Articles

Household contact investigation for the detection of

tuberculosis in Vietnam: economic evaluation of a
cluster-randomised trial
Thomas Lung, Guy B Marks, Nguyen Viet Nhung, Nguyen Thu Anh, Nghiem Le Phuong Hoa, Le Thi Ngoc Anh, Nguyen Binh Hoa,
Warwick John Britton, Jessica Bestrashniy, Stephen Jan, Gregory J Fox

Summary
Background Active case finding is recommended as an important strategy to control tuberculosis, particularly in Lancet Glob Health 2019;
low-income and middle-income countries with a high prevalence of the disease. However, the costs and cost- 7: e376–84

effectiveness of active case finding are unclear due to the absence of evidence from randomised trials. We assessed See Comment page e296

the costs and cost-effectiveness of an active case finding strategy in Vietnam, where there is a high prevalence of The George Institute for Global
Health, The University of New
tuberculosis.
South Wales, Sydney, NSW,
Australia (T Lung PhD,
Methods We conducted an economic evaluation alongside the Active Case Finding in Tuberculosis (ACT2) trial—a S Jan PhD); Faculty of Medicine
pragmatic cluster-randomised controlled trial in 70 districts across eight provinces of Vietnam. Patients aged 15 years and Health, University of
Sydney, NSW, Australia
and older with smear-positive pulmonary tuberculosis were recruited to the trial if they lived with one or more other
(T Lung, W J Britton PhD, S Jan,
household members. Household contacts were verbally invited to the clinic by the index patient with tuberculosis. G J Fox PhD); South Western
ACT2 compared a combination of active and passive case finding with usual care (passive case finding) of household Sydney Clinical School,
contacts of patients with tuberculosis from a health system perspective. Clustering occurred at the district and University of New South Wales,
Kensington, NSW, Australia
household level. Districts were the unit of randomisation, and we used minimisation to ensure balance of intervention (G B Marks PhD); Woolcock
and control districts within each province. In the intervention group, participants were invited to attend screening at Institute of Medical Research,
baseline, 6 months, 12 months, and 24 months. We determined health-care costs with a standardised national costing Glebe, NSW, Australia
survey and reported results in 2017 $US. The primary outcome of our study was disability-adjusted life years (DALYs) (G B Marks, N T Anh PhD,
N L P Hoa MSc, L T N Anh BSc,
averted over a 24-month period. ACT2 was registered prospectively with the Australian and New Zealand Clinical J Bestrashniy PhD, G J Fox);
Trials Registry, number ACTRN126.100.00600044. National Lung Hospital,
Ba Dinh, Hanoi, Vietnam
Findings Between Aug 11, 2010, and Aug 11, 2015, 10 964 index patients and 25 707 household contacts completed the (N V Nhung PhD, N B Hoa PhD);
Hanoi Medical University,
ACT2 study. There were 10 069 household contacts in the intervention group and 15 638 household contacts in the Hanoi, Vietnam (N V Nhung);
control group. The incremental cost-effectiveness ratio per DALY averted was $544 (330–1375). Centre for Operational
Research, International Union
Interpretation Active case finding was shown to be highly cost-effective in a setting with a high prevalence of tuberculosis. Against Tuberculosis and Lung
Disease, Paris, France (N B Hoa);
Investment in the wide-scale implementation of this programme in Vietnam should be strongly supported. and Centenary Institute of
Cancer Medicine and Cell
Funding Australian National Health and Medical Research Council. Biology, University of Sydney,
Camperdown, NSW, Australia
(W J Britton)
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND
Correspondence to:
4.0 license. Dr Thomas Lung, The George
Institute for Global Health,
Introduction those with whom individuals live in close proximity. The University of New
Tuberculosis is one of the top ten causes of death New strategies are required to enhance case detection South Wales, Sydney,
NSW 2042, Australia
worldwide and affected around 10 million people in and reduce the morbidity and mortality associated with tlung@georgeinstitute.org.au
2017.1 The milestones set by the WHO End TB Strategy the disease.
require a 4–5% annual decline in incidence of the Active case finding has been endorsed by WHO as a
disease. On the basis of current trends, this target is strategy to reduce the burden of tuberculosis, particularly
unlikely to be achieved without a substantial increase in in low-income and middle-income countries (LMICs)
efforts to detect and treat tuberculosis. For most with a persistently high incidence of the disease.2,3
countries with a high burden of the disease, the usual Household contacts (people occupying a housing unit) of
model of tuberculosis care consists of symptomatic patients with tuberculosis have a high risk of developing
patients presenting to health-care facilities before they the disease,4 and are a potentially high-yield population
can be diagnosed and treated. Known as passive case for active tuberculosis screening. A meta-analysis
finding, this practice is unable to identify individuals including 95 studies from LMICs estimated the preva-
with minimal symptoms and can lead to substantial lence of tuberculosis among household contacts to be
diagnostic delay. This delay increases the risk of 3·1% (95% CI 2·1–4·5%), with the highest incidence
transmission of the infection to others, particularly to occurring in the first year after tuberculosis exposure.4

