Combination Therapy for Post-Kala-Azar Dermal Leishmaniasis: A Literature Review of Current Evidence

Abstract

Post-kala-azar dermal leishmaniasis (PKDL) is a neglected skin disease that has tremendous epidemiological significance as a reservoir of Leishmania parasites. Relapse, drug resistance, non-compliance to prolonged treatment, poor health-seeking behaviour, along with limited therapeutic options pose a significant impact on the management of PKDL. In this study, we aimed to review the efficacy, safety and tolerability data of combination therapies for PKDL in the published literature. We have also described patients’ compliance with treatment and associated co-infections in PKDL. A comprehensive literature search was conducted in PubMed, Scopus and Google Scholar to identify the relevant articles. A total of nine studies were eligible for inclusion in this review. Drug combinations used in India were miltefosine-liposomal amphotericin-B, miltefosine-paromomycin, miltefosine-amphotericin-B, sodium stibogluconate (SSG)-immunotherapy and SSG-rifampicin. However, in Sudan, except one, all studies have used SSG-based combinations viz. SSG-rifampicin, SSG-paromomycin and SSG-immunotherapy. The efficacy and safety of miltefosine in combination with liposomal amphotericin-B as well as conventional amphotericin-B were found to be excellent in a limited number of patients. These combinations are said to have better patient compliance and shorter treatment duration. Another combination of miltefosine and paromomycin was found to be satisfactory with a final cure rate of 83.3%. SSG in combination with paromomycin had a good clinical outcome among severe PKDL patients in Sudan, though pain at the injection site was experienced by all patients. There is a lack of data on combination therapies for PKDL through large-scale randomised controlled trials (RCTs). Therefore, multicentric randomized controlled trials with a sufficiently large sample size are urgently needed to verify the efficacy, safety, and other advantages of combination therapies for PKDL. With the availability of liposomal amphotericin-B, miltefosine and immunotherapy, clinical management of PKDL appears promising.

Introduction

Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis, caused by the protozoan parasite, Leishmania donovani. Infected female phlebotomine sand flies transmit the disease. Lesions of PKDL appear on the skin as hypopigmented macules, papules, nodules or their combinations all over the body including the face.[1] This disease commonly affects poor people living in rural areas. Earlier visceral leishmaniasis (VL) patients treated with sodium antimony gluconate (SSG) used to manifest lesions of PKDL.[2] Nevertheless, recent studies have documented PKDL occurrences with all available antileishmanial including AmBisome®,[3] miltefosine,[4] paromomycin[5] and miltefosine-paromomycin combination.[6] Besides, people with no history of VL have developed PKDL.[7] India and Sudan, where L. donovani remains the predominant leishmanial species, render the highest burden of PKDL in the world. Only a few chemotherapeutic drugs are approved for the treatment of PKDL amidst a growing threat of widespread drug resistance that in turn is limiting the treatment options.

In East Africa, PKDL is generally self-limiting and only severe cases need treatment. The standard treatment regimen for PKDL in East Africa is SSG and an alternative option is liposomal amphotericin-B.[1,8] In India, miltefosine remains the sole oral, first-line drug for the treatment of PKDL. It is used at a daily dose of 2.5mg/kg body weight in children and 100mg in adults for 12 weeks.[9] The efficacy of miltefosine was found as 85% in the treatment of PKDL.[9] However, the efficacy of miltefosine is gradually decreasing over time.[9] A major adverse effect associated with this therapy is gastrointestinal disturbances that limit its widespread acceptability.[10] Conventional amphotericin-B is another treatment option i.e. effective at a dose of 1 mg/kg for 60-80 infusions but, nephrotoxicity remains a major concern.[11] Besides, long treatment duration increases the risk of treatmentnon-compliance. AmBisome® is a liposomal formulation of conventional amphotericin-B shown to be safe and effective in the treatment of PKDL.[12] AmBisome® has added advantage over conventional formulations in terms of nephrotoxicity. A recent study from Bangladesh, reported a complete cure rate of 78% with AmBisome® when administered as a total dose of 15mg/kg divided into 3mg/kg biweekly for 3 weeks.[12] No serious toxicity was reported. Paromomycin is an aminoglycoside antibiotic tried for the treatment of PKDL but did not show a satisfactory response (cure rate 62.5%).[13] SSG was the main drug used for the treatment of leishmaniasis since 1920. The most common side effects of SSG include cardiac arrhythmias and severe pancreatitis, which can be fatal in some situations.[14,15] Because of several toxicities and longer treatment duration, patients face difficulty in tolerating and complying with this treatment.[16] Over the last decade, the use of SSG in the Indian subcontinent has largely decreased because of widespread resistance.[17] Remarkably, the antibacterial drug rifampicin was found effective in leishmaniasis.[18] The reported cure rate ranged from 0% to 80% when rifampicin was used as monotherapy at doses ranging from 600 to 1200 mg/day.[18] Reports of the effectiveness of rifampicin in the treatment of PKDL are rare or incomplete.

