Title Page: Wingfield et al Original Research Article

Title: A household-randomized controlled evaluation of socioeconomic support to improve tuberculosis preventive therapy initiation and increase tuberculosis treatment success, Peru

Authors: Wingfield T (MRCP DTMH PhD),1,2,3,4 Tovar MA (MD MSc),2,5 Huff D (MPHTM PA-C),2,6 Boccia D

(MSc PhD),2,7 Montoya R (RGN),2 Ramos E (MSc),5 Datta S (MD),1,2 Saunders MJ,1,2,5 Lewis JJ (MSc PhD),2,7

Gilman RH (MD DTMH PhD),8 Evans CA (FRCP DTMH PhD)1,2,5

Author affiliations:

1) Infectious Diseases & Immunity, Imperial College London, and Wellcome Trust Imperial College

Centre for Global Health Research, London, UK

2) Innovación Por la Salud Y Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, Perú

3) The Monsall Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK

4) Institute of Infection and Global Health, University of Liverpool, Liverpool, UK

5) Innovation For Health And Development (IFHAD), Laboratory of Research and Development,

Universidad Peruana Cayetano Heredia, Lima, Perú

6) Tulane University School of Public Health and Tropical Medicine, New Orleans, USA

7) Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine,

London, UK

8) Johns Hopkins Bloomberg School of Public Health, Baltimore, USA

Corresponding Author: Dr Tom Wingfield, NIHR Academic Clinical Lecturer and ST7 Specialist Registrar

in Infectious Diseases, Institute of Infection and Global Health, Ronald Ross Building, 8 West Derby

Road, Liverpool, L69 7BE. Tel: 0151 7959667. Email: tom.wingfield@ifhad.org

Short running title: A randomized controlled evaluation of socioeconomic support to enhance TB

prevention measures and TB treatment success

Key words: TB; social protection; socioeconomic support; social determinants; poverty; conditional

cash transfers; TB control; TB prevention; TB treatment success; WHO End TB Strategy

Manuscript word count: 3046

Table: 1 Figures: 5 Box: 1

Statement of competing interests: all authors declare no conflicting or competing interests

1

Research in context

Evidence before this study: The World Health Organization (WHO) post-2015 End TB Strategy highlights socioeconomic support as a key pillar in the global response to TB. To identify existing evidence concerning such interventions, we searched PubMed using the terms “Tuberculosis/economics”[Mesh] OR “Tuberculosis, pulmonary/economics”[Mesh] OR “Tuberculosis/prevention and control”[Mesh] AND “Economic support/intervention”[Mesh] OR “Social support/intervention”[Mesh] OR “Socioeconomic support/intervention”[Mesh] OR “Cash transfers”. Articles were excluded that concerned socioeconomic support which: related specifically to HIV/ AIDS (such as the IMAGE study);1 did not have a control group or impact assessment;2,3 or provided economic support in the form of food4 rather than cash or bank transfers. This search found no randomized controlled evaluations of integrated socioeconomic support to improve TB preventive therapy or TB treatment but did find one randomized controlled evaluation of economic support alone to improve tuberculosis treatment outcomes, from South Africa. 5 The study showed no improvement in TB treatment success rates in patients who were randomized to the economic intervention, which consisted of monthly vouchers throughout treatment. However, the impact was limited by low fidelity to the intervention, which lacked a social support element. This is relevant because research in the field of HIV has suggested that economic support complemented by social support (e.g. education, information, and mutual-support groups) is likely to have a greater impact on health outcomes.6

New knowledge contributed by this study: Building on a decade of research addressing the social determinants of TB in Peru,7–11 we aimed to generate rigorous evidence on the impact of socioeconomic support on TB control to inform the WHO End TB strategy. To do this, we carried out one of the world’s first randomized controlled evaluations of a TB-specific integrated socioeconomic support intervention to improve TB prevention measures and increase TB treatment success. Our novel intervention was acceptable and feasible in the challenging setting of impoverished shantytowns of Callao, Peru.12 Moreover, the intervention had a measurable positive impact on health and economic outcomes by: reducing the likelihood of TB-affected household’s incurring catastrophic TB-related costs;13 increasing treatment success in TB patients; and improving initiation of TB preventive therapy in household contacts of these TB patients. These findings expand the limited literature supporting the use of economic support for TB-affected households and provide preliminary, rigorous evidence to inform implementation of socioeconomic support as mandated by the End TB strategy. The next step is to evaluate the impact of the intervention on TB prevention during the Community Randomized Evaluation of a Socioeconomic Intervention to Prevent TB (CRESIPT) project.

