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Oral miltefosine in post‐kala‐azar dermal leishmaniasis – experience in three cases

2010; Wiley; Volume: 49; Issue: 5 Linguagem: Inglês

10.1111/j.1365-4632.2010.04326.x

1365-4632

Sujay Khandpur, Pankaj Chaturvedi, Uttam Kumar, Binod K. Khaitan, J. C. Samantaray, Vinod Sharma,

Trypanosoma species research and implications

Post-kala-azar dermal leishmaniasis (PKDL) is a relatively common dermatosis in the Indian subcontinent that develops as a sequel to visceral leishmaniasis (VL) in 5–15% cases. For years, sodium antimony gluconate (SAG) has been the mainstay of therapy for PKDL. However, parenteral mode of administration, long duration of therapy, development of local and systemic complications and fall in cure rate because of drug resistance are some of its disadvantages.1 Oral agents have shown limited efficacy.2–5 Hence, there is need for an orally administered, safe and effective agent that can produce high cure rates within short periods. Oral miltefosine has shown good efficacy in both VL and PKDL.6,7 We report our experience with oral miltefosine in three cases of PKDL with extensive involvement. A 45-year-old man, resident of Bihar, presented with nodulo-ulcerative lesions over hands and feet, hypopigmented macules over trunk and diffuse infiltration over face and earlobes that had been present over the last 6 years. (1, 2). He had kala-azar 25 years prior for which he was successfully treated with intravenous SAG for 18 d. There was no hypoesthesia, peripheral nerve thickening or neurological deficit. (a) Case 1 – Erythematous plaques over dorsa of hands in PKDL pre-treatment. (b) Case 1 – Complete resolution of all plaques 8 weeks post-treatment with miltefosine (a) Case 1 – Erythematous plaques over dorsa of feet in PKDL pre-treatment. (b) Case 1 – Complete resolution of all plaques 8 weeks post-treatment with miltefosine His hematological and biochemical investigations were normal. Slit skin smears (SSS) taken from ear lobes and nodular lesions showed Leishmania Donovan (LD) bodies within macrophages. Stain for acid fast bacilli were negative. Qualitative estimation of antibodies to recombinant K39 antigen was strongly positive. Skin biopsies from various lesions showed dense dermal inflammatory infiltrate of plasma cells, lymphocytes and histiocytes with multiple LD bodies within macrophages (Fig. 3a). A diagnosis of PKDL was made. (a) Case 1 – Photomicrograph showing dense infiltrate of lymphocytes, histiocytes and plasma cells throughout the dermis in PKDL pre-treatment (H & E ×100). (b) Reduction in the dermal infiltrate after 4 weeks of treatment with miltefosine. (c) Significant reduction of dermal infiltrate with localization to perivascular and periappendageal sites after 8 weeks of treatment with miltefosine He was started on oral miltefosine (Cap. Impavido, Zentaris Ltd, AEterna Laboratories Inc., (AELA), Germany), 50 mg twice a day. After 2 weeks, the papulonodular lesions started flattening and after 4 weeks there was 70% flattening of nodules, reduction in erythema and infiltration. At the end of 8 weeks, there was complete flattening of lesions and subsidence of facial and earlobe infiltration and erythema (1, 2). The hypopigmented macules persisted. SSS at week 8 revealed no LD bodies. Repeat skin biopsy showed significant reduction in dermal inflammation, with localization to perivascular and peri-appendageal areas at 4 weeks and being very sparse at 8 weeks, with no LD bodies (Figs 3b,c). Serology for rK-39 remained positive. Treatment was stopped at week 8. He developed no side-effects and hematological and biochemical investigations were also normal after 8 weeks. There was no relapse during next 7 months. A 25-year-old man presented with multiple erythematous to skin colored translucent papules and nodules on centrofacial area including forehead, nose, and chin on background of diffuse infiltration and hypopigmented macules over both forearms present for the past 4 years without any lesional hypoesthesia or motor weakness (Fig. 4a). He had kala-azar 10 years prior. He was diagnosed as PKDL based on SSS positivity for LD bodies, histopathology, and serology for recombinant K-39 antigen. He was initiated on oral miltefosine 100 mg/d. Improvement started on the 12th day as flattening of papulonodules. Erythema, papules and nodules showed significant resolution after 8 weeks (Fig. 4b). He also showed microbiological (SSS negative) and histological (significant reduction in inflammatory infiltrate) cure, although serology for rK-39 remained positive. He complained of nausea and vomiting after taking miltefosine, which resolved with antiemetic (Tab. Domperidone). He did not develop any other side-effects and all laboratory parameters were normal. Treatment was stopped at the end of 8 weeks. After 3 months of stopping therapy, papules became prominent on ala nasi and chin that demonstrated LD bodies on SSS and histology was consistent with PKDL. He was labeled as a relapse and restarted on miltefosine. There was again flattening of the lesions after 1 week, which was sustained throughout the treatment period. (a) Case 2 – Erythematous nodules and infiltration over face in PKDL pre-treatment. (b) Case 2 – Significant resolution of nodules and infiltration 8 weeks post-treatment with miltefosine A 45-year-old woman from Bihar presented with multiple erythematous succulent plaques and nodules ranging from 5 mm to 7–8 cm in size, over the elbows, buttocks, thighs, and