“The VxWG has been a great source of knowledge, to guide countries on our road to malaria elimination by 2030. Controlling vivax is a huge challenge, but sharing experiences provides encouragement and confidence for us all to attempt what seems impossible. Decision makers in our Ministries are fed new information from the VxWG which support the dream of malaria elimination. ” Albino Bobogare, Co-Chair of the Vivax Working Group, National Malaria Control Program, Solomon Islands
APMEN’s Vivax Working Group (VxWG) is a dynamic forum that brings together national malaria control programs with partners from academia, industry, public private partnerships, funders and other malaria related networks. Its objective is to address key bottle-necks for the control and elimination of malaria in the Asia-Pacific region.
VxWG was formed in 2010 at a time when, despite a rise in the proportion of malaria due to P. vivax, the tools and strategies to control and eliminate the parasite were lacking. The overall objective of the working group is to rectify this, by providing new ways to diagnose patients with vivax malaria and identify individuals with G6PD deficiency at risk of drug-induced haemolysis, and promoting novel treatment strategies to ensure safe and effective delivery of the radical cure of malaria.
The working group has a cyclical approach to prioritise its activities: starting with identifying key knowledge gaps, building consensus regarding priority areas, generating necessary evidence and then facilitating translating findings into policy and practice.
The VxWG is currently supported by the Bill & Melinda Gates Foundation with a 3-year award (2017-2020). This has funded: systematic reviews to identify key knowledge gaps, capacity building, operational research, and workshops and annual meetings to disseminate new knowledge and facilitate discussions. Activities are centred around three main themes to ensure the greatest relevance to antimalarial policy and practice: diagnostics, treatment and surveillance.
Diagnosing patients with low density infections and identifying patients at risk of primaquine or tafenoquine induced haemolysis, are key bottle-necks in providing safe and effective radical cure of P. vivax. Over the last 5 years major gains have been made in product development, but few studies have investigated these tools under field conditions.
- Are new point-of-care diagnostics for P. vivax and G6PD deficiency reliable and ready for clinical use?
To answer this a standardised approach was developed to test new products in multiple locations. The ACROSS Surveys stands for: APMEN health Care facility & community assessment to determine populations at Risk Of malaria and primaquine-induced haemolysiS. In October 2017 an open call was made for applicants to undertake these surveys. There were 10 applications, of which 8 were selected for APMEN funding. With additional funding from DFAT and the Wellcome Trust the remaining 2 applicants were also funded. The selected study sites are in: Bangladesh, Bhutan, China, India, Indonesia, Laos, Nepal, Pakistan and Vietnam.
- Is it cost effective to test patients for G6PD deficiency before treating with primaquine?
To address this question, information was collected on the costs of P. vivax illness as well as those incurred in managing patients with drug-induced haemolysis and household productivity losses. On the Thai-Myanmar border G6PD testing before primaquine treatment was cost-effective (Devine et al PLoS NTD 2017). Since these results are likely to be context specific, an online app was created in which key parameters can be varied by control programs to represent local conditions (https://malaria.shinyapps.io/g6pd_screening).
Systematic reviews to identify knowledge gaps and guide practice: A systematic review of 42 studies evaluating the Accessbio/Carestart G6PD RDT was undertaken, with individual patient data contributed from 11 studies for a pooled analysis. Under research conditions the RDT reliably diagnoses G6PD deficiency (Ley et al 2019). Another systematic review of spectrophotometry (the gold standard for diagnosing G6PD deficiency) from 34 studies found major variation in measurements between different laboratories, highlighting important challenges for standardising diagnosis across diverse populations (Pfeffer et al 2019).
Capacity Building: The VxWG is supporting two regional reference centres for G6PD testing: at the Eijkman Institute of Molecular Biology, Jakarta, Indonesia and the International Centre for Diarrhoeal Disease Research (icddr,b), Dhaka, Bangladesh. With the VxWG’s support icddr,b has become the only WHO reference centre for G6PD diagnostics in the region. A further five laboratories (in Bangladesh, India, Indonesia, Pakistan and Vietnam) are being supported to participate in the WHO-UK NEQAS program for external quality assessment (EQA) for molecular diagnostics for malaria to quantify subpatent parasitaemia and the validity of novel ultrasensitive diagnostics.
