Hansen's Disease Therapeutics
by PatrĂcia D. Deps,
and Marco Andrey Cipriani Frade.
History of Hansen’s Disease treatment
Hansen's Disease (HD), as one of the oldest diseases known to the world, and it has been the object of diverse and empirical therapeutic attempts over the ages. The first effective treatment was introduced by Mouat in 1854, when he used the oil extracted from the seeds of the Chaulmoogra tree(1). Although only modest results were obtained from the use of this oil, seeds and seedlings began to be exported from Southeast Asia and acclimatized in various parts of the world. Salts and esters were improved and used via oral and intravenous routes and in hypodermic applications and, even with significant side effects, Chaulmoogra oil was the main treatment for HD until the arrival of sulfone (2).
The story of sulfones in the treatment of HD began in 1941, when Guy Faget and collaborators experimented with sodium glycosulfone (Promin®) in HD patients in Carville, USA (3). Sulfones had been known since 1833 and were used as artificial tannins and insecticides until the appearance of DDT. The first of the sulfones, diaminodiphenyl sulfone (DDS or Dapsone), was synthesized by Fromm and Whittmann in Germany in 1908 (4), the same year that sulfonamides were synthesized. In the absence of adequate toxicological and safety studies at the time, use of analogous doses of the two drugs was associated with side-effects which rendered their use impossible for many years.
Following Faget, HD specialists in India (Cochrane and collaborators (5), Lowe (Nigeria) (6), and Floch (French Guyana) (7), confirmed the activity of the drug in smaller doses and orally, bringing about a change in the management of the disease which until then had been based mainly on isolation and segregation of patients.
In 1960, Shepard (8) achieved the multiplication of M. leprae in the mouse's paw pad and was able to demonstrate sulfone activity and experiment with new drugs. A few years later, the first clinical suspicion of sulfone resistance was demonstrated by the same method (9).
The advent of secondary resistance in increasing prevalence in several countries led the World Health Organization (WHO) in 1976 to recommend a treatment regimen with two drugs in place of sulfone monotherapy. Rifampicin, the drug that would be combined with Dapsone, had high bactericidal activity and had been used for the first time in 1963 by Opromolla (11).
The use of dapsone alongside rifampicin aimed to prevent the emergence of secondary resistance to Dapsone, but in 1977, Pearson (12) described sulfone resistance in five patients who had not been previously treated. This prompted a new recommendation in 1981 that the standard regimen should comprise three drugs. The chosen third drug was clofazimine, an iminophenazine dye derived from aniline, first synthesized in 1954.
Multidrug therapy (MDT)
The combination of three antimicrobial drugs for the treatment of HD as recommended by WHO (MDT/WHO) constitutes the greatest advance in the fight against the disease (13).
The number of registered cases decreased dramatically, mainly due to the effectiveness and shorter duration of MDT. However, the number of new cases has remained at worrying levels, demonstrating the need to evaluate and study the problem that prevents the elimination of endemic HD in many countries (13).
The treatment of HD patients is the essential action to eliminate HD as a public health problem. Treatment should therefore be as early and effective as possible to break the epidemiological chain of disease transmission, avoid the resistance of M. leprae to monotherapy, and stop the progression of the disease and thereby prevent physical and social disability in the patient (13,14).
Full treatment of a person diagnosed with HD is based not only on MDT, but also includes evaluation of the patient during the monthly administration of supervised doses of medication, to monitor the evolution of skin lesions, neural involvement and to verify the presence of reactional conditions and neuritis. Furthermore, patients should receive guidance on techniques to prevent disabilities (15).
MDT is very effective, but resistant strains have begun to appear in the past two decades, reaching 2% among new cases and 5% among adequately treated relapse cases. Resistance is mainly to rifampicin, the only bactericidal drug in the MDT regimen (16). In these cases, which should be evaluated in a HD reference service, MDT can be repeated or a specific substitutive regimen used (15).
If intolerance to one of the MDT drugs is indicated in adults or children, they ought to be referred for evaluation in a HD reference service and a substitutive regimen used (15).
MDT drugs are administered by supervised dose (monthly) in the health unit, plus self-administered doses (daily) at home. The supervised doses are given, ideally, with an interval of 28 days. The patient is discharged as cured after the administration of the number of doses recommended by the therapeutic scheme and according to the result of a dermatoneurological examination, based on a simplified neurological evaluation and the degree of physical disability (15).
