Mpac Sept2015 Erg Mda Report
Mpac Sept2015 Erg Mda Report
Mpac Sept2015 Erg Mda Report
Summary
Mass drug administration (MDA) has received renewed interest over the past decade in the
context of malaria elimination, as part of multidrug resistance containment and (more recently)
in emergency situations such as the West African Ebola outbreak. To develop WHO
recommendations, a group of experts met in April 2015 to review recent evidence on the use of
MDA, mass screening and treatment (MSAT) and focal screening and treatment (FSAT) in
specific epidemiological settings.
The following recommendations were proposed by the WHO evidence review group, for
consideration by the WHO Malaria Policy Advisory Committee.
Proposed recommendations
This document was prepared as a pre-read for the meeting of the Malaria Policy Advisory Committee and is not an official
document of the World Health Organization.
WHO/HTM/GMP/MPAC/2015.9
1 Background
Mass drug administration (MDA) refers to mass treatment of all, or a section of, the population,
whether or not symptoms are present. MDA has been implemented by national malaria control
programmes (NMCPs) in the past as a way to control epidemics, or to reduce or interrupt
transmission, and has generally been used in conjunction with indoor residual spraying (IRS).
Based on a review of the results of 19 MDA projects during the period 1932–1999 (1), and a
technical consultation held in 2003 (2), WHO concluded that there was little evidence that MDA
is effective in reducing transmission, although in some cases a reduction in parasite prevalence
and a transient reduction in mortality and morbidity were documented. Therefore, WHO
recommended mass treatment of symptomatic patients for epidemic and complex emergency
situations, combined with an active search for febrile patients, to ensure that as many cases as
possible are treated.
Over the past decade, MDA has received renewed interest, both in the context of malaria
elimination initiatives, and as part of efforts to contain multidrug resistance. In 2010, a WHO
consultation reviewed the potential role of MDA to eliminate multidrug resistance in the
Greater Mekong subregion (GMS), based on evidence of the impact of existing interventions,
and operational and modelling considerations (3). The consultation recommended immediate
planning of a pilot MDA operation in western Cambodia or eastern Thailand, and the collection
of essential information on the safety and efficacy of candidate drugs for MDA.
The 2010 consultation also reviewed the potential role of mass screening and treatment
(MSAT), in which all the people in a broad geographical area are screened, regardless of
whether they have symptoms of malaria. MSAT generates important information on the
epidemiology of malaria, which can be useful for further containment efforts. However, this
approach is resource intensive and logistically challenging, especially in view of the lack of field-
ready, high-throughput, diagnostic tests that are sensitive enough to detect submicroscopic
parasites. When applied in a defined geographical area (sometimes households), the strategy is
defined as focal screening and treatment (FSAT), in which everyone is screened, and treatment
is provided for those who test positive. FSAT is operationally more feasible than MSAT, but is
not delivered simultaneously in the whole of an area sustaining malaria transmission; hence, it
is unlikely to contribute significantly to elimination efforts. In 2010, WHO experts concluded
that the contribution of MSAT and FSAT in reducing transmission needs to be confirmed (3).
Abbreviations
2.2 Objectives
Specific objectives of the ERG were to:
1. Review all available published and unpublished reports on the impact of MDA, MSAT
and FSAT on malaria transmission, building on the recent Cochrane review (4), and a
recent qualitative review (5).
2. Review the results of experiences and unpublished studies of large-scale
implementation of MDA in Comoros, Sierra Leone, the Myanmar–Thai border, Vanuatu
and Viet Nam; and of MSAT and FSAT in Cambodia, Kenya, Zambia and Zanzibar.
3. Evaluate the role of the concomitant administration of single low-dose primaquine (PQ)
(0.25 mg base/kg) as a gametocytocide of Plasmodium falciparum, together with the
artemisinin-based combination therapy (ACT) deployed for MDA.
4. Define the specific conditions for application of MDA, MSAT and FSAT to reduce malaria
transmission in terms of endemicity, medicines and dosages, use of diagnostics, timings
and number of MDA rounds, concomitant implementation of vector-control measures,
best strategies to ensure community uptake and pharmacovigilance (PV).
2.3 Process
Data are presented under the following topics:
1. Cochrane systematic literature review and qualitative reviews on the use of MDA for
malaria.
