Stakeholders' views and perspectives on treatments of visceral leishmaniasis and their outcomes in HIV-coinfected patients in East Africa and South-East Asia: A mixed methods study.

BACKGROUND: In visceral leishmaniasis (VL) patients coinfected with human immunodeficiency virus (HIV), combination therapy (liposomal amphotericin B infusion and oral miltefosine) is being considered as an alternative to liposomal amphotericin B monotherapy. We aimed to assess the views of stakeholders in relation to these treatment options.
METHODOLOGY: In a mixed methods study, we surveyed and interviewed patients, government functionaries, programme managers, health service providers, nongovernmental organizations, researchers, and World Health Organization (WHO) personnel. We used the Evidence to Decision (EtD) framework for data collection planning and analysis. Constructs of interest included valuation of outcomes, impact on equity, feasibility and acceptability of the treatment options, implementation considerations, monitoring and evaluation, and research priorities. PRINCIPAL FINDINGS/
CONCLUSION: Mortality and non-serious adverse events were rated as "critical" by respectively the highest (61%) and lowest percentages (47%) of survey participants. Participants viewed clinical cure as essential for patients to regain productivity. Non-patient stakeholders emphasized the importance of "sustained" clinical cure. For most survey participants, combination therapy, compared with monotherapy, would increase health equity (40%), and be more acceptable (79%) and feasible (57%). Interviews revealed that combination therapy was more feasible and acceptable than monotherapy when associated with a shorter duration of hospitalization. The findings of the interviews provided insight into those of the survey. When choosing between alternative options, providers should consider the outcomes that matter to patients as well as the impact on equity, feasibility, and acceptability of the options.

Introduction

Visceral leishmaniasis (VL) is an opportunistic infection in individuals infected with human immunodeficiency virus (HIV) [1]. Initially reported from southern Europe in the mid-1980s, Leishmania and HIV coinfections have progressively been reported from 45 countries worldwide [2]. In countries reporting fully on HIV status in VL patients (positive, negative or status unknown), the proportion of coinfections has increased (1.6%, 2.6% and 3.8% in 2016, 2017 and 2018, respectively) [3]. In 2020, <1% of VL cases were reported to be co-infected in the African Region (AFR), 12.3% in the Region of the Americas (AMR) and 2.8% in the South-East Asia Region (SEAR) [4]. These proportions vary from country to country depending upon the extent of HIV screening in VL patients. For example, in India, the percentage of Kala-azar (KA) cases tested for HIV increased from 47% in 2015 to 98% in 2020, representing an increase in the proportion of KA–HIV co-infected cases from 0.5% in 2015 to 4.1% in 2020 [5].

Both HIV/AIDS and VL pose clinical, diagnostic, therapeutic, and public health challenges as they are mutually reinforcing conditions with synergistic detrimental effects on each other. Immunosuppression caused by AIDS reduces the response to VL treatment, with lower cure rates, higher drug toxicities, higher relapses, and higher mortality rates than in immunocompetent patients. With each episode of relapse, therapeutic response becomes challenging with decreased relapse-free interval. While data on the impact of HIV–VL coinfection on patients’ quality of life are scarce, the perception is that the impact is devastating [6]. While timely VL treatment is essential for reducing morbidity and mortality of these patients, adequate management of HIV is also important (e.g., HIV testing, selection of antiretroviral therapy (ART), timing of ART and careful consideration of drug-drug interactions while selecting appropriate regimen), contributing most importantly to reducing risk of VL relapse.

Treatment of VL in HIV–coinfected patients is constrained by reduced numbers of therapeutic options due to few clinical trials, ineffectiveness, or drug toxicity. Until recently, clinical studies were available only on L. infantum from Mediterranean countries, with no data on L. donovani from Africa or Asia. This is a major challenge considering that L. infantum has different drug susceptibilities and less virulence than L. donovani and that relapses due to L. donovani occur at a lower CD4+ count. While currently the World Health Organization (WHO) recommends monotherapy of liposomal amphotericin B infusion at a dose of 3–5 mg/kg daily or intermittently for 10 doses (days 1–5, 10, 17, 24, 31 and 38) up to a total dose of 40 mg/kg as the first-line treatment [1], new evidence on combination regimens has become available from clinical trials recruiting HIV–VL coinfected patients in East Africa [7] and South-East Asia [8]. The regimens consist of combination of liposomal amphotericin B infusion (at a dose of 5 mg/kg on days 1, 3, 5, 7, 9 and 11, up to a total dose of 30 mg/kg body weight) and oral miltefosine (100 mg in divided doses for 14 days in South-East Asia and 28 days in East Africa respectively). Generally, in this patient population, the duration of admission or further treatment depends upon a case-by-case basis and upon a variety of factors such as delay in knowing HIV status, delay in seeking VL treatment, other comorbidities and opportunistic infections.

The emerging evidence on combination regimens has created the need for WHO to propose evidence-based region-specific treatment recommendations. The WHO guideline process follows the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology that uses the Evidence to Decision (EtD) framework to structure the development of recommendations [9]. The EtD framework addresses both the evidence for the comparative effects of treatment options under consideration, and evidence about contextual factors. These factors include the valuation of the outcomes of interest, as well as the impact on equity, feasibility and acceptability of the treatment options [10, 11].

The overall objective of this study was to assess the views of stakeholders in relation to the medication treatment options of VL in HIV-coinfected patients (combination therapy of liposomal amphotericin B infusion and oral miltefosine, and monotherapy of infusion of liposomal amphotericin B). To meet that objective, we followed a mixed methods study design. Our findings were intended to help inform the panel judgements about the factors depicted in the EtD framework for the above-mentioned WHO recommendations [10, 11].

The specific objectives by study design were:

Quantitative design: to assess stakeholders’ rating of the importance of outcomes, and their views on equity, feasibility, and acceptability;

Qualitative design: to explore the reasons underlying stakeholders’ rating and views;

Mixed methods design: to integrate the findings from the quantitative and qualitative components of the study.

Methods

Ethics statement

We obtained ethical approval from the Research Ethics Review Committee (ERC) at WHO, the local Institutional Review Board at the University of Gondar in Ethiopia and the Indian Council of Medical Research (ICMR)-Rajendra Memorial Research Institute of Medical Sciences (RMRI) in India. We obtained written informed consent from survey participants and oral consent from interview participants.

Overall design

Following an a priori protocol that was peer-reviewed independently by two subject experts, we used a mixed methods approach that included a cross-sectional survey and semi-structured interviews. We collected the data between February and July 2020. We followed the Good Reporting of A Mixed Methods Study (GRAMMS) guidelines [12].

