|Year : 2020 | Volume
| Issue : 1 | Page : 1-4
Second-line anti-leprosy drugs: Indian experience
Vivek V Pai
Director, Bombay Leprosy Project, Mumbai, Maharashtra, India
|Date of Submission||25-Nov-2019|
|Date of Decision||28-Nov-2019|
|Date of Acceptance||20-Apr-2020|
|Date of Web Publication||23-Jun-2020|
Dr. Vivek V Pai
Bombay Leprosy Project, 11, Vidnyan Bhavan, VN Purav Marg, Sion, Chunabhatti, Mumbai - 400 022, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Pai VV. Second-line anti-leprosy drugs: Indian experience. Indian J Drugs Dermatol 2020;6:1-4
Since the implementation of multidrug therapy (MDT), there has been a marked decline in the prevalence of the disease and total caseload of leprosy. This has been possible owing to the steps taken during the last more than four to five decades.
Killing of the causative organisms (Mycobacteriumleprae) by treating the patients with effective antimycobacterial drugs has been the most important means of reducing the quantum of infection in the community. Before the introduction of MDT, dapsone was the mainstay in the treatment of leprosy.
| Short-Course Chemotherapy With Second-Line Drugs|| |
The concepts of chemotherapy of leprosy have undergone a phenomenal change over the past decade. Although the current WHO-MDT is quite effective, a relentless search for newer drugs is on. Recently, ofloxacin, minocycline, and clarithromycin have been considered as second-line newer drug regimens along with rifampicin as alternatives to standard MDT.
| Newer Chemotherapeutic Agents in Leprosy|| |
The reasons for the development of new drugs and regimens are many. From the operational point of view, the recommended duration of treatment particularly for multibacillary (MB) leprosy is still too long. Secondly, two of the components of currently administered drugs for MB leprosy, i.e. dapsone and clofazimine are weakly bactericidal against M. leprae. Hence, further shortening the duration of treatment by this regimen might result in a higher relapse rate. Supervisioon of administration of the daily components dapsone and clofazimine is also an important issue. Lastly, patients who cannot tolerate any of the drugs in standard WHO-MDT-MB need a safer and an effective alternative.
Chemotherapy coupled with immunotherapy, the research on which is increasing, may alone be the answer for those who are eager to achieve maximum clinical results. To further improve the efficacy of treatment and shorten the duration of treatment, several newer drugs are being studied in combination with rifampicin to achieve a better cure in paucibacillary (PB) and MB leprosy. There are various groups of drugs available.
Fluoroquinolones: ofloxacin, pefloxacin, sparfloxacin, temafloxacin, moxifloxacin, and sitafloxacin. This group of drugs acts by blocking DNA gyrase, thereby inhibiting the coiling and supercoiling of DNA. Ofloxacin has remarkable efficiency, as it kills over 99.99% of viable M.leprae in less than 1 month of therapy. Moxifloxacin has a bactericidal activity close to that of rifampicin.
Adverse effects are mild and include nausea, diarrhea, headache, insomnia, and dizziness. Because of the effect on the growth of cartilage, fluoroquinolones are not used in children.
Tetracyclines: minocycline is bactericidal for M.leprae though bacteriostatic for other bacteria. It inhibits protein synthesis by binding to the 30s ribosomal subunits of bacteria. Being tremendously lipophilic, it easily enters the bacteria and results in inhibition of protein synthesis. It can cause diarrhea, dizziness, drowsiness, oral ulcers, and headache. It causes discoloration of teeth in young children.
Macrolides: clarithromycin is bactericidal, and it inhibits protein synthesis by binding to the 50s ribosomal subunits of bacteria. It can cause gastrointestinal upsets, dizziness, and confusion.
On account of the sequential action of minocycline and clarithromycin in inhibiting protein synthesis, a marked synergism of action has been found in leprosy.
Ansamycins like rifabutin, rifapentine, and R-76-1 act by blocking the DNA-dependent RNA polymerase of the bacteria. Dihydrofolate reductase inhibitors are brodimoprim and K-130. Fusidic acid is bacteriostatic and inhibits protein synthesis by preventing the translocation of elongation factor G from the ribosome. Beta-lactam antibiotics like cephaloridine, cefuroxime, and amoxicillin plus clavulanic acid act by inhibiting the synthesis of the peptidoglycan layer of the bacterial cell wall. Bedaquiline (Diarylquinoline R207910) is bactericidal. It targets the subunit c of mycobacterial adenosine triphosphate synthase. It was shown to have an activity against M. leprae in mice similar to that of moxifloxacin and rifampicin. Bedaquiline is being used, especially for drug-resistant TB. It persists for long periods in the tissues and can cause arrhythmias and a prolongation of QT interval.
