Short-term Impact of Mass Drug Administration With Dihydroartemisinin Plus Piperaquine on Malaria in Southern Province Zambia: A Cluster-Randomized Controlled Trial
Short-term Impact of Mass Drug Administration With Dihydroartemisinin Plus Piperaquine on Malaria in Southern Province Zambia: A Cluster-Randomized Controlled Trial
Thomas P. Eisele 2
Adam Bennett 1
Kafula Silumbe 6
Timothy P. Finn 2
Victor Chalwe 5
Mulakwa Kamuliwo 4
Busiku Hamainza 4
Hawela Moonga 4
Emmanuel Kooma 3
Elizabeth Chizema Kawesha 4
Joshua Yukich 2
Joseph Keating 2
Travis Porter 2
Ruben O. Conner 0
Duncan Earle 6
Richard W. Steketee 0
John M. Miller 6
0 PATH-MACEPA, Seattle , Washington
1 Malaria Elimination Initiative, Global Health Group, University of California San Francisco
2 Center for Applied Malaria Research and Evaluation, Department of Tropical Medicine, Tulane University School of Public Health and Tropical Medicine , New Orleans, Louisiana
3 Zambia Ministry of Health , Southern Provincial Health Office, Choma
4 National Malaria Control Centre, Zambia Ministry of Health, Chainama Hospital , Lusaka
5 Institute for Medical Research and Training, University Teaching Hospital
6 PATH-Malaria Control and Elimination Partnership in Africa (MACEPA), National Malaria Control Centre, Chainama Hospital College Grounds
Background. Mass drug administration (MDA) using dihydroartemisinin plus piperaquine (DHAp) represents a potential strategy to clear Plasmodium falciparum infections and reduce the human parasite reservoir. Methods. A cluster-randomized controlled trial in Southern Province, Zambia, was used to assess the short-term impact of 2 rounds of community-wide MDA and household-level ( focal) MDA with DHAp compared with no mass treatment. Study end points included parasite prevalence in children, infection incidence, and confirmed malaria case incidence. Results. All end points significantly decreased after intervention, irrespective of treatment group. Parasite prevalence from 7.71% at baseline to 0.54% after MDA in lower-transmission areas, resulting in an 87% reduction compared with control (adjusted odds ratio, 0.13; 95% confidence interval, .02-.92; P = .04). No difference between treatment groups was observed in areas of high transmission. The 5-month cumulative infection incidence was 70% lower (crude incidence rate ratio, 0.30; 95% confidence interval, .061.49; P = .14) and 58% lower (0.42; .18-.98; P = .046) after MDA compared with control in lower- and higher-transmission areas, respectively. No significant impact of focal MDA was observed for any end point. Conclusions. Two rounds of MDA with DHAp rapidly reduced infection prevalence, infection incidence, and confirmed case incidence rates, especially in low-transmission areas. Clinical Trials Registration. NCT02329301.
Mass testing and treatment interventions, wherein individuals
are tested with a rapid diagnostic test (RDT) and treated if results
are positive, have had limited impact on malaria in Southern
Zambia and elsewhere [3–7], primarily because RDTs miss
many low-density parasite infections [8–10]. When combined
with universal coverage of vector control, good access to case
management and strong surveillance, mass drug administration
(MDA) (ie, where everyone in a target area is treated with a
longacting antimalarial, such as dihydroartemisinin plus piperaquine
[DHAp] [11–14]) may be a potential strategy to shorten Zambia’s
timeline toward elimination. Focal MDA (fMDA) is similar but
provides presumptive treatment to household members only
when ≥1 resident is confirmed positive by RDT.
