Treatment of uncomplicated Plasmodium vivax with chloroquine plus radical cure with primaquine without G6PDd testing is safe in Arba Minch, Ethiopia: assessment of clinical and parasitological response.

BACKGROUND: Ethiopia rolled out primaquine nationwide in 2018 for radical cure along with chloroquine for the treatment of uncomplicated Plasmodium vivax malaria in its bid for malaria elimination by 2030. The emergence of anti-malarial drug resistance would challenge the elimination goal. There is limited evidence on the emergence of chloroquine drug resistance. The clinical and parasitological outcomes of treatment of P. vivax with chloroquine plus radical cure using low dose 14 days primaquine were assessed in an endemic area of Ethiopia. METHODS: A semi-directly observed 42-days follow up in-vivo therapeutic efficacy study was conducted from October 2019 to February 2020. Plasmodium vivax mono-species infected patients (n = 102) treated with a 14 days low dose (0.25 mg/kg body weight per day) primaquine plus chloroquine (a total dose of 25 mg base/kg for 3 days) were followed for 42 days to examine clinical and parasitological outcomes. Samples collected at recruitment and days of recurrence were examined by 18 S based nested polymerase chain reaction (nPCR) and Pvmsp3α nPCR-restriction fragment length polymorphism. Asexual parasitaemia and the presence of gametocytes were assessed on the scheduled days using microscopy. Clinical symptoms, haemoglobin levels, and Hillmen urine test were also assessed. RESULTS: Of the 102 patients followed in this study, no early clinical and parasitological failure was observed. All patients had adequate clinical and parasitological responses within the 28 days of follow up. Late clinical (n = 3) and parasitological (n = 6) failures were observed only after day 28. The cumulative incidence of failure was 10.9% (95% confidence interval, 5.8-19.9%) on day 42. Among the paired recurrent samples, identical clones were detected only in two samples on day 0 and day of recurrences (day 30 and 42) using Pvmsp3α genotyping. No adverse effect was detected related to the low dose 14 days primaquine administrations. CONCLUSION: Co-administration of CQ with PQ in the study area is well tolerated and there was no recurrence of P. vivax before 28 days of follow up. Interpretation of CQ plus PQ efficacy should be done with caution especially when the recurrent parasitaemia occurs after day 28. Therapeutic efficacy studies with appropriate design might be informative to rule out chloroquine or primaquine drug resistance and/or metabolism in the study area.

Insecticide resistance in Anopheles arabiensis from Ethiopia (2012-2016): a nationwide study for insecticide resistance monitoring.

BACKGROUND: Indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) remain the cornerstones of malaria vector control. However, the development of insecticide resistance and its implications for operational failure of preventative strategies are of concern. The aim of this study was to characterize insecticide resistance among Anopheles arabiensis populations in Ethiopia and describe temporal and spatial patterns of resistance between 2012 and 2016. METHODS: Between 2012 and 2016, resistance status of An. arabiensis was assessed annually during the long rainy seasons in study sites from seven of the nine regions in Ethiopia. Insecticide resistance levels were measured with WHO susceptibility tests and CDC bottle bioassays using insecticides from four chemical classes (organochlorines, pyrethroids, organophosphates and carbamates), with minor variations in insecticides tested and assays conducted between years. In selected sites, CDC synergist assays were performed by pre-exposing mosquitoes to piperonyl butoxide (PBO). In 2015 and 2016, mosquitoes from DDT and deltamethrin bioassays were randomly selected, identified to species-level and screened for knockdown resistance (kdr) by PCR. RESULTS: Intense resistance to DDT and pyrethroids was pervasive across Ethiopia, consistent with historic use of DDT for IRS and concomitant increases in insecticide-treated net coverage over the last 15 years. Longitudinal resistance trends to malathion, bendiocarb, propoxur and pirimiphos-methyl corresponded to shifts in the national insecticide policy. By 2016, resistance to the latter two insecticides had emerged, with the potential to jeopardize future long-term effectiveness of vector control activities in these areas. Between 2015 and 2016, the West African (L1014F) kdr allele was detected in 74.1% (n = 686/926) of specimens, with frequencies ranging from 31 to 100% and 33 to 100% in survivors from DDT and deltamethrin bioassays, respectively. Restoration of mosquito susceptibility, following pre-exposure to PBO, along with a lack of association between kdr allele frequency and An. arabiensis mortality rate, both indicate metabolic and target-site mutation mechanisms are contributing to insecticide resistance. CONCLUSIONS: Data generated by this study will strengthen the National Malaria Control Programme's insecticide resistance management strategy to safeguard continued efficacy of IRS and other malaria control methods in Ethiopia.