In Fluoroquinolones, Perfloxacin and Ofloxacin have shown high bactericidal activity in mice and humans, while moxifloxacin has shown very high bactericidal activity in both. Clarithromycin and Minocycline, belonging to the class of macrolide and tetracycline, respectively, have shown high bactericidal activity in both mice and humans. In Rifamycin class, Rifapentine has shown very high bactericidal activity in mice while human trials are not done yet.
Trials were undertaken to reduce the duration of treatment to 28 days in MB and PB leprosy with a combination of rifampicin and ofloxacin. However, a recent report by the WHO shows that in a group of patients given rifampicin and ofloxacin for 28 days in Brazil, there were 19 relapses after 5 years of follow-up, indicating a high relapse rate of 38.8% and hence withdrawn.
Rifampicin, ofloxacin, and minocycline trial (single-dose therapy)
A multicentric randomized double-blind controlled clinical trial by the WHO to compare the efficacy of Rifampicin + Ofloxacin + Minocycline (ROM) with that of the WHO PB-MDT in 1483 patients with one skin lesion and no peripheral nerve trunk involvement was conducted in India. The study showed ROM to be almost as effective as the standard WHO PB-MDT. No further observations were reported as ROM for single skin lesion leprosy was withdrawn from the program for operational reasons.
In a multicentric double-blind controlled clinical trial with single-dose ROM in patients with two to three skin lesions, clinical improvement was seen in both regimens. A long-term follow-up study of these patients showed no correlation in the pattern of clinical problems and chemotherapy regimens, also clinical events were manageable, and also relapses and treatment failures in both regimens were not in alarming proportions. Another cohort study with a follow-up of 2 years that compared the efficacy of one and three ROM pulse doses for PB (two to five lesions) patients found that a single-dose of ROM was adequate. Some delayed clinical problems such as appearance of new lesions, extension and persistence of existing lesion, and even relapse have been reported in single skin lesion and PB (two to five lesions) patients. Long-term follow-up of these patients was expected to answer the doubts raised on this issue, but most of the events appeared to be within limits manageable by field workers.
Rifampicin, ofloxacin, and minocycline trial (intermittent therapy)
The World Health Organization later initiated further clinical trials with ROM given intermittently in both MB and PB leprosy. The supervised dose was given once a month without any treatment in between. The objective was to see clinical response, side effects, and reactions (erythema nodosum leprosum and reversal) which might occur during and after the end of treatment.
Follow-up data on this study are not yet available. However, only two other studies have been reported using multiple doses of ROM in lepromatous leprosy: one in the Philippines and another from Brazil; patients had a mean bacillary index (BI) of 4+ at the entry to the study, and the fall in BI was similar to the group on WHO MB-MDT. Skin lesions improved as did the histological changes in their skin biopsies during treatment. In the Philippines study, the BI continued to fall after the completion of treatment, and no relapses were recorded during the subsequent 64 months (>5 years).
Uniform multidrug therapy
The objective was to provide 6-month MDT for all types of leprosy patients and assess the treatment response in terms of relapse rates; an interim analysis available for 2930 patients out of 3396 at the end of 3 years showed that uniform MDT (U-MDT) appears to be promising with respect to the clinical status of skin lesions. It was concluded that U-MDT of 6-month duration was well tolerated and effective in patients with PB leprosy but was too short a regimen to adequately treat patients with MB leprosy.
Accompanied multidrug therapy
Accompanied MDT (A-MDT) was recommended by the WHO to address frequent problems in the field program by providing certain patients with a full course of treatment on their first visit to the leprosy clinics after diagnosis. The WHO recommends that A-MDT is user friendly, and it is suitable for mobile population and patients living in remote areas and areas of civil strife. Although MDT coverage is reported as 100% by all countries, there are still some underserved populations such as those living in hard to reach border areas or in urban slums or the migrant laborers. As an innovative approach to ensure that such underserved groups have access to MDT and other services, the WHO strongly recommended that A-MDT would give better access to MDT for patients in general and in particular for those unable to visit the health center regularly for a variety of reasons.