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 Articles
Research in context
Evidence before this study
We searched PubMed for economic evaluation studies of
active case finding up to May 25, 2018, with the search terms
(“economic evaluation” OR “cost-effectiveness”) AND (“TB”
OR “tuberculosis”) AND (“active case finding”). Previous
cost-effectiveness studies of active case finding modelled
long-term costs and outcomes on the basis of effect estimates
derived from observational data. We did not identify any
economic evaluations alongside a randomised controlled trial.
The milestones set by the WHO End TB Strategy require a
4–5% annual decline in tuberculosis incidence. Without a
substantial increase in efforts to detect and treat tuberculosis,
this decline in incidence is unlikely to be achieved. For most
countries with a high burden of the disease, passive case
finding is used to diagnose and treat patients with
tuberculosis. In this method, diagnosis and treatment occur
when symptomatic patients present to health-care facilities,
but individuals with minimal symptoms cannot be identified,
which might lead to substantial diagnostic delay. Members of
households of patients with tuberculosis are at an increased
risk of infection. Active case finding is a WHO-recommended
strategy to improve case detection and earlier uptake of
treatment for patients with tuberculosis. However, evidence
on the cost-effectiveness of active case finding in low-income
and middle-income countries is scarce.
Added value of this study
To our knowledge, this is the first cost-effectiveness analysis
of active case finding compared with usual care done
The Active Case Finding in Tuberculosis (ACT2)
trial—a cluster-randomised controlled trial comparing
active case finding plus passive case finding with passive
case finding alone among household contacts of patients
with infectious tuberculosis in Vietnam—showed that
active case finding among household contacts of patients
with infectious tuberculosis increased case detection and
reduced all-cause mortality.5 This study supports WHO
recommendations for systematic screening of household
contacts of patients with tuberculosis in low-prevalence
and high-prevalence settings.2,6 However, little progress
has been made in scaling up such policies because of the
uncertain economic consequences for contacts and
health systems.
Assessment of the costs and benefits of active case
finding compared with standard care is important when
evalu­ating the most appropriate interventions to
strengthen tuberculosis control in resource-constrained
health-care systems. However, there is a paucity of
evidence available to inform the economic case for
implementation of active case finding in resource-
constrained settings. A Cambodian study7 compared
active case finding and passive case finding with passive
case finding alone among a population-based cohort of
household contacts of patients with tuberculosis. The
e377 www.thelancet.com/lancetgh Vol 7 March 2019
alongside a randomised controlled trial over a 24-month
period. The Active Case Finding in Tuberculosis (ACT2) trial is a
large-scale cluster-randomised controlled trial comparing
active case finding and passive case finding with passive case
finding alone in 25 707 household contacts of patients with
tuberculosis in Vietnam. This study provided an unbiased
estimate of the number of registered tuberculosis cases in a
high-prevalence setting. Costs of staff, medications, and
diagnostic tests were taken from a costing survey of the
Vietnam National Tuberculosis Control Programme. We
presented cost-effectiveness estimates and found that active
and passive case finding of household contacts of patients
with tuberculosis is highly cost-effective compared with
passive case finding alone, and active case finding could yield
substantial benefits for reducing morbidity and mortality.
Implications of all the available evidence
Our results support evidence from cost-effectiveness estimates
derived from observational data, which found active case
finding among household contacts of patients with
tuberculosis to be cost-effective. Active case finding could yield
a higher number of tuberculosis cases and has the potential to
reduce the overall burden and prevent further disease
transmission in the community. Investment in wide-scale
implementation of this programme across Vietnam should be
strongly supported. Efforts to establish the feasibility of
allocation of additional health-care resources to expand active
case finding into the Vietnam National Tuberculosis Control
Programme are needed.
study found the cost-effectiveness to be US$330 per
disability-adjusted life year (DALY) averted. This result
suggested that active case finding was likely to be highly
cost-effective in that setting. Similarly, cost-effectiveness
modelling studies in Peru, Uganda, South Africa, China,
and India suggested that active case finding plus passive
case finding is likely to be highly cost-effective compared
with passive case finding alone.8–10 A common limitation
of these studies is the absence of a suitable control arm.
Extrapolation of historical trends or reliance upon case-
notification data to estimate the yield due to passive
approaches might be biased. Furthermore, assumptions
about the incremental yield of active case finding are
subject to selection bias and confounding because of
non-random group allocation.2 This important problem
can be addressed by doing an economic evaluation
within the context of a randomised trial.11
We conducted a trial-based economic evaluation of the
ACT2 trial in Vietnam, where there is a high prevalence
of tuberculosis.5
Methods
Study setting and target population
Vietnam is a middle-income country in southeast
Asia with a high burden of tuberculosis. In 2016,
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106  527 patients were treated for tuberculosis and