Survey study

Study population and sampling

Participants were from VL-endemic countries in East Africa and South-East Asia, and included national neglected tropical disease officers, national ministry of health functionaries, subnational programme managers, district and referral hospital physicians and nurses, nongovernmental organizations, academic researchers, respective regional and country office WHO personnel, and members of WHO’s South-East Asia Regional Technical Advisory Group for VL. We employed a convenience sampling methodology, by sending invitation emails to relevant listservs (computerized list of names and e-mail addresses). We obtained email addresses of stakeholders from databases available within WHO headquarter office, and contacted WHO regional offices for the African Region, Eastern Mediterranean Region and the Region for South-East Asia. The Ministry of Health of India, and WHO partners like Médecins Sans Frontières (MSF), Drugs for Neglected Diseases Initiative (DNDi) and Leishmaniasis East Africa Platform (LEAP) were also contacted. Based on obtained email addresses (n = 260), the majority of invited participants were from South-East Asia (n = 197, 76%). Those who accepted the invitation received the consent form and the online survey.

Data collection

We developed the survey tool based on questionnaires previously developed for other WHO guidelines [13-16], and pre-tested it before sending to potential participants. The questionnaire covered participant demographics, valuation of the outcomes of interest, and judgements related to impact on equity, acceptability, and feasibility of the two interventions being compared (S1 Appendix). It also included open-ended questions on implementation considerations, monitoring and evaluation, and research priorities. The latter were similar to those asked during the semi-structured interviews (see below). We asked participants to rate the importance of the outcomes of interest on a 9-point Likert scale. For the remaining measures, we used the response options provided in the EtD. We sent two reminder emails after 7 and 13 days respectively. We used DataForm online tool from LimeSurvey. The landing page started with a consent form; participation was voluntary and participants could decline or exit the survey at any stage. Data were collected anonymously and independently by a data manager.

Data analysis

We categorized the responses to the valuation of outcomes into critical (values of 7, 8 and 9), important (values of 4, 5 and 6), and of limited importance (1, 2 and 3). We used Stata (version 13) to conduct descriptive analyses. We analysed responses to open-ended questions along with the data from the semi-structured interviews.

Semi-structured interviews

We included the same stakeholder groups as in the survey study (referred to as “non-patient stakeholders”), as well as VL patients with HIV-coinfection. For the non-patient stakeholders, we invited those who had responded positively to a question about their willingness to participate in a semi-structured interview. The lead investigator (JK) conducted the interviews with non-patient stakeholders after obtaining informed oral consent. At the treatment centre in Ethiopia where the clinical trial was conducted [7], physicians attempted to contact all the patients who had participated in the trial, while ensuring voluntary participation, confidentiality, and anonymity. A similar process was followed in India [8], except that a random sample of patients was contacted. Wherever possible, attempts were made to contact all VL patients under trial by the treating physicians. Patients were given information about this study and were invited for the interview. Local principal investigators (DP and NM) then contacted patients who volunteered and expressed their willingness, obtained their informed oral consent and conducted the interviews.

We developed an interview guide and discussed it with interviewers to maximize consistency. It covered the same constructs as the questionnaire but sought deeper views. Interviews with non-patient stakeholders were conducted in English, while interviews with patients were conducted in local language, using simplified language. We interviewed patients over the telephone, and non-patient stakeholders using an online meeting platform, and audio recorded all interviews. We stopped recruiting patients when we reached data saturation. We anonymized all transcripts using a unique identifier per interviewee.

We used the framework thematic analytical approach guided by the EtD framework, which consisted of the following seven stages [17]: (1) transcription of the recordings verbatim (AEH and JK). Since interviews with patients were conducted in local language, the local investigators (DP and NM) translated interviews to English and transcribed them at the same time; (2) familiarization with the transcripts (AEH, CR and JK); (3) data indexing, which consisted of labeling each meaningful datum, initially applied to a few transcripts using the predetermined constructs of EtD framework (AEH, CR and JK). Texts that did not fit the predetermined constructs were also labeled; (4) discussion of labels leading to the creation of categories, forming the basis for the analytical framework (AEH, CR, JK and GHA); (5) application of the analytical framework to all transcripts, adding new labels that did not fit into the existing analytical framework when encountered (AEH, CR and JK); (6) charting and examining allocation of subcategories for each category, and reexamination of the labels that did not fit the existing analytical framework (AEH, CR and JK); (7) comparison and contrasting of categories and subcategories to finalize the results (AEH, CR, JK and GHA). All coders (AEH, CR and JK) first coded the same interview as part of a calibration exercise. The rest of the interviews were coded by one person. Coders met to determine the analytical framework, and compare and contrast findings. At the end of the process, we generated a complete narrative of the findings, supplemented with quotes from individual interviews.

Mixed methods integration

We used a convergent mixed methods research design (Fig 1) [18]. At the methods level, we used the survey as a gateway to sampling non-patient stakeholders. In addition, when collecting data, we used the same constructs for the survey and interviews. We compared and merged findings from the quantitative and qualitative analysis, and further analysed the findings for concordance, discordance or expansion. At the interpretation and reporting level, we followed the contiguous approach to integration [18].

Fig 1

Mixed methods design.

Results

Online questionnaire survey

Out of 260 invitations, we received 177 complete responses (overall response rate = 68%, response rate in South-East Asia = 72%, response rate in East Africa = 51%). The collected data is presented in S2 Appendix. Most participants were males (n = 148, 85%), aged 31–50 years (n = 115, 65%), from South-East Asia (n = 142, 81%), and with a masters, doctoral or medical degree (n = 130, 74%). They belonged most commonly to two stakeholder groups: health providers (n = 62, 35%) and national neglected tropical diseases officers or subnational programme managers (n = 52, 30%). Half of the participants belonged to nongovernmental organizations (n = 88, 50%) (Table 1). S3 Appendix presents survey participants’ characteristics per region.