The primary goal of using 2 rounds of MDA or fMDA with
DHAp in Zambia is to reduce the malaria parasite infection
prevalence and incidence to preelimination levels during peak
transmission in low-transmission areas  and to halve
prevalence and incidence in high-transmission areas. It is then
anticipated that such gains can be sustained by strong surveillance,
community case management, and universal coverage of vector
control. In this context, we present results from a trial aimed at
quantifying the relative effectiveness of 2 rounds of MDA and
fMDA with DHAp, against no mass treatment, for reducing
malaria infection prevalence and incidence in Southern
Province, Zambia. The follow-up period presented here is for 5
months during the high-transmission season after the first
mass treatment round. Although additional mass treatment
rounds and longer-term follow-up are ongoing, measures of
short-term impact of the first 2 rounds are important to ensure
these strategies can significantly reduce malaria in this context.
If impact is shown, less aggressive strategies could be used to
sustain the gains in the longer term, with the goal of eventual
elimination from this area.
The full protocol for this trial has been published elsewhere
. Ethical approval was obtained from Tulane University,
Western Institutional Review Board, the University of Zambia,
and the Zambia Medicines Regulatory Authority. Informed
consent was obtained from all enrolled subjects. Written
informed consent (or assent for those ≥6 and <18 years old)
was obtained from each participant before enrollment.
Study Design and Participants
A cluster-randomized controlled trial (CRCT) was used to
evaluate the impact of the mass treatment interventions on study
end points. The trial area was stratified into higher- and
lower-transmission strata above and below 10% parasite
prevalence at randomization. The study was conducted in Southern
Province, Zambia along Lake Kariba in 60 health facility
catchment areas (HFCAs) in 10 districts (Figure 1). The entire study
area was enumerated by a geographic information system in
2013 and 2014 using personal digital assistants. Approximately
330 000 individuals in 56 000 households, primarily of the
Tonga ethnic group, live in this area. Malaria parasite
prevalence in children ranges from <1% in areas inland from the
lake to >25% in areas closer to the lake. The season for high
malaria transmission lasts from January to May, coinciding with
HFCAs served as the unit of randomization (Figure 2). After
stratification by transmission and HFCA population size, 60
HFCAs were randomly assigned to the MDA, fMDA, or control
group using the random allocation rule, resulting in 10 HFCAs
per transmission stratum in MDA, fMDA, and control groups.
Allocation of intervention could not be blinded.
The entire study area received the standard of care in Zambia
irrespective of treatment group, which consists of diagnosing
all suspected cases presenting to the health system with either
an RDT or microscopy and treating all individuals with positive
results with the first-line drug artemether-lumefantrine (AL)
. Household coverage rates for long-lasting
insecticidetreated nets and indoor residual spraying were 85% and 30%,
respectively, in the study area. Since 2014, Zambia has scaled
up community diagnosis and case management in Southern
Province, including reactive case detection in areas with
manageable case counts, representing an enhanced standard of
care across the entire study site.
DHAp (Eurartesim; Sigma-Tau) was used presumptively to
treat Plasmodium falciparum infections during the mass
treatment rounds. All individuals meeting the inclusion criteria to
receive DHAp were offered an age-appropriate 3-day course
of DHAp based on manufacturer’s recommendations and
national treatment guidelines . The first and last courses
were given as directly observed therapy by the study team.
All individuals in intervention clusters were tested for
parasite infections using an RDT (SD Bioline Malaria Antigen P.f
test for detecting histidine-rich protein 2 antigen) during each
of the 2 house-to-house mass treatment rounds. MDA consisted
of offering all eligible individuals DHAp, irrespective of RDT
result (Supplementary Figure 1). fMDA consisted of offering
DHAp to all eligible individuals who resided in a household
where anyone tested positive by RDT (Supplementary Figure 2).
The control group received the standard of care, described
above, but did not receive any mass treatment intervention.
Children <3 months old and pregnant women in their first
trimester were excluded from receiving DHAp, according to
the manufacturer’s recommendations; they were instead offered
the appropriate dose of antimalarial treatment according
to Zambian national policy if RDT positive (Supplementary
Figures 1 and 2). All individuals with suspected severe malaria
or other severe illness were referred to the nearest health facility
and omitted from the study.
