Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: A prospective cohort study.

BACKGROUND: Delays in seeking and accessing treatment for rifampicin-resistant tuberculosis (RR-TB) and multi-drug resistant (MDR-TB) are major impediments to TB control in high-burden, resource-limited settings.
METHOD: We prospectively determined health-seeking behavioural patterns and associations with treatment outcomes and costs among 68 RR-TB patients attending conveniently selected facilities in a decentralised system in Harare, Zimbabwe.
RESULTS: From initial symptoms to initiation of effective treatment, patients made a median number of three health care visits (IQR 2-4 visits) at a median cost of 13% (IQR 6-31%) of their total annual household income (mean cost, US$410). Cumulatively, RR-TB patients most frequently first visited private facilities, i.e., private pharmacies (30%) and other private health care providers (24%) combined. Median patient delay was 26 days (IQR 14-42 days); median health system delay was 97 days (IQR 30-215 days) and median total delay from symptom onset to initiation of effective treatment was 132 days (IQR 51-287 days). The majority of patients (88%) attributed initial delay in seeking care to "not feeling sick enough." Total delay, total cost and number of health care visits were not associated with treatment or clinical outcomes, though our study was not adequately powered for these determinations.
CONCLUSIONS: Despite the public availability of rapid molecular TB tests, patients experienced significant delays and high costs in accessing RR-TB treatment. Active case finding, integration of private health care providers and enhanced service delivery may reduce treatment delay and TB associated costs.

Introduction

Multi-drug resistant (MDR) tuberculosis (TB) remains a public health crisis and health security threat [1]. The social and economic burden associated with TB and MDR-TB treatment [2], compounded by the HIV epidemic, places a disproportionate burden of disease on Sub-Saharan African countries [3, 4]. TB diagnosis, treatment, and prevention are strongly associated with socio-economic and behavioural factors [5-7]. Operational challenges related to weak, poorly resourced health systems are a barrier to TB prevention and control activities. For MDR-TB, timing delays can significantly determine treatment outcomes and are likely to increase the infectiousness and disease transmission in a community [4]. The resultant delays to diagnosis and effective treatment related to health system weaknesses are further informed by patient choices and behaviour [8]. Ultimately, such delays increase community transmission and may worsen treatment outcomes [9].

Despite the availability of free TB treatment in the public sector and the goal of universal health coverage (UHC) [10], the economic consequences for families affected by TB are often severe [11]. These include direct medical costs, direct non-medical costs and income loss (resulting from indirect or opportunity costs) [12]. The World Health Organization (WHO) defines TB-associated health care expenditures above a certain proportion (typically 20%) of available annual income as “catastrophic”, though the specific threshold is expected to vary by setting and circumstances [13, 14]. Resulting impoverishment may be high in settings such as Zimbabwe, where 85% of the total workforce is employed within the informal sector [15].

RR-TB has conventionally been used as a reliable proxy for MDR-TB, particularly in resource limited settings [16]. We conducted a prospective cohort study to understand healthcare seeking behaviour, healthcare expenditures, and associations with treatment outcome (24-month survival) among RR-TB patients starting treatment in conveniently selected out-patient facilities in Harare, Zimbabwe.

Materials and methods

Study population

RR-TB patients initially seeking health care within the Harare Metropolitan area between November 2011 and November 2012 were recruited from eight conveniently selected health facilities. Detailed enrolment and diagnosis criteria have previously been described [17]. Briefly, persons who had a history of prior TB treatment or were suspected of having drug-resistant pulmonary TB were recruited into a prospective cohort study. Presumptive drug-resistant TB patients were identified as symptomatic patients presenting with a history of > = 1 month of prior TB treatment (relapse, treatment after loss to follow up or treatment failure), contact with a person with known or possible drug-resistant TB; or with a rifampicin-resistant result on Xpert MTB/RIF. RR-TB diagnosis was confirmed by molecular TB assay and/or phenotypic drug susceptibility testing. At the time our study was undertaken, a partially decentralized MDR-TB/RR-TB treatment system was in place in Harare. Patients could only be diagnosed and recommended for treatment via a central MDR-TB clinic (i.e., at Wilkins Hospital) based in Harare, but MDR-TB/RR-TB treatment could be dispensed through peripheral, local health clinics. We estimated that approximately 60% of the population base was likely included in our sample [17].

