High relapse rate among lepromatous leprosy patients treated with rifampin plus ofloxacin daily for 4 weeks.

Fifty-one lepromatous leprosy patients, all of whom had relapsed after previous dapsone (DDS) monotherapy, were treated between 1990 and 1991 with 600 mg of rifampin (RMP) plus 400 mg of ofloxacin (OFLO) daily for 4 weeks, and the great majority of the patients were followed up at least once a year after completion of the treatment. After only 173 patient-years of follow-up, 5 relapses had been detected; the overall relapse rate was 10.0% (confidence limits, 1.7 and 18.3%), or 2.9 relapses (confidence limits, 0.4 and 5.4) per 100 patient-years. The unacceptably high relapse rate indicated that 4 weeks of treatment with daily RMP-OFLO was unable to reduce the number of viable Mycobacterium leprae organisms to a negligible level. In addition, the M. leprae from one of the relapses were proved to have multiple resistance to DDS, RMP, and OFLO. To avoid further relapses, the follow-up was terminated and the great majority of the patients were retreated with the standard 2-year multidrug therapy from 1994. No further relapse has been diagnosed since the beginning of retreatment.

Effect of HIV infection on leprosy: a three-year survey in Bamako, Mali.

From February 1992 until June 1994, all patients with histologically proven leprosy examined at the Leprology Unit of the Institut Marchoux in Bamako, Mali, were screened for HIV serology. In total, 740 leprosy patients have been tested; 553 known, previously treated leprosy cases and 187 new cases, mainly self-reporting and referred cases. The global seroprevalence in the sample was 1.5% (11/740), and increased from 1.3% in 1992 to 3.1% in 1994. HIV seroprevalence was higher in paucibacillary (PB) than in multibacillary (MB) cases (3.8% versus 0.8%, p < 0.05), and was slightly higher in new cases than in known, already treated cases (2.1% versus 1.3%), although not significantly. Among the 553 known, already treated leprosy patients, 1 out of 7 HIV-seropositive patients relapsed, as opposed to 34 out of 546 HIV-seronegative cases (14.2% versus 6.2%, p = 0.36). Among the new cases, none of the 37 patients with reaction and/or neuritis was HIV positive. In known, treated leprosy cases, there was no difference in the frequency of reactions and/or neuritis between HIV-positive and HIV-negative cases. Migration in a neighboring country appeared to be a risk factor for HIV seropositivity in our sample (chi 2 = 4.5, p = 0.04). In order to estimate the association of HIV with leprosy as compared to the general population, a control group of blood donors was set up, matched for age and sex. There was, however, no difference in HIV seroprevalence between the control group (9/735, 1.2%) and the leprosy group (1.5%). Although leprosy patients recruited for this study constitute a highly selected sample, it appears that HIV infection has little effect on leprosy, particularly on the PB/MB ratio, leprosy reactions and neuritis, but there is a suggestion the HIV infection might be associated with increased frequency of relapse.

PIP: HIV infection is a major risk factor for tuberculosis and other mycobacteria, but its association with leprosy remains unclear. From February 1992 to June 1994, all leprosy patients examined at the Leprology Unit of the Institut Marchoux, a reference center for leprosy in Mali, were screened for HIV infection. 740 leprosy patients were tested over the period; 553 known, previously treated cases and 187 newly diagnosed leprosy cases. 584 patients were multibacillary (MB) cases and 156 were paucibacillary (PB), with a large majority of MB cases among the known cases, due to the selected recruitment of those patients. There were 539 men of mean age 39.3 years and 201 women of mean age 37.7. New and known cases were of mean ages 30.7 and 41.6 years. Overall, 1.5% (11/740) were identified as HIV seropositive, increasing from 1.3% in 1992 to 3.1% in 1994. HIV seroprevalence was 3.8% among PB cases and 0.8% among MB cases, and was slightly higher in new cases than in known, already treated cases. Among the 553 known, already treated leprosy cases, 1 out of 7 HIV-seropositive patients relapsed, compared to 34 of 546 HIV-seronegative cases. Among the new cases, none of the 37 patients with reaction and/or neuritis was HIV positive. It appears that HIV infection has little effect upon leprosy, especially upon the PB/MB ratio, leprosy reactions and neuritis, but HIV infection may be associated with increased frequency of relapse.

Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, against Mycobacterium leprae in patients.

Fifty patients with newly diagnosed lepromatous leprosy were allocated randomly to one of five groups and treated with either a month-long standard regimen of multidrug therapy (MDT) for multibacillary leprosy, a single dose of 600 mg of rifampin, a month-long regimen with the dapsone (DDS) and clofazimine (CLO) components of the standard MDT, or a single dose of 2,000 mg of clarithromycin (CLARI) plus 200 mg of minocycline (MINO), with or without the addition of 800 mg of ofloxacin (OFLO). At the end of 1 month, clinical improvement accompanied by significant decreases of morphological indexes in skin smears was observed in about half of the patients of each group. A significant bactericidal effect was demonstrated in the great majority of patients in all five groups by inoculating the footpads of mice with organisms recovered from biopsy samples obtained before and after treatment. Rifampin proved to be a bactericidal drug against Mycobacterium leprae more potent than any combination of the other drugs. A single dose of CLARI-MINO, with or without OFLO, displayed a degree of bactericidal activity similar to that of a regimen daily of doses of DDS-CLO for 1 month, suggesting that it may be possible to replace the DDS and CLO components of the MDT with a monthly dose of CLARI-MINO, with or without OFLO. However, gastrointestinal adverse events were quite frequent among patients treated with CLARI-MINO, with or without OFLO, and may be attributed to the higher dosage of CLARI or MINO or to the combination of CLARI-MINO plus OFLO. In future trials, therefore, we propose to reduce the dosages of the drugs to 1,000 mg of CLARI, 100 mg of MINO, and 400 mg of OFLO.

[Anatomopathologic study of five cases of leprosy in HIV seropositive patients]. / Etude anatomopathologique de 5 cas de lèpre chez des sujets séropositifs pour le virus de l'immunodéficience humaine (VIH).

In an effort to establish whether the human immunodeficiency virus (HIV) modifies the histological image of lepromatous skin lesion, a comparative study was conducted in 1994 at the Marchoux Institute in Bamako, Mali, on persons newly suffering from leprosy who had been tested seropositive and seronegative for the HIV virus. These new leprosy patients had never been treated and could be grouped as follows: 5 HIV-positive (1 TT, 1 BT, 1 BL, 2 LL) and 10 controls testing HIV-negative, selected according to the following criteria: each seropositive leprosy subject was matched with two seronegative controls having the same clinical features, same stage under the Ridley classification system, same age and sex. No discordance between the clinical classifications and the histological features in the subjects testing HIV-positive has been observed. They display features similar to those testing negative, with the presence of histiocytes, in particular epithelioid cells and giant cells in normal proportion depending on the form of leprosy. The only remarkable difference was a greater incidence of oedema in the subjects testing seropositive, compared with patients testing seronegative. In conclusion, HIV infection does not appear to cause major modifications in cellular response to Mycobacterium leprae, and no changes should be made in leprosy control programmes.

Relapse after long-term follow up of multibacillary patients treated by WHO multidrug regimen. Marchoux Chemotherapy Study Group.

Thirty-five multibacillary (MB) leprosy patients were treated with 2 years of multidrug therapy (MDT) and followed up regularly for relapse. Relapse was defined as: a) an increase of the bacterial index (BI) by 2+ over the previous value from any single site of old lesions and b) the occurrence of definite new skin lesion(s) which demonstrated a higher BI than any pre-existing lesion. After a mean duration of 72.7 +/- 17.3 months of follow up per patient, seven relapses were diagnosed; the mean incubation period of relapse was 62.7 +/- 18.7 months. The overall relapse rate was 20.0% (or 3.3 per 100 patient-years), very significantly higher than the figures obtained from the same group of patients analyzed 2 1/2 years earlier, indicating that relapses occurred late (at least 5 +/- 2 years) after stopping MDT. Further analysis indicated that the relapse rate was closely correlated with the bacterial load of the patient, occurring far more frequently among patients with a BI of > or = 4.0 before MDT or with a BI of > or = 3.0 at the end of MDT. To avoid the alarmingly high relapse rate, it is proposed that the duration of MDT be doubled to 4 years in patients with an average BI of > or = 4.0 before MDT.

Relapses after a single dose of rifampin in skin-smear negative multibacillary patients after dapsone monotherapy.