13 000 people died of the disease.1 Consequently, 1 chest radiograph

tubercu­ losis remains a substantial public health

problem. Vietnam spends US$70 million per year to
deliver quality-assured subsidised treatment for Normal, test for Abnormal,
tuberculosis throughout its national network of clinics presence of administer
and hospitals. symptoms further tests

The ACT2 trial has previously been described in detail.12

Briefly, ACT2 was a parallel-group, cluster-randomised
trial in 70 districts across eight provinces in Vietnam.
No symptoms, Symptoms present,
Clustering occurred at the district and household level. no further testing administer further
Districts were the unit of randomisation, and we used required tests
minimisation to ensure balance of intervention and
control districts within each province.
2 sputum smears 2 sputum smears
Patients aged 15 years and older with smear-positive 2 sputum cultures 2 sputum cultures
pulmonary tuberculosis were recruited to the trial if
they lived with one or more other household members.
Household contacts were verbally invited to the clinic
by the index patient with tuberculosis. Written Positive diagnosis, Negative Positive diagnosis, Negative
administer diagnosis administer diagnosis
informed consent was provided by study participants or first-line first-line
their parents. In the intervention group, contacts were medication medication
screened for active tuberculosis four times in 2 years.
Sputum was collected for culture among individuals
with an abnormal chest radiograph or respiratory Successful Treatment failure, Successful Treatment failure,
symptoms exceeding two weeks in duration. We treatment administer treatment administer
followed up household contacts in both groups for second-line second-line
medication medication
24 months after enrolment, and the incidence of
notified cases of disease was ascertained from clinic
tuberculosis registers. The study was implemented by Figure 1: Treatment algorithm to screen and identify patients with tuberculosis when presenting at hospital
more than 250 government staff working at 70 district-
level tuberculosis clinics within the Vietnam National Furthermore, the greatest benefits probably would result
Tuberculosis Control Programme. Patients diagnosed from reductions in health-care service use because of
with tuberculosis were treated through this programme. early detection of disease and reduced tuberculosis
Diagnostic testing for drug-resistant disease only transmission.
became available after 2012, when the Xpert MTB/RIF At baseline, enrolled contacts in both the intervention
assay became available across the country. Before this, and control groups were provided with written infor­
patients who did not respond to treatment were treated mation that instructed them to seek care at a tuberculosis
empirically with so-called Category 2 regimens or clinic if they developed symptoms typical of tubercu­
referred to central facilities for drug susceptibility losis—persistent cough, fever, or weight loss. No
testing. systematic screening occurred for contacts at control
Ethics approval was provided by the Human Research clinics. If contacts in the control group developed
Ethics Committee at the University of Sydney and the symptoms of tuberculosis and presented at the district
Scientific Committee of the Vietnam Ministry of Health. clinic, care was provided according to the standard
ACT2 was registered prospectively with the Australian diagnostic algorithm (figure 1).
and New Zealand Clinical Trials Registry, number In accordance with WHO treatment guidelines at
ACTRN126.100.00600044. the time of the study, patients diagnosed with active
pulmonary or extrapulmonary tuberculosis were treated
Procedures with a first-line intensive regimen comprising isoniazid,
We conducted a within trial economic evaluation of the rifampicin, streptomycin, and ethambutol for the first
ACT2 trial12 over the 24 month follow-up period. ACT2 2 months, followed by a continuation phase of 6 months
compared a combination of active and passive case of isoniazid and ethambutol.1 All treatment was provided
finding with usual care (passive case finding) of through the Vietnam National Tuberculosis Control
household contacts from a health system perspective. Programme. Screening and treatment for latent tubercu­
We chose this perspective as it estimates the costs and losis infection were not offered in either group.
effects incurred from the Vietnamese health-care Contacts in the intervention group were invited to be
system, providing guidance to relevant decision makers screened for tuberculosis at the district clinic at
or funders who could invest in active case finding. enrolment (baseline) and at 6 months, 12 months, and