Combination therapies in the treatment of different disorders have been widely accepted for many years owing to the enhancement of efficacy. Besides, combination therapy may cover a broader antiparasitic spectrum, elicit synergistic effects and delay the risk of drug resistance that may arise because of selection pressure. It also shortens the duration of treatment; thereby, it may reduce the cost and improve compliance.[19] These attributes of combination therapies may eventually improve treatment outcomes. Combination therapy has been playing a significant role in the treatment of HIV,[20] malaria[21] and tuberculosis.[22] It has been increasingly approved for the treatment of infectious and life-threatening diseases. The use of combination therapy in the treatment of PKDL is advocated by many researchers.[9,23,24] To the best of our knowledge, no exclusive review is available on combination therapies in PKDL. Therefore, we aimed to summarise the available evidence pertaining to the efficacy and safety of combination therapies used in PKDL. This article also describes treatment compliance and co-infection associated with PKDL.

Methodology

We searched over various platforms such as PubMed, Scopus and Google Scholar. The following keywords were used in electronic search, either alone or in combination: (‘PKDL’ OR ‘Post Kala-azar Dermal Leishmaniasis’) AND (‘Treatment’ OR ‘Management’ OR ‘Antimony Sodium Gluconate’ OR ‘Sodium Stibogluconte’ OR ‘Meglumine Antimoniate OR ‘Amphotericin-B’ OR ‘AmBisome’ OR ‘Liposomal Amphotericin -B’ OR ‘Paromomycin’ OR ‘Miltefosine’ OR ‘Combination therapy’ OR ‘Compliance’ OR ‘Co-infection’). This search was confined to English-language studies published before December 2021. Clinical trials, cohort studies, case reports and case series that reported treatment outcomes with any combination therapy in PKDL patients and were available in full text were included for abstract screening. Monographs, secondary research, commentaries, review articles and editorials were excluded. We evaluated the abstracts of identified papers to determine whether they met our study inclusion criteria. To find other potentially suitable studies, the reference lists of all selected studies were also reviewed. Data on the following variables were collected: first author, year of publication, study design, sample size, drug combinations, dose, treatment duration, adverse events, initial cure and final cure. The detailed search strategy is shown in Figure 1.

Figure 1.