2

Abstract (250 words)

Objective. The End TB Strategy advocates socioeconomic support for TB-affected households but

there is limited impact assessment. We evaluated the impact of socioeconomic support on TB:

preventive therapy initiation in contacts; and treatment success in patients, and refined the support

for the “Community Randomized Evaluation of a Socioeconomic Intervention to Prevent TB”

(CRESIPT) project.

Methods. Design: An un-blinded household-randomized controlled study.

Setting: 32 shantytown communities, Peru.

Participants: All consenting patients treated for TB disease by the Peruvian TB Program and their

contacts aged <20 years.

Randomisation: Patient households were randomly assigned to control (received Peruvian TB

Program standard of care) or intervention (additionally received socioeconomic support) arms.

Socioeconomic support: consisted of economic support (conditional cash transfers ≤230 United

States dollars) integrated with social support (household visits and community meetings)

throughout TB treatment.

Outcomes: compared intervention versus control households using logistic regression adjusting for

household-clustering.

Findings. Between February 2014 and August 2014, 90% (282/312) of patients participated, 135

randomized to intervention and 147 to control arms. Primary outcome was TB preventive therapy

initiation in contacts aged <20 years (n=410). This increased from 25% in controls to 43% in the

intervention arm (adjusted odds ratio, aOR=2.2, 95% confidence interval, CI=1.1-4.2, p=0.02).

Secondary outcome was an intention-to-treat analysis of patient TB treatment success (cure or

completed treatment). This increased from 53% in controls to 64% in the intervention arm (OR=1.6,

95%CI=1.0-2.6, p=0.05). This increase was equitable, independent of poverty.

Conclusion. A TB-specific socioeconomic support intervention improved TB preventive therapy

initiation and TB treatment success.

Funding. Joint Global Health Trials consortium of Wellcome Trust, Medical Research Council, and

Department For International Development; British Infection Association; Wellcome Trust; Bill and

Melinda Gates Foundation; and the charity Innovation For Health And Development (IFHAD)

3

Introduction

It has been estimated that one third of the world’s population has latent tuberculosis (TB) infection.

In 2015, 10.4 million people developed TB disease.14 Those at highest risk of TB disease include:

household contacts of patients with TB and people living in poverty.15 A number of trials have shown

that TB preventive therapy decreases the risk of progression to TB disease by 60-90%.15–17 Despite

this proven benefit, the global impact of preventive therapy on TB control is severely limited

because people with latent TB infection are infrequently identified18 and infrequently take TB

preventive therapy,7,19 hampering global TB control.20,21 Difficulty adhering to medicines is common

and reduces their intended benefits.19,20,22 TB patients who do not take adequate TB treatment are

more likely to: have adverse outcomes (including death, treatment failure, and TB recurrence);23

transmit TB, especially to households contacts;24 and develop multi-drug resistant TB (MDR-TB),25 an

increasing global public health threat.18

The current predominantly biomedical approach to TB control is not reducing TB incidence rates to

levels required to eliminate TB as envisioned in the World Health Organisation’ (WHO) End TB

Strategy.26,27 Enhancing access to and initiation of TB preventive therapy and TB treatment is likely to

improve TB prevention and treatment success but requires strategies complementary to biomedical

care, including socioeconomic support. Social protection interventions include conditional cash

transfers and aim to reduce poverty and vulnerability by improving people’s capacity to manage

social and/or economic risks.8,28–34 Although these and socioeconomic interventions are common

tools in HIV/AIDS and maternal health,6,35 there is extremely limited evidence of their impact on TB

care or prevention.8,29,30,36

Our research group (www.ifhad.org) has been funded to undertake the Community Randomized

Evaluation of a Socioeconomic Intervention to Prevent TB (CRESIPT) project. The planning, design,

and economic impact of the intervention have been described.12,13 Here we report the final results of

the initial phase of CRESIPT, consisting of: a household-randomized controlled study to evaluate the

impact of TB-specific socioeconomic support on TB preventive therapy initiation and TB treatment

success, and refine the intervention for CRESIPT.