Data collection

Data were collected using a mixed methods approach via an open-ended healthcare-seeking behaviour questionnaire designed to capture both quantitative and qualitative responses through in-depth patient interviews. The open-ended questionnaire allowed respondents to provide detailed responses on their health-seeking pathways and reasons for delay in seeking care. A trained research nurse administered the questionnaire. Quantitative data included basic socio-demographic information. Health-seeking behaviour included type of facilities or health care provider from which treatment was first sought; delays in seeking health care; reasons for delays; and direct and indirect costs incurred. Additional variables included whether patients had been referred from outside Harare, HIV and antiretroviral treatment status, TB treatment history and TB symptoms. Final clinical outcome was defined as 24-month patient survival, ascertained through review of medical records and contact with next-of-kin. Data were electronically captured in Research Electronic Data Capture tools (REDCap) [18] hosted at the University of California, San Francisco.

Definitions

Patient delay was defined as the time from onset of disease-associated symptoms to first health care visit. Health system delay was defined as the time from first medical facility visit to initiation of effective RR-TB treatment. Total delay was defined as the sum of patient and health system delays and included both diagnostic delay and repeat visits before initiation of treatment. Direct costs were those directly associated with health care such as diagnostic tests, doctors’ fees or medication costs. Indirect costs included travel, lodging or food expenses indirectly associated with health care seeking. Total costs were defined as the sum of direct and indirect costs incurred by a patient accessing care. A polyclinic was defined as a patient’s local government clinic (usually the first point of contact in this setting). Informal employment was defined as engagement in an economic activity that is not taxed or formally registered. Final clinical outcome was defined as 24-month patient survival.

Statistical analysis

Statistical analysis was performed using Stata Version 13 (StataCorp, College Station, TX, USA) and R software (version 3.5.3). Descriptive statistics for numeric variables (such as age or income) were computed and are reported as median and interquartile range (IQR). Chi-square tests were used to compute associations between continuous and categorical variables. We used the Kruskal Wallis test to analyse the associations between health care facility first attended; delays (patient and total time delays) and cost (both first visit and total costs incurred) to patients. Mann Whitney tests were used to compute associations between delay and clinical outcomes. Results are reported as medians, IQRs or proportions.

Both simple and multiple linear regression analyses were used to assess the associations between delay and explanatory variables. Potential risk factors for delay and variables associated with delay in the bivariate analysis (P ≤0.2) were included in a final multiple linear regression model. A p-value of less than 0.05 was considered statistically significant. R software (version 3.5.3) was used to compute the visual pathways of care. Thematic analysis was used to identify and analyse patterns and trends within the qualitative data gathered from the open-ended questionnaires [19].

Ethical approval

The Medical Research Council of Zimbabwe (MRCZ/A1552), and the Institutional Review Board of Biomedical Research and Training Institute, and Human Research Protection Programme, University of California, San Francisco (USCF) provided ethical approval (10–05115). All participants gave written informed consent before enrolling in the study.

Results

Study participants

Of 139 participants with RR-TB in the main study, 73 (53%) agreed to participate in the health-seeking behaviour (HSB) survey (Fig 1). A final sample of 68 participants with follow-up data was included in the final analysis: five participants were lost to follow up during the study period and were excluded from further analysis. More than 70% (48/68) of study participants were female, mainly from the economically active age group (median 34 years, IQR 29–42 years); with more than 73%, (50/68) educated up to secondary level (Table 1). Forty-five percent (30/67) of participants were employed in the informal sector; median monthly income was US$175 (IQR US$100-$300). Two-thirds of the sample (43/68) were HIV-positive, among whom 31 (73.8%) were on antiretroviral therapy. Overall, 37 (55.2%) of participants presented with new RR-TB, while other participants had experienced from one to three prior TB episodes (29.9% and 3.0% respectively).