Flow diagram of search strategy

Mechanism of Action of Commonly Used Antileishmanial Drug

Miltefosine is the first-line drug for the treatment of PKDL in the Indian Subcontinent. The mechanism of antileishmanial action of this drug is not clear, multiple mechanisms have been proposed by different studies. It induces apoptosis-like death in L. donovani promastigotes.[25] Miltefosine inhibits the cytochrome c oxidase in mitochondria thus reducing oxygen consumption and production of ATP in leishmania donovani.[26] This drug also exerts its effect by inhibiting phosphatidylcholine (PC) biosynthesis.[27] Disruption of Ca⁺² homeostasis of the parasite was also documented in a recent study.[28] Amphotericin-B is another leishmanicidal drug that acts by binding to ergosterol of the cell membrane and altering the cell membrane permeability. Resulting in, an increase in the leakage of essential ions and small solute molecules followed by cell death. This drug also induces oxidative stress in leishmanial amastigote.[29] The mechanism of the antileishmanial action of sodium stibogluconate is unknown, several mechanisms have been reported, but it is believed to be because of the decrease in available ATP and GTP, which is likely secondary to a blockage of the citric acid cycle and glycolysis.[30] This drug also acts by inhibition of DNA topoisomerase I.[31] Pentavalent antimonial [Sb (V)] converted into more toxic and active Sb (III) and induced apoptosis by oxidative stress, raising intracellular Ca⁺².[32,33] Wyllie et al. reported that [Sb (III)] inhibits trypanothione reductase thereby disulfide forms of trypanothione and glutathione accumulate inside the leishmanial amastigote.[34] Paromomycin, an aminoglycoside antibiotic was also found to be effective in leishmaniasis. The clear antileishmanial mechanism of this drug needs to be elucidated. It was proposed that it binds with the ribosomal 30S subunit and inhibits protein synthesis of leishmanial amastigote.[35] Study has also reported that paromomycin inhibits the metabolism and mitochondrial respiration of leishmania.[27] The mechanism of action of commonly used antileishmanial drugs in the treatment of PKDL is presented in Figure 2.

Figure 2.

Mechanism of action of commonly used antileishmanial drugs in PKDL

Studies on Combination Therapy Used in PKDL

Tables 1 and 2 present nine selected studies on PKDL combination therapy including two randomised controlled trials, three cohort studies, two retrospective observational studies, one case report and a case series. Five studies were conducted in India and four in Sudan. Various drug combinations tried in PKDL were miltefosine plus liposomal amphotericin-B,[36] miltefosine plus paromomycin,[37] miltefosine plus amphotericin-B,[38] SSG plus Rifampicin,[39] SSG plus paromomycin,[40,41] SSG plus immunotherapy[42,43] and itraconazole plus terbinafine.[44] The detailed efficacy and safety parameters are presented here.

Table 1.

Characteristics of the included studies

Author/Ref.	Year	Journal	Country	Study population	Dose/Duration	Age group (year)	Study design
Ramesh et al.[36]	2020	J. Infect. Dis.	India	LAmB + MIL=16 MIL=16	3 injections of LAmB, 5 mg/kg + MIL100 mg/day (45 days) 100mg/day (for 90 days)	9-60	Cohort study
Pandey et al.[37]	2017	Br. J. Dermatol.	India	MF + PM=30	2.5mg/kg + 11mg/kg for 30 days	5-65	RCT
Abongomera et al.[40]	2016	PLOS One	Sudan	SSG + PM=77	20 mg/kg/day + 11mg/kgfor 17 days	≥5	Retrospective observational study
Younis et al.[41]	2015	Int J Res Med Sci.	Sudan	SSG + PM=9	20mg/kg + 11mg/base/kg/day for 30 days	5-17	Case series
Ramesh et al.[38]	2014	Acta DermVenereol	India	AmB + MIL=3	50 mg AmB for 20 days + 50 mg oral MIL thrice daily for 40 days	Case1=20 Case2=24 Case3=26	Case report
Ramesh et al.[42]	2010	Indian J Dermatol Venereol Leprol	India	Group I SSG=32 Group II SSG + ALP=10 SSG + RMF=6 SSG + ALP + RMF=5 SSG + MW vaccine=8	20 mg/kg/day (total dose 1 gm) 20 mg/kg/day (total dose 1 gm) + 800 mg/day 20 mg/kg/day (total dose 1 gm) + 15 mg/kg varied from 750-900 mg/day. 20 mg/kg/day (total dose 1 gm) + 800 mg/day + 15 mg/kg varied from 750-900 mg/day. 20 mg/kg/day (total dose 1 gm) + 0.1 ml	18-65	Retrospective study observational study
Musa et al.[43]	2008	Trans R Soc Trop Med Hyg	Sudan	ALM + BCG + SSG=15 Placebo + SSG=15(control)	100 mcg + one-tenth of the 0.1 ml of dose used in TB for 4 weekly doses + 20 mg/kg/day for 40 days 20mg/kg for 40 days	7-60	RCT
Sharma et al.[39]	2007	Indian J Dermatol VenereolLeprol	India	SSG + RMF=8	10mg/kg/day + 900mg/daily for 120 days	18-39	Cohort study
Khalil et al.[44]	1996	Trans R Soc Trop Med Hyg	Sudan	TRF + ITZ=9	250 mg/day + 200 mg/day for 4 weeks	>18	Cohort study

