Global response plan for pfhrp2/3 deletions

MPAC 17-19 October, 2017

Jane Cunningham

The global response plan

for pfhrp2/3 mutations that limit the effectiveness of HRP2-based RDTs comprises a global framework to support national malaria control programmes and their implementing partners to address this problem pragmatically.

Objectives

• define the frequency and distribution of diagnostically relevant pf-hrp2/3 mutations in circulating P. falciparum strains;

• provide concrete guidance to countries on malaria diagnosis and treatment in settings where such mutations are found to be frequent;

• identify gaps in knowledge about the genesis and spread of strains with pfhrp2 and/or pfhrp3 deletions and the actions required to develop new, accurate tests for malaria based on alternative target antigens; and

• coordinate advocacy and communication with donors, policy-makers, test developers, research agencies, technical partners and disease control programmes to assist in planning.

Background

• Overview of RDTs – how they work, targets, quality assurance, utilization/market trends

• Evolution of pfhrp2/3 deletion mutants & key conclusions: • There are clear local “hot spots” - Amazonian regions of Colombia

and Peru and in Eritrea. • The prevalence of P. falciparum that do not express HRP2 varies by

province in any given country. • pfhrp2/3 deletion mutants can cause outbreaks which may be

missed by HRP2-based RDTs ie. in Tumbes, Peru. • In many studies, the methods by which patients were selected

resulted in overestimates of the true prevalence of pfhrp2/3 deletion mutants eg. reporting prevalence of pfhrp2 deletions based on total discordant samples instead of all microscopy + Pf cases.

Background

• Depending on survey design, it is also possible to underestimate the prevalence of pfhrp2-deleted strains due to: o cross-reactivity of HRP2-based RDTs with HRP3 o the circulation of strains with pfhrp2 deletions which may

be masked by co-infection with P. falciparum strains without such deletions (infection with more than one strain type).

• The absence of PCR amplification of pfhrp2/3 may be due to an inadequate quantity of parasite DNA. o In many studies, the methods used to obtain DNA did not

provide enough material to detect single-copy genes like pfhrp2/3.

Scenarios NMCPs and their implementing partners: Scenario 1: 5% local prevalence of false-negative HRP2 RDTs due to gene deletions warrants a change in testing strategy nationwide Scenario 2: suspected false negative RDTs – collect initial evidence (HRP2 RDT neg; Pf microscopy + or pf-pLDH +) and if molecular analysis confirms pfhrp2 deletion - implement survey Scenario 3: national assessment of prevalence of pfhrp2/3 deletion mutants – highest priority for countries bordering those with confirmed reports

Ethiopia

Source: http://www.moh.gov.et/malaria

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Am J Trop Med Hyg. 2017 Aug 7

Survey Protocol

Repeat survey in two years

Change RDT nationwide and prioritize based on

prevalence in other provinces

Depending on resources:

- Continue enrolling patients

- Repeat survey in 1 year

- Repeat survey in 2 years

Actions based on outcomes:

Alternative RDT options ?

• Currently very limited and further challenged by new requirements of WHO PQ in 2018

• 2 pan-only and 1 pf-pLDH + pan-pLDH combo test that meet performance criteria; only 1 of the pan-pLDH tests is prequalified

• Some tests must be assessed against pfhrp2/3 deleted strains to determine performance ie. HRP2 and pf-pLDH on the same test line

• Performance criteria “loosened” for selection of pf-pLDH RDTs for surveys

Laboratory strengthening

• Meeting the requirement for capacity to assess suspected false-negative HRP2-based RDTs and for surveys will require quality-assured microscopy and/or staff trained and ready to use correctly non-HRP2-only RDTs that are not in routine use in the NMCP.

• Confirming the presence of genetic deletions will require sampling, labelling and preparation of dried blood spots for shipping and multiple PCR analyses in regional or international laboratories.

Estimating

volume of

PCR testing

required

Total: 136 50,320 1,007 2,518 5,032

• A number of international reference laboratories with experience in pfhrp2/3 molecular analysis are already collaborating with WHO

• National programmes themselves may have an interest in using or strengthening local capacity for PCR; however, the lack of PCR standardization and of a malaria molecular assay approved by a stringent regulatory authority will make comparison of results between studies and between laboratories problematic

• countries embarking on national HRP2 deletion surveys should have a molecular assessment plan that includes the capacity to ship samples internationally to collaborating laboratories with the necessary capacity and quality control.

Research

• understand the factors that drive the evolution and spread of pfhrp2/3 deletion mutants;

• operational and technical research to simplify the process of identifying and tracking the distribution of these strains

Research & Development

• new protein targets;

• optimization of monoclonal antibodies or other ligands, to increase their robustness, thermostability and affinity.

Coordination of the response

• many different interests involved in the discovery, development, quality control, selection, procurement, distribution, storage and use of RDTs;

• coordinating mechanism/consortium needed to provide structure for harmonized action

Hosted by WHO ?

