Malaria rapid diagnostic tests (RDTs) have transformed malaria control, enabling better targeting of treatment and improved surveillance. Globally, 2.7 billion RDTs for malaria were sold between 2010–2019, the majority distributed in Sub-Saharan Africa to diagnose P. falciparum (Pf) infection by targeting one of its antigens, histidine-rich protein 2 (HRP2). This current cornerstone of P. falciparum diagnosis is under serious threat as a result of the emergence of parasites not expressing the HRP2 protein due to mutations in the genes that encode it. Consequently, HPR2-based RDTs are unable to detect infections with such parasites, putting patients at risk of misdiagnosis, significant morbidity and potentially death. These gene deletions were first reported a decade ago in Peru and were subsequently found in neighbouring countries. This lead to a reversion to microscopy as the primary diagnostic tool in this region. Over the past 6 years, an increasing number of African and Asian countries where diagnosis is heavily reliant on HRP2-based RDTs have reported histidine-rich protein 2 and 3 gene (pfhrp2/3) deletions, raising the threat to a new level.
In response, WHO issued in 2017 information notes on: the implications for case management; the procedures for investigating suspected false-negative RDT results due to pfhrp2/3 gene deletions; the criteria for RDT change (see note); and subsequently in 2019 released a response plan to pfhrp2 gene deletions; and has made available surveillance protocols. An interactive web-based interface for tracking all published reports of pfhrp2/3 deletions is available on WHO Malaria Threat Map.
The Horn of Africa appears to be disproportionately affected, with high prevalence of pfhrp2/3 deletions reported in areas of Ethiopia, Eritrea, Djibouti and to a lesser extent in Sudan and South Sudan; the root cause of many false negative RDT results are currently under investigation in Somalia. Recent surveys in the Horn of Africa region found that many (> 50%) P. falciparum cases are missed by HRP2 RDTs. Failure to detect and treat infection can result in increased disease, including severe disease and death.
The Malaria Policy Advisory Group (MPAG) reviewed available information during its April 2021 meeting and called for urgent action in addressing the increased prevalence of pfhrp2 gene deletions in all endemic countries and most expeditiously in the Horn of Africa. Although alternate diagnostic choices are limited, some non-HRP2 based rapid tests options, approved through the Global Fund Expert Review Panel for Diagnostics (see here and here) are available. MPAG emphasized that it is imperative that all countries start and maintain surveillance and respond when the prevalence of pfhrp2/3 gene deletions exceeds the WHO criteria for RDT replacement by changing to quality-assured non-HRP2 RDTs to prevent unnecessary morbidity and deaths and to safeguard inroads that have been made towards malaria elimination particularly in sub-Saharan Africa.
Note:
WHO recommends that a ≥ 5% local prevalence of pfhrp2/3 deletions causing false-negative HRP2 RDTs warrants an immediate change in testing strategy and preparation for nationwide change. This cut-off was selected because it is at about that level that public health gains will be obtained in changing from HRP2 detecting RDTs to those targeting non-HRP2 antigens i.e. pLDH antigens. At this threshold the proportion of cases missed by less sensitive non-HRP2-based tests are likely to be lower than those associated with continued use of HRP2-based tests. Based on modelling and repeat surveys for pfhrp2/3 deletions over time it is expected that strains carrying pfhrp2/3 deletion mutations will continue to expand and spread.