MIL-miltefosine, PM-paramomycin, TRF-terbinafine, ITZ-itraconazole, ALM-alum-precipitatedautoclaved Leishmaniamajorvaccine, BCG-Bacille Calmette-Guerin, SSG-sodium stibogluconate, RMF-rifampicin, LAmB-liposomal amphotericin-B, AmB-amphotericin-B, ALP- Allopurinol, RCT-Randomized controlled trial

Table 2.

Treatment outcome of combination regimen

Author/Ref	Initial cure (at the end of treatment)	Final cure	Lesion type	Adverse events
Ramesh et al.[36]	MIL + LAmB initial cure rate NR 16 (100%) cured in MLF group	16 (100%) [18 months follow up] 12 (75%) cured and 4 (25%) relapsed [18 months follow up]	4 macular, 5 papular, 7 nodular. 6 macular, 6 papular, 4 nodular.	Moderate anorexia in all cases, vomiting in some cases. and vertigo in 6 patients.
Pandey et al.[37]	100%	Final cure rate was 83.33% &16.67%relapsed. (1 year follow up)	Macular (46.7%), Papular (6.7%), Nodular (10%), Maculopapular (26.7%) Polymorphic (10%)	Pain at injection site, increased hepatic enzymes, eosinophilia and vomiting, hypokalaemia, gastritis, swelling of legs.
Abongomera et al.[40]	75 cured 2 relapsed	75 cured 2 relapsed	Grade 3 or grade 2 in all patients	Pain at injection site.
Younis et al.[41]	8 cured 1 relapsed	Follow up period was varied 3 cured [10 months follow up] 1cured [8 months follow up] 1cured [9 months follow up] 1cured [6 months follow up] 3 cured [>12 months follow up] 1 relapsed	Grade 2:1 (5/9 cases) with 2 cases of grade 1:1, one case of grade 1:2, and one had grade 3:3.	Pain at injection site experienced by all patients.
Ramesh et al.[38]	all 3 cases (100%)	100% [2 years follow up]	Case 1- Mix of macular & nodular Case 2- Nodular Case 3- polymorphic	Vomiting
Ramesh et al.[42]	Group I 5/32 SSG Group II 3/10 SSG + ALP within 110 days 2/6 SSG + RMF 0/5 SSG + RMF + ALP 2/8 SSG + MW vaccine	5 (Group I) [follow up 1-2 year] 4/7 (Group II) [follow up 1-2 year]	All the patients had mixed or polymorphic lesions	Postural hypotension, body aches, giddiness, metallic taste, loss of appetite, severe joint pain, vomiting and febrile illness
Musa et al.[43]	13 healed completely and 2 shows improvement within 60 days - ALM + BCG + SSG group 8 healed completely and 1 shows improvement within 60 days- SSG + placebo group	11 cured [90 days follow up] 9 cured [90 days follow up]	The majority of PKDL was 2:2 grade.	Injection site indurations and ulcers, myalgia.
Sharma et al.[39]	5 cured 5 lost to follow up	5 cured [mean follow up 1 year]	Maculopapular in all patients and larger nodules in 4 patients.	Myalgia, thrombophlebitis Headache, mild leukopenia, and elevated hepatic enzymes
Khalil et al.[44]	1 patient showed a good clinical response after 2-3 weeks. Other 8 patients relapsed	NR	4 maculopapular 4 papular 1 papulonodular	Mild albuminuria in one patient

