What are the potential side effects of Multi-Drug Therapy (MDT) for leprosy?

Side Effects of Multi-Drug Therapy (MDT) for Leprosy

MDT for leprosy causes predictable hematologic, dermatologic, and gastrointestinal adverse effects, with dapsone-related hemolysis and clofazimine-related skin pigmentation being the most common, though most patients complete treatment without drug discontinuation.

Hematologic Side Effects

Dapsone-Related Effects

• Dose-related hemolysis occurs in almost all patients, manifesting as 1-2 g hemoglobin loss, reticulocytosis (2-12%), shortened red cell lifespan, and methemoglobinemia, with more severe effects in G6PD-deficient patients 1
• Reticulocyte elevation (>1.5%) occurs in 90% of patients on dapsone, with Heinz bodies detected in 6.6% 2
• Hemolytic anemia and methemoglobinemia are the principal hematologic complications requiring monitoring 3, 4, 1
• G6PD deficiency screening is mandatory before initiating dapsone to identify patients at highest risk for severe hemolysis 3, 5, 4
• Regular complete blood count monitoring is required throughout dapsone therapy 3, 5, 4

Frequency and Management

• Adverse effects attributed to dapsone occur in 41-45% of patients, though most are managed with supportive treatment without drug discontinuation 6, 7
• Dapsone was stopped in only 24% of patients experiencing adverse effects in Brazilian studies 7
• Rifampicin and clofazimine do not increase the incidence of hematologic effects during long-term treatment 2

Dermatologic Side Effects

Clofazimine-Related Effects

• Brownish-black skin pigmentation occurs in 75-100% of patients within 1-4 weeks, resolving 6-12 months after stopping the drug 8, 3
• Ichthyosis develops in 8-20% of patients 8
• Mean duration for clofazimine adverse effects is 7.13 months from treatment start 6
• The RMM regimen (rifampin, moxifloxacin, minocycline) avoids skin hyperpigmentation entirely, as demonstrated in a US case series where no patients experienced pigmentation changes 9

Dapsone Hypersensitivity Syndrome

• Dapsone Hypersensitivity Syndrome (DHS) occurs in approximately 2% of leprosy patients, requiring permanent drug withdrawal 10
• Phototoxicity can occur with dapsone 1

Gastrointestinal Side Effects

• Gastrointestinal intolerance occurs in 40-50% of patients on clofazimine 8
• Nausea, vomiting, and abdominal pain are reported with dapsone 1
• Pancreatitis is a rare but serious complication of dapsone 1
• Clofazimine should be taken with meals or milk to maximize absorption and reduce gastrointestinal effects 3

Cardiovascular Side Effects

• QT interval prolongation occurs with clofazimine, especially when combined with other QT-prolonging medications 8, 3
• Baseline ECG is mandatory before starting clofazimine, with repeat monitoring at 2 weeks and after adding any QT-prolonging medications 3, 4
• Tachycardia has been reported with dapsone 1

Neurologic Side Effects

• Peripheral neuropathy is an unusual but definite complication of dapsone therapy in non-leprosy patients, with motor loss predominating 1
• If muscle weakness appears, dapsone should be withdrawn immediately; recovery is usually substantially complete through axonal regeneration 1
• Vertigo, blurred vision, tinnitus, insomnia, headache, and psychosis are reported with dapsone 1
• In leprosy patients, distinguishing drug-induced neuropathy from leprosy reactional states is critical 1

Hepatic and Renal Effects

• Hepatic and renal evaluation by biochemical parameters shows rare and occasional changes of no apparent clinical significance 2
• Regular liver function test monitoring is required during dapsone therapy 3, 5, 4
• Albuminuria, nephrotic syndrome, hypoalbuminemia without proteinuria, and renal papillary necrosis are rare complications 1

Other Serious Adverse Effects

• Pulmonary eosinophilia, drug-induced lupus erythematosus, and infectious mononucleosis-like syndrome are rare complications of dapsone 1
• Male infertility has been reported with dapsone 1
• Fever is a common systemic manifestation 1

Treatment Discontinuation Rates

• In prospective studies, 45% of patients experienced adverse effects from at least one MDT component 6, 7
• Dapsone was the most common drug requiring discontinuation (46 patients in one study), followed by rifampicin (5 patients), with clofazimine rarely stopped 7
• Only 2.5% of patients treated with clofazimine-containing regimens had treatment discontinued due to adverse events in matched analyses 8
• All 10 patients in a US case series completed the RMM regimen without treatment interruptions or significant side effects 9

Critical Distinction: Leprosy Reactions vs. Drug Side Effects

• Type 1 reversal reactions and Type 2 erythema nodosum leprosum (ENL) are immunologic reactions to treatment, not drug toxicity, and require continuation of MDT with addition of anti-inflammatory therapy 3, 5, 4, 1
• Type 1 reactions occur in borderline or tuberculoid patients soon after chemotherapy starts, manifesting as swelling of existing skin and nerve lesions 1
• ENL occurs mainly in lepromatous patients (approximately 50% in first year), presenting with fever, tender erythematous nodules, and systemic symptoms 1
• Premature treatment discontinuation due to leprosy reactions worsens outcomes; reactions require corticosteroids or other anti-inflammatory agents while continuing MDT 3, 4

Risk Factors for Adverse Effects

• Low Body Mass Index (BMI) correlates significantly (P < 0.05) with increased adverse effects 6
• G6PD deficiency increases severity of dapsone-related hemolysis 1, 2

Alternative Regimens for Patients with Adverse Effects

• Rifampicin and clofazimine alone (without dapsone) provide satisfactory treatment for both paucibacillary and multibacillary patients who require dapsone discontinuation 10
• All 36 slit-skin smear positive patients treated with rifampicin and clofazimine had satisfactory fall in bacterial index with no relapses 10
• The RMM regimen (monthly rifampin, moxifloxacin, minocycline) demonstrates excellent tolerability with rapid improvement of skin lesions and no skin hyperpigmentation 9

Monitoring Protocol

• Complete blood count and liver function tests at baseline and regularly during treatment 3, 5, 4
• ECG at baseline, 2 weeks, and when adding QT-prolonging medications for clofazimine 3, 4
• G6PD screening before initiating dapsone 3, 5, 4
• Clinical assessment for neuropsychiatric symptoms, skin changes, and signs of leprosy reactions at each visit 3, 5