Fig 1

Participant flowchart (n = 68).

Table 1

Socio-demographic and clinical characteristics of RR-TB patients, Harare, Zimbabwe.

Variable Name	Total sample (N = 68)
Female, n (%)	48 (70.6)
Age, years, median (IQR)	34 (29–42)
Referred from outside Harare, n (%)	12 (19.4)
Highest education*, n = 66
Primary	11 (16.2)
Secondary	50 (73.5)
Tertiary	5 (7.6)
Occupation*, n = 67
Informal employment	30 (44.8)
Formal	7 (10.5)
Unemployed	20 (29.9)
Student	10 (14.9)
Monthly income, $US, median (IQR)	175 (100–300)
HIV positive, n (%)	43 (65.2)
On ART	31 (73.8)
TB history
New TB	37 (55.2)
Retreatment TB	30 (44.8)
Number of Prior TB episodes, n (%) *	N = 67
0	37 (55.2)
1	20 (29.9)
2	8 (11.9)
3	2 (3.0)
TB symptoms at presentation, n (%)
Cough	68 (100)
Fever	45 (66.2)
Weight loss	54 (79.4)
Night sweats	48 70.6)
	49

*Missing Information: HIV status, n = 2; Education, n = 1; Occupation, n = 1; TB history, n = 1; Prior TB incidents, n = 1.

Time delays and costs associated with health care visits

Patients delayed seeking care by a median of 26 days (IQR 14–42 days) from onset of TB symptoms (Table 2). Median health system delay (i.e., time from first health care visit to initiation of effective RR-TB treatment) was 97 days (IQR 30–215 days). Health system delay was longest when the first point of contact was government polyclinics (median 150 days, IQR 18–300 days), followed by private clinics (median 102 days, IQR 30–154 days) and pharmacies (median 97 days, IQR 67–210 days). Median total delay (i.e., patient plus health system delay) was 132 days (IQR 51–287 days). Total delay was longest when a polyclinic was the first health system contact (median, 221 days, IQR 45–338 days). Costs associated with first visit were highest for private clinics (median US$30, IQR $14–45 days) and lowest for polyclinics (median $US0, IQR $0–4), across facilities visited (p<0.001). Cumulative costs were highest for participants who first visited a pharmacy (median US$45, IQR $19–80) and private clinics/hospital (median US$40, IQR $15–56), but least for those first visiting government polyclinics (median US$8, IQR $5–16). Overall, a median of 13% (IQR 6–31%) of total annual household income, (equivalent to a mean cost of US$410), was spent on seeking RR-TB health care. At least 30% (23/68) households incurred TB related costs which can be considered as catastrophic i.e., above 20% of annual household income.

Table 2

RR-TB patients’ first visit to a health care facility, patient time delays, total delay and associated costs to begin effective MDR-TB treatment.

Health facility visited	Patient delay days, median (IQR)	Health system delay days, median (IQR)	Total delay days, median (IQR)	First visit cost $US, median (IQR)	Total cost $US, median (IQR)
Pharmacy	21 (14–26)	97 (67–210)	116 (88–247)	10 (5–18)	45 (19–80)
Government polyclinic	30 (14–60)	150 (18–300)	221 (45–338)	0 (0–4)	8 (5–16)
Centralised RR-TB clinic	18 (14–38)	56 (33–163)	58 (21–81)	6 (5–13)	26 (5–40)
Private clinic	30 (18–70)	102 (30–154)	139 (45–226)	30 (14–45)	40 (15–56)
Other†	30 (21–30)	52 (9–248)	105 (56–278)	8 (1–14)	14 (6–21)
Overall	26 (14–42)	97 (30–215)	132 (51–287)	6 (2–16)	23 (10–55)
p-value	0.084	0.786	0.586	<0.001	0.004

†HIV testing clinic (n = 1), herbalist (n = 1), project clinic (n = 1), grocery shop (n = 2), missing (n = 1).

