A phase II, non-comparative randomised trial of two treatments involving liposomal amphotericin B and miltefosine for post-kala-azar dermal leishmaniasis in India and Bangladesh.

BACKGROUND: In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF. METHODOLOGY/PRINCIPAL FINDINGS: An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred. CONCLUSIONS/SIGNIFICANCE: Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia. TRIAL REGISTRATION: CTRI/2017/04/008421.

Vector control by insecticide-treated nets in the fight against visceral leishmaniasis in the Indian subcontinent, what is the evidence?

Visceral leishmaniasis (VL) is a deadly vector-borne disease that causes an estimated 500 000 new cases a year. In India, Nepal and Bangladesh, VL is caused by Leishmania donovani, which is transmitted from man to man by the sandfly Phlebotomus argentipes. In 2005, these three countries signed a memorandum of understanding to eliminate VL from the region. Integrated vector management is one of the pillars of this elimination strategy, alongside early case detection and treatment. We reviewed the evidence of effectiveness of different vector control methods, to examine the potential role of insecticide treated bednets (ITNs). Indoor residual spraying has shown poor impact for various reasons and resistance to DDT is emerging in Bihar. Environmental management performed poorly compared to insecticide based methods. ITNs could give individual protection but this still needs to be proven in randomized trials. Given the constraints of indoor residual spraying, it is worthwhile to further explore the use of ITNs, in particular long lasting ITNs, as an additional tool in the VL elimination initiative.

Antimonial treatment of visceral leishmaniasis: are current in vitro susceptibility assays adequate for prognosis of in vivo therapy outcome?

In most of the Indian subcontinent, the first line treatment for visceral leishmaniasis (VL) is sodium stibogluconate (SSG), an antimonial drug, but the efficacy of the drug varies according to region. We aimed to characterize the in vitro antimony susceptibility of clinical isolates of Nepalese VL patients, and to correlate this in vitro parasite phenotype to clinical therapy outcome. Thirty-three clinical isolates of L. donovani were taken from patients with known disease history. These isolates were typed and the susceptibility of intracellular amastigotes to pentavalent (SbV) and trivalent (SbIII) antimonials was determined. We observed (i) 22 SbV-resistant isolates out of 33 tested and (ii) 3 SbIII-resistant isolates out of 12 tested. Amongst the latter, there were three combinations of in vitro phenotypes: (i) parasites sensitive (n=4) or (ii) resistant to both drugs (n=3) and (iii) resistant to SbV only (n=5). There was no geographical clustering in terms of in vitro susceptibility. The relation between the in vitro susceptibility to antimonials and the corresponding in vivo treatment outcome was ambiguous. Our results highlight the need to adjust the currently used Leishmania drug susceptibility assays if they are to be used for prognosis of in vivo SSG treatment outcome.

Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh.

BACKGROUND: AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh. METHODS: The safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually randomized clinical trial. Patients from 5 to 60 years with uncomplicated primary VL were recruited from the Community Based Medical College Bangladesh (CBMC,B) and the Upazila Health Complexes of Trishal, Bhaluka and Fulbaria (all located in Mymensingh district), and randomly assigned to one of the treatments. The objective was to assess safety and definitive cure at 6 months after treatment. RESULTS: 601 patients recruited between July 2010 and September 2013 received either AmBisome monotherapy (n = 158), AmBisome + paromomycin (n = 159), AmBisome + miltefosine (n = 142) or paromomycin + miltefosine (n = 142). At 6 months post- treatment, final cure rates for the intention-to-treat population were 98.1% (95%CI 96.0-100) for AmBisome monotherapy, 99.4% (95%CI 98.2-100) for the AmBisome + paromomycin arm, 94.4% (95%CI 90.6-98.2) for the AmBisome + miltefosine arm, and 97.9% (95%CI 95.5-100) for paromomycin + miltefosine arm. There were 12 serious adverse events in the study in 11 patients that included 3 non-study drug related deaths. There were no relapses or PKDL up to 6 months follow-up. All treatments were well tolerated with no unexpected side effects. Adverse events were most frequent during treatment with miltefosine + paromomycin, three serious adverse events related to the treatment occurred in this arm, all of which resolved. CONCLUSION: None of the combinations were inferior to AmBisome in both the intention-to-treat and per-protocol populations. All the combinations demonstrated excellent overall efficacy, were well tolerated and safe, and could be deployed under field conditions in Bangladesh. The trial was conducted by the International Centre for Diarrhoeal Disease Research (ICDDR,B) and the Shaheed Suhrawardy Medical College (ShSMC), Dhaka, in collaboration with the trial sites and sponsored by the Drugs for Neglected Diseases initiative (DNDi). TRIAL REGISTRATION: ClinicalTrials.gov NCT01122771.