MIL-miltefosine, PM-paramomycin, TRF-terbinafine, ITZ-itraconazole, ALM-alum-precipitated autoclaved Leishmania major vaccine, BCG-Bacille Calmette-Guerin, SSG-sodiumstibogluconate, RMF-rifampicin, LAmB-liposomal amphotericin-B, AmB-amphotericin-B, ALP-Allopurinol

Miltefosine based combination

Miltefosine-Paromomycin (MF-PM)

Pandey et al. assessed miltefosine plus paromomycin combination in 30 PKDL patients.[37] In that, patients of group-A received a combination of paromomycin injection, daily (10 days) at a dose of 11 mg/kg plus miltefosine capsule orally at 2.5 mg/kg/day (10 days) for two courses at a gap of 15 days; group-B received a combination of paromomycin injection plus miltefosine capsules in the same dose for three courses. Patients of group-A did not improve after completion of two courses hence, all group-A patients were treated with one more course of miltefosine at 2.5mg/kg plus paromomycin 11mg/kg for 10 days. The Initial cure rate after completion of therapy was 100%. The final cure rate was 83.3% and 16.67% of cases relapsed at 12 months of follow-up. A total of 63 adverse events (AEs) were reported in 26 patients. The most common AEs were pain at the injection site followed by increased hepatic enzymes level, eosinophilia, hypokalemia, vomiting, gastritis and swelling of the legs andface. This study also reported an excellent compliance rate as none of the patients were lost to follow-up. The recommended dose of miltefosine is 2.5 mg/kg for 12 weeks (84 days) in PKDL but in combination with paromomycin, it was given for a period of 60 days (approximately 9 weeks) including the interval between each course. This indicates that combination therapy reduces the treatment duration and shortens the period of hospitalization besides being cheaper. MF-PM combination therapy showed excellent efficacy and safety in visceral leishmaniasis with cure rate of 98.7%.[45]

Miltefosine-Amphotericin-B (MIL-AmB)

In a preliminary study, Ramesh et al. treated two PKDL cases with MIL-AmB.[38] The first patient was given a dose of 50 mg MIL thrice daily for 40 days in combination with intravenous infusions of 50 mg amphotericin-B daily for 20 days. However, in the second case, the dose of MIL was reduced to twice daily for 60 days to avoid vomiting. Apart from these two cases, he also treated another PKDL patient with a daily IV infusion of amphotericin-B alone at a dose of 50mg/day, resulting in a total dose of 4.5 g, over 100 days. All three cases were cured, and no sign of relapse was observed at 2 years of follow-up. This indicates that the dose and treatment duration could be significantly reduced when the two drugs are given in combination. When used alone, the risk of nephrotoxicity due to AmB,[11] and the gastrointestinal side-effects of MIL increases drastically.[10] The authors concluded that the MIL AmB combination[38] is the preferred regimen for wide-ranging extensive PKDL cases over AmB or MIL alone. An animal study also reported that the combination of MIL-AmB was safe and effective in VL.[46]

Miltefosine-Liposomal amphotericin -B (MIL-LAmB)

In a study by Ramesh et al., 16 PKDL cases were treated with the combination of MIL-LAmB.[36] In which, miltefosine was used at a dose of 100 mg/day for 45 days and LAmBat 5 mg/kg for 3 injections whereas, in another arm, an equal number of patients received treatment with miltefosine monotherapy at a dose of 100 mg/day for 90 days. This study was based on the fact that LAmB and MIL, both are highly effective in PKDL as a monotherapy[12,23] hence, their synergistic effect in combination may augment the cure rate and reduce the rate of relapse. A rapid decline in parasite load resulted in a 100% cure, without any relapse at 18 months of follow-up in the combination group was observed. Whereas, with MIL monotherapy, clinical cure was seen with a gradual decrease in parasite load and 25% relapsed within 18 months of follow-up. None of the patients in combination therapy developed renal toxicity. Apart from two patients who developed vomiting, no other adverse event was reported with the combination therapy. Concurringly, an RCT with the combination of MIL-LAmB was found to be excellent (cure rate of 97.5%) in the treatment of VL.[45]

SSG based combination

It was observed that PKDL does not respond to the curative dose of SSG for VL, which is 10 mg/kg/day for 21 days. In India, SSG is typically administered intramuscularly or slowly intravenously at a daily dose of 20 mg/kg, up to a maximum of 850 mg/day (equivalent to 8.5 mL of SSG or 10 mL of Meglumine antimoniate), for a minimum of 120 days for the treatment of PKDL.[47] In contrast, the optimum recommended duration for Sudanese PKDL is 2 months.

