Ethics statement

Study sites and populations

Using a comprehensive interview topic guide [26], individual semi-structured interviews of about one-hour duration, related to their disease experiences, preferences and expectations, were conducted with 33 CL patients at four sites in Austria, Brazil and Colombia. Under the assumption that this would cover the range of patients’ profiles and experiences, we purposively sought maximum variation along characteristics such as patients’ gender, age, treatment status (before, during, after treatment), clinical lesion presentation and causative New-World Leishmania species. We took the socioeconomic context into consideration by including participants from a high-income country (Austria) and low- and middle-income countries (Brazil and Colombia).

Austria: Three interviews were conducted at the Vienna General Hospital, Austria, which is the largest hospital in Austria and manages most CL cases imported into Austria. Austria is considered a non-endemic country for leishmaniasis, although two presumably autochthonous cases have been reported [28,29].

Brazil: Ten interviews were conducted at the Centro de Referência em Leishmaniose do Instituto René Rachou (CRL-IRR), Belo Horizonte, Brazil. CRL-IRR works as a reference center for management of CL for the state of Minas Gerais, in southeastern Brazil, the third Brazilian state in CL cases. Most patients were residents in small towns or rural areas within a radius of 500 kilometers from the center.

Colombia: Ten interviews were conducted at the CIDEIM facilities in Cali and Tumaco. The Cali facility works as a reference center for management of CL in south-west Colombia. Tumaco is a municipality located in southern Colombia, where there is endemic transmission of CL, and it is one of the areas reporting most cases of CL in Colombia. CIDEIM operates as a primary health and research facility. Patients of these two facilities are mostly civilians. Furthermore, researchers from the PECET (Program for the Study and Control of Tropical Diseases) of the University of Antioquia conducted ten interviews with soldiers who were in the Leishmaniasis Recovery Center of the national army in Boyacá. The program for management of CL for the Colombian military includes a special facility, Directly Observed Therapy (DOT) and follow-up lab tests and medical support until the end of treatment. In Colombia, the military population due to their professional duties (fight against armed groups and drug traffickers) is one of the groups most affected by CL. Interviews occurred prior to signing the peace agreement with the FARC guerrilla.

Data collection

Interviews were conducted in the patients’ mother tongues by four researchers (MC, GC, JK, LLC) and audio recorded; interviewers took notes. Interviews from Colombia and Brazil were conducted as part of the study published by Erber et al. [26], and the Austrian interviews were conducted in 2019 following the same protocol and interview guide. Each recording was transcribed into the language in which the interview was conducted, and subsequently translated into English for analysis. Quality of the original transcripts and translations were verified by the researchers conducting the interviews.

Data analysis

Transcripts were analysed using a framework approach [30,31], with pre-defined categories imported into Nvivo 12 (QSR International) as nodes for coding of transcripts. As a framework, we used the TPP developed by DNDi specifically for CL treatment [32]. Two additional categories (Perceived barriers and Other development needs) were added as they emerged from the interviews and were deemed realistic to address in a broader drug development context. Two categories (Target species and Stability) were omitted as they were not addressed in the interviews. Coding of transcripts was conducted independently by two researchers (MC and ACE), and results discussed. During analysis, the coding framework was subject to continuous updating. The final coding framework is shown in Table 1.

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Table 1. Coding framework.

The coding framework is based on the TPP developed by DNDi [32]. TPP categories are in bold; existing ones were amended by two added during the coding process (denoted with an asterisk *).

https://doi.org/10.1371/journal.pntd.0011975.t001

Themes, concepts or propositions that describe, help to interpret and explain aspects of the data [31] were articulated and developed by comparison between and within interviews by two researchers (MC and ACE). Themes were then assessed for potential incorporation into a TPP, and for being considered during drug development in general. In line with the exploratory nature of the study, we did not want to prioritize; therefore, we did not count the number of times a specific aspect was mentioned (frequency analysis) and did not present themes within a TPP category in a particular order.

1 Safety/Tolerability

Patients described their experience with the types, timing and sequence of tests required to monitor the treatment safety. These descriptions were most detailed for the Colombian soldier population, the majority of them treated with systemic meglumine antimoniate. Information on preferences of monitoring was limited. Among these, two patients mentioned how monitoring needs determine the treatment location: One Colombian patient decided to stay in a city during the treatment to have better monitoring of the treatment, while one Austrian patient preferred to be treated in a hospital instead of on an outpatient basis, due to the severity of the experienced side effects. When speaking about systemic antimonials, some patients preferred a lower volume of drug to be administered due to the pain and adverse events (AEs) experienced.