For the treatment of children under 15 years old, weight should be the most important determinant of dosage. In children weighing more than 50 kg, use the adult dose; from 30-50 kg, use the children's blisters (brown/blue); and for children under 30 kg, dose adjustments should be made (15).
Pregnancy and breastfeeding do not contraindicate standard MDT. In the case of co-infected patients and those being treated for HIV/AIDS, the MDT/WHO scheme is maintained according to the operational classification (15).
MDT for paucibacillary (PB) and multibacillary (MB) patients
The MDT regimen for paucibacillary (PB) patients consisting of two drugs (Rifampicin and Dapsone in green color blister pack for adult or blue for infant) will be used until the end of 2020 in Brazil, when the Ministry of Health will follow the WHO guidelines (2018) (17).
Following WHO guidelines published in September 2018, both types of patients (PB and MB) will now use the same MDT scheme comprising three drugs (Rifampicin, Dapsone and Clofazimine), as shown in Table 1 (15).The regimens are differentiated only by duration of treatment: 6 supervised monthly doses (up to 9 months) for those classified as PB and 12 supervised monthly doses (up to 18 months) for MB patients (17). PB and MB? patients who still have many skin lesions at the end of MDT may need 12 additional doses of MDT.
Table 1.
Children under 30kg:
For these patients, the dose should be adjusted according to the following scheme:
Table 2. Dosagens da poliquimioterapia para a hansenĂase.
A unified regimen, U-MDT, that aims to simplify MDT as a 6-month 3-drug regimen for all patients (PB or MB) has been proposed (18), but the WHO has no robust evidence yet of its effectiveness.
Substitutive therapeutic regimens
If any of the drugs used in MDT/WHO are contraindicated from use, substitutive regimens should be considered. However, the patient must be evaluated in a reference service. In general, drugs, ofloxacin (OFX) OR minocycline (MNC) can be used, as summarized in Tables 3-7.
Dapsone intolerance (DDS)
The treatment time remains the same as for standard MDT/WHO. Note that EITHER minocycline (MNC) OR ofloxacin (OFX) can be used (15).
Table 3. Substitutive regimen for dapsone intolerance (DDS)
Clofazimine intolerance (CFZ)
Similar to dapsone intolerance, the treatment time remains the same as for standard MDT/WHO and EITHER minocycline (MNC) OR ofloxacin (OFX) (15) can be used, as shown in the table below:
Table 4. Substitutive regimen for clofazimine intolerance (CFZ)
Ribampicin Intolerance (RFM)
Note that EITHER minocycline (MNC) OR ofloxacin (OFX) can be used (15).
Table 5. Substitutive regimen for rifampicin intolerance (RFM)
RFM and DDS Intolerance
In the MDT/MB scheme, ofloxacin and minocycline should be used together for the first 6 months. From the 7th month of treatment until the 24th month they are used separately again, that is, either OFX or MNC (15).
Table 6. Substitutive regimen for RFM and DDS intolerance.
DDS and CFZ intolerance
You must follow the treatment scheme below, using Rifampicin (RFM), Ofloxacin (OFX) and Minocycline (MNC). Treatment available for the adult age group (15).
Table 7. Substitutive regimen for DDS and CFZ intolerance.
Treatment of Hansen's Disease reactions
Patients should be monitored closely for suspected reactional episodes. The type of HD reaction is fundamental to indicating the treatment for the patient. Therefore, a detailed knowledge of reactions in HD is of great importance. A thorough neurological examination must be carried out. In some patients, the clinical condition may be compromised. Appropriate treatment should be started within 24 hours, usually on an outpatient basis by a doctor. In some cases, hospitalization will be required, including for surgical decompression of nerves.
Treatment of Type 1 Reactions
Corticotherapy (prednisone) is the elective treatment for Type 1 reactions. The recommended dose at the beginning of treatment is 1 mg/kg/day, and this must be maintained until the regression of the reaction condition and then slowly reduced to fixed intervals according to clinical evaluation (13). Evaluate all risks of long-term oral corticotherapy use – note weight, fasting glycemia, blood pressure, and prophylactic treatments for strongyloidiasis and osteoporosis (15). Corticoid pulse therapy should be considered in cases of neuritis that are difficult to control.
In cases of neuritis, the affected limb should be immobilized. MDT/WHO should not be discontinued, unless indicated by medical evaluation.