Table 1

Survey participants’ characteristics (N = 177).

	n (%)*
Gender
Female	26 (15)
Male	148 (85)
Age (years)
18–30	23 (13)
31−50	115 (65)
51−64	31 (18)
> 64	8 (5)
Region **
South-East Asia	142 (81)
East Africa	32 (18)
Other	1 (1)
Highest attained educational degree
Doctoral degree	65 (37)
Master’s degree	65 (37)
Bachelor’s degree	35 (20)
Certificate or diploma	4 (2)
None of the above	7 (4)
Stakeholder group
Health providers/clinical officers	62 (35)
National NTD officers/subnational programme managers	52 (29)
Researchers	25 (14)
Nongovernmental organizations	14 (8)
Regional and country office WHO staff	5 (3)
Policy-makers	3 (2)
Members of WHO’s Regional Technical Advisory Group on VL	2 (1)
National ministry of health staff	1 (1)
Not specified	13 (7)
Affiliation
Nongovernmental organization	88 (50)
Governmental organization	48 (27)
International intergovernmental organization	21 (12)
Academic institution	16 (9)
Private for-profit organization	2 (1)
Not specified/other	2 (1)

*Numbers do not always add to 177 due to missing data. Percentages represent valid percentages.

**Total of 14 countries

Abbreviations: NTD: neglected tropical diseases; WHO: World Health Organization; VL: visceral leishmaniasis

Valuation of the outcomes of interest

The outcome rated by the highest percentage of participants as “critical” was mortality (n = 105, 61%). This was followed by clinical cure at 6 months and clinical cure at the time of treatment completion (n = 99, 58%), relapse (n = 97, 57%), serious adverse events (n = 97, 57%), patient satisfaction (n = 97, 57%), and disease complications (n = 92, 54%). The outcome rated as “critical” by the lowest percentage of participants was non-serious adverse events (n = 81, 47%) (Fig 2).

Fig 2

Valuation of each of the outcomes of interest.

Impact on equity, acceptability, and feasibility of treatment alternatives

When comparing combination therapy with monotherapy, the majority of participants (n = 105, 60%) responded that providing combination therapy would result in increased health equity (n = 70, 40% “increased”, n = 35, 20% “probably increased”). Most participants (n = 139, 79%) responded that combination therapy is more acceptable (n = 97, 55% “more acceptable”, n = 42, 24% “probably more acceptable”), and that combination therapy is more feasible than monotherapy (n = 100, 57%; n = 58, 33% “more feasible”, n = 42, 24% “probably more feasible”) (Fig 3).

Fig 3

Impact on equity, acceptability, and feasibility of combination therapy as compared with monotherapy.

We interviewed 19 patients (nine from Ethiopia and 10 from India), and 10 non-patient stakeholders (two from Ethiopia and eight from India). Eight patients were from the combination therapy arm, and 11 were from the monotherapy arm. Non-patient stakeholders included four members of nongovernmental organizations, three physicians, two programme managers, and one representative of a national programme. Patients were mostly males (n = 17), and belonged to the following age groups: 18−30 years (n = 4), 31−50 years (n = 10), 51−64 years (n = 5). S2 Appendix provides the collected data, and S4 Appendix provides a detailed tabular presentation of the qualitative findings organized by construct with supporting quotes. The findings are summarized below.

Valuation of the outcomes of interest

Table A in S4 Appendix presents findings about the valuation for the following outcomes: mortality, disease-related complications, clinical cure, relapse, non-serious side effects, serious side effects, and patient satisfaction. The valuation of an outcome was driven by both the experience of the outcome itself (e.g., burden of relapse on the patient) and its consequences (e.g., relapse leading to mortality). For certain outcomes, it was also driven by the coinfection status of the patients (i.e., outcomes being more important in this specific population than in mono-infected or any patients).

Both patient and non-patient stakeholders considered reducing mortality as an important outcome. While non-patient stakeholders highlighted death as a critical outcome for any disease, they also noted the importance of mortality as an outcome in this specific population, since coinfection and immunosuppression place them at increased vulnerability. Patients considered survival as a “miracle” (India, P7), and recounted experiences of death among close relationships. Non-patient stakeholders were highly concerned about disease-related complications, for the possibility of being irreversible, being life-threatening, and having financial impacts. All participants perceived clinical cure as an opportunity for patients to resume their daily activities and be socially and economically productive. Non-patient stakeholders additionally placed a higher value on clinical cure at 6 months compared with clinical cure at the time of treatment completion, due to the increased risk of relapse among these patients.

Non-patient stakeholders described relapse as “the main feature of HIV-VL” (India, NP8) and “the biggest challenge” (India, NP5). This was due to how commonly relapse occurs, the risk of recurrent relapses, the resultant patient suffering and patients’ doubts about treatment effectiveness, the impact on patients’ mental health, and the ensuing risk of mortality. Relapse was also perceived to have negative effects from the health provider and community perspectives. From the community perspective, relapse could contribute to spreading the infection to other individuals, as patients are an “important reservoir for the infection” (India, NP2).

Non-patient stakeholders valued non-serious side effects less than the other outcomes, especially as compared with serious side effects. They considered non-serious side effects to be expected, well tolerated and easily treated, whereas serious side effects were viewed to result in additional burden on patients, and increased risk for permanent damage and mortality. Also, non-patient stakeholders were concerned about the risk of additive, more serious side effects, since this patient population is often receiving treatment for other diseases.

Participants rated patient satisfaction as an important outcome, for any patient and any disease. However, one non-patient stakeholder noted that satisfaction is usually overlooked: “we do not look at it normally” (India, NP7).

Impact on equity

Most participants perceived no differential effect on equity between treatment alternatives as both are currently available free of charge and require hospitalization. They also noted that combination therapy is equally accessible for different geographical, gender and age groups. Nevertheless, few participants were concerned that pregnant women and women of childbearing age who may not prevent pregnancy were ineligible to receive combination therapy (particularly administration of miltefosine in this category of patients), and that it may negatively impact equity.

In addition, a number of views on general equity issues relevant to patients with HIV–VL coinfection emerged (see Table B in S4 Appendix for additional details). To note that half of the patient participants from India reported initially receiving care at a private health facility for substantial amounts of money (range: US$ 133–2600) before receiving care at a government health facility.

Feasibility

Longer duration of hospitalization was generally perceived to be less feasible due to the economic burden on the health system, the patients and their caregivers. Overall, there were no concerns for adherence issues with combination therapy, due to the treatment being completed at the hospital. One feasibility issue with combination therapy was the added difficulty of counselling-related contraindication in pregnant women (Table C in S4 Appendix,).

Acceptability

Participants considered combination therapy to be more acceptable than monotherapy, when associated with a shorter duration of hospitalization. Both patient and non-patient stakeholders highlighted the burden of a longer duration of hospitalization on patients and their families, in terms of lost wages and need for accompaniment. In addition, some patients mentioned that they were less comfortable at the hospital than at home, that longer duration of hospitalization resulted in separation from their families and in inability to undertake daily tasks. Nonetheless, few participants preferred longer duration of hospitalization due to medical supervision available at the hospital and poor living conditions at home. The only two female participants noted that use of contraception was not an issue (see Table D in S4 Appendix for additional details).