Patients’ descriptions of multiple adverse events in response to pentavalent antimony, pentamidine and miltefosine are in line with the literature. Many discussed tolerability of treatment and reported adverse events (AEs), at times in an emotional manner, describing the often-complex considerations they face. Patients often saw AEs as an inevitable part of the treatment, and accepted them. Fears of receiving treatment due to the injections and the side effects were illustrated by two Colombian soldiers. They met others requiring more than one course of antileishmanial treatment and were afraid of receiving a second treatment and its potential consequences (“it seems like a common pimple, but what they inject you for that pimple it’s what hits you hard" -CP02-).

In contrast, three Brazilian patients described their positive experiences with intralesional administration of antimonials. Trade-offs made are reflected in how patients chose to ‘ignore’ the risks associated to the treatment when weighted against the need of being cured.

2 Contraindications

Patients described the reasons for which the systemic antimonial treatment was contraindicated, including hypertension and arrhythmia, and alternative therapies offered to them. Some participants, mainly soldiers, highlighted the need for self-care or ‘taking care’, such as avoiding certain food or activities, to contribute to the healing process. Notably, one Brazilian patient with contraindications described moments of shared decision making with the treating medical team, which was not observed in other groups. One Colombian patient described discussing the location of treatment, based on the need of need of monitoring, with his family.

3 Efficacy

Treatment efficacy was discussed extensively by patients. Efficacy was understood as clinical cure in relation to the lesion, the absence of sequelae, scar formation and the prevention of disease relapse/reinfection. As part of a larger study on outcomes, a number of aspects were already reported on in a separate publication [27]. In this category, we identified efficacy as an important driver in the trade-offs made about treatment (Table 3). Patients discussed the preference for an effective treatment in healing the wound, regardless of scar appearance, potential side effects or treatment duration.

As described in Tolerability, part of the fear of disease relapse and reinfection was having to repeat the treatment. Some patients were aware and afraid of the risk of reinfection when living in an endemic area. Thus, long-term sequelae of the treatment, particularly antimonials, and fears of sequelae related to the disease itself, such as disease progression, could be avoided by successful treatment.

4 Formulation

In general, patients preferred oral and topical treatments due to the easier administration and being perceived as ‘fitting’ the disease. This conceptually interesting discussion was mentioned by different patients, who expressed that, since the infection is local, they would prefer the treatment to be also applied locally: a topical treatment for a local infection. This in addition to the perceived contrast between the treatment and the perceived disease severity, i.e., a long parenteral treatment for a ‘pimple’. By some patients, oral formulations are seen as easier, and an ideal treatment when compared to systemic antimonials.

Most Colombian patients, both from the military and the civilian population, had a preference for ointments over injections. One mentioned the potential timeliness of applying a cream to the wound, assuming than an early treatment may limit the infection. Physical therapy in the form of thermotherapy was only mentioned by Austrian patients.

When discussing parenteral formulations, patients often reported ‘fear of needles’—an aversion, or even a trauma, against injections. In contrast, some patients perceived injections as working faster and more effective than alternative modes of administration. While others, such as two Colombian patients, reported injections as the only treatment option. Mainly Colombian military patients discussed localized (directly on the lesion) versus systemic administration of antimonials. In this context, some patients prefer intravenous infusion (against intramuscular) due to the volume of medication, and less pain. However, intralesional injections were seen as preferable by being ‘stronger’, faster, and requiring fewer doses. This highlights the trade-offs between efficacy and other product characteristics.

5 Treatment regimen

Treatment regimen was found to be a TPP category rich in themes and trade-offs. Patients perceived long treatment durations as burdensome, particularly against the need to balance work obligations, and in connection with indirect costs (days of work lost). These were more marked for those living in remote areas. Twenty days to one month were seen as acceptable by some patients, corresponding to their experience, although they prefer the faster option to heal the skin lesion. In contrast, two patients at the military treatment center wanted additional recovery time before being sent back to operations. Patients described alternatives to mitigate the impact of the long treatment, including seeking help from others, often relatives, to administer the drug at or near home. Long treatments were accepted as a trade-off to achieving clinical cure.

The theme of compliance was central. In general, being treated, and taking the full treatment course, was seen as important to avoid relapse and sequelae. Many respondents continued treatment despite side effects. Reasons for this were the fear of disease progression and its consequences. Other patients reported treatment being paused, or suspended, due to adverse events, thus prolonging the overall treatment duration.