4

Methods

Setting. Thirty-two contiguous shantytowns in Callao, Peru, the northern coast extension of the capital

Lima. This regions has a population of one million, considerable poverty, zones with frequent drug

addiction and gun crime, and an annual TB case notification rate of 123 new cases/100,000

people/year in 2014, the highest rate nationally (Figure 1).37

Design. This household-randomized controlled study evaluated the impact of a socioeconomic

support intervention (Box 1) on TB preventive therapy uptake by patients’ household contacts aged

<20 years and treatment success for patients with TB.

Participants. Inclusion criteria were households of patients commencing treatment for TB disease

administered by the Peruvian National TB Program (NTP) in the study communities. These

households were invited to participate with an informed written consent form that explained the

randomization process, completed by the patient on the household’s behalf. For patients who were

minors, a parent or guardian was invited to give informed written consent and the patient was

invited to assent. Exclusion criteria were inability or unwillingness to consent. During a household

visit, individuals who the patient had reported as being in the same house as the patient for over 6

hours/week in the two weeks prior to the patient’s TB diagnosis were identified and validated and

are henceforth described as “contacts”. Any contacts declared or discovered following

randomization (but not during initial recruitment) were not included in the analysis nor invited to

participate in the intervention.

Randomization was done following recruitment of patient’s households. Randomization was

performed using random number tables, which generated an individual household randomization

sequence for each health post restricted in blocks of 30. The randomization assigned a patient

household at a ratio of 1:1 to either the control arm in which households received Peruvian NTP

standard of care, or the intervention arm in which households additionally received the integrated

socioeconomic support package. The mechanism for allocation concealment consisted of cards

placed in pre-numbered sealed envelopes detailing allocation to the intervention or control arm.

Once patients gave informed consent to participate, a project nurse opened the envelope in front

of the patient and informed them of their household’s allocation.

Data collection. A locally-validated questionnaire7,10 was used to collect health, wellbeing, and

socio-demographic data at baseline (the time that treatment commenced) and again 24 weeks later

(28 weeks if treatment was prolonged, including due to suboptimal treatment adherence). Both

interviews included measurement of height and weight to calculate body mass index (BMI), and

assessment of socioeconomic position.10,12

5

Preventive therapy. The Peruvian NTP guidelines that applied throughout this study recommended

that for contacts of patients with pulmonary TB that was not known to be caused by MDR-TB,

preventive therapy should be provided to all contacts under five years old (unless the contact was

known to have had previous TB disease) without tuberculin skin testing, and be considered for

contacts aged five to 19 years who have a positive tuberculin skin test.10 However, tuberculin was

generally unavailable throughout this study. Preventive therapy consisted of a six-month course of

daily isoniazid collected weekly from health posts and taken unsupervised in their home.10 Data

concerning preventive therapy initiation, adherence, and completion were collected collaboratively

from Peruvian NTP records, which included the number of weeks of preventive therapy collected

(herein defined as preventive therapy taken) from the health-post for each household contact.

Treatment. The Peruvian NTP offered free TB diagnostic testing to all people with symptoms

suggestive of TB who, if diagnosed, received free anti-TB treatment with directly observed therapy

(DOT) of every dose, which were administered at health posts.10 As an incentive and benefit for

participation, all patients, regardless of their randomisation, were offered an additional sputum test

with Xpert MTB/rif™ performed by our research laboratory for rapid rifampicin susceptibility

testing, which was not otherwise routinely available. TB treatment outcome data were collected

collaboratively with the Peruvian NTP from each individual patient’s treatment card at the time of

final follow-up and were not influenced by this research.

Treatment outcome definitions. Peruvian NTP outcomes were consistent with those defined by

WHO.14 The Peruvian NTP guidelines defined “cure” for patients with bacteriologically-confirmed

drug-susceptible TB at diagnosis if they completed treatment, had a negative sputum smear during

the final month of treatment, and a favourable clinical assessment by an NTP physician who

evaluated symptoms, examination, weight, and when necessary chest radiographs and blood tests.10

Patients who completed their TB treatment course without evidence of treatment failure but did not

complete the required sputum testing and/or physician review were classified as having “completed

treatment”. Patients with “treatment success” were those who completed treatment or were cured.