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Intervention districts Control districts

Index patients with Household contacts Index patients with Household contacts
tuberculosis (n=4894) (n=10 069) tuberculosis (n=6070) (n=15 638)
Number of household contacts 2·3 (1·4) NA 2·9 (1·6) NA
Age (years) 45·9 (17·1) 34·5 (18·4) 45·6 (16·6) 33·5 (19·3)
Sex
Male 3663 (74·8%) 3856 (38·3%) 4498 (74·1%) 6568 (42·0%)
Female 1231 (25·2%) 6213 (61·7%) 1572 (25·9%) 9070 (58·0%)
Current smoker 2003 (40·9%) 1259 (12·5%) 2343 (38·6%) 1830 (11·7%)
History of tuberculosis* 197 (4·0%) 268 (2·7%) 269 (4·4%) 293 (1·9%)
Setting
Urban 3380 (69·1%) 6978 (69·3%) 3981 (65·6%) 9289 (59·4%)
Rural 1514 (30·9%) 3091 (30·7%) 2089 (34·4%) 6349 (40·6%)
Region
Northern Vietnam 388 (7·9%) 711 (7·0%) 251 (4·1%) 762 (4·9%)
Central Vietnam 255 (5·2%) 631 (6·3%) 621 (10·2%) 2293 (14·7%)
Southern Vietnam 4251 (86·9%) 8727 (86·7%) 5198 (85·6%) 12 583 (80·5%)
Data are mean (SD) or n (%). NA=not applicable. *Self-reported history of tuberculosis at the time of enrolment in the study.

Table 1: Baseline characteristics

Source Unit cost Intervention (n=10 069) Control (n=15 638)

Staff and intervention costs
Physician (annual salary) Minh et al (2017)14 $5042 $34·05 $23·21
Laboratory technician (annual salary) Minh et al (2017)14 $2593 $17·51 $11·94
Nurse (annual salary) Minh et al (2017)14 $3053 $41·24 $28·11
Administration (annual salary) Minh et al (2017)14 $2135 $28·84 $19·66
Conditional cash transfer (per visit) Trial records $1 $2·83 $0·007
Diagnostic costs
Chest radiograph Minh et al (2017)14 $0·94 $2·78 $0·013
Sputum smear test Minh et al (2017)14 $0·18 $1·02 $0·002
Sputum culture test Minh et al (2017)14 $7·16 $40·53 $0·10
Transportation cost per sputum sample Trial records $4·40 $12·45 $0·03
Medication costs
Intensive and continuation phase of tuberculosis medications Minh et al (2017)14 $20·54 $0·13 $0·08
Mean costs per person ·· ·· $181·38 $83·22
Unit of currency for cost is discounted 2017 $US.

Table 2: Unit costs, sources of costs, and mean intervention and health-care use costs per person in 24 months

24 months. Each screening visit included a physical
examination, chest radiography, and a questionnaire
regarding patient symptoms administered by staff. The
management algorithm was consistent with the
Vietnam National Tuberculosis Control Programme
guidelines at the time of the trial (figure 1). Patients
identified as having presumptive tuberculosis on the
basis of history and chest radiography were requested
to submit two sputum samples for smear and
mycobacterial culture. Samples were processed in four
regional laboratories. The diagnosis of tuberculosis was
made by use of a combination of clinical, micro­
biological, and radiological criteria2,13 by staff who
worked within the Vietnam National Tuberculosis
Control Programme.
Government expenditures and health system-related
costs were included. We collected costs associated with
supplies and transportation of sputum samples to
laboratories for testing in the form of primary data from
one urban and one rural lung disease hospital. Costs
associated with district-level staff (physician, laboratory
technician, nurse, and administrative staff) salary,
screening, diagnostics (chest radiograph, sputum smear,
and sputum culture), and tuberculosis medications were
supplemented with a published standardised national
costing survey of tuberculosis diagnosis and treatment in
Vietnam.14 We ascertained the number of staff working at
each health facility through trial records. As part of the
trial and for both intervention and control groups, a
conditional cash transfer of $1 was provided to cover the

