Implementation Research to Assessing the Feasibility of Combining Dihydroartemisinin Piperaquine and Primaquine for Malaria Mass Drug Administration in High Endemic Communities in the Eastern Region of Ghana

Malaria remains the leading cause of mortality and morbidity especially among children and pregnant women in sub-Sahara Africa. In 2019 it killed 409,000 people with 67% (274,000) being under-5-years children in Africa while in 2018, Nigeria and Ghana had the highest absolute increase in malaria cases. Reducing malaria transmission by 90% by 2030 is one of the major WHO strategic goals. Recent reports reveal an upward trend of malaria prevalence in children between the age of 5 and 14 years There is renewed call to implement mass drug administration (MDA) in endemic communities which could drastically reduce the parasite level and pave the way for elimination. The Ghana National Malaria Elimination Programme (NMEP) is on track to engage malaria pre-elimination and has earmarked six districts for elimination with slide positivity rate of less than 10%. There is need to assess the impact of implementing MDA on parasitaemia prevalence in communities with holo-endemic transmission as well as resistance markers. Presently, there is paucity of data to inform the programming and implementation of MDA in Ghana. Though seasonal malaria chemoprevention is being implemented in Northern Ghana, it does not include the Southern part of the country which is holoendemic for malaria. Intermittent Preventive Treatment (IPT) of children in southern Ghana has demonstrated a parasite load reduction of over 90%.

In an ongoing mass testing, treatment and track study in Ghana, the coverage of more than 75% was achieved in target communities and reduced asymptomatic parasitaemia by 24% in one year following 4 rounds. However, in mass testing the low sensitivity of RDTs at detecting very low parasitaemia (sub-microscopic) and gametocytes leads to some cases missing treatment. Sub-microscopic parasitaemia and gametocytes are not often targeted by ACTs and can refuel transmission, hence making MDA a better option as all participants are treated. Our ongoing pilot has demonstrated that 8 rounds of MDA can reduce malaria parasite prevalence by more than 95% using AL. Could this be the case with DHAP? However, the fluctuating level of decline shows that there is a need for gametocytes to be cleared in the population for results to be sustainable. We hypothesize that implementing MDA using DHAP-alone and DHAP+PQ will reduce gametocide level and improve sustainability of reduction of parasite level.

On the other hand, there are concerns that implementing MDA in endemic communities could cause development of drug resistance due to participants not adhering to treatment. To circumvent this shortcoming, we will implement directly observed treatment (DOT). There is a need for continuous surveillance as the presence of variants of the validated markers of artemisinin resistance in the kelch 13 propeller domain of the malaria parasites has been reported in Ghana and Rwanda. Secondly, to limit continuous re-fuelling of transmission from residual parasitaemia in mosquitoes, we will conduct MDA intervention six time a year (bimonthly) as well as include a drug that target stage V gametocytes (single low dose Primaquine). The bimonthly interval is important as it reduces the potential for re-establishment of transmission when interrupted. Thirdly, we will compare the effect of using DHAP+PQ to DHAP-alone and to the standard of care in the control sites. The findings of this trial will provide data that will support policymaking. Some of the questions that need to be answered included: to what extent does MDA affect malaria asymptomatic and symptomatic parasitaemia prevalence? Does MDA affect prevalence of anaemia? Is there a possibility of a re-bound in malaria especially in under 5 children following malarias MDA? Does MDA affect the level of resistance markers in the population? What is the cost effectiveness of implementing MDA in an endemic area in Ghana? Though ongoing studies have demonstrated that MTTT is feasible and acceptable, it is not clear whether this could be the same for MDA using DHAP. The aim of this study is to assess impact of implementing MDA in endemic communities. This study will generate evidence that would inform policy on the choice of drugs and programming for the rollout of MDA in Ghana.

Serological surveillance and targeted MDA: P. falciparum is known to cause a rapid and sustained increase in variant-specific antigen (VSA) antibody levels in children. A study in The Gambia has shown that households and neighbouring compounds constitute local transmissions clusters. The acquisition of natural immunity against malaria increases with age and in Ghana anti-VSA antibodies have been reported to persist in children following infection and that some of these antigens could serve as markers of infections. A recent Gambian study has suggested that serological responses could differentiate between past and present infections as well as reflect reservoirs of infection. As malaria transmission is interrupted, the use of serological surveillance becomes inevitable in targeting asymptomatic foci of infections using MDA both at the individual and the community levels. We will use serology during surveillance for both passive and active cases. This is the first attempt to assess the impact of MDA on the population acquired immunity using serological tools for surveillance in the Pokrom sub district, Eastern Region of Ghana.

On the other hand, drug pressure presents the risk of selecting for isolates with drug resistance associated alleles and could lead to emergence of de novo resistance against artemisinins. Resistance to most partner drugs already exist, though this does not significantly affect clinical treatment outcomes with ACTs in Africa. Nonetheless, ACTs have up until this study, been mostly used for clinical management of uncomplicated malaria. The additional pressure presented by the 6 rounds of treatment requires monitoring of resistance. This is especially so in the Savannah zone of Ghana, where delayed clearance phenotype has been previously reported for some ACTs. It has been reported that widespread use of AL to treat malaria increased the frequencies of Pfmdr-1 wild alleles N86 and D126 but decreased sensitivity to lumefantrine in Uganda and Kanya it is not clear what the situation will be for DHAP. This necessitates aggressive surveillance for drug resistance markers when DHAP is use in a large scale though its efficacy in Ghana is >90% countrywide.