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Continuing Medical Education
PMID: 20944307

New emerging drug regimens for leprosy

Kiran Katoch
 Deputy Director, Central JALMA Institute for Leprosy(ICMR), Tajganj, Agra - 282 001, India

Correspondence Address:
Kiran Katoch
Deputy Director, Central JALMA Institute for Leprosy(ICMR), Tajganj, Agra - 282 001
How to cite this article:
Katoch K. New emerging drug regimens for leprosy. Indian J Dermatol Venereol Leprol 1997;63:139-147
Copyright: (C)1997 Indian Journal of Dermatology, Venereology, and Leprology

During the last three decades, rapid advances have been made in the treatment and management of leprosy. This progress has provided confidence to propose the goal of elimination of leprosy as a public health problem by the year 2000. The WHO recommended chemotherapy for leprosy is well accepted, tolerated and has greatly helped in controlling the disease in our country. However, some problems still exist and efforts are being made to overcome them and further improve the treatment of these patients.

Newer, more effective, and also operationally less demanding regimens are required so that the duration of treatment is further reduced, more so in MB patients. Secondly the incidence of "reactions" and "relapses" need to be reduced after the stoppage of treatment. Moreover, it would be operationally very helpful if the same treatment schedule with different time durations could be given to both PB and MB patients.

1. Alternate Drugs / Agents

Several alternative drugs / agents have been identified and proposed to be used in different combinations for the treatment of leprosy.[1] Important agents are:

i The Fluoroquinolones

This group of compounds act by inhibiting the alpha sub unit of the enzyme DNA gyrase thereby interfering with the bacterial DNA replication. Among the quinolones, ofloxacin, pefloxacin and sparfloxacin have been observed to be active against M leprae.[2] Ofloxacin is the current favourite, whereas sparfloxacin appears to be emerging.[3] Pefloxacin is active,[4] but is not preferred due to various considerations which include the dosage (800mg needs to be administered in two divided dosage) to get the same effect as single 400mg dose of ofloxacin. Clinical trials have demonstrated that a daily dose of 400mg of ofloxacin (OFLO) is bactericidal against M leprae although less so than a single dose of rifamicin (RMP). When given daily in the above dose for 22 days it killed 99.9% of the viable organisms. Experiments (In vitro and Vivo) have demonstrated that on weight for weight basis, sparfloxacin (SPFX) is more active than OFLO against M leprae.[5] However, because the manufacturers of SPFX recommend that patients be treated by no more than 200mg daily, the greater activity is likely to be offset by the lower dosage. This group of drugs are well absorbed orally and reach a peak serum concentration after 2 hours, and have a serum half-life of about 7 hours. They are excreted mainly unchanged by the kidneys. Side effects include nausea, diarrhoea, other gastrointestinal complaints, and a variety of central nervous system complaints, including insomnia, headache, dizziness, nervousness and hallucinations. Serious problems are infrequent, and only occasionally require discontinuation of the drug.

In a trial of OFLO alone and its combination with dapsone (DDS) and clofazimine (CLF), 24 patients with newly diagnosed lepromatous leprosy were allocated randomly to three treatment groups and treated for 56 days by OFLO daily, 800mg OFLO daily, or 400mg OFLO combined with 100mg DDS and 50mg CLF daily plus 300mg CLF once every 28 days.[6] The bactericidal activities of the above regimens were measured by titrating the proportion of viables in normal and nude mice. More than 99%, > 99.99%, and > 99.99% of the viable M leprae were estimated to be killed by 14, 28, and 56 days of treatment respectively. Bactericidal activity did not differ significantly among the three groups.

(ii) The Macrolides

Several members of this group, including erythromycin have been evaluated and clarithromycin (CLARI) appears the most promising. Studies in mouse footpad have demonstrated the potent bactericidal activity of this drug but it is less bactericidal than RMP. When administered in a dosage of 500mg daily to leprosy patients, the drug killed 99% of M leprae by 28 days, and 99.9% by 58 days.[2] It is readily absorbed from the gastro-intestinal tract and converted to its active metabolite, 14-OH-CLARI. It acts by linking to the 50s sub-unit, thus inhibiting bacterial protein synthesis. Peak serum concentration is reached 1-4 hours after a 500mg dose, and its serum half-life averages 6-7 hours. Tissue concentrations are higher than those in the serum. It has been reported that the concurrent administration of RMP decreased the serum CLARI concentration by 80%, but the serum concentration of the 14-OH metabolite remained unchanged.[7] It is relatively non-toxic. Gastrointestinal irritation, nausea, vomiting and diarrhoea are the common side effects observed with this drug. In MB leprosy patients treated daily with 500mg CLARI, the clinical response, the MI decrease and the killing of viable M leprae were also of the same order as that of OFLO and minocycline (MINO)