Workshops: The VxWG has supported 4 workshops to promote better use of diagnostics in APMEN countries:
- In October 2017 a training workshop was held for groups undertaking the ACROSS Surveys to standardise local protocols for field testing novel diagnostics.
- In March 2018, a Social Science Training Course was run, by Institute of Tropical Medicine (Antwerp) in Vietnam to train investigators on assessing social science components on the qualitative assessment of diagnostics.
- In November 2018, a large workshop held in Jakarta brought together 18 participants from 10 countries to discuss novel tools for G6PD diagnosis and how these can be applied in clinical practice.
- In October 2019, icddr,b, FIND and Menzies held a workshop with support from the National Malaria Control Program in Bangladesh to develop and pilot training materials on the G6PD SDBiosensor. This has led to a qualitative study to assess hurdles to rolling out quantitative G6PD diagnosis.
- How do novel G6PD diagnostics perform in routine clinical practice?
In collaboration with FIND and the Walter and Eliza Hall Institute, studies are underway to investigate the reliability of a novel rapid diagnostic test (PvRST) to identify individuals with recent P. vivax infection and thus at high risk of P. vivax relapse. In collaboration with FIND and PATH, the VxWG will now focus field studies on the reliability of novel diagnostics in routine clinical care.
The radical cure of P. vivax, requires killing both the blood and liver stages of the parasite, to prevent recurrent infections from reactivation of dormant liver stages (relapses), that drive morbidity, mortality and ongoing transmission. Treatment options available have changed little in over the last 60 years. Primaquine is usually administered once daily for 14 days, but when unsupervised this is poorly adhered to and lacks effectiveness.
- What is the risk of haemolysis after P. vivax with and without primaquine and how can this be minimised?
Following feedback from its 2017 annual meeting, the VxWG is helping to generate evidence on how to promote adherence to primaquine regimens. Working with the Institute of Tropical Medicine in Antwerp, qualitative studies are embedded in the ACROSS surveys and clinical studies, to identify patient and caregiver perceptions of malaria, reasons for non-adherence and develop suitable strategies to tackle this.
In 2019 two major clinical trials transformed the radical cure landscape.
These pivotal studies offer new hope for delivering radical cure more effectively. However, both increase the risk of drug-induced haemolysis and require G6PD testing to exclude patients with G6PD deficiency.
Other key questions that the VxWG is addressing:
- What is the risk of haemolysis after P. vivax with and without primaquine and how can this be minimised? What is the best artemisinin combination therapy for treating P. vivax malaria?
Systematic reviews to identify knowledge gaps and guide practice: In collaboration with the World Wide Antimalarial Resistance Network (WWARN), the VxWG has undertaken a systematic review of all P. vivax antimalarial efficacy studies, the results of which are available online (https://www.wwarn.org/tracking-resistance/vivax-surveyor). Global research partners contributed individual patient data from 53 studies enrolling 11,465 patients (including partners in 12 APMEN countries who contributed data from 38 studies and 8,612 patients).
Findings from these pooled meta-analyses include demonstrating: the current dose of chloroquine is likely suboptimal in children; the addition of primaquine reduces early recurrent infections by more than 90% in all endemic locations; DHA-piperaquine is superior to artemether-lumefantrine in preventing early P. vivax recurrences; in G6PD normal patients primaquine improves haematological recovery by day 42.
Capacity Building: In 2019 and 2020 the VxWG is supporting clinical trials capacity in Nepal, Indonesia and Bangladesh. Three studies, co-funded by the Australian Academy of Science, will address questions regarding optimal radical cure raised by NMCPs: whether short-course low-dose primaquine in Nepal is as effective as the current 14-day regimen and whether universal primaquine radical cure has a role in Bangladesh and Indonesia.
Workshops: The VxWG has supported two workshops to explore country partner priorities for delivering safe and effective radical cure.
- In October 2017, a training workshop was conducted at the annual VxWG meeting in Bali, to define how adherence to primaquine can be quantified and explore suitable interventions to improve adherence. The proceedings of the workshop were published in the Malaria Journal in 2018.
- In October 2019, on the final day of the annual meeting in Kathmandu, a workshop for 19 Country partners was convened to discuss key bottle necks to implementing novel tools for radical cure and develop country-specific roadmaps for implementing G6PD testing and treating with tafenoquine or primaquine.