Other outcomes consistent with WHO guidance were “death” (all-cause mortality before starting or

during TB treatment); and “treatment failure” (positive sputum microscopy or culture at month five

or later of treatment). Patients whose treatment was interrupted for at least 30 consecutive days or

discontinued treatment having taken less than 30 days were defined as “lost to follow-up” (that was

locally termed “abandoned” and was shorter than the two months or more treatment interruption

in the WHO definition). Treatment outcome could not be assessed in patients who had no treatment

outcome assigned including cases transferred out to another treatment unit or patients who were

6

still on treatment at our 28 week follow-up interview (including MDR-TB patients whose treatment

duration commonly extended to 24 months).

Primary study outcome was TB preventive therapy initiation in contacts aged <20 years who were

available for follow-up. This compared intervention versus control households.

Secondary study outcome was TB treatment success (cure or completed treatment, as defined

above) in patients with TB analysed on an intention-to-treat basis, including patients with an

unknown outcome, using data from NTP records. This compared intervention versus control

households.10

Sample size calculations estimated that a study with 400 household contacts would have 80%

statistical power to detect a 50% increase in the primary outcome comparing intervention versus

control households with two-sided 5% significance, based on data from the study site.7

Blinding. It was not feasible for households or the research team to be blinded to allocation.

Peruvian NTP staff were not informed of and were generally unaware of household allocation, but

were not confirmed to be blinded.

Analysis. Socioeconomic variables were combined into a composite index of household

socioeconomic position using principal component analysis, as described.10 Data at the household

and individual (patient and contact) level were used to analyse study outcomes. The primary and

secondary outcomes were analysed by crude univariable logistic regression. For the primary study

outcome, multivariable logistic regression was also used to adjust for household clustering with

robust standard errors, generating adjusted odds ratios (aOR). Time-to-event analysis was

performed to generate a crude, unadjusted log-rank value comparing the number of weeks of

preventive therapy taken by contacts from intervention versus supported households.

Approvals included the ethics committees of DIRESA Callao (regional ministry of health), Imperial

College London, UK, and Asociación Benéfica PRISMA, Peru.

7

Results

Participants. Recruitment commenced 10th February 2014, the intended sample size was reached

14th August 2014, and follow-up was completed 1st June 2015. 312 households of patients with TB

were invited to participate, 90% (282/312) were recruited and randomized to the intervention

(n=135) and control (n=147) arms. 9% (24/282) of patients had MDR-TB, none of whom completed

treatment during the study. Patients from the 282 recruited households had a total of 1297

contacts (mean average five contacts per household). Of these contacts, 40% (518/1297) were aged

under 20 years old of whom 79% (410/518) completed follow-up (Figure 2). There were no

substantive imbalances found between households randomised to the intervention or control arm

(Table 1).

Intervention. 90% (122/135) of households randomized to the intervention arm received at least

one conditional cash transfer. A total of 890 conditional cash transfers were made (80% of potential

conditional cash transfers) with an average total of 520 Peruvian Soles (186 US Dollars) received per

household of a maximum 640 Peruvian Soles (230 dollars) available per household.10,12

Primary outcome of TB preventive therapy initiation in contacts aged <20 years was 25% in the

control arm and 43% in the intervention arm. This difference was statistically significant, both in

crude analysis (OR=2.2, 95%CI=1.4-3.3, p<0.001) and analysis adjusting for household clustering

(aOR=2.2, 95%CI=1.1-4.2, p=0.02), Figure 3a.

Secondary outcome intention-to-treat analysis of patient TB treatment success (cure or completed

treatment) was 53% in the control arm and 64% in the intervention arm. This difference was

statistically significant in crude analysis (OR=1.6, 95%CI=1.0-2.6, p=0.05), Figure 4a. No analysis

adjusted for household clustering was required because there was only one patient per household.

Supplementary analyses:

WHO treatment outcomes: Patients from intervention households were also more likely than those

from control households to be cured (51% [95%CI=43-60%] versus 37% [95%CI=30-45], p=0.02).

Cure and other WHO-defined treatment outcomes are shown in Figure 4b.

Adherence: The intervention was associated with a statistically significant approximate doubling in

preventive therapy initiation (aOR 2.2, primary outcome described above, figure 2a) and this

increase was maintained throughout the 24 weeks of recommended preventive therapy.