SSG-Rifampicin

Sharma et al., documented the safety and efficacy of combination therapy with SSG 10 mg/kg/day I.V plus oral rifampicin 900 mg/day for 120 days in eight PKDL patients.[39] Only six patients completed the treatment. Five of them responded well at the end of therapy. The response began within a week, and all five patients responded after three weeks of therapy. Except for one patient, all five patients showed excellent response, and no relapse was observed till the one-year follow-up. A total of five patients experienced adverse events such as myalgia, thrombophlebitis, headache, joint pain, leukopenia and increased hepatic enzymes. Despite the longer treatment duration, compliance with the therapy was good. The study concluded that a 120-day course of SSG plus rifampicin is effective and reasonably safe.

SSG-Paromomycin (SSG-PM)

A retrospective study by Abongomera et al. reported the effectiveness of the SSG-PM combination in PKDL.[40] In this combination, SSG was administered intramuscularly at a dose of 20 mg/kg/day (with a minimum daily dose of 200 mg and no maximum dose), while PM was administered intramuscularly at a dose of 15 mg sulfate/kg/day (equivalent to 11 mg/base/kg/day) for a duration of 17 days (with a minimum daily dose of 50 mg and a maximum dose of 1,150 mg). The reported cure rate for the SSG-PM combination was 97%, whereas the cure rate with SSG monotherapy was 90%. The cure rate was not differentiated as initial and final cure in this study. A total of 77 patients’ data were included in which all the patients had either grade-2 or grade-3 lesions. PKDL lesions are graded as grade-1when macular, papular or nodular lesions appear on the face, with or without the involvement of the upper chest and arms. Grade-2 is characterised by the appearance of dense macular, papular or nodular lesions on most of the face and spreading to the chest, back, upper arms and legs, with few rashes on the forearms and legs. Whereas, in grade-3 dense macular, papular or nodular lesions appear on most of the trunk, including hands and feet, mucosa of the lips and palate with the presence of crusting and scaling. It was concluded that the SSG-PM combination had more favourable outcomes in terms of shorter treatment duration, low cost and lower default rate compared with SSG. Pain at the injection site was a common adverse event experienced by all patients. In VL, the efficacy of SSG-PM combination for 17 days was found as 91.4% with a good safety profile.[14] This combination has been recommended for use in the treatment of VL in East Africa.[14] In another study, Younis et al. treated nine PKDL patients with an SSG-PM combination for a period of 30 days.[41] Five patients were cured and one (1/9; 11.1%) relapsed after completion of 30 days of SSG-PM combination therapy. The remaining three patients (3/9; 33.3%) who failed to cure previously with SSG were completely cured after 40 days of combination therapy with SSG-PM. Similar to the study performed by Abongomera et al. this study also reported pain at the site of injection as one of the common AEs among all patients.[40]

SSG-Immunotherapy and antifungal based combination

Response of immunochemotherapy was also found satisfactory for PKDL in Sudan.[43] An interventional study by Musa et al. reported that a combination of alum-precipitated autoclaved Leishmania major (Alum/ALM) vaccine + BCG with SSG is safe and effective for PKDL treatment.[43] Another SSG-based retrospective study was reported by Ramesh et al., in which SSG was combined with allopurinol, rifampicin and the Mycobacterium W vaccine.[42] No major difference was observed with these combinations when compared with SSG alone. An earlier study by Khalil et al. reported that antifungal drugs itraconazole-terbinafine combination failed to heal PKDL lesions.[44]

Only a few studies on combination therapy for PKDL are available in the existing literature. Most of the studies have limitations of inadequate sample size, non-confirmatory diagnostic method, variable study design and follow-up duration. Among the various combinations tried, miltefosine in combination with liposomal amphotericin-B or conventional amphotericin-B in India and SSG-paromomycin in Sudan showed promising results. Hence, these combinations can be considered for future therapeutic options for PKDL.