Regarding treatment frequency, daily administration of parenteral drugs was considered as too frequent, and patients preferred weekly injections. This was partly related to the logistics of daily parenteral drugs, for example, having a different health provider during the weekends at the hospital, which may not be familiar with the case or the drug. In contrast, daily administration of oral treatment or a drug that can be used at home, was accepted.

The availability of the drug or trained healthcare providers also influenced the decisions of where to receive treatment. When facing this situation, a Brazilian patient opted for the weekly injections in another city instead of daily ones near their residence.

6 Target population

Not all respondents addressed this category; often interviewers were being asked to clarify. Most agreed that everyone should be treated, for reasons such as an intrinsic right to treatment, patients’ quality of life, or to avoid disease progression. A few patients noted that special populations, such as children, should not be treated due to the pain and frequent adverse events of the medication. Findings are available in more detail in S2 File, as they were difficult to interpret and incorporate in a TPP.

7 Cost

Costs were frequently mentioned by patients, especially those related to procedures such as administration of injections, consultations, diagnostic tests, and transport. Inadequate or over-the-counter medications before CL diagnosis were also discussed, but rarely costs related to antileishmanial drugs, in line with the treatment being provided for free in Austria, Brazil and Colombia. One Colombian patient mentioned paying for administration of the injections outside of the health care system. Costs of diagnostic and pre-treatment tests required to define eligibility to systemic antileishmanial drugs (e.g., blood cell count) were sometimes paid by patients to expedite the initiation of treatment.

In a high-income setting, an Austrian patient describes paying a 140 EUR (154 USD) fee for specialized care to shorten waiting times, while a Brazilian patient described the challenges trying to access specialized care in their town, both due to the costs of the appointment and limited of availability of specialists. Some patients, particularly among those living in remote areas, reported significant transport costs to treatment facilities using a variety of means of transport, as well as time lost due to the journey. One patient describes pawning and borrowing money to afford transportation costs. This aspect is closely related to Geographical barriers (S2 File).

Indirect costs were mainly related to days of work lost and were mentioned as significant. Taking time off during treatment without payment was considered difficult for patients who worked as day laborers, or self-employed, some were not able to work at all during treatment, or not able to find work. Having to stay away from home for treatment was another reason for indirect costs and often affected patients’ income prospects. This contrasted with patients with formal employment, such as the Colombian soldiers or the Austrian patients. One Austrian received a sick leave of 4–5 weeks, noting that she was lucky and was not afraid of losing her job, due to her employer being treated for CL at the same time.

8 Perceived barriers

Patients reported barriers including geographical location, availability of treatment, migratory status or occupation (for example, civilian patients from Colombia reported difficult or no access to CL treatment for patients employed in illegal professions, or migrant workers) S2 File. Often there was a combination of different barriers that resulted in indirect costs and delayed initiation of treatment.

9 Other development needs

Patients emphasized the need for investments in research, to develop alternative drugs with a better safety profile. In addition, some patients emphasized the need to invest in vaccine development, knowing the risk of reinfection for people living in endemic areas.

In addition, patients emphasized the need for general information and dissemination activities, including information about the disease, such as the mode of transmission and treatment options, as well as campaigns to de-stigmatize the disease.

Incorporation of patients’ preferences in the TPP process

Central among the barriers to involving patients in drug development is the lack of methodological guidance, as reported by drug developers, patients and patient advocates, regulators and funders [47,48]. Recent initiatives have addressed this at a general level [16,17], and our study provides methodological guidance using an open, exploratory approach taking an NTD as an example. We designed and published an interview topic guide that allows an in-depth exploration of experiences and preferences [26], and reflections upon these, instead of focusing on TPP categories a priori. This interview topic guide could be adapted for similar diseases, in particular skin NTDs. Similarly, as done in this study with DNDi’s TPP, a coding framework for analysis could be adapted from existing TPPs for any particular disease or condition of interest, or guidance documents [6].

We thus advocate for incorporating patient preferences during technical discussions with experts and stakeholders when a TPP is being initially constructed, and then during revisions (often happening at regular intervals, or as required) [5]. This could inform the definition of ideal, acceptable or minimal requirements for each category, which very often feature in TPPs [6], in addition to parameters such as safety or efficacy endpoints which could, in turn, be considered in clinical studies. We posit that exploring patients’ perspectives would add value by bringing up aspects not otherwise considered by stakeholders and may also guide the R&D agenda. For example, the findings reported under other development needs highlight the importance of research into better treatments and a vaccine for CL [49].