Residual activity and integrity of PermaNet® 2.0 after 24 months of household use in a community randomised trial of long lasting insecticidal nets against visceral leishmaniasis in India and Nepal.

The World Health Organization (WHO) recommends several brands of long lasting insecticidal net (LN) for protection against insect vectors but also advises national programmes to monitor and evaluate performance under local conditions to help them select the most suitable LN for their setting. During the course of a community randomised trial of LNs against visceral leishmaniasis in northern India and Nepal, opportunity arose to assess the efficacy of PermaNet 2.0 (Vestergaard-Frandsen, Denmark) after two years of use against sandfly vectors. Between 63% (India) and 78% (Nepal) of LNs became holed over the course of two years, deltamethrin residues fell from 55 mg/m(2) to an average of 11.6 mg/m(2) (India) and 27.9 mg/m(2) (Nepal), but on the basis of bioassay criteria all LNs tested still met the WHO Pesticide Evaluation Scheme standard for LN effectiveness. Nets had on average only been washed 2.5 times (India) and 0.6 times (Nepal) by householders over the course of two years. The loss of insecticide was attributed to factors which had little or nothing to do with washing, such as handling, friction and torsion during daily use. Under conditions pertaining in this region of south Asia, and for two years at least, this brand of net continues to meet the criteria established by WHO for LNs.

Visceral leishmaniasis: elimination with existing interventions.

The world's burden of infectious diseases can be substantially reduced by more-effective use of existing interventions. Advances in case detection, diagnosis, and treatment strategies have made it possible to consider the elimination of visceral leishmaniasis in the Indian subcontinent. The priority must now be to effectively implement existing interventions at the community level by actively finding cases in endemic villages and treating them with single-dose liposomal amphotericin B at primary-health-care centres. Once the elimination target of one case per 10,000 population has been reached, combination therapies involving miltefosine and paromomycin can be introduced to ensure long-term availability of several drugs for visceral leishmaniasis and to protect against resistance.

Population preference of net texture prior to bed net trial in Kala-Azar-endemic areas.

Prior to a community-based efficacy trial of long-lasting insecticidal nets (LLINs) in the prevention of visceral leishmaniasis (VL; also called kala-azar), a pilot study on preference of tools was held in endemic areas of India and Nepal in September 2005.LLINs made of polyester and polyethylene were distributed to 60 participants, who used the nets sequentially for 7 d. Acceptability and preference were evaluated via indirect indicators through questionnaires at three defined time points before and after use of the LLINs and through focus group discussions (FGDs). In the latter, preferences for color and size were also assessed. Untreated bed nets were owned by 87% of the households prior to the study. All users liked textures of both LLIN types after 7 d of use, but had a slight preference for those made of polyester if they were to recommend a LLIN to relatives or friends (p<0.05), mainly because of their relatively greater softness in comparison to polyethylene LLINs. Users reported that both net types reduced mosquito bites and number of insects, including sand fly (bhusana; genus Phlebotomus), inside the house. Side effects were minor and disappeared quickly.The large-scale intervention trial considered the preferences of the study population to decide on the best tool of intervention--light-blue, rectangular, polyester LLINs of different sizes.