Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018.

BACKGROUND: The use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania. METHODS: A single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety. RESULTS: A total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan-Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania. METHODS: This was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy. RESULTS: A total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).

Outdoor biting and pyrethroid resistance as potential drivers of persistent malaria transmission in Zanzibar.

BACKGROUND: Low-level of malaria transmission persist in Zanzibar despite high coverage of core vector control interventions. This study was carried out in hot-spot sites to better understand entomological factors that may contribute to residual malaria transmission in Zanzibar. METHODS: A total of 135 households were randomly selected from six sites and consented to participate with 20-25 households per site. Mosquito vector surveillance was carried out indoors and outdoors from 6:00 pm-7:00 am using miniaturized double net trap (DN-Mini™). Additional collections were done indoors using mouth aspirators to retrieve resting mosquitoes from wall and ceiling surfaces, and outdoors using resting bucket and pit traps. All collected mosquitoes were morphologically and genetically (PCR) analysed in the laboratory. All collected anopheline and blood-fed mosquitoes were analysed for sporozoite infection and blood meal host preferences by Circumsporozoite Protein ELISA and blood meal ELISA, respectively. The differences between indoor and outdoor mosquito biting rates were analysed using generalized linear mixed models. Levels of resistance to commonly used insecticides were quantified by WHO susceptibility tests. RESULTS: Out of 704 malaria vectors collected across 135 households, PCR analysis shows that 98.60% were Anopheles arabiensis, 0.6% Anopheles merus and 0.6% Anopheles gambiae sensu stricto. Sporozoite ELISA analysis indicates that all mosquitoes were negative for the malaria parasite. The results show that more An. arabiensis were collected outdoor (~ 85%) compared to indoor (~ 15%). Furthermore, large numbers of An. arabiensis were caught in outdoor resting sites, where the pit trap (67.2%) collected more mosquitoes compared to the outdoor DN-Mini trap (32.8%). Nearly two-thirds (60.7%) of blood-fed mosquitoes had obtained blood meals from non-human hosts. Mosquitoes displayed non-uniform susceptibility status and resistance intensity among the tested insecticides across the study sites to all WHO recommended insecticides across the study sites. CONCLUSION: This study suggests that in contexts such as Zanzibar, testing of novel techniques to complement indoor protection and targeting outdoor biting and/or resting mosquitoes, may be warranted to complement existing interventions and contribute to malaria elimination efforts. The study highlights the need to implement novel interventions and/or adaptations of strategies that can target outdoors biting mosquitoes.

Evaluation of long-lasting insecticidal net distribution through schools in Southern Tanzania.

Universal coverage with effective vector control remains the mainstay of malaria vector control in sub-Saharan Africa. Tanzania has utilized a number of mechanisms for the maintenance of long-lasting insecticidal net (LLIN) coverage over time. Schools have been identified as one potential channel for continuous distribution of LLIN. This research aims to evaluate an annual school-based LLIN distribution programme in Tanzania that began in 2013, called the School Net Programme (SNP). Following each of the first four rounds of SNP distribution, a household survey was conducted in intervention and comparison districts in Southern and Lake zones of Tanzania (N = 5083 households). Measures of ownership, access and use were compared between intervention and comparison districts. Determinants of reach were assessed in intervention districts. Population access to an LLIN increased from 63.1% (95% CI: 58.8, 67.5) to 76.5% (95% CI: 72.9, 80.0) in the intervention districts between the first and last surveys. Access also rose in the comparison districts from 51.4% (95% CI: 46.9, 55.9) to 79.8% (95% CI: 77.3, 82.0) following mass distribution and implementation of school-based distribution during the study period. LLIN use increased in intervention districts from 44.9% (95% CI: 40.5, 49.3) to 65.6% (95% CI: 59.4, 71.8) and from 57.2% (95% CI: 49.7, 64.7) to 77.4% (95% CI: 69.3, 85.5) specifically amongst primary school-aged children. Households reached by the SNP were wealthier households with children enrolled in school. The SNP in Tanzania was able to maintain population level LLIN ownership, use and access in the absence of mass distribution. The SNP successfully reached households that housed school-aged children. Alternative delivery strategies may need to be considered to reach households without children enrolled in schools that experienced fewer benefits from the programme.

Psychedelic Psychiatry and the Consult-Liaison Psychiatrist: A Primer.