Implementation considerations, monitoring and evaluation, and research priorities

Participants reported on a number of implementation considerations, including but not limited to access to care, discrimination and stigma, patient involvement, compassion by health providers, counselling, and holistic care. Monitoring and evaluation suggestions included the parameters (e.g., adverse events, drug interactions) and logistics (e.g., tools, checklists) of monitoring. Research priorities included disease epidemiology, diagnostic aspects, prevention, disease progression and prognosis, need for additional data, treatment-related issues, immunology, relationship with HIV, and health systems issues. More detailed findings are provided in S5 Appendix for the survey study and Table E in S4 Appendix for the semi-structured interviews.

Integrated findings

For the valuation of outcomes of interest, the qualitative and quantitative findings were generally concordant, in terms of all treatment outcomes being important to a certain extent. However, the qualitative findings had higher discriminatory ability than the quantitative findings. Indeed, while there were very small differences in the survey ratings of the different outcomes, the qualitative findings showed that some outcomes (such as mortality and relapse) were more valued that the rest of the outcomes (such as non-serious adverse events). One area of expansion was through qualitative findings providing justifications for valuation of outcomes.

For the contextual factors, quantitative and qualitative findings were also concordant, with combination therapy being more acceptable and feasible. Qualitative findings expanded on the reasons behind the ratings resulting from the quantitative study. Of note, 28% of participants indicated that combination therapy was “probably less feasible” or “less feasible”. The qualitative study did not provide further insight into these findings.

Discussion

Summary of findings

We conducted a mixed methods study consisting of a cross-sectional survey and semi-structured interviews to assess the views of stakeholders as they relate to the treatment of VL in HIV- coinfected patients. Mortality and non-serious adverse events were rated as “critical” by respectively the highest and lowest percentages of participants. Most survey participants perceived that combination therapy, compared with monotherapy, would increase health equity, is more acceptable, and is more feasible. The findings of the interviews were concordant with those of the survey, and provided important insight into the survey results. The one equity issue raised is related to the contraindication of combination therapy in pregnancy. Combination therapy associated with a shorter duration of hospitalization had higher feasibility and acceptability.

Strengths and limitations

To our knowledge, this is the first study assessing the valuation of treatment outcomes and contextual factors in relation to treatment alternatives for VL patients with HIV. The mixed methods approach allowed us to maximize the respective benefits of quantitative and qualitative studies. While the quantitative survey study allowed us to reach a diverse sample of stakeholders with considerable sample size, the qualitative study provided further insight into their views. The qualitative study also allowed us to include patients with HIV–VL coinfection who would have had difficulties responding to the online survey.

We employed different strategies to enhance the rigour of our qualitative approach at the levels of sampling, data collection, analysis and reporting. These included recording of interviews, using the survey as a gateway to non-patient stakeholder participants, having the same person conducting the interviews with non-patient stakeholders being involved in the analysis (JK), discussions among the team, triangulation of data from patient and non-patient stakeholders, and objectivity in reporting (i.e. reporting of details which were not very commonly addressed). The validity of our mixed methods approach was enhanced by multiple-level integration (as mentioned above).

We included multiple types of stakeholders to reflect alternative perspectives. In fact, research on valuation of the outcomes by different stakeholders’ groups often shows some differences in views among these groups [19, 20].

Using the EtD as the basis for the development of the survey and interview guide and as our analytical framework allowed us to tailor the findings to the specific recommendations under consideration by WHO. While collecting information for EtD purposes, we used a comparative approach (e.g., comparing the effects of combination therapy and monotherapy on equity). In addition, we addressed aspects related to the condition and its management in general (e.g., equity in relation to access to treatment).

One limitation of the study is that some patients were not very open about their views, even after probing. This could be due to patients being uncomfortable with discussion due to stigma and discrimination associated with their condition [6]. We are uncertain whether the use of face-to-face interviews would have yielded more in-depth information. However, they were not feasible given that this study was conducted during the COVID-19 pandemic. Another limitation is that this study had a smaller number of participants from East Africa as compared to South-East Asia. This was mainly due to unavailability of email addresses of health personnel in East Africa, and a lower response rate from East Africa as compared to South-East Asia. However, no obvious differences in perceptions between the two settings were noted. It is also interesting to note that in Ethiopia, some patients provided false phone numbers, while in India some of the phone numbers obtained from the hospital records were inaccurate. Finally, if the duration of the combination in practice will be longer compared to the trial protocols (e.g., due to repeated regimens), our findings need to be interpreted accordingly.

Comparison with similar research

Nair et al. conducted a qualitative study to explore factors influencing the quality of life of patients coinfected with HIV and VL in India. They found that the most important indicators of “good quality of life” were income and livelihood [6]. This is consistent with our finding that the opportunity for the patient’s earlier return to productivity was one of the drivers behind increased acceptability and feasibility of combination therapy. Another highly valued outcome was permanent cure [6], consistent with the views of non-patient stakeholders in this study. In addition, patients included in this study seemed to value resolution of symptoms higher than side effects, which is consistent with the literature on other conditions [21, 22].

Also consistent with our findings, Nair et al. found that patients in India reported high out-of-pocket expenditures when accessing treatment in the private sector [6]. Barriers to accessing medical care in the government system reported by participants in that study included long queues, poor quality of medicines, poor attendance by health professionals, and poor overall care. However, patients believed that they would achieve early cure through private care and preferred to seek private care for illnesses that they believed to be minor in nature [6].

Implications for practice

When counselling patients on treatment alternatives, explanation of benefits and harms associated with the respective treatments should address the outcomes that matter to patients. Furthermore, when choosing one alternative over the other, health providers should address potential acceptability and feasibility concerns of patients.

Some themes such as general equity issues and implementation considerations are also important when implementing a therapeutic regimen. One has to ensure a holistic approach to patient care, addressing psychosocial, economic, and treatment needs. This is further confirmed by evidence showing that income, social support, and nutritional status are predictors for improvement in most quality of life domains after receiving treatment for patients with HIV, with and without VL [23].

Access to care remains paramount, given the geographical obstacles and importance of specialized care in treatment centres and provision of treatment free of charge. This could be facilitated by increasing awareness about free treatment among these patients, and addressing barriers to appropriate care in the governmental health sector. Given the concerns for adverse events and additive toxicity in combination therapy, pharmacovigilance systems also need to be strengthened.

