Hansen's Disease Therapeutics
by Patrícia D. Deps,
and Marco Andrey Cipriani Frade.
History of Hansen’s Disease treatment
Multidrug therapy (MDT)
MDT for paucibacillary (PB) and multibacillary (MB) patients
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.
Children under 30kg:
Table 2. Dosagens da poliquimioterapia para a hanseníase.
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
Treatment of Type 2 Reaction - Erythema Nodosum in Hansen’s Disease (ENHD)
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).
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).
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).
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