Miltefosine May Be Losing Ef ﬁ cacy in the Treatment of Leishmaniasis Fifteen Years of Remarkable Progress in Preventing Malaria in Africa, With Much Left to Do

Ramesh V, Singh R, Avishek K, et al. Decline in clinical efficacy of oral miltefosine in treatment of post kala-azar dermal leishmaniasis (PKDL) in India. PLoS Negl Trop Dis 2015; 9:e0004093. Ghosh S, Das NK, Mukherjee S, et al. Inadequacy of 12-week miltefosine treatment for Indian post-kala-azar dermal leishmaniasis. Am J Trop Me Hyg 2015; 93:767–9. Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis due to Leishmania donovani. It most often occurs at least 6 months after apparent cure of the disseminated infection, although it may occur much earlier. Although PKDL spontaneously heals in the majority of African cases, this is rarely the case in India. In addition to the morbidity it causes in individuals, patients with PKDL serve as a parasite reservoir, contributing to its ongoing transmission. Ramesh and colleagues in New Delhi examined the results of treatment of patients with PKDL with 1 of 2 miltefosine regimens over a 5-year period. Regimen 1 consisted of miltefosine 50 mg orally twice daily for 3 months (n = 56) or 2.5 mg/kg/day for 3months in children (n = 4), whereas regimen 2 was 50 mg thrice daily for 2 months (n = 26). At the beginning of the 5-year period, regimen 2 was initially prescribed for all patients, but 8 patients were switched to regimen 1 because of gastrointestinal intolerance and this regimen was then prescribed for all subsequent patients. A total of 73 patients completed their course of therapy: 57 and 16 received regimens 1 and 2, respectively. Marked improvement was observed at the end of therapy in all 73 patients, with initial clinical and parasitological cure in 70; the remaining 3 achieved initial cure after extension of their treatment duration at the higher dose. However, 2 of the 73 (4%) relapsed by 12 months and 11 relapsed by 18 (15%) months. Relapse occurred significantly more frequently in patients who received regimen 2 (31%), compared with those who received regimen 1 (10.5%) (P < .005). Relapse was significantly associated with a higher parasite load prior to initiation of treatment. The miltefosine median inhibitory concentration (IC50) of post-relapse leishmania isolates was approximately twice that of pretreatment isolates. Ghosh and colleagues enrolled 27 patients in Kolkata with PKDL in an openlabel trial of miltefosine administered once daily for 16 weeks. The dose was either 100 mg daily (for those weighing >25 kg), 50 mg daily (for those <25 kg), or 2.5 g/kg (for those aged 2–11 years). Nine of the 27 left the study by 4 weeks because of gastrointestinal intolerance. Three of 7 who completed 12 weeks of therapy and none of the 11 who completed 16 weeks suffered relapse. Miltefosine is the only orally administered agent generally accepted as effective in the treatment of various forms of leishmaniasis in a number of geographic locations [1]. Unfortunately, observations such as those of Ramesh and colleagues suggest that its efficacy may be waning, as has been suggested with regard to its use in the treatment of visceral leishmaniasis. In addition, a previous study, published in 2011 (and which may have included some of the same patients as in the 2015 study reviewed here), of oral miltefosine therapy (50 mg 3 times daily for 60 days) of 23 patients with PKDL in the same region of India reported a 96% cure rate and, in contrast to the more recent data, no relapses at 12 months [2]. The finding of an increase in miltefosine IC50 in the current study relative to baseline isolates suggests that this may be related to selection of organisms with reduced susceptibility. Failure of miltefosine therapy of visceral leishmaniasis has been associated with low steadystate serum concentrations of the drug [3]. Another factor in preventing relapse, however, may be the duration of therapy. Thus, the results presented by Ramesh and colleagues suggest that a 3-month course is superior to a 2-month course, even when a (poorly tolerated) higher dose is used for the shorter duration. But 12 weeks may not be enough; the study by Ghosh and colleagues suggests that a 16-week course may be associated with even fewer relapses. At any rate, the potential loss of efficacy of miltefosine in the treatment of leishmaniasis would provide a significant blow to attempts to control this disease. Additional orally administered agents that could be used in combination in an attempt to prevent further loss of efficacy are urgently needed. In the meantime, prolongation of treatment, possibly to 16 weeks, appears to be the optimal approach to preventing relapse of PKDL.