BACKGROUND: Psychedelic compounds such as lysergic acid diethylamide (LSD), psilocybin, and 3,4-Methylenedioxymethamphetamine (MDMA) share a long and complex history with psychiatry. A half century ago, psychedelics were widely employed by psychiatrists in investigational and clinical settings, with studies demonstrating promising findings for their use in the treatment of mental illness and substance use disorders. However, concerns were also raised about their abuse potential and other adverse effects. Owing to these worries and psychedelics' association with the counterculture movement, psychedelics were largely outlawed in the United States in 1970, bringing research on their therapeutic potential to a halt. However, in recent years, a resurgence of psychedelic research has revealed compelling, though early, evidence for the use of psychedelic-assisted therapy in treating alcohol use disorder, nicotine use disorder, posttraumatic stress disorder, and depression. OBJECTIVE: Here we provide an overview of psychiatry's complicated relationship with psychedelics, while reviewing contemporary findings on psychedelic-assisted therapy, safety of psychedelic-assisted therapy, and risks of nonmedical use. We also make the case that psychiatry should consider preparing now for the possibility of Food and Drug Administration approval of psychedelic-assisted therapies in the near future. We conclude by discussing how growing societal interest in psychedelics could impact the work of consult-liaison psychiatrists, while also exploring how consult-liaison psychiatrists might contribute to future delivery of psychedelic treatments. METHODS: We reviewed literature on psychedelic-assisted therapies and adverse events resulting from nonmedical psychedelic use. RESULTS: We found a small, but rapidly growing literature indicating that psychedelic-assisted therapies may have treatment potential for mental illness and addiction. Our search also revealed a variety of rare adverse events stemming from nonmedical psychedelic use. CONCLUSIONS: Despite past concerns about psychedelics, current data indicate psychedelic-assisted therapy may potentially reduce suffering owing to mental illness and addiction if administered thoughtfully and cautiously by trained professionals in medical settings.

Describing the current status of Plasmodium falciparum population structure and drug resistance within mainland Tanzania using molecular inversion probes.

High-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programmes, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania countrywide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, approximately separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from nearby districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts (including two infections carrying pfk13-R561H), and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared.

Malaria vector species composition and entomological indices following indoor residual spraying in regions bordering Lake Victoria, Tanzania.

BACKGROUND: Vector control through long-lasting insecticidal nets (LLINs) and focal indoor residual spraying (IRS) is a major component of the Tanzania national malaria control strategy. In mainland Tanzania, IRS has been conducted annually around Lake Victoria basin since 2007. Due to pyrethroid resistance in malaria vectors, use of pyrethroids for IRS was phased out and from 2014 to 2017 pirimiphos-methyl (Actellic® 300CS) was sprayed in regions of Kagera, Geita, Mwanza, and Mara. Entomological surveillance was conducted in 10 sprayed and 4 unsprayed sites to determine the impact of IRS on entomological indices related to malaria transmission risk. METHODS: WHO cone bioassays were conducted monthly on interior house walls to determine residual efficacy of pirimiphos-methyl CS. Indoor CDC light traps with or without bottle rotator were hung next to protected sleepers indoors and also set outdoors (unbaited) as a proxy measure for indoor and outdoor biting rate and time of biting. Prokopack aspirators were used indoors to capture resting malaria vectors. A sub-sample of Anopheles was tested by PCR to determine species identity and ELISA for sporozoite rate. RESULTS: Annual IRS with Actellic® 300CS from 2015 to 2017 was effective on sprayed walls for a mean of 7 months in cone bioassay. PCR of 2016 and 2017 samples showed vector populations were predominantly Anopheles arabiensis (58.1%, n = 4,403 IRS sites, 58%, n = 2,441 unsprayed sites). There was a greater proportion of Anopheles funestus sensu stricto in unsprayed sites (20.4%, n = 858) than in sprayed sites (7.9%, n = 595) and fewer Anopheles parensis (2%, n = 85 unsprayed, 7.8%, n = 591 sprayed). Biting peaks of Anopheles gambiae sensu lato (s.l.) followed periods of rainfall occurring between October and April, but were generally lower in sprayed sites than unsprayed. In most sprayed sites, An. gambiae s.l. indoor densities increased between January and February, i.e., 10-12 months after IRS. The predominant species An. arabiensis had a sporozoite rate in 2017 of 2.0% (95% CI 1.4-2.9) in unsprayed sites compared to 0.8% (95% CI 0.5-1.3) in sprayed sites (p = 0.003). Sporozoite rates were also lower for An. funestus collected in sprayed sites. CONCLUSION: This study contributes to the understanding of malaria vector species composition, behaviour and transmission risk following IRS around Lake Victoria and can be used to guide malaria vector control strategies in Tanzania.

