Relapses in multibacillary patients treated with multi-drug therapy until smear negativity: findings after twenty years.

The Schieffelin Leprosy Research and Training Center at Karigiri, India participated in several of the World Health Organization (WHO) trials. The first trial on combined therapy in multi-bacillary leprosy was initiated in 1981. The main objectives of this field trial were to evaluate the efficacy of WHO recommended regimens in preventing relapses, especially drug resistance relapses. This paper reports on the relapses twenty years after patients were inducted into the WHO field trial. Between 1981 and 1982, 1067 borderline lepromatous and lepromatous patients were inducted into the WHO field trial for combined therapy in multi-bacillary leprosy trial. Among them, 357 patients were skin smear positive. During the follow-up in 2002, only 173 of them could be traced and assessed. The mean duration of follow-up was 16.4 +/- 1.83 years. Two patients relapsed 14 and 15 years after being released from treatment, the relapse rate being 0.07 per 100 person years follow-up. Drug susceptibility tests done on one of the relapsed patients revealed drug sensitive organisms to all multi-drug therapy drugs.

Effectiveness of multidrug therapy in multibacillary leprosy: a long-term follow-up of 34 multibacillary leprosy patients treated with multidrug regimens till skin smear negativity.

The World Health Organization (WHO) Field Trials of multidrug therapy (MDT) started at Schieffelin Leprosy Research and Training Centre (SLR & IC), Karigiri, India in December 1981. The patients were treated with two MDT regimens. The first (regimen A) consisted of 600mg rifampicin and 300mg of clofazimine given under supervision on 2 consecutive days monthly, 225mg injection of acedapsone bimonthly and dapsone 100mg daily. The second regimen (regimen B) was the conventional MDT (WHO/MDT), rifampicin 600mg and clofazimine 300mg supervised once a month, dapsone 100mg and clofazimine 50mg daily, unsupervised. Both the regimens were administered for a minimum period of 2 years or until skin smear negativity, whichever occurred later. Thirty-four newly detected previously untreated MB patients, 16 of whom received regimen A and 18 regimen B, were reassessed. Both regimens were well accepted and well tolerated by the patients. Clofazimine discolouration was the only adverse effect of MDT seen in these patients. After completion of treatment with MDT, the patients were followed up for a total duration of 466 person-years with a mean of 13.7 +/- 1.4 years per patient. No relapse was seen.

Chemoprophylaxis is effective in the prevention of leprosy in endemic countries: a systematic review and meta-analysis. MILEP2 Study Group. Mucosal Immunology of Leprosy.

OBJECTIVE: To quantify the efficacy of chemoprophylaxis against leprosy. METHOD: Literature searching of Medline and Embase databases, hand-searching of references and correspondence with investigators. STUDY SELECTION: published papers relating to the prevention of leprosy and the use of chemotherapy in leprosy were identified for critical appraisal. Trials were selected and grouped into three categories according to study design and control groups. DATA ANALYSIS: the relative risks (RR) with 95% confidence intervals were calculated from the original data using a random effects model. To assess the cost-effectiveness of chemoprophylaxis, a further analysis of the rates of disease in the trial and control groups was done based on the numbers needed to be treated (NNT) to prevent one new case of leprosy. RESULTS: A total of 14 trials were identified from 127 published papers on chemoprophylaxis of leprosy. The trials were categorized into randomized controlled trials, non-randomized controlled trials, and uncontrolled trials. The overall results of the meta-analysis shows that chemoprophylaxis gives around 60% protection against leprosy. The NNT are low in trials of household contacts. CONCLUSIONS: The evidence shows that chemoprophylaxis against leprosy is an effective way to reduce the incidence of leprosy, particularly in household contacts. The role of chemoprophylaxis needs to be re-examined using newer drugs given the continuing case detection rates globally.

Relapse as histoid leprosy after receiving multidrug therapy (MDT); a report of three cases.

The histoid type of leprosy has been described as occurring in lepromatous leprosy patients who relapse after many years of apparently successful dapsone monotherapy. Three patients who had received the World Health Organization-recommended regimens of multidrug therapy (WHO/MDT) relapsed as histoid leprosy 12-15 years after completion of treatment. In one patient, through mouse foot pad studies, the bacilli were found to be sensitive to rifampin and clofazimine and resistant to dapsone. In the other two patients mouse foot pad studies were inconclusive. The patients were re-started on WHO/MDT. Two patients took regular treatment and improved, both clinically and bacteriologically. One patient was irregular in treatment, and 1 year after re-starting WHO/MDT nodules were still present although the bacterial index had fallen slightly.

[Bacteriologic study in patients with multibacillary leprosy treated with rifampicin and acedapsone]. / Estudio bacteriológico en pacientes con lepra multibacilar tratados con rifampicina y acedapsone.

A bacteriologic study of 116 patients with multibacillary leprosy from Guantanamo City is made. Samples for bacteriologic examination were derived from both auricular lobules, the two elbows, and the middle phalanges of the third finger. The microscopic examination found acid-alcohol-resistant bacilli in 19% of patients, while failure to find any of these organisms occurred in 81%.

Blood dapsone levels in leprosy patients treated with acedapsone.