Study End Points
The primary end point was malaria parasite infection
prevalence among children ≥3 months to <6 years old, defined as
the proportion of children with a malaria parasite infection
by RDT. Secondary end points included the cumulative
infection incidence rate among all persons ≥3 months old (No. of
RDT parasite infections in a prospective cohort divided by
total time of exposure during 5-month follow-up [January–
May 2015]), and the confirmed malaria case incidence rate
(No. of outpatient laboratory-confirmed malaria cases for all
ages per 1000 population per year).
Malaria Parasite Infection Prevalence
Malaria parasite infection prevalence in children was measured
by a simple random sample of households during the
hightransmission season (April–May) before the mass treatment
rounds in 2014 (baseline) and again after the mass treatment
rounds in 2015 (follow-up). A sample size of 2820 children at
each survey round was required to detect a 50% reduction in
infection prevalence with 80% power taking into account the
cluster randomization, as described elsewhere . RDTs and
microscopy were used to assess the malaria parasite infection
status among included children. RDT-positive children were
treated with AL, according to national guidelines .
Cumulative Infection Incidence
The cumulative infection incidence rate was measured in
individuals enrolled in a prospective cohort followed from
December 2014 through the end of May 2015 (Supplementary
Figure 3). A target sample size of 2250 individuals was sought
to detect a 50% reduction in infection incidence between either
mass treatment group and control, with 80% statistical power
taking into account the cluster randomization, as described
elsewhere . Cohort participants were drawn from a simple
random sample within each HFCA (39 persons within 13
households in each HFCA). The start of the cohort coincided
with round 1 of the mass treatment interventions. Individuals
enrolled from MDA and fMDA HFCAs received those
interventions; all RDT-positive individuals in the control group
were cleared of their malaria parasite infection at enrollment
using AL . All individuals in the cohort were followed up
monthly with RDTs and microscopy. All RDT-positive
individuals at monthly follow-up visits were treated with AL, except
during the second mass treatment round for those in MDA
and fMDA groups.
Confirmed Malaria Case Incidence
Routine data from the health management information system
on monthly laboratory-confirmed outpatient malaria cases were
ascertained from all 60 healthcare facilities in the study area
from January 2011 onward. Confirmed case counts were
standardized by the estimated midyear populations of each HFCA
to obtain the incidence per 1000 population.
The CRCT study design was accounted for by including the
cluster (HFCA) as a random effect in all analyses. All analyses
were intention-to-treat analyses wherein all individuals were
assumed to receive the treatment assigned to their HFCA at
randomization. The treatment effect between the MDA/fMDA and
control group for malaria infection prevalence in children was
estimated for the 2015 follow-up ( posttest) survey time point,
using a crude odds ratio (OR) in a bivariate logistic regression
model. A secondary model, defined a priori, adjusted for child
age (in years), sex, household wealth, rainfall, the enhanced
vegetation index, household elevation, and household
protection vector control.
Crude incidence rate ratios (IRRs) were used to estimate the
treatment effect of the MDA/fMDA on the cumulative infection
incidence, compared with the control group, using a negative
binomial model. Individuals present at enrollment that
completed ≥3 months of follow-up were included in the analysis.
The treatment effect of MDA/fMDA on the confirmed
malaria case incidence, compared with the control group, was
estimated using a negative binomial model, standardized by
midyear HFCA population. The model controlled for previous
month’s cases, calendar month, and anomalies in monthly
rainfall and enhanced vegetation index. The baseline
preintervention period was January–May 2013 and January–May 2014,
and the follow-up postintervention period was January–May
2015. Because there were significant differences across
treatment groups in the monthly confirmed malaria case incidence
during the baseline period, a difference-in-differences model
was used to account for baseline differences.
Rounds 1 and 2 of the MDA and fMDA were successfully
implemented in December 2014 and February–March 2015,
respectively. Based on the 2015 follow-up survey, household
coverage by MDA teams was 88.1% and 72.0% for rounds 1
and 2, respectively, and 62.5% and 54.0% for fMDA,
respectively (Supplementary Table 1). The rate of adherence to a full
course of DHAp was >85%, and the rate of refusal to partake
in the study was very low across treatment rounds at <1%.