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Intervention
Disability-adjusted life-years per registered 0·391 (0·224–0·558)
tuberculosis diagnosis
Average number of registered 1788 (1246–2299)
tuberculosis contacts per 100 000 people
Average number of smear-positive 1390 (911–1875)
tuberculosis contacts per 100 000 people
Mean cost per individual screened at $181·38 (177·79–184·97) $83·22 (83·15–83·30)
24 months
Data are mean (95% CI). Unit of currency for cost is discounted 2017 $US.
Table 3: Mean outcomes, mean costs, and difference at 24 months per person for 1000 bootstrapped pairs and point estimate of incremental cost-
effectiveness ratios
cost of travel for each individual visit to the tuberculosis
clinic. Costs were presented in 2017 US$.
Outcomes
The primary outcome was the number of DALYs averted
among household contacts of patients with tuberculosis
over a 24-month period. We quantified DALYs according
to the WHO and Global Burden of Disease definition, as
the sum of the years of life lost due to premature
mortality in the population and the years lived with
disability for people living with the health condition or
its consequences (appendix).15,16 We estimated the
morbidity of registered tuberculosis with tuberculosis-
specific disability weights of 0·33 (95% CI 0·22–0·45),17
and deaths of individuals registered with tuberculosis
were recorded either in the clinic or by phone interview
with family members after the completion of follow-up.
The cause of death among household contacts of
patients with tuberculosis was assessed by verbal
autopsy, as described previously.5 Remaining life
expectancy in Vietnam was estimated using 2016 age
and sex-specific life table estimates.18 Secondary
outcomes were the number of registered cases of
tuberculosis identified and the number of smear-
positive confirmed cases.
Statistical analysis
All analyses were done with Stata SE version 14.2. We
used a discount rate of 3% per year to account for the
differential timing of costs and DALYs. We compared
total costs and DALYs between the intervention and
control participants. We calculated incremental cost-
effectiveness ratios (ICERs) to estimate the additional
expenditure required to generate an additional unit of
benefit.19 We expressed ICERs as cost per DALY averted
and cost per additional case of tuberculosis diagnosed.20
For the primary analysis only, an intervention was
considered cost-effective if the ICER per DALY averted
was less than 3 times the gross domestic product (GDP)
per capita of the country the intervention was held in,
and very cost-effective if the ICER per DALY averted
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Control Mean difference Mean incremental cost
effectiveness ratio per
additional outcome
0·571 (0·511–0·632) 0·181 (0·074–0·287) $544 (330–1375)
703 (525–889) 1084 (721–1410) $9053 (7083–12 914)
237 (136–380) 1154 (776–1495) $8507 (6622–12 254)
$98·16 (94·64–101·67) ··
was less than 1 times the GDP per capita.21 Vietnam’s
2016 GDP per capita was reported to be $2214.22
Therefore, the primary threshold for which an ICER
would be considered cost-effective is $6642 per DALY
averted.
We derived costs and DALYs from patient-level data—
to account for uncertainty around sampling methods,
we used separate linear mixed models for costs and
DALYs to account for clustering at the district and
household level. The random effects variables were
districts and index cases within districts, with
assignment to the intervention or control as a fixed See Online for appendix
effect variable. Probabilistic sensitivity analysis was
conducted using bootstrapping with replacement,
generating 1000 cost and effect pairs, and these
bootstrapped samples were plotted on an incremental
cost-effectiveness plane. We derived a cost-effectiveness
acceptability curve to capture the uncertainty around
the probability that the intervention is below the cost-
effectiveness threshold given a decision maker’s
willingness to pay for less DALYs averted.23
We did one-way sensitivity analyses on two scenarios—
salary of staff and screening and medication of tubercu­
losis—to account for uncertainty around published cost
estimates. For each scenario, we adjusted costs by 25%
(both positively and negatively) around the published
point estimate.14 We investigated a scenario in which we
increased screening costs for the control group, since
household contacts who tested negative for tuberculosis
were not captured by the primary analysis. The scenario
assumed that the control group would screen about 30%
of the total contacts screened in the intervention group
(at 6 months, 12 months, and 24 months) because of
investigations triggered by the onset of symptoms and
self-referral to the clinic. In another scenario, we
assumed patients in the control group had a delayed
diagnosis that resulted in hospitalisation. The costs for
this scenario were taken from a global systematic review
of tuberculosis-related costs.24 We assumed that 50% of
the diagnosed tuberculosis cases (that is, the difference
in number of registered tuberculosis cases between the
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Change in variable ICER per DALY ICER ICER per