A combination consisting of newer drugs is the regimen which was recommended at the Pre-Congress Workshop (Proceedings of the 17th International Leprosy Congress, Hyderabad, 2008) on Chemotherapy. The regimen consists of a combination of rifapentine (900 mg) or rifampicin (600 mg) with moxifloxacin (400 mg) and clarithromycin (1000 mg) (or minocycline 200 mg) (PMMX), all drugs administered once monthly under supervision (the doses are for adults).
Some preliminary reports suggest the use of a combination of moxifloxacin with rifapentine and minocycline. However, these are not supported by any randomized controlled trial.
In recent years, moxifloxacin (a fluoroquinolone) and rifapentine (a long-acting rifamycin derivative) have been identified as having highly promising antimycobacterial activities. Observations on clinical trials in leprosy using moxifloxacin-based regimens were reported for the first time in 2009. Further observations on clinical parameters were reported in 2013 and 2019. Based on our investigations and our experience in a larger series of patients in an open-ended observational comparative study on a selected sample of 290 MB patients, 145 patients were smear positive (age group of 16–71 years) and another group of 145 patients were smear positive (age group of 16–70 years). In an ongoing clinical study, patients received moxifloxacin 400 mg, rifampicin 600 mg, and minocycline 200 mg (MRM at monthly intervals for 12 months). The comparative group received additional clofazimine (MRMC) to ascertain its anti-inflammatory property in preventing reactions as this group received 300 mg clofazimine in addition under supervision along with MRM, followed by unsupervised doses of 50 mg daily clofazimine, and patients in MRM and MRMC groups were studied for yearly BI status assessed in both groups and relapse. In MB smear-negative patients, they received MRM and MRMC in two groups, whereas in PB patients, they received MRM for 6 months and were assessed using clinical, neurological, and photographic assessment.
Good and early clinical improvement was seen in cases of MB and PB, although reactions were predominant features in smear-positive MB patients. BI decline in both smear-positive groups was comparable. The addition of clofazimine did not appear to influence the occurrence of reactions. While long-term observations are in progress, the average BI in both groups with initial mean BI of >3.0+ showed a steady decline, and no relapse was observed in patients followed so far. Long-term observations are in progress.
How concepts on the duration of treatment for MB and PB leprosy have changed over the years and how chemotherapy of leprosy has evolved over years from dapsone monotherapy to current combination therapy is interesting.
Initially, dapsone monotherapy was prescribed for 10 years in cases of PB leprosy and for a lifelong duration in MB leprosy. Then came modified WHO-MDT for MB leprosy for 24 months duration or till skin smears are negative. So called fixed duration therapy (FDT) was initially advocated for 24 months in MB leprosy which was reduced to 12 months later. Treatment duration of PB leprosy at this point of time with FDT regimen was 6 months. Concept of monthly ROM (Rifampicin + Ofloxacin + Minoycycline) came for 12 months in MB leprosy (ROM-12) and for 6 months in PB leprosy (ROM-6). Another regimen of daily administration of rifampicin and ofloxacin (RO) for both MB and PB leprosy evolved later. For the treatment of single skin lesion (SSL) leprosy, single dose of ROM called as ROM-1 therapy was advocated. Then came moxifloxacin based regimens. One day single dose of rifapentine, minocycline, moxifloxacin was advocated for MB leprosy (PMMx-1). Similar to monthly ROM therapy, a regimen containing moxifloxacin, rifampicin and minocycline was administered every monthly for 12 months in MB leprosy (MxRM-12) and for 6 months in PB leprosy (MXRM-6).
Other regimens for special situations
Special regimens are required for some patients who cannot benefit from rifampicin because of allergy or intercurrent diseases such as chronic hepatitis, or who have been shown to be infected with rifampicin-resistant M.leprae. Some patients refuse to accept clofazimine because of the discoloration. The WHO Study Group in 1993 recommended the use of ofloxacin 400 mg daily or minocycline 100 mg daily as substitutes for clofazimine. The committee suggested that they could also be treated by monthly administration of ROM for 24 months. Patients harboring rifampicin-resistant M.leprae are very often also resistant to dapsone, and their treatment depends almost entirely on clofazimine. Daily treatment with the combination of ofloxacin plus minocycline shows promising bactericidal activity against M.leprae in mice and patients.