Patterns of human exposure to malaria vectors in Zanzibar and implications for malaria elimination efforts.

BACKGROUND: Zanzibar provides a good case study for malaria elimination. The islands have experienced a dramatic reduction in malaria burden since the introduction of effective vector control interventions and case management. Malaria prevalence has now been maintained below 1% for the past decade and the islands can feasibly aim for elimination. METHODS: To better understand factors that may contribute to remaining low-level malaria transmission in Zanzibar, layered human behavioural and entomological research was conducted between December 2016 and December 2017 in 135 randomly selected households across six administrative wards. The study included: (1) household surveys, (2) structured household observations of nighttime activity and sleeping patterns, and (3) paired indoor and outdoor mosquito collections. Entomological and human behavioural data were integrated to provide weighted estimates of exposure to vector bites, accounting for proportions of people indoors or outdoors, and protected by insecticide-treated nets (ITNs) each hour of the night. RESULTS: Overall, 92% of female Anopheles mosquitoes were caught in the rainy season compared to 8% in the dry season and 72% were caught outdoors compared to 28% indoors. For individual ITN users, ITNs prevented an estimated two-thirds (66%) of exposure to vector bites and nearly three quarters (73%) of residual exposure was estimated to occur outdoors. Based on observed levels of ITN use in the study sites, the population-wide mean personal protection provided by ITNs was 42%. DISCUSSION/CONCLUSIONS: This study identified gaps in malaria prevention in Zanzibar with results directly applicable for improving ongoing programme activities. While overall biting risk was low, the most notable finding was that current levels of ITN use are estimated to prevent less than half of exposure to malaria vector bites. Variation in ITN use across sites and seasons suggests that additional gains could be made through targeted social and behaviour change interventions. However, even for ITN users, gaps in protection remain, with a majority of exposure to vector bites occurring outdoors before going to sleep. Supplemental interventions targeting outdoor exposure to malaria vectors, and groups that may be at increased risk of exposure to malaria vectors, should be explored.

Monitoring the durability of the long-lasting insecticidal nets Olyset® and PermaNet® 2.0 in similar use environments in Zanzibar.

BACKGROUND: Malaria transmission in Zanzibar has dramatically reduced in recent years but vector control interventions such as long-lasting insecticidal nets (LLIN) must continue to reach malaria elimination. To achieve this, the Zanzibar Malaria Elimination Programme needs actionable evidence of the durability of the LLIN brands distributed. This study compared physical and insecticidal durability of two LLIN brands: Olyset® and PermaNet© 2.0 in two similar districts on the islands of Unguja and Pemba. METHODS: This was a prospective cohort study of representative samples of households from two districts, recruited at baseline 4 months after the mass campaign. All campaign nets in these households were labelled and followed up over a period of 33 months. Primary outcome was the "proportion of nets surviving in serviceable condition" based on attrition and integrity measures and the median survival in years. The outcome for insecticidal durability was determined by bio-assay from sub-samples of campaign nets. RESULTS: A total of 834 campaign nets (121% of target) from 299 households were included in the study. Definite outcomes could be determined for 86% of the cohort nets in Unguja (PermaNet® 2.0) and 89% in Pemba (Olyset®). After 33 months, physical survival in serviceable condition was 55% in Unguja and 51% in Pemba. Estimated median survival was lower in Pemba at all time points with 2.3-2.7 years compared to 3.1-3.3 yeas in Unguja. Multivariable Cox proportionate hazard models confirmed the difference between brands (p < 0.0001) and identified household net-care attitude (p = 0.007) and folding of hanging nets during the day (p < 0.0001) as significant determinants, in addition to exclusive use of nets by adults (p = 0.03) and use only over a finished bedframe (p = 0.01). Optimal insecticidal effectiveness was 80% or higher for both brands at all time points when both cone bio-assays and tunnel tests were applied. CONCLUSIONS: After 3 years of follow-up, Olyset® LLIN showed significantly lower physical survival compared to PermaNet® 2.0 LLIN even after adjusting for other variables of net-use environment and net handling. This suggests that the differences were driven by the textile characteristics of the LLIN brands.

Sustaining LLIN coverage with continuous distribution: the school net programme in Tanzania.