Reasons for delays in seeking care

Most study participants (n = 59/68, 88%) who delayed seeking care for their first health care visit reported not feeling sick enough to warrant a visit to the clinic or thinking that they had a minor cough, which could be treated using over-the-counter remedies. Participants who did not first seek care at primary care facilities (polyclinics) reported anticipating longer waiting times; inadequate testing facilities or poor service at the clinic as reasons for not first seeking care at the clinic.

Pathways to care and health-seeking visits

Based on qualitative interviews conducted among patients, urban residents preferred to visit pharmacies and supermarkets for home-based and over-the-counter remedies before visiting polyclinics or primary care facilities. When the care received was inadequate or symptoms were not improving, these patients would later attend government administered clinics and be referred to TB-referral clinics. Rural patients from outside Harare had a different typical care pathway characterised by home-based care, attendance at a rural hospital or clinic, followed by referral to a RR-TB treatment facility in Harare (Fig 2).

Fig 2

Cyclic care-seeking pathways and repetitive visits followed by study participants.

Different colours correspond to the health facility where patients sought care. The different arrows represent successive care-seeking visits as shown in the figure key.

Healthcare facilities attended

Health-seeking behaviour among study participants was cyclic, with participants making up to six visits (median, three visits) before initiating RR-TB treatment. Repeat visits at the same health facility were more common for polyclinics and private healthcare facilities. For their first visit, most participants attended a polyclinic (37%) followed by a pharmacy (30%), and private health care providers (24%) (Fig 2). Cumulatively, for the total 215 health care visits recorded in the study, nearly half (n = 90/215, 42%) were at the polyclinic with participants making up to five polyclinic visits (Fig 3).

Fig 3

Different Health care facilities attended by study participants and the proportion (%) of participants attending each facility as a proportion of all health care visits for each health care visit (Visit 1–6).

Different colours correspond to the health facility where patients sought care while different arrows represent successive care-seeking visits. *Four patients were admitted to hospital on first contact with the health system and are not included in this figure.

Association of total delay with clinical outcomes

We found that after adjusting for age and gender, living with HIV and being employed were associated with shorter total delay, (p = 0.11, median 98 days and p = 0.25, median 104 days respectively), and TB retreatment was likely to be associated with a longer delay (p = 0.20). We found no significant associations with mortality and median total delay or total cost incurred (Table 3). However, our sample size limited our ability to make conclusive determinations about the associations between delay and the risk factors that were assessed.

Table 3

Association between delay, cost and 24-month survival.

	Died (n = 6)	Survived (n = 62)	p-value*
Total delay (days)	168.5 (83.3–309.25)	132.0 (49.8–280.8)	0.77
Patient delay (days)	30 (23.3–30)	21 (14–42)	0.62
Total cost (dollars, US)	24.5 (8–40.3)	21.5 (10.3–55.5)	0.75

*Mann-Whitney test.

Discussion

Our study demonstrates that substantial delays in both seeking and accessing care for persons with confirmed RR-TB are common. Overall delay was highest among patients first attending government polyclinics, with a median of seven months (221 days) from onset of symptoms to effective treatment. Most participants first sought care at private health care facilities outside of the national TB program, citing long waiting periods, mistrust and inadequate facilities and services as barriers to accessing public sector care. Patient costs averaged approximately 13% of monthly income with at least 30% of the households incurring costs that may be considered “catastrophic”.