Specifically, amongst those who initiated preventive therapy, the average weeks of preventive

therapy taken were similar for intervention and control arms (18, standard deviation, SD=7.7 versus

8

18, SD=7.8 weeks respectively, p=0.9). Consequently, the overall average weeks of preventive

therapy taken was significantly greater in intervention than control arms (7.8, SD=10, versus 4.8,

SD=8.9, p=0.002, Figure 3b). Time-to-event analysis demonstrated that the intervention was

associated with greater overall preventive therapy uptake (log-rank p=0.005, Figure 3b). The study

sample size was selected to test for an effect of the intervention on the whole study population, as

described above, so the study did not have statistical power to test for effects in sub-groups. Thus,

although the intervention was associated with an approximate doubling in preventive therapy

completion (20%, 95%CI=14-25 versus 12%, 95%CI=7-16), this effect in this minority of the study

population was statistically significant only in crude analysis (OR=1.9, 95%CI-1-1-3.2, p=0.03) but

not in adjusted analysis (aOR=1.9, 95%CI=0.78-4.5, p=0.2).

Equity: To assess the equity of the intervention, we compared the study outcomes in the most

versus less vulnerable subpopulations. Vulnerability was assessed as the poorest tercile of the

population, and for preventive therapy initiation also for child contacts in the age groups <5 years

versus contacts aged 5-19 years. Figure 3b and Figure 4b demonstrate that the effect of the

intervention was similar for these subgroups that were most versus less vulnerable and that the

intervention was associated with increases in both primary and secondary outcomes in all these

subgroups. Furthermore, the statistical significance of the intervention effect on preventive

therapy uptake was independent of age group (aOR=2.2 95%CI=1.1-4.2, p=0.02) and was

independent of poverty group (aOR=2.2, 95%CI=1.1-4.1, p=0.02). The intervention was associated

with a trend towards increased treatment success after adjusting for poverty group (aOR 1.7,

p=0.07). These analyses suggest that the intervention was equitable, benefiting more as well as less

vulnerable subgroups, independent of age and poverty.

9

Discussion

During this initial phase of the CRESIPT project, we designed, implemented, refined,12 and evaluated

a novel TB-specific socioeconomic support intervention including cash transfers in a resource-

constrained setting. The intervention proved to be feasible12 and improved rates of TB preventive

therapy initiation in household contacts and TB treatment success in patients with TB.

Previous evidence assessing interventions to improve TB prevention measures and/or TB treatment

adherence has been limited by lack of randomization, small sample sizes, and/or being conducted in

high-resource settings with restricted patient groups (e.g. HIV-infected people,38 homeless people,39

migrants,40 or injecting drug users15,41). Recent systematic reviews concluded there was no existing

evidence on the impact of incentives including cash transfers on TB preventive therapy completion42

and minimal evidence to guide WHO recommendations on implementation and scale-up of TB-

specific socioeconomic support in resource-constrained settings.43 Our study informs global TB policy

and contributes new knowledge to fill this evidence gap5,7

Current shortages in the worldwide supply of tuberculin have made effective management of

household contacts of TB patients difficult to achieve44 and commercial interferon-gamma release

assays are rarely performed due to being too expensive (~200 US dollars/test in the study site),

technically demanding, and not routinely available in resource-constrained settings, including Peru.

Despite these logistical challenges in the study setting, the intervention approximately doubled TB

preventive therapy initiation, highlighting the strength of the impact of the socioeconomic support

received. Although 24 weeks preventive therapy with isoniazid is recommended in Peru, the

protective effect increases with more prolonged administration and longer courses are

recommended elsewhere.16,17 Therefore, our finding that the intervention increased the number of

weeks of TB preventive therapy taken is important because non-adherence to TB preventive therapy

is frequent20,45,46 and improving initiation whilst maintaining adherence could potentially decrease

rates of secondary TB disease. Moreover, supplementary analyses showed that this effect seemed to

be maintained in younger contacts and contacts from poorer households, suggesting that the

intervention was equitable.

While the above findings are encouraging, supplementary analyses showed that socioeconomic

support almost doubled, but did not statistically significantly increase completion of 24-weeks TB

preventive therapy. Potential reasons for this include: this was an exploratory analysis that was not

powered to assess this outcome, with a small number of contacts completing preventive therapy in

each study arm; unlike TB treatment, conditional cash transfers for preventive therapy were not

given monthly; the conditional cash transfer for preventive therapy completion were only made

10

when all eligible household contacts achieved it; and the conditional cash transfers received did not

completely mitigate direct out-of-pocket expenses, suggesting that the financial burden of TB was

still high for many intervention households.47,48 We have since optimised the economic support for

the main CRESIPT project to completely mitigate direct expenses and to offer monthly conditional

cash transfers to individual household contacts to further enhance TB prevention measures and

prevent incident TB.