To avoid physical disability, the patient’s peripheral nerve function should always be monitored by simplified neurological evaluation with attention to the degree of disability.
Treatment of Type 2 Reaction - Erythema Nodosum in Hansen’s Disease (ENHD)
Thalidomide (alpha-N-pthali-midoglutarimide) is recommended as the drug of choice for the treatment of ENHD (15,19-21), but the use of corticosteroids is mandatory when there is associated neural involvement, reactive hand and foot, neuritis, iritis, iridocyclitis, orchitis, nephritis and necrotizing ENHD (15).
Thalidomide should be used at a dose of 100-400 mg/day depending on the severity of ENHD.
The main contraindications of thalidomide are pregnancy and women of fertile age. Thalidomide should only be considered in fertile women who use at least two effective methods of contraception (at least one being a barrier method), and even then only in cases where the benefit of thalidomide cannot be obtained by other treatments. Please note RDC No 11 of March 22, 2011 and Law No 10.651 of April 16, 2003 (15).
If thalidomide cannot be used for a type 2 reaction, pentoxifylline at a dose of 400 mg in a 8/8 hours regimen should be used, combined or not with prednisone at a dose of 1mg/kg/day or dexamethasone at the equivalent dose (0.15 mg/kg/day). General precautions for the use of systemic corticosteroids should be followed.
When corticosteroids are used with thalidomide, acetyl salicylic acid should be prescribed at 100mg/day to avoid thromboembolism (15).
MDT/WHO must be maintained during treatment of HD reaction. of The involved limb should immobilized in cases of associated neuritis. Dosage of thalidomide and corticoid should be reduced (slowly) according to the therapeutic response.
Betamethasone (22), pentoxifylline (23), clofazimine (24,25), acetyl salicylic acid (26), chloroquine (26), indomethacine (26,27), and levamisole (28) have been tested in the treatment of ENHD. Clofazimine proved effective at 300mg/day. (ref?)
In type 1 or 2 HD reactions with little improvement using the regimens described above, the presence of comorbidity, such as concomitant infections, hormonal changes, emotional stress, anxiety disorders, reinfection, and diabetes should be considered (15).
Clinical treatment for severe (uncontrolled) neural pain
The need for surgical decompression should be evaluated by a HD reference service. Antidepressants such as amitriptyline hydrochloride at a dose of 25-300 mg per day or nortriptyline hydrochloride at a dose of 10-150 mg per day may be considered for use. Also, neuroleptics such as chlorpromazine 25-200 mg/day should be considered. Anticonvulsants such as carbamazepine at a dose of 200-3000 mg per day and gabapentin at 900-2400 mg per day can be used (15).
Treatment of Hansen's Disease's reactions in children
In type 1 reactions and neurites, corticoid is the drug of choice in doses that can vary from 0.5 mg to 1 mg per kg/day. The same dosage should be used in type 2 reactions. Regarding the use of thalidomide in type 2 reactions, there is no evidence on the safety of the drug in children under 12 years. Use in post-menarche girls is contraindicated because of the risk of pregnancy.
MDT side effects
The frequency of side effects caused by MDT has varied widely, from 1% to 45% of patients under treatment. Although not severe enough to prevent the continuation of treatment, the most commonly observed side effect is a change in skin pigmentation which occurs in most patients who receive clofazimine (14,29–32).
Dapsone
Dapsone (diamino-diphenyl-sulfone (DDS)) is a bacteriostatic drug. Its mode of action is to compete with paraminobenzoic acid for the enzyme dihydropteroate synthetase, thereby preventing the formation of folic acid by the mycobacterium. Although considered a safe drug in the dosage used by MDT (29), it is the drug in the regimen that causes most serious side effects.
According to WHO (31), the main side effect of dapsone are allergic reactions ranging from pruritic rashes to exfoliative dermatitis. However, dapsone has also been reported to cause hemolytic anemia, metahemoglobinemia, jaundice, psychotic reactions, and dapsone syndrome (14,29-32). Table 8 summarizes the frequency of side effects found in a study of 174 patients receiving MDT in the Metropolitan Region of Grande VitĂłria, EspĂrito Santo, Brazil (14) Liver changes when they occur are more frequent in the first 3 months of treatment. These generally manifest as an increase in bilirubin and transaminases, with or without jaundice (14).