Our study showed community delays to effective rifampicin-resistant TB treatment despite the availability of molecular TB diagnostics such as Xpert. These findings are in agreement with studies from this era that have documented similar delays in accessing care. Total treatment delay among TB patients were shown to be 126 days in an urban study [20]; 70 days in a rural study [21] and up to 170 days in a rural study [22] in three South African TB studies. Although our study was in an urban setting and among RR-TB patients, we observed patterns of prolonged delays averaging 97 days (overall) for health system, and as high as 150 days for polyclinics. While for the South African studies delays to treatment initiation were mainly attributed to late presentation, [21, 22] in our study, delays were largely health system related. In contrast, a systematic review on 23 studies from India reported shorter average patient delays of 18.4 days and total delays of 55 days from when symptomatic patients with active TB first contacted a health care provider [23]. Differences between the Indian studies and our findings could be attributed to the health care system setting in the different countries. Across a number of other studies, delays in treatment initiation were mainly attributed to a combination of diagnostic delays and late presentation for care [23-26]. Prolonged diagnostic and treatment initiation delays pose serious challenges as TB treatment may only be initiated after disease has progressed, potentially worsening prognosis and treatment outcomes [27, 28].

Indirect costs remain a deterrent to seeking health care for many patients, despite TB treatment being nominally free in government facilities in most countries [11, 29, 30]. Loss of income due to time taken when sick or to seek treatment is a major issue and an indirect expense particularly when employment is informal or seasonal. The majority of our study participants who delayed seeking treatment were informally employed with limited safety nets. It is of concern that many patients visited private health care facilities or pharmacies as their first point contact, incurring additional expenses in the process. Our findings corroborate studies in other settings where patients incurred higher costs and a circuitous path to care, [24] resulting in significant delays in accessing treatment [31]. The economic burden of TB treatment remains considerable, especially in poorer and developing countries without universal health coverage (UHC), including our study setting [5, 32]. For many, the cost of accessing care can push already poor families to the brink of poverty. Furthermore, as we have shown, repeat visits in care-seeking pathways increased cumulative costs and delayed diagnosis and treatment initiation. Studies from India, Indonesia, Thailand, South Africa and other similar settings have shown that the cost of TB can be catastrophic especially for low-income households [6, 12, 32–35]. According to WHO, catastrophic costs are incurred when patients spend a considerable proportion of their annual income on both direct and indirect medical costs [34]. Other unaccounted (indirect) costs for TB may include income loss due to seeking treatment and loss of productivity due to illness or when household members assume carer roles for a bedridden TB patient. The financial burden of TB is evident from the low average income per household and proportion of costs (up to a maximum of 31% of annual household income) incurred on TB-treatment costs reported by participants in this study. Up to 30% of households reportedly spent more than 20% of annual household income on TB related costs, a threshold which has been previously described as catastrophic [12].

In 2016, the WHO issued revised guidance recommending MDR-TB treatment for all RR-TB patients regardless of confirmatory resistance testing as well as the use of line probe assays for drug sensitivity testing [36]. At the time of our study, MDR-TB diagnosis was done by culture, and drug susceptibility testing was done to confirm isoniazid resistance at a central reference laboratory (although many patients would be treated on the basis of rifampicin resistant test), increasing delays to treatment initiation. Our findings point to a need to improve public sector care services to ensure that they are the preferred first contact for TB patients and that patients access treatment promptly once they enter the care cascade. This is particularly pertinent given the protracted delay in initiating treatment by patients attending polyclinics that we report in this study. Increased case-finding and educational campaigns would assist in reducing patient-associated delays in seeking care. Furthermore, supportive social protection policies and interventions such as UHC [37] in resource-constrained settings could ensure that TB patients are not deterred from seeking care by exorbitant out-of-pocket costs which may exert financial burden on impoverished families [12, 33]. Our findings corroborate previous studies from other TB burdened settings that showed that consulting private health care providers aggravate delays in TB treatment access as they are not equipped to promptly diagnose and initiate TB treatment [24, 26, 38, 39]. Private-public health partnerships could facilitate prompt TB diagnosis, reduce high costs and reduce treatment delays among presumptive MDR-TB and TB patients as has been previously reported in other studies [40-42]. Taken together, these findings point to a need for interventions including quality improvement (particularly in the public healthcare system), to reduce delays in MDR-TB and RR-TB patient diagnosis and ensure prompt treatment once patients make contact with a health care facility.