Findings could be consolidated by quantitative instruments focusing on selected aspects of interest; identified themes could directly inform questionnaire design. A survey on preferred formulations pre- and post-treatment among patients has been shown to complement clinical trials of CL treatments [50]. The trade-offs identified in our study, and more general, identified risks and benefits could be further investigated using a quantitative discrete-choice-experiment (DCE) or triadic comparisons [51]. DCEs, used in healthcare research [52,53], have been used previously to inform drug development [54–56]. Previous studies have successfully used an initial qualitative phase in order to inform a subsequent discrete-choice experiment [57]. This could be complemented by consultations with drug developers to gain insights into the construction and updating of a TPP, as well as to identify stages where patient input could be useful.

As suggested by others [5,17], considerations related to accessibility in combination with the closely related concept of affordability (as represented by the categories Cost and Perceived barriers) should be embedded within a TPP, in particular in any prospective profile describing preferred product characteristics. Both ideal and acceptable targets for direct and, if possible, indirect costs should be included. Compliance is seen as a central issue across themes, and could be addressed meaningfully; first, by incorporating patients’ preferences in drug development in general and second, by addressing the actual and potential reasons for non-compliance that were brought up, such as experienced adverse events or geographical and availability barriers.

Generalizability and transferability of findings

As this is a qualitative study using a non-probability sample [58], it is therefore not likely to be representative of the entire spectrum of patients across regions. In our study, we paid attention to the transferability of methods, and, to a certain extent, of findings by clearly laying out settings (see Study sites and populations in the Methods section) and limitations (see Strengths and limitations of the study). Furthermore, we found the different settings reflected in the preferences, such as the civilian vs. the military population in Colombia, and a limited number of patients from a high-income, non-endemic area.

We did not include patients suffering from Old-World CL (OWCL) forms, and concentrated our efforts on NWCL forms, by a distinctive Leishmania species spectrum endemic to the Americas with very limited self-healing, and often progression to a mucosal or mucocutaneous form [24,25].

Strengths and limitations of the study

Interviews were conducted in patients’ mother tongues, including German, Portuguese, and Spanish. The analysis of pooled interviews transcripts, translated into English, was performed independently by two researchers, and informed by notes taken during the interviews as well as discussions with the interviewers; this process ensured consistency while taking the cultural context into consideration.

Instead of designing a topic guide focussing on TPP categories a priori and asking for preferences, we chose a broad topic guide to allow for an in-depth exploration of experiences, and reflections upon these. Using such a comprehensive interview guide, other aspects of the lives of patients, such as the impact of disease and treatment on everyday life, or disease-specific topics such as stigmatization due to disfigurement and scars, could be explored as well.

We only interviewed patients with NWCL who had sought, started, or completed their treatments and whom we were able to follow up. Hence, by design we are only able to report on patients’ experiences with therapies, which may influence their perceived ideal and acceptable treatments. In addition, each participating country has marginalized populations disproportionally affected by CL, e.g., refugees or migrant workers, which were found to be difficult to be followed up and reluctant to be interviewed (JK, MCN, personal communication). Finally, we used medical terminology instead of patients’ own words, in line with the aims and existing literature. We are aware that this might compromise presenting the richness of patients’ experiences.

Further research

Future studies could try to include CL patients who were lost to follow-up in trials or routine treatments, or marginalized populations (e.g., immigrants, migrant workers). Methods such as a discrete-choice-experiment (DCE) or triadic comparisons, as outlined above, could provide a quantitative assessment of identified trade-offs, and contribute to the generalizability of results.

The methodology is designed so that it could be adapted for other NTDs, in particular other skin NTDs [59]. Modifications to the sampling strategy, the interview topic guide and, if necessary, the analysis framework (which could be based on an existing treatment TPP) would allow for consideration of the specific context, including patients’ social and cultural circumstances.

Contributors

ACE, BA, EP, GC, LLC, MC and PO conceived of and designed the study, and developed study instruments. MC, JK, GC, MC and LLC collected data. EP, JW, NH and PO supervised data collection and analysis. ACE and MC coded the data, conducted the analysis, and wrote the first draft of the manuscript. All authors contributed to the manuscript and had final responsibility for the decision to submit for publication.

Data sharing

All relevant data are within the paper and its Supporting Information files. The study protocol is published [26].