible to both dapsone and rifampin by mouse foot pad technique. Between 1981 and 1983, the patient was treated with 24 months of rifampin 600 mg and dapsone 100 mg daily, supplemented with prothionamide 500 mg daily during the initial 3 months, and his skin lesions gradually improved during treatment with the combined regimen. Afterward, the patient was kept under surveillance without treatment. From 1984 to 1986, his skin smears were negative, and no bacilli could be found from a skin biopsy taken in 1985. Then in 1987, 52 months after stopping treatment, new skin lesions appeared with a high concentration of Mycobacterium leprae (2 x 10(6)/mg tissue). The drug-susceptibility test again demonstrated that the organisms were fully susceptible to both dapsone and rifampin. Apparently the relapse was due to remultiplication of drug-susceptible persisters.

Isoprodian and rifampicin in the treatment of leprosy: a descriptive evaluation of therapy durations in 475 Paraguayan leprosy patients.

In Paraguay, the National Leprosy/Tuberculosis Program is based on a combined chemotherapy with isoprodian and rifampicin. The aim of this descriptive study was to investigate the therapy durations used so far in the treatment of 475 leprosy patients and to analyze the criteria responsible for the wide-ranging differences in therapy durations. As initial criteria, the following parameters were identified to have a significant influence on the therapy duration: Patients never treated before or pretreated, clinical classification and initial bacteriological index (BI) value. During therapy, conditions like the attendance and BI decrease/year showed a significant correlation with the therapy duration. Even though the studied criteria did not allow to draw a definite conclusion with regard to an 'ideal' therapy duration, they proved to be reliable, as only 2 patients have relapsed so far.

New forms of multidrug therapy for the treatment of leprosy. First report for the practice on rifampicin + sulfamethoxazole-trimethoprim + protionamide and rifampicin + sulfamethoxazole-trimethoprim + isoniazid.

Since 1970, when the lifelong monotherapy with dapsone (DDS) in leprosy could be replaced by short-term combination therapy with rifampicin + isoniazid + protionamide + DDS (Isoprodian-RMP), chemotherapeutic research was faced with two problems: (1) to find alternative treatment regimens for cases of intolerance, and (2) to work out forms of therapy allowing a further reduction of the average treatment time of 2 years. The present paper describes the attempts made to find solutions to these problems. With two new combinations, alternatives have become available, and the average treatment time is shortened to 6 months. Both combinations are also effective in tuberculosis.

Activity of ofloxacin against Mycobacterium leprae in the mouse.

Mice inoculated with 4800 Mycobacterium leprae in the left hind foot pad were treated from day 62 to day 150 after infection with 50 mg or 150 mg of ofloxacin per kg body weight, 150 mg pefloxacin per kg, or 50 mg prothionamide per kg. These drugs were administered by esophageal cannula 5 days weekly with dapsone (0.01 g per 100 g diet). Multiplication of M. leprae in the treated and in untreated control mice was assessed by monthly harvests. The treatment of mice with the smaller dosage ofloxacin, with pefloxacin, prothionamide, or dapsone uniformly resulted in a delay of multiplication of 4 months, compared to the multiplication of M. leprae in the untreated controls. The delay of multiplication (4 months) being 1 month longer than the duration of drug administration (3 months), all of the treatments may be considered as bacteriopausal or moderately bactericidal. In contast with these results, treatment of mice with 150 mg ofloxacin per kg resulted in no growth of the organisms whatever as late as 18 months after inoculation, strongly suggesting that, in that dosage, ofloxacin had killed all of the M. leprae. Such a profound killing activity has been observed only with rifampin. Although the pharmacokinetic characteristics of ofloxacin are different in man from those in the mouse, the daily dosage of 150 mg ofloxacin per kg body weight in the mouse is equivalent to 400 mg per day in man which is the usual therapeutic dosage; thus, the results obtained in the mouse may be extrapolated to man. Therefore, ofloxacin appears a very promising drug for the chemotherapy of leprosy.

Feasibility of multidrug therapy (MDT) in Hansen's disease in an urban population--Curupaiti State Hospital, Rio de Janeiro, Brazil.

The acceptance of the WHO regimen in a group of 220 patients was approximately 84.5%. Only 11% abandoned the treatment, and the substitution of ethionamide or prothionamide for clofazimine due to excessive hyperpigmentation was necessary in only eight cases. The WHO regimens adopted provided a more frequent (monthly) relationship between the patients and their health service. It was necessary to: a) reorganize the technical-administrative infrastructure, with the intention of providing an improved service to the patients for treatment and control; and b) pay more attention to the problem of deformities and health education activities. As for the side effects of the drugs, 54 patients showed alterations in their liver function tests, which were usually mild and which resolved despite continuation of the treatment. Of the reactional episodes observed during MDT, it would not appear that the therapeutic regimens contributed to their occurrence or aggravation.

[5-year assessment of daily multi-drug therapy of leprosy in Guadeloupe since 1980]. / Bilan à 5 ans de la polychimiothérapie quotidienne de la lèpre en Guadeloupe depuis 1980.

In Guadeloupe, from January 1980 to December 1984, 420 leprosy patients were put under daily multidrug therapy: 10 mg/kg RMP plus 100 mg DDS during six months for paucibacillary patients, 10 mg/kg RMP plus 100 mg DDS during 24 months supplemented during the 12 first months with 10 mg/kg of a thioamide, ethionamide or protionamide, for multibacillary patients. The approval to the treatment was satisfactory in all the patients with active leprosy, new cases and relapse cases, less in the inactive patients already treated with dapsone only. The patients's compliance to treatment was satisfactory too. The lepra reactions were observed with a 19% frequency which is not different of the 15% frequency of lepra reactions observed in patients treated with DDS only. Hepatitis were observed only in multibacillary patients treated with PTH and RMP with a 14% frequency. Discontinuing treatment with RMP and PTH but not DDS resulted in recovery. When RMP was resumed without PTH, the hepatitis did not recur. All patients responded favorably under multidrug therapy and no relapse was observed among the 45 paucibacillary patients after a four year-surveillance and among the 16 multibacillary patients after a three year-surveillance.

[Clinical and bacteriological assessment 8 years after triple-drug therapy for multibacillary leprosy in Senegal]. / Bilan clinique et bactériologique huit ans après trichimiothérapie pour lèpre multibacillaire au Sénégal.

Increasing resistance to dapsone (DDS) leads to recommend triple drug chemotherapy (TCT) in multibacillary leprosy (ML). To determinate long term evolution, we evaluated patients who received TCT 8 years ago. Between 1974 and 1976, 30 patients with ML received TCT (rifampicin, prothionamid, and DDS) during 6 or 12 months. At this time satisfactory clinical and bacteriological findings were reported, and from then DDS was given alone. Twelve of the thirty patients have been evaluated in 1983. Six patients had bacteriological index greater than or equal to 2+, three of them had clinical relapse. Seven of the twelve patients did not take regularly DDS; the six relapses belong to this group.