Rifampicin
Rifampicin has potent bactericidal action against M. leprae, acting to inhibit the DNA-dependent RNA polymerase. Few side effects have been reported with monthly administration (13). However, reported side effects include skin rashes, thrombocytopenic purpura, hepatitis, flu syndrome, hemolytic anemia, shock, respiratory failure, and acute renal failure (14,29–31,33,34).
Clofazimine
Clofazimine is a rimino-phenazinic dye with bacteriostatic and anti-inflammatory actions. The mechanism of action is unknown, but it probably acts directly on the bacterial DNA (35,36). Clofazimine is well tolerated with few serious side effects. The main side effects include: hyperpigmentation of the skin, conjunctiva and organic liquids; cutaneous and ocular dryness; and gastrointestinal symptoms. A more serious side effect is small intestine syndrome, characterized by persistent diarrhea, weight loss and abdominal pain (14,35).
Table 8. Side effects related to the drugs used in MDT (14).
A rare side effect of multidrug therapy is hemophagocytic lymphohistiocytosis (HLH). This condition is characterized by fever, splenomegaly, pancytopenia, pronounced hyperferritinemia, hypertriglyceridemia, and histiocytic hemophagocytosis in the bone marrow. HLH occurs because MDT/ WHO cannot reach the bone marrow, which serves as a niche for M. leprae. HLH can be confused with dapsone syndrome and with type 2 reaction, therefore evaluating the patient’s bone marrow is essential for correct diagnosis and management (37-39).
References
Mouat FJ. Notes on native remedies, no. 1. The chaulmoogra. Indian Annals of Medical Sciencies, 1: 646-652.
McCoy, G. (1942). Chaulmoogra Oil in the Treatment of Leprosy. Public Health Reports (1896-1970), 57(46), 1727-1733. doi:10.2307/4584277
Faget GH, Pogge RC, Johansen FA, Dinan JF, Prejean BM, Eccles CG. The Promin treatment of leprosy. A progress report. Public Health Reports, 1943, 58:1729-1741.
Fromm E, Whittmann J. Derivative des p-nitrothiophenols. Berichte der Deustsche Chemischen Gesellschaft, 1908, 41:2264.
Cochrane RG, Ramanujam K, Paul H, Russell D. Two-and-a-half years` experimental work on the sulphone group of drugs. Lepr Rev, 1949, 20:4-64.
Lowe J. Treatment of leprosy with diamino-diphenyl sulfone by mouth. Lancet, 1950, i: 145-150.
Floch HA. Sulfone-resistance of Mycobacterium leprae—monotherapy with diaminodiphenylsufone—the value of triple-drug combinations. Int J Lepr Other Mycobact Dis, 1986, 54(1):122-5.
Shepard CC. The experimental disease that follows the injection of human leprosy bacilli into foot-pads of mice. Journal of Experimental Medicine, 1960, 112:445-454.
Gillis TP, Williams DL. Dapsone resistance in Mycobacterium leprae. Lepr Rev. 2000;71: 91–95.
WHO Expert Committee on Leprosy. Fifth report. Geneva, World Health Organization, 1977 (WHO Technical Reports Series, No. 607).
Opromola DVA. First results of the use of rifamycin SV in the treatment of lepromatous leprosy. Transactions of the VIIIth International Congress of Leprology, vol 2, Rio de Janeiro, 1963, pp 346-355.
Pearson JMH, Haile GS, Rees RJW. Primary dapsone resistant leprosy. Leprosy Review, 1977, 48:129-132.
WHO Multidrug therapy against leprosy. Development and implementation over the past 25 years. Editor: H. Sansarricq. 2004.
Deps PD, Nasser S, Guerra P et al. Adverse effects from multi-drug therapy in leprosy: a Brazilian study. Lepr. Rev. 2007, 78:216-22.
Brasil. MinistĂ©rio da SaĂşde. SVS/DVDT. Diretrizes para vigilância, atenção e eliminação da HansenĂase como problema de saĂşde pĂşblica: manual tĂ©cnico-operacional. DisponĂvel em: http://portalarquivos.saude.gov.br/images/pdf/2016/fevereiro/04/diretrizes-eliminacao-hanseniase-4fev16-web.pdf.
Cambau E, Saunderson P, Matsuoka M, Cole ST, Kai M, Suffys P, et al. Antimicrobial resistance in leprosy: results of the first prospective open survey conducted by a WHO surveillance network for the period 2009-15. Clin Microbiol Infect. dezembro de 2018;24(12):1305–10.