Most malaria-endemic countries have struggled in the past decade to establish effective national-scale continuous distribution mechanisms for long-lasting insecticidal nets (LLINs). Since the implementation of the Tanzania National Voucher Scheme in 2004 and mass-distribution campaigns in 2009-2011 and 2015-2016, Tanzania has been committed to finding new and innovative ways of achieving and maintaining universal bed net coverage. Planning for the School Net Programme (SNP) began in 2011 and in 2013, the country piloted a SNP in three regions. Nets were distributed annually to children attending schools in selected primary and secondary grades. Intra-family re-distribution was assumed, and hence the family as a whole, rather than just the children themselves, were the targeted beneficiaries. The programme has since expanded to 14 regions and has seen six rounds of annual distribution. In its fifth year, 3 million nets were distributed at a cost of USD 3.64 per net and USD 0.60 per person-year of protection (including the net). ITN access and use were maintained at a high level (~ 50-75%) over the first 4 years of distribution within selected evaluation areas, even in the absence of a mass distribution event. Net distribution through primary schools has proven to be a feasible and effective strategy for maintaining consistently high coverage in Tanzania.

Costs of insecticide-treated bed net distribution systems in sub-Saharan Africa.

BACKGROUND: Insecticide-treated nets (ITNs) are one of the most cost-effective measures for preventing malaria. The World Health Organization recommends both large-scale mass distribution campaigns and continuous distributions (CD) as part of a multifaceted strategy to achieve and sustain universal access to ITNs. A combination of these strategies has been effective for scaling up ITN access. For policy makers to make informed decisions on how to efficiently implement CD or combined strategies, information on the costs and cost-effectiveness of these delivery systems is necessary, but relatively few published studies of the cost continuous distribution systems exist. METHODS: To address the gap in continuous distribution cost data, four types of delivery systems-CD through antenatal care services (ANC) and the expanded programme on immunization (EPI) (Ghana, Mali, and mainland Tanzania), CD through schools (Ghana and mainland Tanzania), and a combined community/health facility-based distribution (Zanzibar, Tanzania), as well as mass distributions (Mali)-were costed. Data on costs were collected retrospectively from financial and operational records, stakeholder interviews, and resource use surveys. RESULTS: Overall, from a full provider perspective, mass distributions and continuous systems delivered ITNs at overlapping economic costs per net distributed (mass distributions: 4.37-4.61 USD, CD channels: 3.56-9.90 USD), with two of the school-based systems and the mass distributions at the lower end of this range. From the perspective of international donors, the costs of the CD systems were, for the most part, less costly than the mass distributions (mass distributions: 4.34-4.55 USD, Ghana and Tanzania 2017 school-based: 3.30-3.69 USD, health facility-based: 3.90-4.55 USD, combined community/health facility 4.55 USD). The 2015 school-based distribution (7.30 USD) and 2016 health facility-based distribution (6.52 USD) programmes in Tanzania were an exception. Mass distributions were more heavily financed by donors, while CD relied more extensively on domestic resource contributions. CONCLUSIONS: These results suggest that CD strategies can continue to deliver nets at a comparable cost to mass distributions, especially from the perspective of the donor.

Human behaviour and residual malaria transmission in Zanzibar: findings from in-depth interviews and direct observation of community events.

BACKGROUND: Zanzibar has maintained malaria prevalence below 1% for the past decade, yet elimination remains elusive despite high coverage of core vector control interventions. As part of a study investigating the magnitude and drivers of residual transmission in Zanzibar, qualitative methods were utilized to better understand night time activities and sleeping patterns, individual and community-level risk perceptions, and malaria prevention practices. METHODS: A total of 62 in-depth interviews were conducted with community members and local leaders across six sites on Unguja Island, Zanzibar. Twenty semi-structured community observations of night-time activities and special events were conducted to complement interview findings. Data were transcribed verbatim, coded, and analysed using a thematic approach. RESULTS: Participants reported high levels of ITN use, but noted gaps in protection, particularly when outdoors or away from home. Routine household and community activities were common in evenings before bed and early mornings, while livelihood activities and special events lasted all or most of the night. Gender variation was reported, with men routinely spending more time away from home than women and children. Outdoor sleeping was reported during special events, such as weddings, funerals, and religious ceremonies. Participants described having difficulty preventing mosquito bites while outdoors, travelling, or away from home, and perceived higher risk of malaria infection during these times. Travel and migration emerged as a crucial issue and participants viewed seasonal workers coming from mainland Tanzania as more likely to have a malaria infection and less likely to be connected to prevention and treatment services in Zanzibar. Some community leaders reported taking the initiative to register seasonal workers coming into their community and linking them to testing and treatment services. CONCLUSIONS: Targeting malaria interventions effectively is critical and should be informed by a clear understanding of relevant human behaviour. These findings highlight malaria prevention gaps in Zanzibar, and the importance of identifying new approaches to complement current interventions and accelerate the final phases of malaria elimination. Development and deployment of complementary interventions should consider human behaviour, including gender norms, that can influence exposure to malaria vectors and prevention practices. Expansion of community-level programmes targeting travellers and seasonal workers should also be explored.