Implications for future research

The survey part of this study did not allow adequate discrimination between the different ratings, which has also been observed in previous similar surveys [13, 15, 16]. More research is needed to enhance the discriminatory ability of the survey instruments being used, and ensure its optimal use as part of mixed methods studies.

While the qualitative findings allowed us to capture the views of stakeholders on important contextual factors, future research should collect factual data on some of these factors. One example is field data on feasibility of administering one regimen versus others. Collecting this type of data would help further understand the influence of contextual factors on healthcare quality and decision-making. Also, funding agencies as well as research groups should consider the research topics suggested by participants as priorities. More generally, there is a need for studies assessing the impact of new approaches and interventions on quality of life in the population of interest.

Survey questionnaire.

(DOCX)

Click here for additional data file.

Survey and interview data.

(XLS)

Click here for additional data file.

Survey participants’ characteristics by region.

(DOCX)

Click here for additional data file.

Detailed presentation of the findings from the semi-structured interviews organized by construct.

(DOCX)

Click here for additional data file.

Results of survey questions about implementation considerations, monitoring and evaluation, and research priorities.

(DOCX)

Click here for additional data file.

12 Nov 2021

Dear Dr. Akl,

Thank you very much for submitting your manuscript "Stakeholders’ views and perspectives on treatments of visceral leishmaniasis and their outcomes in HIV-coinfected patients in East Africa and South-East Asia: a mixed methods study" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The aim of the study is unclear. The design looks ok. A mixed study design and a variety of study participants were included. The conclusions could be expected to vary depending on the category of study participant. The sample size for qualitative study is ok. There are no ethical concerns.

Reviewer #2: Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

Yes

Is the study design appropriate to address the stated objectives?

Yes

-Is the population clearly described and appropriate for the hypothesis being tested?

Yes

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

Yes

-Were correct statistical analysis used to support conclusions?

Yes

-Are there concerns about ethical or regulatory requirements being met.

Yes

Reviewer #3: Although the approach is interesting, I have a number of thoughts on the study. My main concerns are on the lack of participation from the East African setting, where the case numbers, challenges and level of expertise in VL-HIV is far higher than in the Indian setting where it is a relatively new phenomenon that is being treated/managed by a very limited group of stakeholders. Secondly, one of the most important parts of this study is the patient involvement. The numbers of patients interviewed (n=19) are really impressive and should have been enough to generate a wealth of evidence in what is one of the most under-described perspectives (I am assuming here that these were VL-HIV patients).

However, the description of the methodology and subsequently the content and richness of the feedback presented in the manuscript does not seem to be adequately covered – recognising that the interviews were done over the phone – but this needs better description and explanation of what transpired and why this was not enough to get some clear thematics.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The figures particularly figure 3 should be revised.

Reviewer #2: Does the analysis presented match the analysis plan?

Yes

-Are the results clearly and completely presented?

Yes

-Are the figures (Tables, Images) of sufficient quality for clarity?

Yes

Reviewer #3: Introduction:

• Note that atypical disseminated leish is defined as a stage 4 defining illness rather than VL.

• For example, in India, the percentage of Kala-azar (KA) cases tested for HIV increased from 47% in 2015 to 98% in 2020, representing an increase in the proportion of KA–HIV co-infected cases from 0.5% in 2015 to 4.1% in 2020 (4).

- I’m unsure about this reference, but this number on proportions tested in India is very wrong. In 2015, barely any VL patients were being tested for HIV (certainly <10%). And 98% testing rates in 2020…its highly unlikely. The limitations of KAMIS need to be at least alluded to (eg there is no zero-reporting for HIV testing).

• This is a major challenge considering that L. infantum has different drug susceptibilities and less virulence than L. donovani and occurs at a lower CD4+ count.

- Unclear what is meant by ‘occurs at a lower CD4 count’? Both infections occur at low CD4 counts.

• The regimens consist of combination of liposomal amphotericin B infusion (at a dose of 5 mg/kg on days 1,3,5,7,9 and 11, up to a total dose of 30 mg/kg body weight) and oral miltefosine (100 mg in divided doses for 14 days in South-East Asia and 28 days in East Africa respectively)

- Note that the East African regimen is required to be repeated in many cases, so treatment duration is doubled. This should be checked and worded accordingly.

Methods:

• It is worth explaining what a listserv is; most people will not know this

• Were all interviews conducted in English/in person? Who coded the transcripts and were these double coded/QA’d by another researcher? There needs to be more robust description of the qualitative methodology in general. I see this is in appendix 2 = the authors should move this into the main manuscript or dedicate more space to describe this in the text.

• More details on the interview method/framework with the patients is needed

Results:

• Did the response split between Asia/Africa reflect the numbers of invitations sent? I.e what proportion were sent to participants from both regions? It’s a very Asia heavy participation, which is odd since the bulk of VL-HIV patients come from the African setting, as does the majority of evidence. Would be important to explain this.

• I think it could be important to split the table so that we can see the characteristics of the participants from Asia and Africa separately. Particularly for Africa, this will allow the reader to contextualise the feedback.

• Table 1: Region: 175/177 are reported – where are the other 2 from? Some of the strata do not add to 177, please check and annotate for missing data (either in the table or in the legend)

• Semi structured interviews with patients – specify if these were VL-HIV patients, and which treatments they had been treated with previously

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Limitations of the study are mentioned. The authors have not officially made specific conclusions and recommendations. However there is a hidden conclusion that for me appears to be unsubstantiated.

Reviewer #2: Are the conclusions supported by the data presented?

Yes

-Are the limitations of analysis clearly described?

Yes

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

Yes

-Is public health relevance addressed?

Yes partly.

Reviewer #3: • The one equity issue raised is related to the contraindication of combination therapy in pregnancy.

Worth re-checking this phraseology – combo treatment is contraindicated in pregnancy, lactation and in women of childbearing age unwilling or unable to take/use contraception

• The patient interviews over the phone are mentioned only at this point, this should be in the methodology section. How were patients selected and invited to participate (also worth mentioning how they were consented). Were their interviews recorded? More details are needed for this component as this is one of the most interesting parts of the study – beneficiary impact perception is critical, but we need to better understand how this was done.

• Where we had insufficient information from the patients’ perspective, we indicated this as part of the above findings..

Is unclear what the authors refer to here, there is no mention of this in the previous text.

• Limitations – it seems that the biggest limitation here is that the African region was massively under-represented; this needs much more discussion on the causes and reasons, as otherwise the study is really only valid for the Indian/South Asian setting

• Again the listserv – it is worth describing which listservs the authors refer to and from where they were acquired. I am surprised that snowball sampling was not conducted – is there a reason why? The VL-HIV world is quite small, and this could have been a very good way of identifying stakeholders...