This research provides evidence supporting the WHO End TB Strategy, which calls for expansion of

the existing biomedical paradigm of TB control by incorporating socioeconomic support

interventions to address poverty and social determinants, the main drivers of the global TB

epidemic.26 While these findings demonstrate that conditional cash transfers can improve patient

outcomes (for example through diminishing food insecurity and improving healthcare access), our

intervention went beyond cash transfers during household visits and participatory community

meetings by offering education and information, and promoting stigma reduction, inclusiveness, and

empowerment. This social support focused on risk factors for non-adherence to TB preventive

therapy and TB treatment such as: lack of TB-related knowledge, being female and/or

marginalized.49 The design of this study did not allow analysis of the differential impact of social

versus economic support on TB treatment and prevention outcomes. Nevertheless, in the field of

HIV, conditional cash transfers interventions have often been complemented by health education for

beneficiaries and, without education or social support, conditional cash transfers may have only

limited impact on health outcomes.6 Thus, optimising social support whilst addressing specific

aspects of poverty such as food insecurity may strengthen the impact of future socioeconomic

interventions.

Limitations of this study include, firstly, the intention-to-treat analysis meant that treatment

outcome could not be evaluated for patients still taking treatment at the final 28-week study

follow-up, including those with MDR-TB. Consequently, the proportion of patients with treatment

success was likely to have been underestimated in both intervention and, perhaps to a greater

extent, control households. However, the majority of patients recruited were HIV negative with

drug-susceptible TB and would be expected to complete treatment by 28 weeks unless there had

been treatment interruption. This supported the intention-to-treat analysis approach in which

patients still on treatment at 28 weeks were classified as not having treatment success. Secondly,

some households could have potentially declared a greater number of household contacts in the

hope of receiving more incentives, although the similar number of contacts per household

comparing the intervention with control households suggests that this did not occur. This issue was

avoided by incentives being provided at household rather than individual level and by inclusion in

11

the intervention of only those household contacts declared prior to randomization, whose validity

was confirmed with a household visit. Thirdly, the patients and study team were un-blinded to the

intervention and there was a conditional cash transfer for households in which the patient achieved

confirmed cure and the relevant contacts completed TB preventive therapy. This could have led to

bias because the patients receiving the socioeconomic intervention could have been more likely to

attend health-posts and request clinical evaluation for confirmation of cure. Furthermore, duration

of preventive therapy taken was calculated from the number of weeks of isoniazid tablets collected

from the health post, which may not necessarily have equated to adherence. Nevertheless, the

study team did not influence NTP staff to initiate such consultations, patient feedback suggested

that seeking confirmation of cure was an empowering element of the intervention,12 and in

supplementary analyses socioeconomic support significantly improved not only treatment success

but also confirmed cure. Finally, the socioeconomic support was integrated, so could only be

evaluated together, precluding assessment of the differential impact of the social versus economic

components. The authors’ original proposal of a 2x2 factorial study (evaluating the impact of

socioeconomic support versus social support only versus economic support only versus standard of

care) was too expensive due to sample size required to achieve sufficient power and instead the

integrated intervention was evaluated. Future larger studies should assess the differential impact of

social and economic support on TB prevention and treatment success and evaluate whether these

results may be replicated in and are generalizable to other patient populations, including those with

high rates of HIV-TB co-infection, rural communities, and those in low income countries.

12

Conclusions

During this initial household-randomised phase of the CRESIPT project, a novel socioeconomic

support intervention in an impoverished setting was feasible, acceptable, enhanced TB preventive

therapy initiation and improved TB treatment success. These findings support the new global End

TB Strategy and highlight the need for larger-scale evaluations, including CRESIPT, to determine the

impact of socioeconomic support on TB care, prevention, control, and potentially TB elimination.