We acknowledge a few limitations in our study. First, we conducted this study within a prospective cohort of RR-TB patients who underwent extensive diagnostic testing at time of referral for RR-T testing and treatment; true programmatic delays may be longer. Second, our study was underpowered to determine associations between clinical outcomes and health-seeking behaviour-related delays. Third, female participants were over-represented in our study, [17] indicating a possible selection bias. Furthermore, data was self-reported and so may be subject to self-report bias.

In conclusion, we found significant delays in accessing TB care in this setting, particularly in the public health sector. The majority of patients preferred private care providers as their first contact, resulting in cyclical care-seeking pathways, significant delays and additional health-care costs, which did not correlate with prompt access to care. As pharmacies are the first point of contact for many patients, we recommend that pharmacists and other private health care providers should be trained in appropriate TB screening and referral of potential TB patients to hasten access to treatment and reduce the cyclic pathways evident in settings such as ours.

(XLSX)

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27 Nov 2020

PONE-D-20-13834

Health care seeking patterns among patients investigated for drug resistant tuberculosis in Harare, Zimbabwe: a prospective cohort study.

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Reviewer #1: Abstract

Pg. 2, L25: are major impediments……

Pg. 2, L28: using s prospective cohort study design

More information on data collection instruments, analysis etc. are required in the methods section

Pg. 2, L33-34 should come first in the presentation of results.

Pg. 2, L29: The socio-demographic characteristics of the participants is missing. It is important for the subject under study

Introduction

Pg. 3, L50-53: Consider making 2 sentences for better coherence

Pg. 3, L53: Remove ‘due to’

Pg. 3, L54: add ‘also’ after may

Pg. 3, L56: Change from…. in the community, which may TO …. in the community and this could….. MAY has been used severally in that paragraph

Pg. 3, L59: add the before availability

Pg. 3, L71: Study area/setting missing

Pg. 4, L87-92: Consider breaking long sentences

Pg. 4, L87, 96: Source of the questionnaire and definitions lacking. More information needed

Results

Pg. 5, L122: More information on this main study is needed in the preceding sections

Table 1: Many variable son this table don’t add up to 68: e.g. age categories, occupation etc.

Pg. 9, L161; This information needs to be reflected in the abstract

Pg. 9, L164; Participants who did not first care at…..

Pg. 9, L168: Qualitative data collection and analysis was not described in the methods, how come these results?

Pg. 9, L176: Figure legend present but figure absent

How does the information presented in L143 differ from L184

Pg. 9, L183: Remove space between visits and recorded

Pg.9, L186: Figure legend present but figure absent

Pg.9, L190: This should have been defined under methods. Pls add clinical outcomes to the definitions. How many people died or survived?

Pg. 11, L212: contacted

Pg.11, L233, 236 : Integrate ref 5 and 29 as one statement as both sentences refer to the same thing

Pg. 12, L241: for a bedridden….

Pg. 12, L254: or by exorbitant….

L257: another recommendation could be integrating private providers in care provision given their high patronage

L264; use because instead of to the extent that

L271, 272: Interviews not discussed in methods section

L275: self-report is another limitation

L281: not discussed in the discussion, see comment above

L284: We recommend the improvement of the quality of care………in order to reduce……….and ensure more prompt……………

Reviewer #2: PONE-D-20-13834

Health care seeking patterns among patients investigated for drug resistant tuberculosis in Harare, Zimbabwe: a prospective cohort study

Thank you for a really interesting and important piece of work. Suggestions below are merely to help you strengthen your work and the final product. I have added comments with reference to specific sections of the work below.