(iii) Minocycline

Minocycline (MINO) is the only tetracycline that exhibits significant activity against M leprae, perhaps because its lipophilicity permits it to penetrate the bacterial wall. The drug is bactericidal against M leprae but less so than RMP. It binds reversibly to the 30S unit of the ribosome thus blocking the binding of aminoacyl transfer RNA to the messenger RNA-ribosomal complex, thereby inhibiting protein synthesis. The drug is well absorbed orally, with a serum half-life of 11 to 23 hours. Side effects include discolouration of teeth of infants and children, occasional pigmentation of the skin and mucous membranes, various gastrointestinal complaints, and central nervous system toxicity, including dizziness and unsteadiness. The prolonged use of the drug for acne indicates that the drug is relatively safe and nontoxic.[1][2]

In a clinical trial, eight untreated consenting adults of lepromatous and borderline lepromatous leprosy were treated with 100mg of MINO alone once daily for three months.[9] The drug was well tolerated, and there was a rapid clinical response. The clearance of viable M leprae from the skin by MINO was faster than that reported for CLF and DDS but slower than that for RMP and similar to that by OFLO. Minocycline has been observed to be effective both in tuberculoid,[10] and lepromatous cases.[9][11] Its administration was associated with lesser reactions especially in lepromatous cases.

(iv) Other Drugs

With the possible exception of fusidic acid,[12] the other drugs that have been demonstrated to be active against M leprae are much less potent. These drugs include the combination of amoxicillin with potassium clavulanate,brodimoprim, deoxyfructoserotonin and several others.[1]

2. Combination of newer anti - leprosy drugs

During the recent years several combinations of newer drugs among themselves and with already established drugs have been suggested and tried. Some of such studies are: Clinical trials of combination of OFLO with DDS and CLF, [6,13] and OFLO with RMP,[14] have been reported to be beneficial in treatment of lepromatous leprosy.

Ji and his colleagues have demonstrated that in mice single doses of the combination of MINO with CLARI with or without OFLO, administered once monthly together with monthly 600mg doses of RMP are fully active against M leprae.[15]

Because of greater bactericidal activity, the addition of OFLO, MINO, or CLARI or some combination of these drugs to WHO/ MDT or substituting one of these drugs might permit shortening of the treatment.[2][5] The results of a trial now in progress of a combination of OFLO and RMP administered daily for one month is awaited. Earlier a one month trial of RMP combined with MINO (both given daily) for one month has been reported to give satisfactory results in a mixed group of 20 PB and MB patients and no relapses were reported after 2 years of follow-up. While the initial results of such intensive short course regimens have been described to be promising,[8] a larger group of patients must be followed up for a much longer period of time in order to demonstrate that the relapse rate is satisfactorily low.

3. Intermittent therapy

For proper implimentation of control programmes intermittent regimens are more desirable. The THEMYC subcommittee has developed several protocols employing combination of new drugs in fully supervised intermittent regimens. The first of these protocols involves the trial of a single dose of a combination of 600mg RMP, 100mg MINO and 400mg OFLO in the treatment of singlelesion PB patients. In another series PB patients will receive a combination of RMP with OFLO and MINO just prescribed once a month for 3 or 6 months. For MB patients the drugs will be administered once monthly for 12 or 24 months. The safety of these regimens will be examined by comparing the 6 and 24 month regimens with WHO/MDT.[2][5]

4. Relapsed Patients

The study group on the chemotherapy of leprosy WHO 1994 has recommended the following treatment regimens for relapsed patients.[16]

(i) Relapse with M leprae sensitive to all standard drugs: These cases essentially require retreatment with WHO-MDT for their type of disease.

(ii) Relapse with dapsone resistant M leprae: The standard WHO-MDT is sufficient in such cases. Thus when relapses occur among cases previously cured with dapsone monotherapy, only standard WHO-MDT is required.