MB patients who cannot tolerate rifampicin may be treated with the WHO recommended regimen for adults with daily administration of 50 mg clofazimine together with 400 mg of ofloxacin and 100 mg of minocycline or 500 mg of clarithromycin for 6 months, followed by daily administration of 50 mg of clofazimine together with 100 mg of minocycline or 400 mg of ofloxacin for at least an additional 18 months. In patients with severe dapsone toxicity, the drug should be stopped immediately. No further modifications are required for MB patients, however in PB patients, clofazimine is substituted for dapsone for a period of 6 months.
There are two aspects of treatment for leprosy in which the current regimens have failed. First, transmission has not been interrupted, and it appears that we need new tools to be able to break the chain of transmission in leprosy. Second, a considerable proportion of people who develop leprosy go on to develop signs and symptoms of nerve damage and much of this damage remains as permanent impairment causing disability and severe social consequences. Chemotherapy does not reduce nerve damage once it is present, although if treatment is started early enough, much of the potential risk for future nerve damage is eliminated. Many people affected by leprosy do not consider themselves “cured,” if they still have signs of nerve damage and other stigmata of the disease. Thus, more effective and safe leprosy chemotherapy development remains a considerable concern.
| Conclusion|| |
It is remarkable that chemotherapy of leprosy has come a long way and has shown great promise and hope in the management of leprosy. The evolution of WHO MDT treatment regimens has undergone a sea change due to consistent research and painstaking follow-up which is necessary in a chronic disease like leprosy to draw practical conclusions to understand the efficacy of several drugs. Newer drugs and regimens hold a great promise but have to be observed carefully for the long-term efficacy including further research.
| References|| |
Ganapati R, Pai VV. Principles governing leprosy elimination. Indian J Dermatol 1997;42:141-7. [Full text]
WHO Expert Committee on Leprosy. Seventh Report. TRS 874. Geneva: WHO; 1998.
Ganapati R, Pai VV. Newer chemotherapeutic agents in leprosy. Indian J Dermatol 1996;41:1-4. [Full text]
WHO Report of Ninth Meeting of Technical Advisory Group on Leprosy Control, Cairo, Egypt; 6-7 March, 2008.
WHO Single Lesion Multicentertrial Group. Efficacy of Single dose multidrug therapy for the treatment of single lesion PB leprosy. Indian J Lepr 1997;69:121-9.
WHO Single dose Multicenter Trial Group. A comparative trial of single dose chemotherapy in paucibacillary leprosy patients with two to three skin lesions. Indian J Lepr 73:131-43.
Ganapati R, Revankar CR, Pai VV, Kingsley S. Single-dose treatment for paucibacillary leprosy; feasibility of long-term follow up. Int J Lepr Other Mycobact Dis 1999;67:308-9.
Pai VV, Bulchand HO, Revankar CR, Ganapati R. Single-dose treatment for paucibacillary leprosy; clinical problems and management. Int J Lepr Other Mycobact Dis 1999;67:310-2.
Revankar CR, Pai VV, Samy Anthony MS and Ganapati R. Single dose treatment for paucibacillary leprosy; field implications. Int J Lepr and Other Mycobact Dis 1999;67:312-4.
Revankar CR, Pai VV, Bulchand HO, Ganapati R. A Cohort study on outcome of ROM treatment in Paucibacillary leprosy. In: Paper presented at 21st Biennial Conference of Indian Association of Leprologists. Abstracts, Chandigarh, India; 1999.
Revankar CR, Pai VV, Bulchand HO, and Ganapati R. Delayed clinical problems in single lesion PB leprosy after single dose ROM treatment (Abstracts) Int J Lepr 1998;66:16A.
World Health Organisation. WHO meeting on chemotherapy research in leprosy. Madras. Lepr Rev 1997;68:285-7.
Ganapati R, Pai VV, Khanolkar S, Shinde M. Clinical trials with Moxifloxacin based regimens in leprosy. A Preliminary Communication. Revista de LEPROLOGIA. Enero - Abril 2009;XXVII:1.49-55.
Pai VV, Khodke A, Khanolkar S, Ashok K, Shinde M, Jadhav V. Moxifloxacin based regimens in leprosy - Clinical Observations on Occurrence of Reactions and Bacteriological Decline. Book of Abstracts. Manila, Philippines: 20th International Leprosy Congress; 2019.
Pai VV, Rao RR, Halwai V. Chemotherapy: Development and Evolution of WHO-MDT and Newer Treatment Regimens. In: Kumar B, Kar HK, editors. IAL Text Book of Leprosy, 2nd
ed. Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2016. p. 448-64.
WHO Expert Committee on Leprosy. Seventh Report, TRS 874, Geneva: World Health Organization; 1998.
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