Between 1982 and 1985, a single 1500 mg dose of rifampin (RMP) was given to 136 multibacillary leprosy patients who had become clinically inactive and skin-smear negative after various durations of dapsone monotherapy, and then antileprosy chemotherapy was totally stopped. By the end of June 1992, 15 relapses were detected among these patients. The overall relapse rate was 11%; the relapse rate per 100 patient-years was 2.1%, which was the highest among those published to date; the cumulative risk of relapse at year 7 of follow up was 8.8%. All of these figures indicate that the relapse rate among this group was at least the same as in other studies where patients received dapsone monotherapy only. Therefore, the administration of a single large dose of RMP could neither prevent relapse nor reduce its rate among multibacillary patients who had already become clinically and skin-smear negative after dapsone monotherapy.

Powerful bactericidal activities of clarithromycin and minocycline against Mycobacterium leprae in lepromatous leprosy.

Thirty-six patients with newly diagnosed lepromatous leprosy were allocated randomly to three groups and treated for 56 days with minocycline (100 mg daily), clarithromycin (500 mg daily), or clarithromycin (500 mg) plus minocycline (100 mg daily). All groups had rapid and remarkable clinical improvement and significant decline of the bacterial and morphologic indices in skin smears during treatment. More than 99% and > 99.9% of the viable Mycobacterium leprae had been killed by 28 and 56 days of treatment, respectively, as measured by inoculation of organisms recovered from skin samples, taken before and during treatment, into the footpads of immunocompetent and nude mice. Clinical improvement and bactericidal activity did not differ significantly among the three groups. Adverse reactions were rare and mild, and no laboratory abnormality was detected during the trial. Both clarithromycin and minocycline displayed powerful bactericidal activities against M. leprae in leprosy patients and may be considered important components of new multidrug regimens for the treatment of multibacillary leprosy.

Relapses in multibacillary leprosy patients after stopping treatment with rifampin-containing combined regimens. Marchoux Chemotherapy Study Group.

During the decade between the mid 1970s and the mid-1980s, 12 rifampin (RMP)-containing combined regimens were tested among lepromatous leprosy patients in the Institut Marchoux. The 384 patients who were seen at least once during the period beginning 12 months after completion of treatment were considered eligible for analysis of the relapse rate. By the end of May 1991, relapse, manifested by a significant increase of the bacterial index (BI) and the appearance of new lesions with a BI greater than that of preexisting lesions, had been observed in 68 (17.7%) of these patients. Relapse was confirmed by the presence of viable Mycobacterium leprae in skin biopsy specimens obtained from 54 of the first 61 cases; virtually all of the isolated strains remained susceptible to RMP. The relapses occurred late, about 5 +/- 2 years after stopping treatment; the shorter the duration of RMP administration, the earlier the appearance of the relapse. The variations of the relapse rate among regimens were considerable: total relapse rate ranged from 2.9% to 27.8%, and the relapse rate per 100 patient-years of observation ranged from 0.8 to 6.9. Among the 12 regimens, only the WHO/MDT yielded an acceptable relapse rate (defined as a rate lower than 1.0 per 100 patient-years). However, because the mean duration of follow up was shortest among the patients treated with WHO/MDT, the relative low relapse rate among these patients must be interpreted with great caution.

Short-term trial of clofazimine in previously untreated lepromatous leprosy.

Forty-five previously untreated lepromatous leprosy patients were allocated randomly to three groups and treated, respectively, with Regimen A, standard dosage of clofazimine (CLO) in multidrug therapy (MDT) regimen; Regimen B, CLO 600 mg once every 4 weeks; and Regimen C, CLO 1200 mg once every 4 weeks. The duration of the trial was 24 weeks. By the end of the trial, although a few patients in each group did not improve at all clinically, the majority of patients showed clinical amelioration but the responses were slow. While the mean morphological index dropped to the baseline after 24 weeks of treatment, the mean bacterial index did not change significantly. About 80% of the patients in each group remained nasal-smear positive at the end of the trial, but the bacterial loads steadily declined. No significant difference has been detected in these parameters among the three groups. The patients tolerated the regimens very well and the side effects were mild. The results of serial mouse foot pad inoculation demonstrated that the positivity rates of multiplication of Mycobacterium leprae in mice and the proportions of viable organisms reduced gradually in all groups. Because the positivity rate at week 24 in Group C did not differ significantly from Group A, but was significantly smaller than that of Group B, we conclude that Regimen C was as active as Regimen A and could be applied for monthly supervised treatment along with rifampin; Regimen B is less effective and should not be used for the treatment of leprosy.