• India phone numbers not being accurate = this is not surprising as people change sim cards very frequently in India.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Major revision is recommended.

Reviewer #2: The paper appears to be good. But I think a few lines about ART and drug interactions need to be mentioned. Also tuberculosis is the most important opportunistic infection in India so a few lines on this treatment modality needs to be mentioned.

Suggestion Accept with minor revision.

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: General comments:

This is an interesting manuscript that analyses outcomes, impact on equity, feasibility and acceptability of the treatment options in HIV co-infected VL patients.

For this manuscript to have impact on policy, a few issues need to be transparently discussed and to revisit the aim of this manuscript. Given that no effective treatment exists for such patients, I wonder why the authors chose to carry out comparison of two treatment regimens: combo and monotherapy? The report will have more impact if it can highlight the critical gaps in therapeutic options for HIV co-infected VL patients rather than comparing two regimens that are both sub-optimal. As the NP stakeholders have identified relapse as the main feature of HIV-VL and the biggest challenge in treatment; valuations of outcome, impact on equity, feasibility and acceptability will be meaningful if there was a focus on the biggest challenge and how patients and stakeholders recognize the challenges and perceive public health constraints in this domain.

In a recent published report of a northern Ethiopia study, efficacy of total dose of 40mg/kg of ambisome monotherapy at day 29 was 50%, and the combination of Ambisome (30mg/kg total dose) and 28-day regimen of miltefosine resulted in 67% initial cure. At day 56 cure rate was 55% in the monotherapy arm, but 88% in the combo when treatment was extended by additional 28 days. Data on extended treatment is not available for the monotherapy, as it was not planned in the mentioned trial of northern Ethiopia. These findings show that the treatment of HIV co-infected patients will remain to be a challenge. Given that the monotherapy was horribly ineffective at the tested regimen, the comparative approach taken in this study does seem to be biased and in favour of the combination treatment obviously due to the better (but sub-optimal) efficacy. In the follow-up report of the above-mentioned study involving 54 patients, it was shown that the probability of relapse-free survival at one year was 50% (53% in 22 patients with baseline CD4 count > 200/µl hence not having secondary prophylaxis; and 46% in 29 patients with CD4 cells < 200/µl who were on secondary prophylaxis). It is important to avail such information to study participants (P & NP) to enable them to make a fair judgement and valuation. The fact that the NP stakeholders emphasized on the importance of the 6-month cure is indicative of the recognition of the challenges in treatment., i.e., the high risk of recurrent relapses and death. The premise (and context) for the qualitative and quantitative studies of patient outcomes should be clearer and well informed.

Specific comments

1. This study reveals that combination therapy was more feasible and acceptable than monotherapy mainly due to a shorter duration of hospitalization. Because the trial results are yet to be translated to policy, and the policy/guideline recommendations are yet to come; iIt is not yet clear how patients would be treated in the routine health settings using the combo or monotherapy to reveal which regimen has a shorter duration of hospitalization. The combo treatment regimen for South-East Asia and Eastern Africa regions are varied and necessitate the disaggregation of the data by geographic regions. In the case of the Eastern Africa region, the 28-day miltefosine in the combo (which will be 56 days when extended) is no shorter than the monotherapy that lasts 24 days (days 1,2,3,4,5,10, 17,24). In assessing acceptability, equity and feasibility comparing the combo with monotherapy; the tools (questionnaire) were not reinforced with specific questions that could help to substantiate claims on better acceptability, feasibility, and equity of the combo treatment regimen. A second layer of questions should have been included why P/NP study participants believe a treatment regimen was more acceptable, more feasible, and more equitable. It would have been preferred if context was projected, and explicit information why combo was found to be more equitable, more acceptable, and more feasible was interrogated. Furthermore, looking carefully at the narrations of the results, equity was not an issue either in the combo or monotherapy. Similarly, concerning feasibility, the only issue was the contraindication in pregnant women. Prolonged hospitalization could be an issue of feasibility and acceptability, but only in South-East India. As mentioned above, the crux of the investigations in this report would preferably focus on the management of recurrent relapses, i.e., the need for management of the chronic conditions and quality of life including the need for secondary prophylaxis. To my opinion, the authors did not demonstrate the existence of consensus to support the claims of feasibility, equity and acceptance of the combo more than the monotherapy. It is important to recognize that even with the best treatment options available today, the expectancy of survival in HIV co-infected patients is short (3 years at maximum). Given this, the emphasis on assessing quality of life of patients would have helped to advocate for further studies on new approaches and avenues of intervention to improve quality of life and to prolong years of survival - as in the case of ARTs in HIV/AIDS patients.

2. Table 1 gives 26 females. Does it mean the number of males was 151? The table does not give the figure for males.

3. Figure 3 is presented in a biased way favouring the combo or focussing on combo (in a non-comparative way). For instance, the figure on acceptability is exclusive to combo (not showing rates for monotherapy). Only the feasibility component is presented in a comparative way. It is difficult to see from the figure the valuations about the monotherapy concerning acceptability and equity.

4. Figures 1,2, 3 lack title and legend.

Reviewer #2: The paper appears to be good. But I think a few lines about ART and drug interactions need to be mentioned. Also tuberculosis is the most important opportunistic infection in India so a few lines on this treatment modality needs to be mentioned.

Suggestion Accept with minor revision.

Reviewer #3: (No Response)

--------------------

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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13 Jan 2022

Submitted filename: Response letter_20220107.docx

Click here for additional data file.

13 Mar 2022

Dear Dr. Akl,

Thank you very much for submitting your manuscript "Stakeholders’ views and perspectives on treatments of visceral leishmaniasis and their outcomes in HIV-coinfected patients in East Africa and South-East Asia: a mixed methods study" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Helen P Price, PhD

Deputy Editor

PLOS Neglected Tropical Diseases

Helen Price

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The aim of the study still is unclear.

Reviewer #3: Second Review of PNTD-D-21-01369-R1

The responses below cover the author responses to Reviewer 3:

• The difference of participation from the two regions still needs further description, as does the implication on the overall validity of the study. It seems from the author reply that there were 32 stakeholders responded; however they then go on to describe 177 completed responses being received – this is confusing. It would important to be clear on the number of participants from each region at each stage of the study – please add absolute numbers to the percentages.