knees (Fig. 5a) present for the past 5 years. There was no sensory or motor deficit. There was no past history of kala-azar. She had received WHO MB-MDT for leprosy for 2 years without any improvement. She also had pulmonary tuberculosis. SSS, serology, and histology were consistent with PKDL. Encouraged by the response in previous two cases, miltefosine 100 mg/d for 8 weeks was initiated. After 2 weeks, improvement was observed and after 8 weeks, there was significant resolution of nodules and plaques (Fig. 5b). She did not have any treatment-related adverse effects. She was concomitantly treated for pulmonary tuberculosis. At present, the patient has been followed for 4 months with no sign of relapse. (a) Case 3 – Erythematous plaques over both knees and thighs. (b) Case 3 – Significant flattening of all plaques with atrophy 8 weeks post-treatment with miltefosine Post-kala-azar dermal leishmaniasis is considered a reservoir of the parasite Leishmania donovani, which survives and propagates in the dermis in these patients in between epidemics of KA. These cases also seek treatment for mucocutaneous manifestations that strikingly mimic lepromatous leprosy. Various agents administered either parenterally or orally, have shown variable efficacy. SAG, besides being a parenteral therapy, is associated with significant adverse effects like pain and abscess formation at intramuscular injection site, thrombophlebitis when given I/V, elevated serum amylase, ECG changes, nephrotoxicity, arthralgias, and abdominal pain. Also decrease in cure rates from 90 to 95% reported initially to 80% and even down to 30% in VL in highly endemic areas with relapse rate of up to 65% in both VL and PKDL have prompted clinicians to look for alternate modalities.1,8 Amphotericin B remains the most important second line antileishmanial drug for SAG-refractory cases with cure rates of 90–98%, but side-effects like infusion reactions, refractory hypokalemia, nephropathy, myocarditis, and even fatal outcomes, associated with high cost, limit its use.9 Liposomal amphotericin B has relatively lower toxicity than amphotericin B, quicker action and shorter duration of therapy, but high cost is a disadvantage.10 Oral agents such as allopurinol, ketoconazole, itraconazole, rifampicin, and sitamaquin have shown only limited efficacy.2–5 Miltefosine, an alkylphosphocholine and a membrane-active synthetic ether-lipid analog was originally developed and tried in 1992 for treatment of cancer; however, the dose required for such treatment had pronounced side-effects. In vitro studies have shown striking activity against L. donovani and Leishmania infantum by inducing cell death with numerous cytoplasmic, nuclear, and membrane features of metazoan apoptosis.11 It is well absorbed orally, widely distributed, and has a long half-life of about 8 d. High efficacy and safety of miltefosine has been observed in VL and PKDL in various clinical trials. It was first approved in India in 2002 for adult VL. Sunder S et al. achieved cure in all VL cases in doses ranging from 100 to 250 mg/d for 28 d, but with side-effects at doses of 200 and 250 mg/d.6 In a large randomized comparative trial between miltefosine (50 and 100 mg/d for 28 d) and amphotericin B (1 mg/kg intravenous every other day for 15 d), initial cure was achieved in all cases in both groups with no relapse in 94 and 97% cases, respectively after 6 months.12 It has been found safe and effective in childhood VL with cure rate of 95%.13 Berman JJ after reviewing all articles published during 2005–2008 concluded that for unusual forms of disease that require long periods of treatment such as diffuse cutaneous leishmaniasis (DCL) and PKDL, oral miltefosine is probably the treatment of choice.14 In a study from India on PKDL, miltefosine 150 mg/d led to initiation of response on the 17th day and complete resolution of all lesions except the hypopigmented macules on 54th day without any relapse after 6 months.7 A case on antiretroviral therapy was cured with 100 mg/d given for 28 d.15 On the contrary, another HIV-positive case who did not respond to miltefosine was cured with amphotericin B.16 All our PKDL patients had extensive involvement with pleomorphic lesions. In view of the advantages of miltefosine over SAG described above, this drug was initiated, with complete/significant resolution of all types of lesions after 8 weeks except the hypopigmented macules. This was accompanied by parasitological and histological clearance. In one patient (case 2), there were drug-associated GIT symptoms and relapse after 3 months of stopping therapy. Cases of DCL treated with miltefosine for variable periods (75–218 d) had dramatic clinical and parasitological response during drug administration, but with a single exception, all patients relapsed after suspension of treatment.17,18 Relapse after miltefosine treatment may be attributed to ineffectiveness of the drug in improving host immunity and its anti-leishmanial activity being solely a consequence of direct effects on the parasite. Side-effects reported with miltefosine are generally mild, tolerable, and reversible and include gastrointestinal side-effects like nausea, vomiting, diarrhea, and transient transaminitis, and reversible nephrotoxicity.6,12 It is teratogenic and should not be administered to pregnant women. In conclusion, miltefosine is a safe and effective oral therapy for PKDL. To prevent relapse, combination treatments with agents that enhance host immune responses should be considered.