averted per additional additional
registered smear-positive
tuberculosis case tuberculosis case
DALY weight associated with tuberculosis Upper 95% CI $744 ·· ··
Lower 95% CI $438 ·· ··
Staff (salary of physician, laboratory Increased by 25% $597 $9946 $9346
technician, nurse, and administrative staff) Decreased by 25% $490 $8161 $7669
Diagnosis (chest radiograph, sputum smear, Increased by 25% $605 $10 043 $9465
and sputum culture test) and medication costs Decreased by 25% $482 $8034 $7550
Diagnosis costs for control participants at Control group screen around 30% of the total $543 $9045 $8500
6 months, 12 months, and 24 months contacts screened in the intervention group
Assume 50% of treated tuberculosis 55 control participants incurred $380 in a $536 $8930 $8392
participants in the control arm required one tuberculosis-related admission to hospital
tuberculosis-related admission to hospital
Base case scenarios: $544 per DALY averted; $9053 per additional registered tuberculosis case; $8507 per additional smear-positive tuberculosis case. Unit of currency for
cost is discounted 2017 $US. ICER=incremental cost-effectiveness ratio. DALY=disability-adjusted life-year.

Table 4: Sensitivity analysis adjusting specific variables and ICERs

110 Registered tuberculosis case

group. Intervention and control participants were similar
Smear-positive tuberculosis case with regard to demographic characteristics of age, sex,
105 smoking status, and whether a patient had a history of
Incremental cost ($US)

100
95
90
85
–0·05 0 0·05 0·15 0·25 0·35 0 500 100
Additional DALY averted Additional tuberculosis case (per 100 000)
Figure 2: Incremental cost-effectiveness plane of 1000 bootstrap replications assessing the additional cost
per additional unit of effectiveness from active case finding for DALYs averted and registered and
smear-positive tuberculosis cases
DALY=disability-adjusted life-year.
intervention and control group) would go to hospital as a
result of worsening tuberculosis over time. Finally, we
adjusted the tuberculosis-specific DALY weight by the
upper and lower 95% CIs.17 We estimated an ICER for
each sensitivity analysis.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of
the report. The corresponding author had full access to
all the data in the study and had final responsibility for
the decision to submit for publication.
Results
Between Aug 11, 2010, and Aug 11, 2015, 10 964 index
patients and 25 707 household contacts completed the
ACT2 study. There were 10 069 household contacts in the
intervention group and 15 638 household contacts in
the control group. Participants’ baseline characteristics
are shown in table 1. There were a mean 2·9 contacts
per household (excluding the index patient) in the control
group and 2·3 contacts per household in the intervention
tuberculosis.
We investigated the unit costs of staff, medication, and
diagnostics, and the conditional cash transfer (table 2). The
major cost of the intervention was attributed to increased
diagnostic costs, with 28 496 diagnostic tests recorded as
being done for investigation of presumptive tuberculosis
1500 2000 over the 24-month period. This amounted to an average
diagnostic cost of US$56·78 in the inter­ vention arm,
with an additional cash transfer of $2·83 per person.
By contrast, average diagnostic costs in the control group
were around $0·15 per person. When we included all
costs, the mean costs per person were $181·38 (95% CI
177·79–184·97) for the intervention group and $83·22
(83·15–83·30) for the control group (p<0·0001).
We investigated the point estimate and bootstrapped
estimates of incremental cost and incremental benefit
of the intervention (table 3). The additional number
of registered tuberculosis contacts identified over a
24-month period was 1084 per 100 000 people (95% CI
721–1410) and the additional number of smear-positive
tuberculosis contacts identified was 1154 per 100 000 people
(776–1495) in the intervention group compared with the
control group. The estimated ICER per DALY averted was
$544 (330–1375). The mean ICER was $9053 (7083–12 914)
per additional registered tuberculosis case and $8507
(6622–12 254) per additional smear-positive tuberculosis
case over a 24-month period.
Our sensitivity analysis presents ICERs by varying the
assumptions of different variables (table 4). The ICERs
were fairly robust to change, suggesting parameter
uncertainty had a minor effect on the cost-effectiveness
results. Use of the upper and lower 95% CI values for
tuberculosis-specific DALY weights resulted in the
largest changes, with ICERs per DALY averted ranging
from $438 to $744. Intervention-specific changes