Polymerase chain reaction amplifying DNA coding for species-specific rRNA of Mycobacterium leprae.

The sensitivity of the polymerase chain reaction (PCR) on the DNA coding for the species-specific fragment of 16S rRNA of Mycobacterium leprae studied on mouse foot pad harvests and human skin biopsies varies widely between 1 and 3 x 10(4) organisms. This is probably the result of variations in the proportions of organisms with sufficiently intact DNA suitable for PCR. Preserving human skin biopsies for 3 weeks at an ambient temperature even after boiling for 6 minutes gives rise to a 10-fold decrease in sensitivity. Fixation of tissues in formol 10% or Lowy fixative or preserving in Dubos OAA broth is very harmful to the PCR, mainly due to the enhancement of an inhibitory effect on the PCR reaction. For preservation, the best choice at the moment seems to be alcohol 70%. Sample preparation of five cycles of freeze-boiling is simple and generally more efficient than proteinase K treatment and DNA extraction.

Evaluation of five treatment regimens, using either dapsone monotherapy or several doses of rifampicin in the treatment of paucibacillary leprosy.

The objective of the present study was to define short-course treatment regimens for PB leprosy and to compare them with the 'classical' dapsone treatment and the WHO-PB regimen. Five treatment regimens were studied and evaluated by the histologic evolution. The regimens were: (1) dapsone 100 mg daily, non-supervised for 3 years; (2) RMP 900 mg supervised, once weekly, 8 doses; (3) idem 12 doses; (4) RMP 600 mg, once monthly, supervised, 6 doses and during this treatment dapsone 100 mg daily unsupervised; (5) RMP 600 mg together with dapsone 100 mg daily, supervised for 6 days. For each of these regimens there were between 114 and 195 person-years of follow-up. Results are comparable for the 5 treatment regimens, and reach 65-75% cure rates at 36 months and 80-90% at 48 months after the start of therapy. The relapse rate for all groups is about 0.5% per year. The difficulty for the diagnosis of relapse in PB leprosy is discussed. It is concluded that treatment of PB leprosy can be relatively simple but that a relatively long time is needed to evaluate its effect.

[Supervised bimonthly quadruple chemotherapy in 72 paucibacillary leprosy patients in French Guyana]. / Quadruple chimiothérapie bimensuelle supervisée chez 72 paucibacillaires en Guyane française.

In French Guyana we have treated 72 paucibacillary leprosy with an association of Rifadine + Lamprene + Trecator + Disulone given twice monthly under supervision during 6 months. Results have been satisfying and side effects rare. The sequential character of treatment shows a substantial advantage on the operational side but may appear to be favorable to bacterial resistance.

Interleukin-1 released by blood-monocyte-derived macrophages from patients with leprosy.

In highly purified blood-monocyte-derived macrophages collected from patients with leprosy and from healthy individuals and cultured in vitro with mycobacterial antigens such as Mycobacterium bovis BCG or Mycobacterium leprae, we nonspecifically induced the synthesis of interleukin-1. Normally, all supernatants from cultured macrophages of all subjects tested produced similar amounts of interleukin-1. However, only in patients with lepromatous leprosy, M. leprae, but not BCG, induced high-level synthesis of prostaglandin E2, which acted as a suppressor factor in the mouse thymocyte proliferative assay used to measure the interleukin-1 content of the supernatants. Normal interleukin-1 content of those supernatants was demonstrated by blocking the prostaglandin E2 synthesis by the addition of indomethacin to the medium throughout the experimental procedure. We also tested the efficiency of a combination of BCG and M. leprae in reducing the prostaglandin E2 synthesis, but with the methodology used, we did not observe any beneficial effect of such a combination. These results demonstrate the possible role of M. leprae in the induction of at least one of the suppressive monokines and are additional arguments for the involvement of macrophages in the suppression of the specific cell-mediated immunity to M. leprae observed in lepromatous leprosy.