The safety and efficacy of miltefosine in the long-term treatment of post-kala-azar dermal leishmaniasis in South Asia – A review and meta-analysis

Abstract

Background Miltefosine (MF) is the only oral drug available for treatment of visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). Although the drug is effective and well tolerated in treatment of VL, the efficacy and safety of MF for longer treatment durations (>28 days) in PKDL remains unclear. This study provides an overview of the current knowledge about safety and efficacy of long treatment courses with MF in PKDL, as a strategy in the VL elimination in South Asia. Methodology/Principal findings Literature was searched systematically for articles investigating MF treatment in PKDL. A meta-analysis included eight studies (total 324 PKDL patients) to estimate the efficacy of MF in longer treatment regimens (range 6–16 weeks). We found a per-protocol (PP) initial cure rate of 95.2% (95%CI 89.6–100.8) and a PP definite cure rate of 90% (95%CI 81.6–96.3). Descriptive analysis showed that 20% of patients experienced adverse events, which mostly had an onset in the first week of treatment and were likely to get more severe after four weeks of treatment. Gastrointestinal (GI) side effects such as vomiting, nausea, diarrhoea, and abdominal pain were most common. Conclusions/Significance Longer treatment regimens with MF are effective in PKDL patients in India, however with the caveat that the efficacy has recently been observed to decline. GI side effects are frequent, although mostly mild or moderate. However, on the basis of limited data, we cannot conclude that longer MF treatment regimens are safe. Moreover, VL and PKDL pharmacovigilance studies indicate a risk for serious adverse events, questioning the safety of MF. The provision of safer treatment regimens for PKDL patients are therefore recommended. Until these regimens are identified, it should be considered to halt the use of MF monotherapy for PKDL in order to preserve the drug’s efficacy.

Long-term incidence of relapse and post-kala-azar dermal leishmaniasis after three different visceral leishmaniasis treatment regimens in Bihar, India

“…Recent xenodiagnosis data confirms that PKDL patients are infectious to sand flies, with higher prevalence of infectiousness among nodular than macular cases [10], supporting the contention that PKDL is likely to prove a major obstacle to sustained VL elimination [8]. Treatment of PKDL is challenging, requiring a prolonged drug course which does not always lead to full resolution of lesions [11,12]. Avoidance of future PKDL is therefore a high priority in the search for new VL treatment regimens.…”

Post kala-azar dermal leishmaniasis: A threat to elimination program

“…Miltefosine has been known to trigger heightened proinflammatory Th1 responses in the Indian cohort, thus superseding the SSG based regimen for PKDL treatment [169]. However, the efficacy has recently been declining due to patient noncompliance, which is associated with frequent gastrointestinal complications in cases [170].…”

“…Hence, it would be too early to conclude that prolonged treatment regimens are safe. In light of the evidence from pharmacovigilance studies, miltefosine usage has shown severe adverse reactions [170]. Furthermore, increasing incidence of miltefosine resistance has been seen even in PKDL cases [172].…”

Parasitological and immunological evaluation of a novel chemotherapeutic agent against visceral leishmaniasis

“…8 Alternative therapeutic agents include miltefosine, which was originally developed as an anticancer drug 9 and it was the first orally administered drug in patients with VL. 10,11 However, miltefosine can cause teratogenicity and parasitic resistance to this compound has also been reported, limiting its clinical use to treat VL. 12,13 Therefore, there is an urgent need to identify novel and low-cost antileishmanial agents to improve treatment quality and effectiveness against this disease.…”