Monthly total rainfall amounts during the study period were
similar between treatment groups (see Supplementary Figures 4
Malaria Infection Prevalence
The baseline parasite survey conducted from April–May 2014
before the mass treatment interventions showed child infection
prevalence, child and household demographics, treatment
seeking for fevers, intervention coverage, and climate to be similar
across treatment groups (Tables 1 and 2). There were significant
declines in infection prevalence after the mass treatment rounds
(follow-up survey conducted April–May 2015), irrespective of
treatment group, transmission stratum, or diagnostic method
(Table 2 and Supplementary Table 2). The largest proportional
decline was observed among children in the MDA group in the
lower-transmission setting, in whom infection prevalence
decreased from 7.71% (42 infections among 545 children) at
baseline to 0.54% (2 infections among 372 children) after MDA
(93% decline). This represents a marginally significant relative
reduction of 81% in the crude OR for having an infection
compared with the control group (crude OR, 0.19; 95% confidence
interval [CI], .29–1.28; P = .09), and a statistically significant
87% relative reduction (adjusted OR, 0.13; 95% CI, .02–.92;
P = .04) after accounting for confounding factors. No other
significant differences were observed.
Cumulative Infection Incidence
A total of 2138 individuals were enrolled into the cohort from 1
December 2014 to 16 January 2015 and followed up through 13
June 2015 (Figure 2 and Supplementary Figure 3). A total of
1834 individuals completed ≥3 months of follow-up and were
included in the cohort analysis, resulting in a loss-to-follow-up
rate of 14.22%. Data among individuals enrolled but with <3
months of follow-up (lost to follow-up) showed them to be
similar in age and baseline parasite prevalence; individuals lost to
follow-up in the control group were younger than either mass
treatment group, and more were male. During the 5-month
follow-up period after round 1 of the mass treatment intervention
in the lower-transmission stratum, individuals receiving MDA
had a cumulative infection incidence of 3.44 per 1000
personmonths (95% CI, .94–8.81) compared with 18.71 (11.72–28.32)
in control areas, representing a nonsignificant relative reduction
of 70% (crude IRR, 0.30; 95% CI, .06–1.49; P = .14) (Table 3). In
the higher-transmission stratum, individuals receiving MDA
had a cumulative infection incidence of 35.69 per 1000
person-months (95% CI, 26.89–46.46) compared with 91.27
(76.63–107.90) in control areas, representing a significant
relative reduction of 58% (crude IRR, 0.42; 95% CI, .18–.98;
P = .046). No other significant differences were observed.
Confirmed Malaria Case Incidence
Large declines in the monthly confirmed malaria case incidence
rates were observed after the mass treatment rounds, including
in the control group (Table 4). Among HFCAs in
lowertransmission areas, the monthly confirmed case incidence
declined >3-fold after 2 rounds of MDA, from 7.45 to 2.23 cases
per 1000 HFCA population, representing a significantly (50%)
larger decline than observed in the control group
(difference-indifferences IRR, 0.50; 95% CI, .35–.72; P < .01). No other
significant differences were observed.
Age of children included for parasite testing, %
3 mo to <6 y
Sex of children included for parasite testing, % male
Children with fever in the past 2 wk taken for treatment at a
public or private provider, %
Children included for parasite testing by household wealth
5 (least poor)
Households with ≥1 LLIN, %
Households with IRS in past 12 mo, %a
Total rainfall for February–March 2014, mm
EVI for February–March 2014
Mean Value (95% CI)
MDA (1047 Children/857
fMDA (985 Children/850
Control (976 Children/866
We evaluated the short-term impact of 2 rounds of MDA or
fMDA with DHAp against a control of no mass treatment in
Southern Province, Zambia, in the context of strong prevention
and surveillance efforts. To our knowledge this is the first CRCT
assessing the impact of mass treatment interventions with
DHAp in an African setting.