13

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Box 1: Description of the socioeconomic support intervention12

Related research: The project was informed by the findings of our group’s Innovative Socioeconomic Interventions Against TB (ISIAT) study,7 two systematic reviews of cash transfer interventions,8,12 expert consultations,29 and feedback from civil society and leaders of the Peruvian TB Program.48

Outputs: Socioeconomic support targeted outcomes on the TB causal pathway and promoted equitable access to TB program activities including: i. screening for TB in contacts; ii. initiation of TB preventive therapy and completion of TB treatment; and iii. engagement with social support activities.

Socioeconomic support intervention has been described.12 Briefly, it constituted an integrated package of:

- Social support consisting of household visits and participatory community meetings that aimed to provide information, mutual support, empowerment, and stigma reduction. The household visits were made shortly after patients commenced treatment and provided education on TB transmission, treatment, preventive therapy, and household finances. The community meetings took place monthly in each study site community, were each attended by ~15 patients and their household contacts, and cost ~189 United States (US) dollars per meeting (~13 US dollars per patient per meeting).12 The meetings re-emphasized the educational themes of the household visit and developed “TB Clubs” during which participants shared TB-related experiences within a mutually supportive group (to be reported elsewhere). All household members were invited and encouraged to participate in household visits and community meetings.

- Economic support consisting of conditional cash transfers throughout treatment to defray average household TB-related costs thereby reducing TB risk factors whilst also incentivizing and enabling care. Economic support was designed with the intent that direct out-of-pocket expenses would be completely defrayed in patients who achieved all conditional cash transfers. Such direct out-of-pocket expenses had previously been found to equate to 10% of annual household income in the study setting, 10 equivalent to approximately 230 US dollars. We hypothesized that defraying these direct expenses would decrease a TB-affected household’s financial burden, likelihood of incurring catastrophic costs, and - when combined with integrated social support - enhance access to TB care and improve TB outcomes. During planning of the intervention, it had been estimated that if the intervention were implemented nationally the additional cost per patient would increase Peru’s TB Program budget by approximately 15% per patient.10 Focus group discussions with key stakeholders suggested that such increased expenditure was locally appropriate and affordable.10,12,50 Moreover, review of the relevant literature suggested that interventions that increased per patient TB Program budget by ≤50% and reduced incident TB by one third would likely be cost-effective and sustainable.51,52

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Table 1: Baseline demographic characteristics of the study population.

Footnote: Sputum smear results were defined as positive if acid-alcohol fast bacilli were visualised in NTP reference laboratory and/or our research team’s laboratory from sputum samples prior to starting TB treatment.

20

Figure 1: Map of study site including 32 health post regions and numbers of study participants from each region.

Footnote: the location of the principal Peruvian international airport is shown adjacent to community 21.

21

Figure 2: Study schematic showing participant recruitment, randomisation and participation.

22

Figure 3a: Primary outcome analysis of TB preventive therapy initiation in contacts <20 years old from intervention and control households.

Footnote: Error bars are 95% confidence intervals. Crude analysis was the odds of preventive therapy initiation comparing intervention versus control households without adjustment for household clustering. Adjusted analysis was the odds of preventive therapy initiation comparing intervention versus control households adjusting for household clustering.

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Figure 3b: Supplementary analysis of number of weeks of TB preventive therapy taken by contacts from intervention and control households.

Footnote: the p value shown below average weeks of preventive therapy taken in the final column of the data table is the difference between the mean average number of weeks of preventive therapy taken by contacts aged <20 years in intervention versus control households compared by Mann Whitney U test.

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Figure 3c: Supplementary analysis of initiation of TB preventive therapy by household contacts across age groups and poverty levels

Footnote: Error bars are 95% confidence intervals. “Poorer households” were those in the lowest poverty score tercile and “less poor” households were the remaining households.

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Figure 4a: Secondary outcome analysis of TB treatment success in patients with TB from intervention versus control households.

Footnote: Error bars are 95% confidence intervals. Likelihood of treatment success was analysed by univariable logistic regression of association of being a patient from an intervention household with TB treatment success.

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Figure 4b: Supplementary analysis of TB treatment outcomes in patients with TB from intervention versus control households across poverty levels

Footnote: Percentages in brackets Error bars are 95% confidence intervals. Treatment outcomes were those recorded by the Peruvian NTP in line with WHO guidance and reporting: cured, treatment completed, treatment failed, died, lost to follow-up (locally termed abandoned), and not evaluated. 14

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