2. Lessons learnt from successful use of MDA for elimination of onchocerciasis and
lymphatic filariasis.
3. Use of MDA in the context of complex emergencies.
4. Field application of MDA for malaria elimination in island and mainland settings.
5. Mass PQ prophylactic treatment (MPPT) for P. vivax elimination.
6. Field application of MSAT and FSAT for reducing malaria transmission in low-to-
moderate-transmission settings.
7. Operational aspects of MDA, MSTA and FSAT implementation.
3 Evidence reviewed
3.1 Systematic review of MDA for malaria
A comprehensive systematic literature review was performed to assess the impact of
antimalarial MDA in previously published studies (4). Thirty-two studies from Africa, Asia,
Oceania, and Central and South America met the required eligibility criteria for the review.
Those criteria were controlled studies comparing direct MDA to a control or placebo group, or
uncontrolled before-and-after studies that administered a full treatment course and reported
on one parasitological outcome. Most studies were undertaken during the eradication era, and
therefore used monotherapy drug regimens; only three trials deployed ACTs. The 32 studies
were of various designs:
eight were non-randomized control studies
22 were uncontrolled before-and-after studies
two were cluster randomized trials (CRTs).
In addition, 10 studies included a vector-control component. The targeted population ranged
from 125 people to 2.3 million people, and the number of rounds of MDA varied from a single
round to multiple rounds over a period of up to 2 years. Overall, the quality of evidence was
deemed to be very low to moderate. Studies were stratified in terms of malaria endemicity
using the following brackets: low (<5%), moderate (6–39%) and high (>40%) parasitaemia in
children.
Two studies (one uncontrolled before-and-after study and one CRT) were performed in low-
transmission settings. The before-and-after study was conducted on the island of Taiwan; it
reported a statistically significant reduction in parasite prevalence at 1 and 12 months following
MDA, using a single dose of chloroquine (CQ), in combination with IRS (13).
In moderate endemic settings in India and Kenya, three non-randomized controlled studies (14-
16) and three uncontrolled studies (17-19) reported a decrease in parasite prevalence in the
first month of follow-up after MDA. At 4–6 months of follow-up, this effect was only sustained
in the non-randomized controlled studies (20). In contrast, the uncontrolled studies indicated
Overall, MDA reportedly reduced parasite prevalence in the short term in all regions of
endemicity, but few studies showed a sustained effect beyond 6 months.
A sustained effect was more often observed in low-transmission, highland or small island
settings when MDA was combined with additional vector-control measures.
Resurgence sometimes occurred following the intervention (particularly in settings with
higher transmission).
PQ was used with apparent safety for P. vivax and P. falciparum, without G6PD screening,
although a limited capacity for pharmacovigilance may have contributed to low reporting of
AEs.
3.2 Lessons learnt from successful use of MDA for elimination of NTDs
MDA has formed the cornerstone of transmission elimination programmes for neglected
tropical diseases (NTDs). In 2014, 60 million doses were disseminated to 39 million people for
the treatment of onchocerciasis, lymphatic filariasis (LF), trachoma, schistosomiasis and soil-
transmitted helminths. This global effort was fuelled by drug donations from multiple
pharmaceutical companies.
Ivermectin has been used for twice-yearly MDA at high coverage for elimination of
onchocerciasis in the Americas. This campaign has been successful, achieving a 96% reduction in
cases in the past 23 years, and a reduction in the number of transmission regions from 13 in
1993 to just two in 2014 (28).
The current strategy for interruption of LF transmission is annual MDA using albendazole and
ivermectin at high coverage, for at least 6 years. To ease logistical challenges, LF MDA
campaigns were integrated into existing onchocerciasis MDA programmes. Ten-year campaigns
in Nigeria reported statistically significant decreases in microfilaremia, antigenemia, mosquito
infection rate and mosquito infectivity rate. Transmission was interrupted in five of the 10
sentinel villages; and the other villages maintained low-grade mosquito infection rates of 0.32%
(29). LF was later eliminated through use of long-lasting insecticidal nets (LLINs) (30).
Interviews revealed that community engagement played a crucial role in improving the
perception and acceptance of LF MDA programmes. About 250 000 local volunteers were
deployed as community-directed distributors, each of whom distributed drugs house to house
to 100 people.