Large declines in study end points were observed in both
intervention and control areas. Despite this, results during the
first 5 months of the trial show 2 rounds of MDA with
DHAp to have substantial impact on study end points in this
setting. In areas of lower transmission, MDA was shown to
reduce peak season child parasite infection prevalence from 8%
before to <1% after MDA (87% decline). Individuals receiving
MDA experienced a 3-fold decrease in cumulative infection
incidence in lower-transmission areas (nonsignificant) and a
significant 2-fold decrease in higher-transmission areas. These
results are supported by monthly confirmed case incidence
data derived from the health management information system.
Results from the trial were largely consistent across study end
with no results reaching statistical significance. Second, across
all study end points, the effect size of 2 rounds of MDA was
larger in lower-transmission than in higher-transmission areas.
It is likely that RDTs used during fMDA for treatment
decisions still missed a substantial proportion of individuals with
low-density parasite infections [9, 10]. Furthermore, by design,
fMDA communities received only one-third of the total DHAp
two-thirds of individuals in these areas without
chemoprophypatent infections. New HRP2 RDTs with much higher
sensitivity to identify low-density infections are under
development; these may render fMDA and mass testing and treatment
strategies more effective in the future.
Although we identified many reports describing the short-term
success of MDA campaigns under program settings [11, 12, 18–
24], we identified only 2 randomized trials that assessed the
impact of MDA in the African setting. Both studies evaluated MDA
a significant impact on malaria health outcomes in the short term
setting, are consistent with mathematical modeling showing
MDA-DHAp with the potential to significantly reduce malaria
transmission to the point of interrupting it . Our results
show MDA-DHAp to have a much larger impact on malaria
inand treatment interventions with RDTs and AL [3–7], which is
We observed large decreases in malaria infection prevalence
in children (by 73%) and confirmed malaria case incidence
Treatment Group Lower-transmission stratum MDA fMDA
Positive Results, No.
Cumulative IR/1000 Person-Months (95% CI)
Crude IRR vs Control (95% CI)
(by 43%) in control areas that coincided with mass treatment
implemented in neighboring intervention areas. As a result,
the expected detectable differences in these end points for
comparing the mass treatment interventions to control was much
lower than expected, resulting in lower statistical power than
expected to detect significant differences . It is unclear why
such large declines in control areas occurred, but there are
several potential explanations. First, mean monthly cumulative
rainfall (117.5 mm) was lower during the rainy season just
after the mass treatment rounds (January–April 2015) than
during the previous rainy season in 2014 (137.3 mm), before the
mass treatment rounds (Supplementary Figure 4). However,
the rainfall in 2015 was very similar to that in 2012 (120.5
mm) before a parasite survey in the study area (conducted
April–May) that showed malaria infection prevalence in
children to be 35.6% , compared with an overall 7.9% in the
parasite survey in 2015 (across lower- and higher-transmission
areas). Although the decrease in rainfall probably played a
role in the malaria decline in control areas between 2014 and
2015, it does not seem to fully explain it. We argue that, at
least in part, the very high vector control coverage, strong
surveillance, community diagnosis and case management, and
reactive case detection across the study area may have played a
role in the decline in malaria in control clusters.
Results of this trial should be interpreted in light of several
limitations. First, the follow-up period of 5 months is
insufficient to assess long-term trends in the malaria burden after
mass treatment. However, the short follow-up period does
allow measurement of short-term impact of mass treatment at
driving the malaria burden down to preelimination levels. Two
additional rounds of MDA and fMDA with DHAp were
conducted in October 2015 and February 2016; we are continuing
to collect data on primary end points and will report
longerterm results once available. Second, because of the relatively
small number of clusters (10 HFCAs in each treatment group
in each transmission stratum), there was the potential for
imbalance across treatment groups. However, all analyses of study end
points also included models with potential confounders,
Monthly Confirmed Malaria Case Incidence, Cases/1000
(January–May 2013 and 2014)
Treatment Group Lower-transmission stratum MDA fMDA
Reference 2.23 7.78 6.08
Difference-in-Differences IRR (95% CI)
stipulated a priori in the protocol . It should be noted that
effect estimates between crude and adjusted models were very
similar, suggest that important confounding factors were
balanced across treatment groups.