(iii) Relapses with rifampicin resistant M leprae: Such cases are recommended to be treated with clofazimine 50mg daily for 24 months plus two drugs out of the group: ofloxacin 400mg daily, minocycline 100mg daily and clarithromycin 500mg daily for 6 months, to be followed by either ofloxacin or minocycline daily for an additional 18 months. It is further recommended that such therapy be administered only under direct supervision of a referral centre.

It must be emphasized that none of these regimens have been subjected to long term clinical trials to determine their safety and efficacy. Nonetheless it is quite likely that the study group regimen would be effective, though costly.[16]

5. Immunotherapy

The addition of immunotherapy to chemotherapy aims at achieving more efficient killing of viable bacilli including persister organism as well as faster clearance of dead bacilli and their components from the body. This is expected to result in effectively reducing the duration of treatment and help in greater case holding and better compliances of patients.[17]

Various types of agents have been investigated for their immunotherapeutic potential in leprosy which can be broadly grouped as a) Antigenically related mycobacteria, b) Drugs, and c) Other immunomodulators.[17]

Among the antigenically related mycobacteria BCG, Mycobacterium w, ICRC bacillus and Mycobacterium vaccae are the most prominent. In a trial of combined chemotherapy and immunotherapy at our Institute,[18] untreated BL/LL patients with a initial mean BI of 4+ to 6+ were serially allocated to three treatment groups. The first group received a slightly modified WHO regimen,[19] and live BCG vaccine every 6 months, the second group received the same MDT and killed Mycobacterium w every 6 months, and the third group received the above MDT and distilled water every 6 months and acted as a control for the study. It was observed that in both the groups which received immunotherapy no viable bacilli could be detected after 12 months of therapy as assessed by mouse foot pad inoculation and ATP estimation of the skin biopsies, whereas in the control cases viable bacilli could be detected up to 18 months by the mouse foot pad and 24 months by ATP estimation. While all patients of the MDT+Mycobacterium w group became smear negative by 36 months of therapy, patients of the MDT+BCG group became negative by 42 months. On the other hand patients of the control group who were on MDT+distilled water were still smear positive at the end of 4 years with mean BI of 0.45 and all of them became smear negative by 5 years. Besides this the addition of immunotherapy did not increase the incidence or severity of reactions but rather these patients had reactions only upto the end of two years as compared to the control group which continued to have reactions upto the end of three years.

Zaheer et al also reported on the effect of MDT and Mycobacterium w in BL/LL patients and observed rapid bacteriological clearance and histological upgrading in these patients.[20]

Bhatki and Chulawala investigated the immunotherapeutic potential of single dose of killed ICRC vaccine at the start of therapy who were being treated with conventional MDT. They reported a significant and rapid fall in BI in the vaccinated group as compared to controls.[21]

Stanford et al used BCG + M vaccae as immunomodulator in contacts and patients of leprosy and reported beneficial results.[22] Among the other immunomodulators gamma interferon (INF-γ), [23,24] and interleukin, [2,25] have been successfully tried for altering the energy in lepromatous leprosy. Bannerjee and MacDermott using nude mice, reported a twenty-six enhancement of killing of M leprae in mice treated with RMP and INF-γ, as compared to RMP alone.[24] Kaplan et al[25] and Mathur et al[26] in their studies on the effect of intralesional recombinant INF-γ, have shown a distinct fall in the BI and formation of epithelioid cells at the local site of inoculation. Enhanced bacterial clearance at the local site of gamma interferon injection has also been reported by Sivasai et al.[23]

After reviewing the work of various investigators, and our own experience, it can be safely concluded that immunotherapy is safe and effective adjunct to the chemotherapy. It helps in reducing the duration of treatment and also the incidence as well as duration of reactions in leprosy. [18,27]

5. Same regimen with different duration for MB/PB

Besides the use of newer drugs and addition of immunotherapy to the existing chemotherapy, an attempt has been made to use the same regimen in all patients of leprosy but for different durations so that treatment could be made operationally more feasible for control programmes. With this in view we have conducted a study in which PB patients were randomly allocated to two treatment groups. One group received WHO MDT and acted as control whereas the second group received WHO MDT + 50mg CLF daily. The treatment in both the groups was stopped at 6 months; 13.3% were active in control group whereas only 6.6% were active in the trial regimen. It is too early to conclude about the efficacy of the regimen as sufficient follow-up is required to monitor late reactions and relapses.

Other important / relevant issues

The data reviewed in the preceding paragraphs gives a brief description of the methods that have been contemplated to improve the present day treatment. There are several other drugs which are also being investigated in the laboratories for their potential use but have not been described here as they have not been cleared for mass use and are undergoing feasibility studies.