Key conclusions
Integrating campaigns into existing programmes helped with programme roll-out because of
the existing infrastructure.
Combining MDA with vector control made it possible to interrupt transmission in villages
where MDA alone was not sufficient.
Community engagement was key for acceptance of the LF MDA programme and for
achieving a high level of coverage.
Key conclusions
3.4.1 Mainland
MDA combined with PQ
MDA was deployed to a population of about 6000 in a moderate-transmission setting in
Cambodia during 2003–2006, with the objective of reducing or blocking transmission by
eliminating falciparum asexual and sexual parasite reservoirs. Three rounds of artemisinin-
piperaquine (Artequick™) were combined with 9 mg of PQ, which was given every 10 days for 6
months. Individual G6PD status was not tested, and although some individuals took 25 times
too much PQ, no AEs were reported. MDA reduced parasite carriage from 52.3% to 2.6%, and
no patent parasites were detected in children in eight out of 27 villages; however, it was not
possible to interrupt transmission, and resurgence was observed in some endemic areas (6).
Artemisinin drug resistance
Artemisinin forms the core of therapeutic drug regimens used to treat falciparum malaria.
Emergence of multidrug resistance threatens to reverse the progress made with malaria control
and elimination. Containment of resistant strains is therefore crucial, and is high on the list of
priorities for WHO (31). High prevalence of the K13 gene has been reported in symptomatic
patients, but also in asymptomatic carriers with submicroscopic infections living near the
Myanmar–Thai border. Attempts were made to eliminate the submicroscopic reservoir in four
villages through the use of LLINs, and MDA with dihydroartemisinin-piperaquine (DHA-PPQ)
once daily for 3 days, combined with a single low dose of PQ. A sustained reduction in
submicroscopic prevalence detected through high-volume polymerase chain reaction (PCR) was
not seen for P. vivax (this finding was attributed to the use of too low a dose of PQ).
Nevertheless, submicroscopic P. falciparum decreased from 20% to 0.7% for three out of the
four villages when assessed 1 month after the three rounds of MDA (but was not eliminated),
while clinical incidence declined to <1.4/100 person-years. The fourth village had low
population participation (40%), and therefore did not experience a reduction in cases or
parasite prevalence.
Multidrug resistance and re-introduction of disease
Viet Nam has achieved a considerable reduction in malaria cases since 1989, and is aiming for
elimination by 2020, but emergence of multidrug-resistant parasites is threatening this effort
(32). Targeted malaria elimination (TME), which identifies areas for mass treatment, was piloted
in moderate-transmission (20–30%) villages, with the aim of focal elimination. Screening was
performed using microscopy, RDT and high-volume quantitative PCR (qPCR) (using 1 ml blood
samples) on 50 randomly selected adults, at baseline and once a month, followed by a larger
pool of individuals every 2 months. Three rounds of TME using DHA-PPQ and PQ was piloted in
six villages in the Binh Phuoc province and four villages in the Ninh Thuan province, in
combination with IRS and LLINs. Although parasite positivity by qPCR declined following TME,
this effect was not sustained over a 6–9 month period. Malaria rebound was suspected to be
due to re-introduction of the disease by forest workers, or by those who had visited Cambodia.
This study highlights the need for good understanding of local epidemiology, to identify what is
driving transmission and which regions should be targeted for MDA.
MDA combined with PQ, implemented concurrently with vector control in mainland
moderate-transmission regions, resulted in a decrease in parasite carriage, but did not
eliminate the transmission reservoir.
Similarly, the effects of efforts to reduce parasite positivity through the effectiveness of TME
appear to have been reduced by the pressure of imported cases from the forest and
neighbouring countries.
3.4.2 Islands
Islands present a unique opportunity for interruption of malaria transmission, since an isolated
population can be targeted, with less immediate pressure of introduction of cases from nearby
areas than is the case on the mainland. It is thought that malaria can be eliminated on isolated
islands using MDA and vector control if there is a high enough level of community participation
(33). Evidence from several island studies was reviewed.
