Hansen's Disease Therapeutics

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.

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⁾.

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.

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.

Table 7. Substitutive regimen for DDS and CFZ intolerance.

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.

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.

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 N^o 11 of March 22, 2011 and Law N^o 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⁾.

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⁾.

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.

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 (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 Vitória, Espírito 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 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 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).