Abstract:

Would be good if you could specify what your data source is; as well as outline your study design which I think is a mixed methods study (cross-sectional quantitative data) with qualitative interviews?

General comments:

Please define all abbreviations used in your manuscript.

Page 3, line 64: I think you mean disability, instead of debility.

Page 4, line 74: how many facilities were sampled and how were these facilities selected?

Patients were interviewed at selected health facilities and identified based on the selection criteria outlined.

Page 4, line 87: should read “data were collected…”

Page 4, line 91: where were the other variables collected from if not directly from the patient through patient interviews?

Page 5: under your statistical analysis paragraphs, it might be useful to specify different types of analyses separately. So, for example, perhaps start with describing how you would do your initial descriptive analysis where you are describing your sample. Specify if you are comparing different types of patients in your sample with one another. Then describe how you are setting up your regression analysis where you are wanting to explain your findings related to the time spent in accessing care or you are wanting to understand which variables and how they explain patient and health seeking delays. Then explain which statistical approaches you used and why.

Page 5, line 106: Why did you categorise your continuous variables, was that for the initial reporting in Table 1? In your statistical analysis, it is better if you can use the continuous variables in your model.

Page 5, line 124: It would be helpful if you could report not only the percentage, but to also show the numerator and denominator for the percentage reported, ex. 45% (31 /68) of participants had a history of TB.

On page 6, line 126: How do you define informal employment. It is worth spelling this out a bit more for the reader.

Page 6, line 128: Figure 1 is not showing up in the review document. What were the reasons for patients to not consent to the health seeking behaviour survey? How did your sample reduce from 73 following initial consent to 68 included in your analysis?

Table 1:

High proportion of the sample was female – why is this? Is it a possible sampling bias?

What is the relevance of having been referred from outside Harare? A more detailed description of the setting and DR-TB services in Harare will be needed in your background so that this statement makes sense. Plus, you need to remember that your readers may not know what the health system in Zimbabwe is like, and how people move through care. How do they pay for care? In your introduction, it would strengthen your paper if you could share some of your knowledge of how the system works to give the reader a sense of why your research question is important and what the context is within which they need to understand the results.

When you describe the delays; it would be good to first describe patient delay (as you have done), then health facility delay and then the total delay. This allows the reader to follow how you got to your total delay estimate.

Do you perhaps have any data on what proportion of people first started drug-sensitive TB treatment (DS-TB) before initiating on rifampicin resistant TB treatment?

Page 9, line 161: the results here sounds as if they came from open-ended questions/ or from qualitative work. If so, you need to be clear with the reader where that data came from and how it was analysed. This needs a separate section in the methods section with detailed discussion and justification of the methods used.

Page 9, line 174: Figures 2 and 3 are missing.

In the section “Associations with clinical outcomes” you are reporting important and interesting results. But I think this part of your analysis needs to be more clearly described in your methods section – specifically here I am referring to your comparison of costs and health seeking delays between who die and those who survive. How was this outcome (death) collected and what are the limitations of the approach used? Next, how did you set up your regression analysis and then in the results even if those results are not significant it would still be useful to know what the direction of the relationship between those variables is and even if not significant you can still report the p-value. It would strengthen your paper if you could explore what the determinants of long delays to RR-TB treatment are… for example, it might be accessing a certain facility first, or age or gender… But if you set up your regression analysis to answer this question, the answers would be very helpful to policy makers as it would allow them to construct useful and data-informed interventions.

Your discussion section is great – the work is well positioned. The paper would be even stronger if you added a sentence or two on what your think the policy implications of the work are. What is your advice to the NTP, how should they use your results to improve the service?