Comoros
The number of falciparum malaria cases in various islands of Comoros – Anjouan, Grande
Comore and Moheli – declined significantly following a combination of MDA, LLINs and IRS,
which were deployed from 2007 to 2014. Populations in each of the islands, of between 37 112
and 338 799 people, were targeted with two or three rounds of MDA; LLINs were distributed to
all islands and additional IRS was deployed on Moheli. Treatment using artemisinin-piperaquine
(Artequick™) and PQ (9 mg) was given by DOT (excluding pregnant women in the first
trimester), just before the transmission season.
MDA was implemented in 2007 in Moheli and in 2012 in Anjouan, with high coverage (86–96%).
Case incidence was reduced from 23.57 (per 1000 people) in 2011, to 0.14 in 2014 in Moheli,
after deployment of LLINs in 2013, and of IRS in 2011, 2012 and 2013. Similarly, it decreased
from 64.29 in 2011 to 0.02 in 2014 in Anjouan, after deployment of LLINs in 2013. Although
endemicity in Grande Comore was high before MDA, case incidence decreased from 109.4 in
2011 to 5.47 in 2014, following MDA and LLIN deployment in December 2013. This reduction
was found to be sustained when last surveyed in January 2015, despite the lower MDA coverage
(65%). These successes were thought to be due to the implementation of a combination of
effective and synergistic interventions; that is, use of MDA, LLINs, IRS, systematic testing for
malaria before treatment and intensified surveillance.
Aneityum Island, Vanuatu
Malaria was eliminated in Aneityum Island in Vanuatu through multiple efforts. MDA was first
implemented in 1991 as part of an integrated control programme using a short-term aggressive
approach of 9 weeks of PQ (45 mg per dose), CQ and sulfadoxine-pyrimethamine (SP) (~90%
compliance) combined with high coverage of ITNs (0.94 per person). MDA was disseminated to
the entire population of about 700 people just before the rainy season. For the long-term
strategy, MDA and ITNs were combined with annual re-impregnation of beds nets, use of
larvivorous fish and good surveillance. By 1997, both P. falciparum and P. vivax had been
eliminated, but P. vivax reappeared in 2002. To combat this, a second round of MDA using PQ
(daily 0.25 mg/kg for 14 days) and CQ was deployed to those aged <20 years (who formed the
microscopically detectable parasitaemic reservoir), along with dissemination of ITNs. These
efforts led to a reduction in cases, with occasional relapses, followed by elimination in 2010.
Community engagement was key in preventing re-introduction; local microscopists performed
surveillance by passive case detection in the community and by active case detection (ACD) at
airports (34).
Malaria has been eliminated from some isolated islands through the use of MDA, in
combination with high coverage with vector-control interventions, a high degree of
community involvement, and commitment from political and health authorities. In other
instances, such as Comoros, parasite prevalence was reduced but transmission was not
interrupted.
A synergy of methods contributed to success, including vector control, improvements in
current control programmes, monitoring of imported cases, effective treatment of
infections and mass treatment of the parasite reservoir using PQ.
Continuing interventions beyond case zero (where no parasites were detected) was key to
preventing resurgence and importation of cases in some settings.
Key conclusions
MPPT was safely deployed at a large scale with low reporting of AEs in a region with a well-
developed primary health-care system and low prevalence of G6PD deficiency.
Although the number of cases was significantly reduced, it was not possible to interrupt
P. vivax transmission through the use of MPPT; using vector control might have helped to
reach this goal.
Key conclusions
MTAT, MSAT and FSAT achieved modest reductions in malaria transmission in mainland and
island settings with low-to-moderate transmission, but did not result in elimination.
In one FSAT study, targeting of transmission hotspots with LLINs, IRS, larviciding and FSAT
reduced parasite prevalence in, but not outside, the hotspots. It was not possible to
interrupt transmission in the hotspot using this approach.
Other FSAT studies were observational and were not designed to evaluate impact on
transmission.
RDTs are not considered sensitive enough to detect all relevant infections for use in MTAT,
MSAT and FSAT.
RACD is a resource-intensive surveillance tool and is unlikely to interrupt transmission owing
to the number of cases not detected because they are low-density infections or are not
present at the time of visit.
3.7.2 Coverage
Obtaining high intervention coverage is crucial to success. The following present challenges to
achieving this:
Ideally, timing of MDA should be structured when people are at home and can be
reached.
Mobile, migrant and remote populations can be especially hard to target for multiday
drug regimes.