- Is the 7-day primaquine regimen more effective in practice than the 14-day regimen? Can we ensure that tafenoquine is used safely?
By 2021 the VxWG will provide individual country reports, summarising available evidence on the safety and efficacy of high and low-dose primaquine regimens. As we move towards implementation there is a natural shift in the VxWG’s focus from efficacy to effectiveness. The group will work with country partners to standardise definitions of haemolysis so that the safety and effectiveness of tafenoquine and primaquine can be quantified in a range of endemic real-world settings.
The primary aim of VxWG’s surveillance activities is to identify populations at risk of malaria and those at risk of drug-induced haemolysis. These projects are divided broadly into parasite surveillance (to map hot spots and populations at risk of malaria and drug resistance) and host surveillance (to map the prevalence of G6PD deficiency in different populations).
- What’s the burden of P. vivax and which populations are at particular risk?
Working closely with the Malaria Atlas Project (MAP), the VxWG has facilitated data sharing of 2,916 national and subnational API reports from APMEN countries as well 19,844 prevalence surveys. These data have been compiled and mapped across the vivax endemic world.
Work is ongoing to gather disaggregated data and provide higher resolution maps that will have greater utility for local NMCPs.
These data are critical for modelling exercises that are defining the likely impact and cost effectiveness of radical cure strategies in different endemic locations. Preliminary estimates suggest a global cost of $533 million per annum; if radical cure can be implemented this would potentially avert 5 million cases saving $242 million per annum.
- Can we distinguish between indigenous and imported P. vivax infections?
As countries reach the end stages of malaria elimination, the last cases of malaria are almost invariably imported. Imported infections can originate from long-distance travel, or migrant populations moving across porous borders from neighbouring areas with ongoing transmission. Distinguishing imported from indigenous infections helps to define the required public health interventions. The WHO recommends the use of case definitions to define imported, indigenous and introduced P. falciparum malaria, but these definitions are problematic for P. vivax which can relapse months after initial infection. Working with partners from 11 APMEN countries, and 9 additional countries, the VxWG has used whole genome sequencing of parasites to develop a genetic barcode to reliably identify a parasite’s country of origin. Genetic data can now be shared and analysed on vivaxGEN-GEO, a user-friendly, open-access online portal (https://geo.vivaxgen.org/). Work is ongoing to improve the spatial resolution to resolve the microepidemiology of parasites in border regions, and develop protocols and capacity for country programs to genotype parasites locally.
- What’s the prevalence of G6PD deficiency and the risk of haemolysis in my country?
- What’s the geographical extent of chloroquine resistant P. vivax?
In collaboration with MAP, the VxWG will continue to refine P. vivax cases estimates in children, as well as the proportion of cases occurring in remote areas with poor access to healthcare facilities. These populations are critically important since they will inform cost-effective radical cure strategies for populations at greatest risk of vivax malaria.
Knowledge of the prevalence of G6PD deficiency in endemic populations will inform public health strategies for ensuring safe and cost-effective radical cure such as suitable dosing regimens and the choice of G6PD diagnostic. In many vivax endemic areas, the prevalence or type of G6PD variant remains unknown. To address this gap the VxWG and MAP are undertaking a systematic review to compile an open-access database of G6PD prevalence and variants across the Asia-Pacific region. To date, this comprises 974 prevalence surveys and 137 variant surveys. These data will be updated regularly, including the results of the ongoing ACROSS surveys.
Laboratory and informatics tools are being developed for parasite molecular surveillance. These will be used for identifying the geographical origin of infection and relatedness of the parasite to distinguish relapses from reinfection. As molecular markers of chloroquine resistance are identified these will also be included. The ultimate aim is to provide operationally relevant information that can be generated in a timely manner to inform public health interventions.
Over the last 3 years, the VxWG has fostered dynamic interactions between key stakeholders to guide the development of tools and products for the control of P. vivax. The time has now come to shift the focus from product development to implementation of these new tools into policy and practice. At the recent annual meeting in Nepal, members of 19 National Malaria Control Programs worked together to design feasibility studies and develop roadmaps for the roll out of safer and more effective radical cure of P. vivax. This framework provides a solid foundation for eliminating vivax malaria from the Asia-Pacific region.
Access the report summarising the activities of the working group over the last 3 years HERE.