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(staff salaries, diagnostic costs, and screening costs)
resulted in small changes to the ICER, ranging from
$482 to $605 per DALY averted. A similar robustness to
change was found when registered and smear-positive
tuberculosis cases were used as the outcome, with
ICERs ranging from $8034 to $10 043 and $7550 to $9465,
respectively.
We produced cost-effectiveness planes and cost-
effectiveness acceptability curves of the 1000 bootstrapped
estimates (figures 2, 3; appendix). Bootstrapped estimates
for all three outcomes showed active case finding in
household contacts costed more and was more effective
compared with usual care (passive case finding). Active
case finding in household contacts was shown to be very
cost-effective, with more than 93·6% of bootstrapped
ICERs deemed cost-effective at an acceptability threshold
of $1000 per DALY averted, well below the cost-
effectiveness threshold of $6642 per DALY averted.
Discussion
To our knowledge, this is the first cost-effectiveness
analysis of active case finding of household contacts
of patients with tuberculosis within a randomised
controlled trial. We have shown that active case finding
is highly cost-effective in Vietnam, with an estimated
ICER of $544 (95% CI 330–1375) per DALY averted, well
below the pre-defined threshold of $6642, or 3 times the
GDP per capita. Our sensitivity analysis showed that
the cost-effectiveness results are robust to uncertainty
around the parameters included in the analysis. In
eight different scenarios, the ICERs ranged from
$438 to $744 per DALY averted and $7550 to $10 043
per additional tuberculosis case registered. Similarly,
our probabilistic sensitivity analysis consistently showed
that active case finding intervention was more effective
but also more costly.
A major strength of our study is that it was based
on data from a cluster-randomised trial, ensuring an
unbiased estimate of the number of registered tubercu­
losis cases in a high-prevalence setting, which is
supported by our findings that the demographics of
intervention and control group participants were very
similar. To our knowledge, ACT2 is the largest and
longest trial of active case finding within households to
date, recruiting over 25 000 household contacts of patients
with tuberculosis and following them up for over
24 months. Our within-trial findings over a 24-month
period corroborate the findings of other studies in LMICs
(China, India, and South Africa),8 which have found that
active case finding is extremely cost-effective from the
health system perspective. However, a key difference is
that previous cost-effectiveness studies of active case
finding modelled long-term costs and outcomes on the
basis of effect estimates derived from observational data.25
The fact that our findings are based on robust randomised
trial evidence means that core concerns about the pre-
existing cost-effectiveness evidence have been addressed,
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100
Probability active case funding vs cost-effective (%)
50
0
0 1000 2000 3000 4000 5000 6000 7000
Willingness to pay per DALY averted ($US)
Figure 3: Probability that active case finding is cost-effective at different
willingness to pay thresholds for each DALY averted
DALY=disability-adjusted life-year.
substantially strengthening the investment case for
household contact investigation for tuberculosis.
Our cost-effectiveness estimates are conservative
because of several assumptions made in the analysis.
First, the primary analysis only included diagnostic costs
of those who were registered tuberculosis cases in the
control group. Costs associated with individuals in the
control arm who attended a clinic and negatively tested
for the presence of tuberculosis were not included, as this
was not captured by the trial. For both groups, additional
health-care use (medical services, admissions to hospital,
and additional pharmaceutical treatments) from delayed
diagnosis and treatment of tuberculosis was not captured
and therefore excluded from the analysis. Second, we did
not account for secondary transmission of tuberculosis.
Earlier case detection has been shown to limit the spread
of disease to others in the community26 and reduce the
prevalence of tuberculosis in the general community.27,28
We focused only on household contacts of patients with
tuberculosis; however, it is likely that the intervention
had a wider epidemiological impact in reduction of
transmission to other community members due to early
treatment of tuberculosis among contacts. Finally, a
longer timeframe would potentially yield a higher
number of tuberculosis cases because of the development
of the disease occurring at a later stage.11 Azman and
colleagues8 found that modelling the short-term effects of
an active case finding intervention over 2 years would
dramatically under-​estimate potential longer-term gains