The metabolism of the repository drug acedapsone (DADDS,4,4'-diacetyldiaminodiphenyl sulfone) was studied in 15 individuals receiving 225 mg of DADDS, intramuscularly for a period of 75 days. Plasma levels of DDS were determined on the 2nd, 7th, 15th, 30th, 60th and 75th day after administration of the drug by spectrophoto-fluorometric technique. The mean peak levels of DDS (85.36 ng/ml) were noticed on 7th day followed by a gradual decrease in DDS concentration. The mean half-life level (44.53 ng/ml) of DDS were observed around the 15th day. The mean DDS level for the entire period of observation after one dose was 41.95 ng/ml. On the 75th day, the DDS level reached the minimum value of 14.76 ng/ml which was still about 5 times more than the minimal inhibitory concentration (MIC) level of DDS against M. leprae (3 ng/ml). The results are discussed.

Limited duration acedapsone prophylaxis in leprosy.

A randomized controlled chemoprophylaxis trial was carried out in Madras city using 560 disease-free household child contacts of 264 multibacillary cases as study subjects. In the study, 13 cases were diagnosed among 280 contacts who received 3 injections of acedapsone at 10 weeks interval as against 30 cases among 280 contacts who had the same number of placebo injections, during the follow-up period of 225 weeks. The difference in the incidences in the two groups was statistically significant. (X2 6.45; P less than 0.02). The protection due to the limited duration of acedapsone prophylaxis was 56.7 percent. There were no cases of multi-bacillary leprosy in either group. The efficacy of prophylaxis was significant in male children over 9 years of age and female children in the age-group 1-8 years. The other prognostic factors like the infectivity status of the index cases in the household and the duration of exposure to them could have possibly influenced the effectiveness of prophylaxis in preventing progression from infection to clinical disease among the subjects studied. Their effects could not be assessed in this study.

Long-acting, repository antimalarial agents. Duration of protection in mice and monkeys following administration of pyrimethamine pamoate.

The duration of protection from blood-stage malarial challenge following single injections of pyrimethamine pamoate was assessed in mice and monkeys. This duration was dose-related and ranged from several weeks in mice to over 4 months in the monkeys. Comparisons with the previously reported repository drugs, cycloguanil pamoate and acedapsone (diacetyldiaminodiphenyl sulfone), in mice demonstrated that pyrimethamine pamoate provides an equal or greater duration of protection. Studies with mixtures containing acedapsone gave good protection against a pyrimethamine-resistant strain of Plasmodium berghei.

Activity and effective serum level of repository sulphones (DADDS) in lepromatous leprosy.

35 cases of lepromatous leprosy were studied to evaluate the effective blood level and long depot action of acedapsone (DADDS). It was revealed that serum level of this drug is maintained well above the minimum inhibitory concentration upto 60 days following single intramuscular injection. No significant untoward effects of the drug were encountered except one case of Erythema Nodosum Leprosum and six patients with mild reactional symptoms in the form of fever and arthralgia.

Acedapsone in the prevention of leprosy: field trial in three high prevalence villages in Micronesia.

The 1,659 non-leprous people in a Micronesian population experiencing an annual leprosy incidence rate of about 7/1,000 were offered 15 acedapsone (DADDS) injections during 1967--1970 for leprosy prevention purposes. Subsequent annual surveillance showed an initial cessation of new cases during the 3-year DADDS campaign, followed by a resumption of cases thereafter at a yearly level of about 2/1,000 with a longer pause and slower rise among those who received the full regimen. A secondary wave of cases that has occurred since 1973 among children born after 1968 shows that post-campaign transmission occurred, probably principally from relapsing multibacillary cases with onset before the campaign. Recommendations are made for a balanced, long-term control program with DADDS preventive treatment limited to contacts of multibacillary cases.

Acedapsone treatment of leprosy patients: response versus drug disposition.

In 22 lepromatous Filipino patients receiving their first injection of 225 mg acedapsone (DADDS), dapsone (DDS), and monoacetyl DDS (MADDS) were present in plasma in approximately equal quantities. Peak levels of parent drug, DDS, and MADDS occurred between 22 and 35 days. The half-times of disappearance (T1/2) from plasma were 43 days for DDS and MADDS and 46 days for DADDS. Acetylator phenotyping with sulfamethazine (SMZ) and DDS showed that 17 patients were rapid and 5 patients were slow acetylators. Correlations between acetylation of SMZ and DDS after DDS and of acetylation of DDS after DDS and DADDS were highly significant. However, acetylation of DDS after DADDS did not differentiate the patients into acetylator phenotypes. The T1/2 of DDS after DDS in the patients was directly related to the minimum levels of DDS at 77 days after DADDS treatment. These minimum levels were 8-fold higher than the minimum inhibitory concentration (MIC) of DDS for Mycobacterium leprae in mice and rats, but not all patients responded satisfactorily. No relationship could be demonstrated between the bacteriologic response and any of the pharmacologic parameters examined in these Filipino patients. In a companion study, minimum levels of DADDS, MADDS, and DDS were determined in 447 leprosy patients of all disease types from the Karimui District of Papua New Guinea who had been receiving 225 mg DADDS every 70 to 80 days for the past 5 years. All patients exhibited DDS levels above the MIC of DDS for M. leprae, no significant differences in plasma sulfone levels were found among disease types, no relationship between rate of healing in paucibacillary patients and sulfone levels were found, and type of response in multibacillary patients and sulfone levels were unrelated. No substantial accumulation of the sulfones in the Karimui patients receiving continuous therapy with DADDS for 5 years was indicated from a comparison with the levels in the Filipino patients following a single injection of DADDS.