• The authors are correct regarding what is written in the WHO technical report series 949; however it is common knowledge that this is in conflict with WHO HIV guidelines. Considering the scope of 949 is VL, written by a panel of VL experts (not HIV) it is of minimal relevance with regards to classification of VL as an AIDS defining condition since national programme HIV guidelines (and decisions to initiate ART) are based on the WHO HIV guidelines alone, and not the 949 report. This is reflected in all national HIV guidelines. This is well discussed in the following paper, and I think it is important to state this as this is a WHO-authored manuscript:

van Griensven J, Ritmeijer K, Lynen L, Diro E (2014) Visceral Leishmaniasis as an AIDS Defining Condition: Towards Consistency across WHO Guidelines. PLoS Negl Trop Dis 8(7): e2916. https://doi.org/10.1371/journal.pntd.0002916

• ‘We agree with the Reviewer that both infections occur at low CD4 counts. The sentence meant to highlight that L. infantum occurs at a lower CD4+ count as compared to L. donovani (according to the following reference: https://www.who.int/leishmaniasis/resources/Leishmaniasis_hiv_coinfection5.pdf?ua=1, “Relapses due to L. donovani occur at higher CD4+ counts than is the case with L. infantum in Europe.”)’

The reference refers to relapses, not primary infections. This needs to be corrected or removed.

• "In this paragraph, we are describing the standard recommended regimens as described in the WHO Technical Report Series 949 (https://apps.who.int/iris/handle/10665/44412). However, we agree with the Reviewer that the duration of admission or further treatment depends upon a case-by-case basis and upon a variety of factors, and have added this information at the end of this paragraph"

The 949 report does not include the 14-day regimen; this was first described by Mahajan et al in 2015. The 949 report was written in 2010. Same applies for the E African regimen. The 949 report on page 66 describes only one regimen: Lipid formulations infused at a dose of 3–5 mg/kg daily or intermittently for 10 doses (days 1–5, 10, 17, 24, 31 and 38) up to a total dose of 40 mg/kg are recommended (A). My point is that the East African regimen is repeated as per their publication in the majority of cases; and their conclusion recommends this.

As a side point, I believe the South Asia study has now been published so should be referenced https://pubmed.ncbi.nlm.nih.gov/35147680/

• The authors state in the reply that interviews conducted with patients were performed by telephone or using an on-line platform. Specifically, were the telephone calls with patients recorded (the authors seem to confirm this was the case later on in the responses, but it is important to be explicit here) and how were thematics and answers coded? Normally interviews require quite a lot of transcribing, how was this done and were any interviews double-coded? I can imagine that conducting this sort of interview over the phone must have been exceptionally challenging, and this should be explored in the text.

• "In addition, we would like to clarify that we are aware that in South Asia, e.g., India, the number of stakeholders is high due to the presence an elimination programme. This could explain why we received most email addresses and a massive response for survey participation from this region."

I am not sure I agree with this argument. Regardless of the elimination programme, the numbers of individuals involved with management and treatment of VL-HIV patients in India is extremely small – there are basically two centres that treat these patients (Kolkata and RMRI, Patna), who have been treating patients for the last 5 years or so. On the contrary, there is a vast range of decades worth of experience of VL/HIV in Ethiopia and Sudan, and as you can see from the attendance of meetings and consortiums (take ASCEND recently, for example) there are a wide range of stakeholders in the East African setting ranging from NGO, governmental, academic and beyond. Information and sources are not rudimentary; there are clear individuals and organisations that could have been approached to get a wider buy in when it became obvious that the initial sample framework for East Africa was inadequate. I think it is incorrect for the authors to explain this in this way; it seems rather that there was a greater effort made (unintentionally perhaps) for South Asia than for East Africa. This is important to self-reflect on, as it cuts to the core and validity of the messages and outcomes.

• “Wherever possible, attempts were made to contact all VL patients under trial by the treating physicians. Patients were given information about this study, and were invited for the interview. Local principal investigators (DP and NM) then contacted patients who volunteered and expressed their willingness, obtained their informed consent and conducted the interviews.”

So if I understand correctly, all the VL-HIV patients were those that had previously participated in the phase 3 clinical trial on which the guideline change is based? This needs to be made explicit in the manuscript, and median time from treatment reported as the potential impact of recall bias should be clear, since this study was conducted long after the conclusion of the clinical trials. If correct, this is both a strength and a weakness for the study. A strength as this reflects directly patients who had either one of the treatments – and it will be critical to describe the proportions of those interviewed who received which treatment (eg. If all the patients received one of the treatment arms, they would not be a meaningful qualitative comparison). On the other side, all of these patients received treatment under clinical trial conditions, as such were admitted for the duration of treatment in hospital and receiving a level of care that would not be seen under routine conditions. These should be discussed in the limitations.

• "The terminology “beneficiary impact perception” is not clear to us. We appreciate clarification so we could address it appropriately"

Beneficiary impact perception is the perspective of the beneficiary (i.e. the patient with VL-HIV). I mean the purpose of interviewing this group was to determine their perspectives on the treatments they received – and the impact of the treatment on them. This is a much under-explored area in clinical trial research, and I commend the authors for exploring this – but they should try and go deeper into this as it is really important, especially as the number of patients (19, I believe) is really a huge sample size for such work. The authors state that there was insufficient information from the patient’s perspective – this simply cannot be the case with such a sample size unless there was something fundamentally wrong or lacking with the interview methodology used. If this is the case, that is fine, but it needs to be explained in the text.

• "We agree that snowball sampling would have been a great approach, especially for the qualitative part of our study (interviews). As we already had the survey as our gateway to recruitment for the qualitative study, and as it resulted in a good number of interviewees, we did not need to resort to snowball sampling. Had the survey not yielded a good number of interviewees, we might have resorted to this sampling strategy."

I find this response confusing still. The authors accept that there were insufficient responses from the East African region, but then state here that a ‘good number of interviewees’ were identified… Clearly, the method of participant sampling from East Africa was inadequate as it failed, so this should be expressed/explained.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Yes, results are clear. But one aspect of the investigations, i.e., the comparison of treatment duration, was carried out with a wrong premise. See general comments section below.

Reviewer #3: (No Response)

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusion is unclear. See general comments section below.

Reviewer #3: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Please refer general comments section below..

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The manuscript has been improved substantially and given us a placated understanding of the problems in the treatment of HIV co-infected VL patients. However, I would like to invite the authors to address following:

Concerning the AmBisome monotherapy treatment regimen, the authors have referred us to the WHO Technical Report Series 949, which indeed indicates treatments on days 1-5, 10,17,24, 31 and 38. This regimen has not been used in Eastern Africa endemic region, and the recommendation itself was very general and makes no reference to the endemic regions. At the time of the publication of Serie 949, no RCTs were conducted for VL patients with HIV co-infection.