WHO | Guidelines for the diagnosis, treatment and prevention of leprosy [Internet]. WHO. World Health Organization; [citado 10 de agosto de 2020]. DisponĂvel em: http://www.who.int/lep/resources/9789290226383/en/
Penna GO, BĂĽhrer-SĂ©kula S, Kerr LRS, Stefani MM de A, Rodrigues LC, de AraĂşjo MG, et al. Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients. PLoS Negl Trop Dis. julho de 2017;11(7):e0005725.
Pearson JM, Vedagiri M. Treatment of moderately severe erythema nodosum leprosum with thalidomide–a double-blind controlled trial. Lepr Rev. 1969; 40: 111–116.
Sheskin J, Convit J. Results of a double blind study of the influence of thalidomide on the lepra reaction. Int J Lepr Other Mycobact Dis. 1969; 37: 135–146.
Waters MF. An internally-controlled double blind trial of thalidomide in severe erythema nodosum leprosum. Lepr Rev. 1971; 42: 26–42.
Girdhar A, Chakma JK, Girdhar BK. Pulsed corticosteroid therapy in patients with chronic recurrent ENL: a pilot study. Indian J Lepr. 2002; 74: 233–236.
Sales AM, de Matos HJ, Nery JA et al. Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of type II reaction in leprosy. Braz J Med Biol Res. 2007; 40: 243–248.
Helmy HS, Pearson JM, Waters MF. Treatment of moderately severe erythema nodosum leprosum with clofazimine – a controlled trial. Lepr Rev. 1971; 42: 167–177.
Iyer CG, Languillon J, Ramanujam K et al. WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull World Health Organ. 1971; 45: 719–732.
Karat AB, Thomas G, Rao PS. Indomethacin in the management of erythema nodosum leprosum–a double-blind controlled trial. Lepr Rev, 1969; 40: 153–158.
Ing TH. Indomethacin in the treatment of erythema nodosum leprosum, in comparison with prednisolone. Singapore Med J. 1969; 10:66–70.
Arora SK, Singh G, Sen PC. Effect of levamisole therapy on lepromin reaction in lepromatous leprosy cases. Int J Lepr Other Mycobact Dis. 1985; 53:113–114.
Brasil MTLRF, Opromolla DVA, Marzliak MLC et al. Results of a surveillance system for adverse effects in leprosy’s WHO/MDT. Int J Lepr Other Mycobact Dis. 1996; 64:97-104.
Cunha MGS, Schettini APM, Pereira ES et al. Regarding Brasil, et al. Adverse effects in leprosy’s WHO/MDT and paramedic role in leprosy control program. Int J Lepr Other Mycobact Dis. 1997; 65:257-258.
Goulart IM, Arbex GL, Carneiro MH. Adverse effects of multidrug therapy in leprosy patients: a five-year survey at a Health Centre of the Federal University of Uberlândia. Rev Soc Bras Med Trop. 2002;35:453-60.
White C. Sociocultural considerations in the treatment of leprosy in Rio de Janeiro, Brazil. Lepr Rev. 2002; 73:356-365.
Girling DJ. Adverse reactions to rifampicin in antituberculosis regimens. J Antimicrob Chemother, 1977; 3: 115-132.
Morrone N, Feres WJ, FAZOLO N. Efeitos colaterais dos tuberculostáticos. Rev Bras Clin Terap, 1982; 11: 212-225.
Jopling WH. Side effects of antileprosy drugs in common use. Lepr Rev, 1983; 54:261-270.
Jopling WH. References to “side- effects of antileprosy drugs in common use”. Lepr Rev, 1985; 56: 61-70.
Rastogi P, Chhabria BA, Sreedharanunni S, Pannu A, Varma N, Varma S. Leprosy and bone marrow involvement. QJM. 1o de março de 2017;110(3):189–90.
Saidi W, Gammoudi R, Korbi M, Aounallah A, Boussofara L, Ghariani N, et al. Hemophagocytic lymphohistiocytosis: an unusual complication of leprosy. International Journal of Dermatology. 2015;54(9):1054–9.
Somanath P, Vijay KC. Bone marrow evaluation in leprosy: clinical implications. Lepr Rev. março de 2016;87(1):122–3.