and cost-effectiveness compared with a 10-year period.
The policy implications of the findings of this study are
substantial. This trial used a pragmatic intervention that
was built into the Vietnam National Tuberculosis Control
Programme, with very few additional resources required
in terms of training and staff. Changing to an active
case finding strategy would yield a higher number of
tuberculosis cases, reduce the overall burden of the
disease, and potentially prevent further transmission in
 Articles
the community. However, a large number of diagnostic
and screening tests were required to achieve these goals.
The increases in diagnostic and medication costs have
implications for the ability of the Vietnam National
Tuberculosis Control Programme to supply and provide
adequate health-care resources to deal with the increased
demand of services, particularly in rural and remote
communities. The challenge in future would be
allocation of additional resources to expand active case
finding into the national programme and to compare the
cost-effectiveness of this programme with other non-
tuberculosis-related interventions across the health
sector, ensuring value for money. Reforms to Vietnamese
Social Health Insurance provide a potential funding
mechanism for expanding active case finding among
high-risk populations, which has been achieved for other
infectious diseases.29
A limitation of this study was the use of published
cost estimates from Vietnam to inform the cost-
effectiveness analysis, as costs were not captured as
part of this trial. However, the cost estimates were
based on recent data14 collected by the Vietnam National
Tuberculosis Control Programme in the same setting
and at a similar time to when the study was conducted.
As these data were collected using standardised
methods and included context-specific costs of staff,
diagnostics, and medi­cation,14 it is closely applicable to
the study population in the ACT2 trial. A second
limitation is that participants who were treated for
tuberculosis outside the government system were not
recorded. Thus, the number of cases identified is likely
to be an underestimate. Third, we did not evaluate the
effect of treatment on latent tuberculosis infection, as
the treatment was not widely available in Vietnam at
the time of the study. Given the high proportion of
notified cases occurring after baseline screening,
addition of preventive therapy would probably reduce
the proportion of household contacts of patients with
tuberculosis developing incident disease. Further
studies are required to evaluate the cost-effectiveness of
interventions to combine preventive therapy with active
case finding in this setting. Finally, treatment for multi-
drug resistant tuberculosis was not included in the
analysis, as this information was not captured in the
control arm.
The ACT2 trial found an increase in tuberculosis cases
detected over a 24-month period with active and passive
case finding compared with passive case finding alone.
Our present analysis showed that when accounting for
the effect on morbidity and all-cause mortality in the
form of DALYs averted, active case finding was very cost-
effective. Further research is required to understand the
association between early case detection of tuberculosis
and its effect on health-care use beyond a trial setting,
and to estimate long-term economic implications for the
health-care system of rolling out an expanded active
case finding programme. Nevertheless, the findings
e383 www.thelancet.com/lancetgh Vol 7 March 2019
from this study indicate that active case finding can
be cost-effectively integrated into existing tuberculosis
programmes in Vietnam. There is a strong economic
case for rolling out active case finding across Vietnam
and other comparable settings with a high burden of
tuberculosis.
Contributors
TL did the analysis and drafted the manuscript. JB prepared the data.
SJ and TL conceived the study. GJF and SJ provided guidance on the
analyses. GJF, GBM, SJ, and TL provided crucial review and assessment
of cost-effectiveness outcomes. All authors contributed to revision of the
manuscript.
Declaration of interests
We declare no competing interests.
Acknowledgments
This project was supported by an Australian National Health and
Medical Research Council (NHMRC) project grant (grant no
APP632781). TL is supported by a NHMRC Early Career Fellowship
and National Heart Foundation Postdoctoral Fellowship (NHMRC
grant no APP1141392). GJF was supported by a NHMRC Postgraduate
Award (grant no APP57122) and CJ Martin Postdoctoral Fellowship
(NHMRC grant no APP1054107). JB was supported by a post-doctoral
fellowship supported by the Tuberculosis Centre for Research
Excellence (NHMRC grant no APP1043225). SJ is supported by an
NHMRC Principal Research Fellowship (NHMRC grant no
APP1119443).
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