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

Author summary Efforts to eliminate visceral leishmaniasis (VL) in the Indian subcontinent have had an unprecedented impact on the number of cases over the past decade, however, the disease is known to be cyclical and previous periods of low incidence have been followed by a major resurgence. The disease is thought to be maintained between epidemics as post-kala-azar dermal leishmaniasis (PKDL), a skin disease affecting 5 to 15% of apparently cured VL patients in the Indian subcontinent. PKDL is difficult to cure and since PKDL patients are not systemically ill, they seldom seek treatment, meaning that PKDL is likely to be a major obstacle to elimination. A key question is how different VL treatment regimens affect the risk of subsequent PKDL. We followed-up a cohort of more than 1700 patients treated with three different drug regimens in an effectiveness trial in Bihar and found that patients treated with miltefosine-paromomycin had a lower risk of relapse but higher PKDL incidence, while AmBisome treated patients had the reverse pattern. In order to sustain the gains already made, active surveillance for PKDL and relapse is essential, along with timely treatment, and new VL treatment regimens that avoid future PKDL are needed. Background Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. Methodology/Principal findings A Phase IV trial included 1761 VL patients treated between 2012-2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children Conclusions/Significance Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.