The newer treatment regimens described above have been planned for use but have not undergone extensive clinical trials to prove their safety and efficacy. They have therefore to be used with caution in supervised field trials and at present are not recommended for general use.

In the light of the experience with the response to MDT obtained in the last few years, it is worthwhile to further subclassify the PB and MB patients into two more sub-groups each. The PB patients are divided into patients with single lesions and patients with more than one lesion. The MB patients are also divided into highly bacillated and the less bacillated groups. The highly bacillated group includes patients with a mean BI of 4+ or more at the start of therapy and the rest are grouped into the less bacillated MB group.

Because of the tremendous improvement of case detection, the number of new cases detected every year has increased steadily, and about half of these early cases have only single skin lesion of PB leprosy. It has been argued that as such cases have a strong tendency to self heal and the risk of developing nerve damage is minimal, therefore a single dose of a combination of drugs would be sufficient to treat such cases.[28] The THEMYC Steering Committee of the WHO has initiated a trial in which 1483 newly diagnosed cases were allocated randomly to treatment by either WHO / MDT for PB leprosy for 6 months or single dose of 600mg of RMP + 400mg of OFLO + 100mg of MINO under supervision, followed by a placebo. The results of this trial will be available at the end of 1997 when the treatment code will be broken.[5] Although such endevours are welcome, no proper pilot trials with a reasonable follow up had been undertaken prior to this large field trial to show that such treatment was indeed optimum. Also it is difficult to believe that all the mycobacteria which are present in the host and are in different stages of growth, will all be killed by a single dose of the above drugs.

The other trials which have been started for multi-lesion PB cases are again random allocation to one of the following two regimens.[2]

i) WHO / MDT for PB patients for 6 months: or ii) 600mg of RMP and 400mg of OFLO daily for 4 weeks. In another study PB patients are to be treated by either 3 or 6 monthly doses of 600mg RMP + 400mg OFLO + 100mg MINO for either 3 or 6 moths. After stopping treatment patients will be followed up and results will be compared with those of WHO/MDT. Here again no adequate feasibility and efficacy pilot trials with an adequate follow up were undertaken prior to these studies. Following up the patients for a sufficient duration of time is essential because that is the only way to prove the efficiency of the regimen in leprosy as M leprae cannot be grown in artificial medium, and the disease has a long and variable incubation period.

The THEMYC Steering Committee sponsored MB trials are as follows:[2]

i. WHO MDT for MB leprosy for 12 months. ii. WHO / MDT for MB leprosy for 12 months plus an initial 4 week period of 400mg OFLO daily iii. WHO / MDT for MB leprosy for 24 months iv. Daily treatment with 600mg RMP and 400mg OFLO for 4 weeks followed by placebo. A trial has been undertaken in Myanmar which includes treating these MB patients with either 12 or 24 monthly doses of 600mg RMP + 400mg OFLO + 100mg MINO. In Guinea MB patients are to be given 24 monthly doses of the above regimen. All the results are to be compared with the standard WHO / MDT.

A one year regimen using monthly administration of MINO + OFLO + RMP alongwith CLF and DDS daily is being tried in smear positive MB cases. The patients are being followed up on placebo.

A very high relapse rate of 20% has been reported after 7 to 9 years among highly bacillated MB patients (who begin their treatment with a BI of 4 + or more) who received 2 years of fixed duration WHO MDT.[29] The authors of this report recommend that the duration of treatment be increased to 4 years in these patients. This was also extensively discussed at the International Leprosy Congress held at Orlando in 1994. The recommendations at this workshop were that this group of patients should be treated separately for a longer duration. In an earlier study,[30] we reported the results of follow up of highly bacillated BL/LL patients who discontinued therapy after different durations. It was observed that patients who were treated for 12-18 months relapsed clinically and bacteriologically in 3-5 years after stopping therapy. Patients who had treatment for 36 months responded as patients on continous therapy. In light of the observations in various studies quoted above, it is worthwhile these patients are treated as a separate group with a prolonged time duration or with immunotherapy or with the addition of newer drugs.

The results after a sufficient follow-up of these field trial and other supervised trials will help us to conclude which regimen (s) and for what duration is optimum for treatment of different types of leprosy. It needs to be emphasized that the regimens proposed or that are being tried in the field are just trial regimens. They are not recommended for treatment of patients as of now.

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