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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4 Mar 2021

We have addressed all comments as requested by the Editor and the reviewers (see details in responses to reviewers). Furthermore, we have included a copy of our anonymised data as well as the study questionnaires as requested with submission pack.

Submitted filename: Responses to reviewers_02March2021.docx

Click here for additional data file.

13 Apr 2021

PONE-D-20-13834R1

Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: a prospective cohort study.

PLOS ONE

Dear Dr. Tadokera,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 28 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

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An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Anna Maria Mandalakas, MD

Academic Editor

PLOS ONE

Journal Requirements:

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.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: PONE-D-20-13834R1

My comments were sufficiently addressed. Additional comments, with further information:

In Table 2: show days per unit of time.

Patient population: Rif-resistant

Page 2, from line 35: better to quote the arithmetic mean of costs (in addition to the median). Cost data are typically right skewed. The arithmetic mean is used when we estimate the total cost to a budget (mean cost x number of patients to be treated). This is a common use of health service cost data when considering policy options.

A paper of interest is Thompson & Barber. 2000. How should cost data in pragmatic randomised trials be analysed? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1127588/.

Page 3, line 72: prospective cohort study nested in what?

Page 9, line 202: would be good to specify the variables you adjusted for

Page 9, line217 and page 8, line 173: costs as a percentage of annual income is shown. It would be helpful if you could also report the proportion of patients who faced catastrophic costs. This will bring your paper in line with current literature. For an overview of the topic, see http://www.stoptb.org/wg/dots_expansion/tbandpoverty/assets/documents/Tool%20to%20estimate%20Patients%27%20Costs.pdf.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

17 May 2021

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: No

We have submitted our dataset as per PLOS Data policy and as requested in the previous review (File named: Anonymized Study Data).

In Table 2: show days per unit of time.

We have corrected Table 2 and added the units (days) as suggested by the reviewer.

Patient population: Rif-resistant.

We have also corrected the table heading to include the patient population description, “RR-TB Patients’’. (page 21)

Page 2, from line 35: better to quote the arithmetic mean of costs (in addition to the median).

We have amended this sentence to read “at a median cost of 13% (IQR 6-31%) of their total annual household income (mean cost, US$410” (line 32-33).

Likewise, we have also amended line 172-173 to read “Overall, a median of 13% (IQR 6-31%) or mean cost of US$410 of total annual household income”.

Page 3, line 72: prospective cohort study nested in what?

We have amended this sentence to simply read “We conducted a prospective cohort study….” (line 72)

Page 9, line 202: would be good to specify the variables you adjusted for

We have amended this statement to read “We found that after adjusting for age and gender....” (line 203)

Submitted filename: Responses to reviewers_17May2021.docx

Click here for additional data file.

26 May 2021

PONE-D-20-13834R2

Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: a prospective cohort study.

PLOS ONE

Dear Dr. Tadokera,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 10 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Anna Maria Mandalakas, MD

Academic Editor

PLOS ONE

Journal Requirements:

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.

Additional Editor Comments (if provided):

The team has done an excellent job with revisions. The manuscript looks quite good; I am excited to see this published.

I have one small suggestion for your consideration:

Line 304 (concluding paragraph): please consider revising by inserting the word 'screening' such that the revised text states "should be trained in appropriate TB screening and diagnosis, and referral of potential TB patients...."

The addition of the addition of 'screening' is perhaps more appropriate for the pharmacy level of care.

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Jun 2021

We have made the necessary revision as suggested by the Editor. We look forward to seeing our manuscript published in your Journal.

Submitted filename: Responses to reviewers_28May2021.docx

Click here for additional data file.

23 Jun 2021

Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: a prospective cohort study.

PONE-D-20-13834R3

Dear Dr. Tadokera,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Anna Maria Mandalakas, MD

Guest Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

8 Jul 2021

PONE-D-20-13834R3

Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: a prospective cohort study.

Dear Dr. Tadokera:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Anna Maria Mandalakas

Guest Editor

PLOS ONE