Third, we performed an intention-to-treat analysis;
misclassification of the true exposure between MDA, fMDA, and
control households owing to contamination across HFCA borders
was possible. To mitigate misclassification and contamination,
households within a 3-km buffer of HFCA boarders were
excluded from the sampling frame for malaria parasite
prevalence and cumulative infection incidence. Misclassification
of HFCA into lower- and higher-transmission strata above
and below 10% parasite prevalence was also possible. Fourth,
the cumulative infection incidence analysis used RDTs.
Although slides were collected and read for the cohort, positivity
among slides was only a fraction of RDT positivity, probably a
result of poor slide preparation among the 16 000 samples
collected in the field. It is possible that RDTs were prone to yield
more false-positive results than slides , especially in areas
of low transmission. However, it is unlikely there were
systematic differences in RDT false-positivity across treatment
groups, so any bias would be limited. Finally, the follow-up
survey was used to estimate household coverage of MDA
and fMDA rounds based on respondent recall. It is
hypothesized the much lower coverage of fMDA may have resulted
from poorer recall, because treatment with DHAp in fMDA
areas was only a fraction of that given during MDA. However,
low coverage of the fMDA may have contributed to the
observed lower impact compared with MDA.
Although there is no clear evidence linking MDA to
antimalarial drug resistance , the potential exists for its
development against component compounds of DHAp, especially
when MDA is conducted at scale under routine program
conditions. We used DHAp, the alternate first-line drug for
uncomplicated malaria in Zambia, in part to mitigate resistance against
the first line treatment AL . We continue to monitor
molecular markers of drug resistance and will report our findings
In conclusion, 2 rounds of MDA had a substantial impact on
malaria infection prevalence, cumulative infection incidence,
and confirmed case incidence rates, especially in
lowertransmission areas. It is important to highlight that the trial
was conducted in an area of very high vector control, good
surveillance, and improved access to case management, which we
argue are prerequisite to implementing any MDA strategy in
similar settings. In lower-transmission areas, infection
prevalence among children during the peak transmission season
went down to <1%, suggesting that transmission was reduced
to a point where elimination may be possible. If these gains
can be sustained by continued universal vector control coverage,
strong surveillance, and case management, it may be possible to
eliminate malaria from this area of Zambia.
Supplementary materials are available at http://jid.oxfordjournals.org.
Consisting of data provided by the author to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the author, so
questions or comments should be addressed to the author.
Acknowledgments. We express our gratitude to the study respondents
in Southern Province for participating in this study, and to the Zambia
Ministry of Health at all levels. At the Provincial Health Office, we are
especially grateful for the support of Jelita Chinyonga, the provincial medical
officer, and her staff for moving this effort forward. We would like to
acknowledge Chris Lungu, Muleba Matafwali, Kedrick Katonga, Sosenna
Assefa, Juliana Ngalande, Hazel Chabala, and Elisabeth Wilhem for their
enduring support during study implementation. We also acknowledge
the support of Conceptor Mulube, Brenda Mambwe, Rachel Kasaro and
Mirriam Chibalabala for their support in laboratory sample management
and analyses. Finally, we thank the Bill & Melinda Gates Foundation for
their financial support.
Author contributions. T. P. E., A. B., T. P. F., J. Y., J. K., R. W. S., and
J. M. M. conceived the study aims, research questions, study design, and
statistical analysis plan. T. P. E. led the drafting of the manuscript, with input
from all coauthors. A. B., T. P. F., J. Y., T. P., and T. P. E. performed the
statistical analyses. K. S., T. P. F., V. C., M. K., B. H., E. K., E. C. K., T. P., R. O. C.,
D. E., and J. M. M. helped lead the implementation of the study and data
collection. All authors read and approved the final manuscript.
Disclaimer. The Bill & Melinda Gates Foundation source had no role in
the conduct, analysis, or interpretation of results.
Financial support. This study was funded by the Bill & Melinda Gates
Potential conflicts of interest. All authors: No potential conflicts of
interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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