Evidence for a role of Anopheles stephensi in the spread of drug- and diagnosis-resistant malaria in Africa.

Anopheles stephensi, an Asian malaria vector, continues to expand across Africa. The vector is now firmly established in urban settings in the Horn of Africa. Its presence in areas where malaria resurged suggested a possible role in causing malaria outbreaks. Here, using a prospective case-control design, we investigated the role of An. stephensi in transmission following a malaria outbreak in Dire Dawa, Ethiopia in April-July 2022. Screening contacts of patients with malaria and febrile controls revealed spatial clustering of Plasmodium falciparum infections around patients with malaria in strong association with the presence of An. stephensi in the household vicinity. Plasmodium sporozoites were detected in these mosquitoes. This outbreak involved clonal propagation of parasites with molecular signatures of artemisinin and diagnostic resistance. To our knowledge, this study provides the strongest evidence so far for a role of An. stephensi in driving an urban malaria outbreak in Africa, highlighting the major public health threat posed by this fast-spreading mosquito.

Indoor Residual Spraying Delivery Models to Prevent Malaria: Comparison of Community- and District-Based Approaches in Ethiopia.

BACKGROUND: Indoor residual spraying (IRS) for malaria prevention has traditionally been implemented in Ethiopia by the district health office with technical and operational inputs from regional, zonal, and central health offices. The United States President's Malaria Initiative (PMI) in collaboration with the Government of Ethiopia tested the effectiveness and efficiency of integrating IRS into the government-funded community-based rural health services program. METHODS: Between 2012 and 2014, PMI conducted a mixed-methods study in 11 districts of Oromia region to compare district-based IRS (DB IRS) and community-based IRS (CB IRS) models. In the DB IRS model, each district included 2 centrally located operational sites where spray teams camped during the IRS campaign and from which they traveled to the villages to conduct spraying. In the CB IRS model, spray team members were hired from the communities in which they operated, thus eliminating the need for transport and camping facilities. The study team evaluated spray coverage, the quality of spraying, compliance with environmental and safety standards, and cost and performance efficiency. RESULTS: The average number of eligible structures found and sprayed in the CB IRS districts increased by 19.6% and 20.3%, respectively, between 2012 (before CB IRS) and 2013 (during CB IRS). Between 2013 and 2014, the numbers increased by about 14%. In contrast, in the DB IRS districts the number of eligible structures found increased by only 8.1% between 2012 and 2013 and by 0.4% between 2013 and 2014. The quality of CB IRS operations was good and comparable to that in the DB IRS model, according to wall bioassay tests. Some compliance issues in the first year of CB IRS implementation were corrected in the second year, bringing compliance up to the level of the DB IRS model. The CB IRS model had, on average, higher amortized costs per district than the DB IRS model but lower unit costs per structure sprayed and per person protected because the community-based model found and sprayed more structures. CONCLUSION: Established community-based service delivery systems can be adapted to include a seasonal IRS campaign alongside the community-based health workers' routine activities to improve performance efficiency. Further modifications of the community-based IRS model may reduce the total cost of the intervention and increase its financial sustainability.

Short persistence of bendiocarb sprayed on pervious walls and its implication for the indoor residual spray program in Ethiopia.