PKDL Co-infection

PKDL cases act as a reservoir for Leishmania parasites hence, treatment of PKDL cases is of paramount importance for the elimination of kala-azar (VL). Similar to VL co-infections, PKDL was also found to be complicated by leprosy,[48] tuberculosis[49] and HIV co-infection.[50] In addition, para kala-azar dermal leishmaniasis is a new challenge.[51] Currently, there is no comprehensive treatment guideline available for these emerging problems. Hence, management of leishmaniasis co-infection cases is substantially challenging for the kala-azar elimination program. The available data on the antileishmanial drugs do not support their use in VL co-infection. A study from Ethiopia including HIV-VL co-infected patients used miltefosine at a dose of 100mg/day for 100[52] days. The initial parasitological cure was 64% but all relapsed in a short duration.[52] A cure rate of 85% using liposomal amphotericin-B, at a total dose of 20-25mg/kg/day was achieved in HIV-VL co-infected cases.[53] Combination therapy with liposomal amphotericin-B at 30mg/kg divided into 6 equal doses on alternate days plus miltefosine 50mg twice or once daily showed promising results in HIV-VL patients.[54] In this study, eight patients relapsed out of 100 patients discharged after the initial cure.[42] However, apart from a few case reports, no efficacy and safety assessment of the available drugs and/or their combinations for the treatment of PKDL co-infections has been performed. Co-infected patients are reported to have multiple relapses.[52] Besides, repeated exposure to the same drug increases the risk of emergence of drug-resistant parasites. Miltefosine is the first-line therapy for the treatment of PKDL in the Indian subcontinent and is also used to manage PKDL cases having co-infections. Considering the emergence of miltefosine resistance, combination therapies for co-infections should be evaluated to develop its substitute.

Compliance with Therapy

All available monotherapy of PKDL requires a long-term treatment, which may further get prolonged due to PKDL co-infections. Moreover, all therapies are limited by several toxicities that in turn increase the risk of treatment non-compliance. No study has been conducted to exclusively assess the compliance rate and its determinants for the drugs used in the treatment of PKDL. However, a study from Nepal reported an adherence rate of 83% with miltefosine in VL patients; the adherence rate was better among educated and patients having awareness of the side effecs of the drug.[55] Data from a hospital-based retrospective study by Ramesh et al. reported that approximately 15% of PKDL patients did not complete the course of miltefosine treatment.[23] Non-compliance was also observed in a controlled clinical trial, in which four patients did not complete the treatment including one patient who prematurely interrupted the treatment due to nausea and vomiting.[56] These non-compliant patients may have a high risk of emergence of drug resistance and persistent disease transmission. This may hamper the kala-azar elimination efforts. Therefore, a safe, effective and short-duration treatment regimen is required to improve treatment compliance. Combination formulations shorten the treatment duration and reduce its cost that in turn may improve compliance among PKDL patients. Studies have also recommended implementing ‘directly observed treatment’ with miltefosine for PKDL.[56,57] In addition, clinical pharmacists may be used to educate patients regarding PKDL and its treatment to improve compliance.

Conclusion

Combination therapy has the advantage of reduced dose and duration, and hence, better tolerance and compliance as opposed to monotherapy for PKDL. It would also reduce the chance of the emergence of microbial resistance. Miltefosine in combination with liposomal amphotericin-B or conventional amphotericin-B in India and SSG in combination with paromomycin in Sudan showed good treatment response in limited number of patients. Therefore, a large-scale multicenter study of the above-mentioned drug combination at various doses and frequencies are recommended. Simultaneously, the quest for a short, affordable, safe and effective drug that can be used in ambulatory care with minimal patient monitoring is urgently needed for the elimination of kala-azar from Southeast Asia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.