People may be unwilling to take drugs when they feel well and have not been tested.
People of higher socioeconomic status and young men are generally less likely to
comply with MDA.
Imported cases and recrudescent infections can jeopardize programme impact.
Recommendation 1
Use of MDA to interrupt transmission of falciparum malaria can be considered in endemic
island communities and in low-endemic non-island settings approaching elimination, where
there is minimal risk of re-introduction of infection, good access to treatment, and
implementation of vector control and surveillance.
For elimination of malaria in islands and in mainland areas, MDA should be considered as an
option as part of a detailed and costed elimination plan, but only when access to treatment is
ensured, and vector control and surveillance are implemented concurrently. In the context of an
elimination plan, the role of MDA would be to reduce morbidity, leading to rapid case
reduction. In low-transmission settings where there is minimal risk of re-introduction of
infection, the role would be to contribute to interruption of transmission. The unit of
intervention of MDA should be as small as operationally feasible, to maximize the impact in the
target population. The intervention can be targeted spatially or to specific “at risk” groups or
foci.
4.2.2 Use of MDA to interrupt transmission and contain resistance in Cambodia and
Thailand
Recommendation 2
In view of the threat of spreading multidrug resistance and the need to use extreme measures,
MDA can be considered as a component of malaria elimination efforts in the GMS in areas with
good access to treatment, vector control and good surveillance.
At the Cambodia–Thailand border, P. falciparum has become resistant to almost all available
antimalarial medicines, threatening progress achieved in this region to date. If not contained,
this resistance could lead to a rise in the disease burden in other parts of the world. Elimination
of P. falciparum malaria is the only strategy that can prevent the spread of resistance.
Although the evidence to support the effectiveness of MDA in the GMS is limited, the potential
public health threat of spreading multidrug resistance warrants the use of extreme measures.
The objective of MDA in this setting would be a rapid reduction in parasite burden and the
Recommendation 3
Use of MDA to rapidly reduce malaria morbidity and mortality can be considered for epidemic
control as part of the immediate response, while other interventions are put in place.
Malaria epidemics present as a sudden and unexpected increase of malaria cases and deaths (in
the case of falciparum malaria) in time and space. They differ from the increase in transmission
caused by seasonal fluctuations. Once the epidemic of malaria is confirmed, MDA can be
considered as part of the immediate response to reduce morbidity and mortality while other
interventions – notably case management, vector control and surveillance – are put in place.
The role of MDA in the context of an epidemic would be rapid reduction in malaria morbidity
and mortality, while concurrently alleviating burden on treatment centres. The unit of
intervention would be the whole population within the region suffering from the epidemic,
excluding groups mentioned in Section 4.1.3. The drug regimen can include PQ, to aid reduction
of transmission.
4.2.4 Use of MDA, MSAT and FSAT to reduce morbidity and mortality during exceptional
circumstances
Recommendation 4
Use of MDA to reduce malaria morbidity and mortality can be considered during exceptional
circumstances where the health system is overwhelmed and unable to serve the affected
communities.
Recommendation 5
There is insufficient evidence to provide guidance on use of MDA in settings with moderate or
high transmission; more research is required to inform future recommendations.
Recommendation 6
Using current diagnostic tests, MSAT and FSAT are not suitable as interventions to reduce
malaria transmission.
1 See Table 1 in: Disease surveillance for malaria control. An operational manual. Geneva, World Health
Organization (WHO). 2012 (http://whqlibdoc.who.int/publications/2012/9789241503341_eng.pdf, accessed
08 April 2015).
OBSERVERS
Pedro Alonso, Director, Global Malaria Walter Kazadi, WHO Regional Office for the
Programme Western Pacific Region
Hoda Atta, WHO Regional Office for the Eastern Peter Olumese, Global Malaria Programme
Mediterranean Region
Andrea Bosman, Global Malaria Programme Leonard Ortega, WHO Regional Office for the
South-East Asia Region
Keith Carter, WHO Regional Office for Pan Pascal Ringwald, Global Malaria Programme
American Health Organization
Elkhan Gasimov, WHO Regional Office for the Issa Sanou, WHO Regional Office for Africa
European Region
Stefan Hoyer, Global Malaria Programme Marian Warsame, Global Malaria Programme