Comment
Reappraising the value of the few available effective 3 Gutman J, Kovacs S, Dorsey G, Stergachis A, ter Kuile FO. Safety, tolerability,
antimalarials is more important now than ever. The
global effort against malaria is at a crossroads;12 malaria
incidence seems to be rising again after many years
of decreases. Dihydroartemisinin–piperaquine should
be shed of its cardiotoxic reputation, so that malaria-
endemic areas can benefit from its full potential and to
decrease the toll that malaria still imposes globally.
Pere Millat-Martínez, *Quique Bassat
Barcelona Institute for Global Health, ISGlobal, Hospital Clínic
Universitat de Barcelona, Barcelona, 08036, Spain (PM-M, QB);
Lihir Malaria Elimination Programme (LMEP), Lihir Island, New
Ireland Province, Papua New Guinea (PM-M); Centro de
Investigação em Saúde de Manhiça, Maputo, Mozambique (QB);
ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain (QB); and
Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital
Sant Joan de Déu (University of Barcelona), Barcelona, Spain (QB).
quique.bassat@isglobal.org
We declare no competing interests. QB is a member of the WHO Malaria
Treatment Guidelines Group, which produces global guidance on the treatment
of malaria including decisions about dihydroartemisinin–piperaquine. The views
expressed by the authors are personal opinions and do not represent the
recommendations of WHO.
Copyright © The Author(s). Published by Elsevier Ltd. This is an Open Access
article under the CC BY 4.0 license.
1 WHO. World malaria report 2017. http://www.who.int/malaria/
publications/world-malaria-report-2017/en/. Geneva: World Health
Organization, 2017.
2 Zani B, Gathu M, Donegan S, Olliaro PL, Sinclair D. Dihydroartemisinin-
piperaquine for treating uncomplicated Plasmodium falciparum malaria.
Cochrane Database Syst Rev 2014; 1: CD010927.
HRP-2 deletion: a hole in the ship of malaria elimination
Malaria remains a major health challenge in tropical
and subtropical countries with an estimated incidence
of 216 million cases and 445 000 deaths worldwide in
2016. Every 2 minutes a child under 5 years old dies
because of malaria. India accounts for 80% of malaria
cases and 60% of malaria deaths in the southeast
Asia region (SEAR).1 Plasmodium falciparum malaria
constitutes 63·4 % of total malaria cases in India. More
than 90% of malaria cases in India are reported from
remote, difficult to reach rural and tribal areas, where
the diagnosis of malaria is a challenge in resource-
limited settings.
Malaria rapid diagnostic tests (RDTs) have been
extensively used as diagnostic tools because of their
ease of handling and quick results. The sale of about
1·66 billion malaria RDTs across the globe during
826
and efficacy of repeated doses of dihydroartemisinin-piperaquine for
prevention and treatment of malaria: a systematic review and
meta-analysis. Lancet Infect Dis 2017; 17: 184–93.
4 Eisele TP, Bennett A, Silumbe K, et al. Short-term impact of mass drug
administration with dihydroartemisinin plus piperaquine on malaria in
southern province Zambia: a cluster-randomized controlled trial.
J Infect Dis 2016; 214: 1831–39.
5 European Agency of Medicines. Eurartesim: Summary of product
characteristics. http://www.ema.europa.eu/docs/en_GB/document_
library/EPAR_-_Product_Information/human/001199/WC500118113.pdf
(accessed 18 May 2018).
6 Chan XHS, Win YN, Mawer LJ, Tan JY, Brugada J, White NJ. Risk of sudden
unexplained death after use of dihydroartemisinin–piperaquine for
malaria: a systematic review and Bayesian meta-analysis. Lancet Infect Dis
2018; published online June 7. http://dx.doi.org/10.1016/S1473-
3099(18)30297-4.
7 WHO. WHO Evidence Review Group on the Cardiotoxicity of Antimalarial
Medicines. Geneva: World Health Organization, 2017.