In the recent RCTs conducted in Eastern Africa (mainly Ethiopia), the miltefosine and AmBisome combo was used for minimum 28 days, and up to 56 days while monotherapy at 40mg/kg maximum dose was given in a treatment regimen lasting 24 days (days 1-5, 10, 17, and 24). It looks like the authors were not aware of this information, which had led them believe Ambisome monotherapy required longer duration of treatment. One then wonders if study participants were given the right information about treatment duration concerning HIV co-infection of VL. In one of the annexes/excel file/, responses like “Two drug is more feasible as it will require short duration of hospital stay” has been quoted. It is implied that use of two drugs will have the advantage of shorter hospital stay/treatment duration, which in fact is true in many conditions. However, as mentioned above the monotherapy had shorter duration contrary to what the authors considered. Thus, the section of this manuscript that dealt with duration of treatment is not valid.

Further, the RCTs in Ethiopia have demonstrated poor efficacy of AmBisome monotherapy. Again, one wonders why this article we are reviewing had to deal with comparison of the inefficacious treatment with the combo treatment. In my original review, I asked what the aim of the study was concerning treatment options of HIV co-infected VL patients. I also raised a query about the lack of conclusions. The whole issue concerning feasibility, acceptability, valuation of outcomes and impact on equity makes sense if the interventions in place fulfil a minimum set of criteria related to patient outcomes (cure, relapse free state, improved quality of life). If I may ask the same question again, why was this study conducted given the fact that none of currently available treatments are effective enough? Is it because both regimens (mono and combo) are inefficacious, and that one needs to choose the better of these badly performing treatments?

Reviewer #3: The answers are generally ok, but honestly it feels like the referencing is quite sloppy, and the underlying knowledge of the subject material limited, which is surprising since the author list includes some of the major players in VL. This sort of study -and I really do refer to the patient perspectives rather than the non-patient perspectives (which one could probably guess the answers and in my opinion reveals nothing novel), is critically important and I feel that the authors have really under-sold the study by not focusing much more on the outcomes of the patient interviews, or at least explaining why they were not able to generate decent evidence.

More generally, I think the authors need to be clear and transparent on the failure to include adequate sampling from East Africa, and how that impacts the validity of the results.

--------------------

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Reviewer #1: No

Reviewer #3: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

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Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

17 May 2022

Submitted filename: Response letter_20220511.docx

Click here for additional data file.

30 May 2022

Dear Dr. Akl,

Thank you very much for submitting your manuscript "Stakeholders’ views and perspectives on treatments of visceral leishmaniasis and their outcomes in HIV-coinfected patients in East Africa and South-East Asia: a mixed methods study" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Mitali Chatterjee

Associate Editor

PLOS Neglected Tropical Diseases

Helen Price

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #3: (No Response)

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #3: (No Response)

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #3: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #3: Thank you to the authors, the manuscript is much improved and acceptable for publication with the following slight adjustments:

1) Participation from East Africa:

The authors still insist that the issue was of uptake; this is simply not true. The issue was that only 24% of invitations to participate were to East African stakeholders. In its worst interpretation, the current wording could be interpreted as a lack of interest from East African stakeholders, which is untrue (and honestly abit offensive) when this was rather a failure of methodology, and should be recognised as such. I suggest changing the limitation sentences to:

‘’Another limitation is that this study invited lower participation from East Africa as compared to South-East Asia.”

AND

“As we used the survey as our gateway to recruitment for the qualitative study, the substantially fewer invitations sent to East African participants in the survey study also reflected on the interviews

As a side note - ASCEND is a much bigger and successful programme in East Africa, where there are far more than one representative per country. Again, this response suggests an overly South Asian focus from the researchers..

2) Patients responses:

Suggest making this more explicit and better worded:

Change:

Physicians at the two treating centres in Ethiopia and India where the clinical trials were conducted (7, 8) helped with patient recruitment, while ensuring voluntary participation, confidentiality and anonymity. Wherever possible, attempts were made to contact all VL patients under trial by the treating physicians.”

To:

“At the two treatment centres where the clinical trials were conducted, physicians attempted to contact all the patients who had participated in the trials, while ensuring voluntary participation, confidentiality and anonymity,”

3) Recall Bias:

I disagree with the authors on this point. Even the patients recollection of their experiences with the disease will be impacted by recall bias, and its important from a comparison perspective also; eg. If the median duration was 5 years in Ethiopia vs 6 months in India, it is important to present this so appropriate interpretation on the integrity of the responses can be made. To this effect, please include the median and IQRs of the time-from-treatment to interview for each region.

With regards to treatment, I find it somewhat unrealistic that the physicians were able to explain the ‘other’ treatment to the patients, and then elicit a meaningful opinion from them on which one they feel is better. Its also not possible to detach patient’s attitudes towards the treatments they received and the way they received it – so the fact that they were all treated as inpatients in both countries is important, and is a limitation on the validity of these perspectives in the real world setting where ambulatory treatment is likely to be encouraged, and where the standard of care/follow up/support is going to be far lower in the non-clinical trial context.

My suggestion is to briefly expand on this area; the methodology that the authors have used is extremely valuable and rare in NTD research, and all learning points and evidence should be presented accordingly – as I said in my previous review, the patient feedback is by far the most interesting and novel component of this research.

4) ‘Openness more in telephone interviews’

This concept is surprising to me, and it would be good if the authors can provide some references to support this. In my understanding, for sensitive matters that are significant events, participants feel much more comfortable being interviewed in person, in private, where both a rapport can be built and privacy can be guaranteed. Typically, this done by inviting participants to attend a ‘safe’ place of interview separate to the residence (with travel and wage loss compensation paid). Over the phone, there is no guarantee of privacy, as the interviewer does not know the situation of the interviewee who may not be in a position to express that they are able to talk freely.

I would suggest that the statement “On that note, the use of telephone interviews further conserved confidentiality and anonymity of patients” is removed from the manuscript unless there is clear evidence to support this supposition. I suspect that the reason why patients were not open on the telephone was precisely because it is very difficult to build a rapport over the phone for sensitive subjects, and this should be recognized in the manuscript text as a potential limitation/cause of the poor result yield.

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14 Jun 2022

Submitted filename: Response letter_20220615.docx

Click here for additional data file.

29 Jun 2022

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11 Aug 2022

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