Discussion point #2

Priority areas of work

• mapping the distribution and frequency of pfhrp2/3 deletion mutants with harmonized protocols and creation of a registry of pfhrp2/3 prevalence surveys;

Discussion point #3

Clinical status symptomatic asymptomatic mixed or unknown

Type of deletion pfhrp2 pfhrp2 and 3

Survey type Cross sectional Convenience/screening Case report DHS

Across surveys, the criteria for selecting samples to test for pfhrp2/3 deletions varies. Percentage of samples tested with deletions is presented

Malaria Threat Maps: Data

Malaria Threats Map - online

Vector insecticide resistance 2010 - 2017

bioassays, mechanisms n = 18,712 tests

hrp2/3 gene deletions 1998 – 2017

Confirmed deletions, only n= 125 survey areas; 24 countries

Drug efficacy & drug resistance 2010 - 2017

TES and molecular markers n = 1006 studies

Vector insecticide resistance 1949 - 2017

bioassays, mechanisms n = 29,137 tests

Malaria Threats Map

GMP Databases

hrp2/3 gene deletions 1996 - 2017

Suspected and confirmed n = 131 survey areas; 26 countries

Drug efficacy & drug resistance 2004 - 2017 TES and molecular markers

n = 2133 studies

Global view

Source: WHO Malaria Threats Map, to be launched October 2017

Specific surveys by country

Source: WHO Malaria Threats Map, to be launched October 2017

Site specific data linked to original source

Source: WHO Malaria Threats Map, to be launched October 2017

Priority areas of work

• mapping the distribution and frequency of pfhrp2/3 deletion mutants with harmonized protocols and creation of a registry of pfhrp2/3 prevalence surveys;

• building and funding an international network of laboratories to perform the complex molecular confirmation required for mapping;

• supporting countries in the selection and procurement of new RDTs when a change of testing is warranted and regularly updating policy;

• advising commercial manufacturers of the priorities for new tests, including development of target product profiles and providing the best available market forecasts;

• adapting the WHO malaria RDT product testing programme, which constitutes the laboratory evaluation component of WHO prequalification, to ensure proper validation of tests for the detection of pfhrp2 deletion mutants as part of their intended use;

• working with donor agencies and research institutes to devise a funding plan to support (i) the interim costs for prevalence surveys and the necessary molecular testing (ii) the search for improved diagnostic targets and high-affinity reagent and (iii) short-term operational and technical research to address the problem with clear timelines and financing needs

• strengthening coordination among policy-makers, NMCPs and their implementing partners, molecular testing laboratories, diagnostic industry representatives, donors and technical agencies to maximize efficiency in tracking and responding to this novel situation.

Discussion point #3

Conclusions

• The full extent of the threat posed by pfhrp2 deletions is not yet known and the alternative RDT options ie. pf-pLDH RDTs are extremely limited and currently have inferior performance to HRP2 RDTs for P. falciparum detection

• Information on prevalence in much of the world is spotty

• Must balance risk of missed cases of falciparum malaria due to pfhrp2/3 deleted strains against the equally real risk of missing cases by changing to a less sensitive RDT and the longer term risk of eroding confidence in antigen-based confirmatory testing for malaria

Achieving these goals within the time frame necessary to satisfy the needs of National Malaria Control Programs and the populations they serve will require a focused, staffed, and budgeted effort, and a mechanism for programme management

.

Acknowledgements Mark Perkins, Global Health Diagnostics

Tom Eisele , Tulane University

Joe Keating, Tulane University

Survey protocol

Repeat survey in two years

Change RDT nationwide and prioritize based on

prevalence in other provinces

Depending on resources:

- Continue enrolling patients

- Repeat survey in 1 year

- Repeat survey in 2 years

Actions based on outcomes:

Coordination of the response

• many different interests involved in the discovery, development, quality control, selection, procurement, distribution, storage and use of RDTs;

• coordinating mechanism/consortium needed to provide structure for harmonized action

Hosted by WHO ?

Discussion point #2

Priority areas of work

• mapping the distribution and frequency of pfhrp2/3 deletion mutants with harmonized protocols and creation of a registry of pfhrp2/3 prevalence surveys;

• building and funding an international network of laboratories to perform the complex molecular confirmation required for mapping;

• supporting countries in the selection and procurement of new RDTs when a change of testing is warranted and regularly updating policy;

• advising commercial manufacturers of the priorities for new tests, including development of target product profiles and providing the best available market forecasts;

• adapting the WHO malaria RDT product testing programme, which constitutes the laboratory evaluation component of WHO prequalification, to ensure proper validation of tests for the detection of pfhrp2 deletion mutants as part of their intended use;

• working with donor agencies and research institutes to devise a funding plan to support (i) the interim costs for prevalence surveys and the necessary molecular testing (ii) the search for improved diagnostic targets and high-affinity reagent and (iii) short-term operational and technical research to address the problem with clear timelines and financing needs

• strengthening coordination among policy-makers, NMCPs and their implementing partners, molecular testing laboratories, diagnostic industry representatives, donors and technical agencies to maximize efficiency in tracking and responding to this novel situation.

Discussion point #3