BACKGROUND: With the emergence and spread of vector resistance to pyrethroids and DDT in Africa, several countries have recently switched or are considering switching to carbamates and/or organophosphates for indoor residual spraying (IRS). However, data collected on the residual life of bendiocarb used for IRS in some areas indicate shorter than expected bio-efficacy. This study evaluated the effect of pH and wall type on the residual life of the carbamates bendiocarb and propoxur as measured by the standard World Health Organization (WHO) cone bioassay test. METHODS: In phase I of this study, bendiocarb and propoxur were mixed with buffered low pH (pH 4.3) local water and non-buffered high pH (pH 8.0) local water and sprayed on two types of wall surface, mud and dung, in experimental huts. In the six month phase II study, the two insecticides were mixed with high pH local water and sprayed on four different surfaces: painted, dung, mud and mud pre-wetted with water. The residual bio-efficacy of the insecticides was assessed monthly using standard WHO cone bioassay tests. RESULTS: In phase I, bendiocarb mixed with high pH water killed more than 80% of susceptible Anopheles arabiensis mosquitoes for two months on both dung and mud surfaces. On dung surfaces, the 80% mortality threshold was achieved for three months when the bendiocarb was mixed with low pH water and four months when it was mixed with high pH water. Propoxur lasted longer than bendiocarb on dung surfaces, staying above the 80% mortality threshold for four and five months when mixed with high and low pH water, respectively. Phase II results also showed that the type of surface sprayed has a significant impact on the bio-efficacy of bendiocarb. Keeping the spray water constant at the same high pH of 8.0, bendiocarb killed 100% of exposed mosquitoes on impervious painted surfaces for the six months of the study period compared with less than one month on mud surfaces. CONCLUSIONS: Mixing the insecticides in alkaline water did not reduce the residual bio-efficacy of bendiocarb. However, bendiocarb performed much better on impervious (painted) surfaces than on porous dung or mud ones. Propoxur was less affected by wall type than was bendiocarb. Studies on the interaction between wall materials, soil, humidity, temperature and pH and the residual bio-efficacy of new and existing insecticides are recommended prior to their wide use in IRS.

Time series analysis of trends in malaria cases and deaths at hospitals and the effect of antimalarial interventions, 2001-2011, Ethiopia.

BACKGROUND: The Government of Ethiopia and its partners have deployed artemisinin-based combination therapies (ACT) since 2004 and long-lasting insecticidal nets (LLINs) since 2005. Malaria interventions and trends in malaria cases and deaths were assessed at hospitals in malaria transmission areas during 2001-2011. METHODS: Regional LLINs distribution records were used to estimate the proportion of the population-at-risk protected by LLINs. Hospital records were reviewed to estimate ACT availability. Time-series analysis was applied to data from 41 hospitals in malaria risk areas to assess trends of malaria cases and deaths during pre-intervention (2001-2005) and post-interventions (2006-2011) periods. FINDINGS: The proportion of the population-at-risk potentially protected by LLINs increased to 51% in 2011. The proportion of facilities with ACTs in stock exceeded 87% during 2006-2011. Among all ages, confirmed malaria cases in 2011 declined by 66% (95% confidence interval [CI], 44-79%) and SPR by 37% (CI, 20%-51%) compared to the level predicted by pre-intervention trends. In children under 5 years of age, malaria admissions and deaths fell by 81% (CI, 47%-94%) and 73% (CI, 48%-86%) respectively. Optimal breakpoint of the trendlines occurred between January and June 2006, consistent with the timing of malaria interventions. Over the same period, non-malaria cases and deaths either increased or remained unchanged, the number of malaria diagnostic tests performed reflected the decline in malaria cases, and rainfall remained at levels supportive of malaria transmission. CONCLUSIONS: Malaria cases and deaths in Ethiopian hospitals decreased substantially during 2006-2011 in conjunction with scale-up of malaria interventions. The decrease could not be accounted for by changes in hospital visits, malaria diagnostic testing or rainfall. However, given the history of variable malaria transmission in Ethiopia, more data would be required to exclude the possibility that the decrease is due to other factors.