8 West African Network for Clinical Trials of Antimalarial Drugs. Pyronaridine-
artesunate or dihydroartemisinin-piperaquine versus current first-line
therapies for repeated treatment of uncomplicated malaria: a randomised,
multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet
2018; 391: 1378–90.
9 Kabanywanyi AM, Baiden R, Ali AM, et al. Multi-country evaluation of
safety of dihydroartemisinin/piperaquine post-licensure in African public
hospitals with electrocardiograms. PLoS ONE 2016; 11: e0164851.
10 Coldiron ME, Lasry E, Bouhenia M, et al. Intermittent preventive treatment
for malaria among children in a refugee camp in northern Uganda: lessons
learned. Malar J 2017; 16: 218.
11 Gargano N, Madrid L, Valentini G, et al. Efficacy and tolerability outcomes
of a phase II, randomized, open-label, multicenter study of a new
water-dispersible pediatric formulation of dihydroartemisinin-piperaquine
for the treatment of uncomplicated plasmodium falciparum malaria in
African infants. Antimicrob Agents Chemother 2018; 62: e00596–17.
12 Alonso P, Noor AM. The global fight against malaria is at crossroads.
Lancet 2017; 390: 2532–34.
2010–16 speaks volumes about their utility.1 Improved
sensitivity and heat stability makes P falciparum-
histidine rich protein (HRP) 2 based RDTs the preferred
choice for timely diagnosis of falciparum malaria in
remote areas with poor health-care infrastructure.
Berhane and colleagues have shown high prevalence
(41–80%) of HRP2 gene deletion in P falciparum
and high frequency of false negative RDT results,
irrespective of parasite densities, in a hospital-based
study in Eritrea.2 At a time when India and several other
countries in SEAR are accelerating the pace of malaria
control programmes to achieve the goal of malaria
elimination by 2030, the deletion of HRP2 is a matter of
serious concern, since RDTs are the mainstay diagnostic
tool for community surveys, along with microscopy in
hospitals. The diverse ecological conditions, difficult
www.thelancet.com/infection Vol 18 August 2018

geographical and forested terrains, porous borders,
socio-political unrest, diversity of vector, and presence
of the four major Plasmodium spp make malaria
elimination a daunting task in India.3 The partial or
complete deletion of P falciparum HRP2 and HRP3 genes
could make the task even more difficult.
P falciparum lacking the HRP-2 protein was first
reported from the Peruvian Amazon in 2010,3 since
when the presence of P falciparum with deleted HRP2
and HRP3 has been reported from several countries
of South America, Africa, and Asia.5,6 However, the
global distribution and frequency of deletions of the
P falciparum HRP2 and HRP3 genes in parasites varies
from place to place. The growing body of evidence
suggests that the deletion of HRP2 and HRP3 genes in
P falciparum affects the performance of HRP-2 based
RDTs and might lead to an increase in the frequency of
false-negative results. However, whether the variation
in length of sequence repeats or the combined length
of repeats (type 2 and type 7) of HRP-2 protein affects
the performance of HRP-2 based RDTs is still under
investigation.7 Locations of P falciparum HRP2 and
HRP3 in evolutionarily active subtelomeric regions of
chromosomes have resulted in substantial sequence
variation in the complex repeats and multiple origins of
HRP2 deletion.5,8
Recent reports about the presence and prevalence
of P falciparum parasites without HRP2 and HRP3
genes from malaria-endemic regions warrant regular
surveillance for such mutations. Lack of knowledge of
P falciparum HRP2 and HRP3 gene deletion in parasite
populations and extensive use of HRP-2 based RDTs
might lead to an increase in prevalence of P falciparum
with deleted HRP2 and HRP3 in malaria-endemic areas.5
In India, bivalent RDTs currently in use are coated
with HRP-2 antigen for the diagnosis of P falciparum
and pLDH for Plasmodium vivax. In 2016, about
21·08 million RDTs were distributed and 19·6 million
RDTs were used for the diagnosis of malaria in India.1
However, the actual number of RDTs used for malaria
diagnosis might be much higher, since data from
the private sector are not available. Reports show
that there is a variable prevalence (0–8%) of deleted
P falciparum with deleted HRP2 and HRP3 in the states
of Maharashtra, Madhya Pradesh, Jharkhand, Gujarat,
www.thelancet.com/infection Vol 18 August 2018
Comment
and Odisha.7,9,10 With the formal launch of a malaria
elimination programme by the Indian Government,
the use of RDTs is on rise. However, detection of
low-density parasitaemia, mixed infections, and
P falciparum HRP2 and HRP3 gene deletion are
new obstacles in the path of malaria elimination.
The unrestricted use of HRP2-based RDTs might
create pressure for a selective sweep of P falciparum
HRP2-negative parasite lineages. Therefore, timely
mapping and monitoring of the distribution of
P falciparum parasites without HRP2 and HRP3 is crucial
to malaria elimination. There is an urgent need for
scientific evidence with prudently designed molecular
methods coupled with microscopy and alternative
RDTs to support policy development. Otherwise, this
hole of P falciparum HRP2 and HRP3 deletion might sink
the ship of malaria management and elimination in
India.
Anil Kumar Verma, *Praveen Kumar Bharti, Aparup Das
Division of Vector Borne Diseases ICMR-National Institute for
Research in Tribal Health, PO-Garha, Nagpur Road,
Jabalpur-482003, MP, India
pbharti@nirth.res.in
We declare no competing interests
1 WHO. World Malaria Report 2017. http://www.who.int/malaria/
publications/world-malaria-report-2017/en/ (accessed Feb 2, 2018)
2 Berhane A, Anderson K, Mihreteab S, et al. Major threat to malaria control
programs by Plasmodium falciparum lacking histidine-rich protein 2, Eritrea.
Emerg Infect Dis 2018; 24: 462–70.
3 Gamboa D, Ho MF, Bendezu J, et al. A large proportion of P. falciparum
isolates in the Amazon region of Peru lack pfhrp2 and pfhrp3:
implications for malaria rapid diagnostic tests. PLoS One 2010; 5: e8091.
4 Krishna S, Bhandari S, Bharti PK, Basak S, Singh N. A rare case of quadruple
malaria infection from the highly malaria-endemic area of Bastar,
Chhattisgarh, India. PLoS Negl Trop Dis 2017; 11: e0005558.
5 Akinyi S, Hayden T, Gamboa D, et al. Multiple genetic origins of
histidine-rich protein 2 gene deletion in Plasmodium falciparum parasites
from Peru. Sci Rep 2013; 3: 2797.
6 WHO Global Malaria Programme. Update on Plasmodium falciparum hrp 2/3
gene deletions, 2017. https://pdfs.semanticscholar.org/.../0241d85b97fca
489e06105f639e789f57396.pdf (accessed Jan 16, 2018).
7 Kumar Bharti P, Singh Chandel H, Krishna S, et al. Sequence variation in
Plasmodium falciparum histidine rich proteins 2 and 3 in Indian isolates:
implications for malaria rapid diagnostic test Performance. Sci Rep 2017;
7: 1308.
8 Scherf A. Plasmodium telomeres and telomere proximal gene expression.
Semin Cell Biol 1996; 7: 49–57.
9 Bharti PK, Chandel HS, Ahmad A, Krishna S, Udhayakumar V, Singh N.
Prevalence of pfhrp2 and/or pfhrp3 gene deletion in Plasmodium falciparum
population in eight highly endemic states in India. PLoS One 2016;
11: e0157949.
10 Kumar N, Pande V, Bhatt RM, et al. Genetic deletion of HRP2 and HRP3 in
Indian Plasmodium falciparum population and false negative malaria rapid
diagnostic test. Acta Trop 2013; 125: 119–21.
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