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania.

BACKGROUND: The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance. METHODS: Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440-600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively. RESULTS: Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene. CONCLUSION: The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies. Trial Registration ClinicalTrials.gov NCT03387631.

'To be honest, women do everything': understanding roles of men and women in net care and repair in Southern Tanzania.

BACKGROUND: In Tanzania, the roles of men and women are classified based on the local cultural context. While men are usually the breadwinners, women are traditionally responsible for most domestic chores. Particularly for malaria prevention, studies in Africa have revealed women as being responsible for daily up-keep of the net. Using social role theory, this study explored the role of men and women in net care and repair and gender-related motivation and barriers to net care and repair in Tanzania. METHODS: The study was conducted in the two villages of Ruangwa district in Lindi Region. The study applied qualitative approaches and carried out in-depth interviews and focus group discussions with men, women, women with children under the age of five, and village key informants. RESULTS: Mosquito nets were valued by all participants as a protection measure against mosquitoes. Study findings indicate that net care and repair falls under a woman's daily household responsibilities. While men were said to assist in stitching damaged nets, washing dirty bed nets was regarded inappropriate for men and not traditionally accepted. Motivation for net care and repair was reported to come from both men and women; for a woman keeping the net clean defined a caring and responsible woman, while men indirectly promoted net washing when complaining about nets being dirty. Women reported that men could do everything that women do regarding net care and repair, but that it does not fit into societal norms. CONCLUSION: With increased globalization in Tanzania, more women are becoming part of the workforce, which may limit their full commitment to net care and repair activities, leading to increased net damage, malaria incidences and higher costs for malaria treatment. The National Malaria Control Programme should consider incorporating research-informed gender-transformative messages into their behaviour change communication on mosquito nets and work closely with trusted Community Health Workers to inform communities about the importance of sharing responsibilities in net care and repair. It is acknowledged that changing people's behaviour and practices is a long process, which will require a deep cultural and political shift.

'For the poor, sleep is leisure': understanding perceptions, barriers and motivators to mosquito net care and repair in southern Tanzania.

BACKGROUND: The rate of physical deterioration of long-lasting insecticidal nets (LLINs) varies by household practices, net brand and environment. One way to sustain the protection provided by LLINs against malaria is through day-to-day care, and repairing holes as and when they occur. To ensure LLIN coverage is high between mass campaigns and, as international donor funds decrease, personal responsibility to maintain nets in good condition is becoming more important. This study aimed to understand local barriers and motivators to net care and repair in southern Tanzania in a community that receives free LLINs through a school-based distribution mechanism. METHODS: Qualitative research methods were applied in a rural and peri-urban village in Ruangwa district. Focus group discussions (FGDs) were conducted for five groups of 8-12 participants; (1) key informants, (2) young men (18-24 years old), (3) women (> 18 years) with children under the age of five, (4) older men (> 25 years), and (5) older women with or without children (> 25 years). In each village, five men, five women with or without children, and five women with children under the age of five were recruited for in-depth interviews (IDIs). After each IDI and FGD with women with young children, participants were guided through a participatory activity. The study also counted the number and size of holes in nets currently used by IDI participants to determine their physical degradation status. RESULTS: A general willingness to care and repair mosquito nets was observed in Ruangwa district for the love of a good night's sleep free of mosquito bites or noises. Net care was preferred over repair, especially among women who were the primary caretakers. The main motivation to look after nets was protection against mosquito bites and malaria. Washing nets occurred as frequently as every other week in some households to ensure cleanliness, which prevented other dirt-related problems such as sneezing and headaches. Barriers to net care included care not being a priority in the day-to-day activities and lack of net retreatment kits. Net repair was reported to be a temporary measure and necessary as soon as a hole was identified. However, during the net assessment and participatory activity, it became clear that people did not actually repair smaller holes. Protection against mosquitoes, malaria and cost saving from replacing nets were identified as motivators for net repair. Barriers to net repair included it not being a priority to repair holes that could be tucked under the mattress and lack of knowledge on when to repair nets. CONCLUSION: In Ruangwa, net care was defined as overall net maintenance, such as cleanliness, and not directly associated with the prevention of damage as reported in other studies. Net repair was reported as a temporary measure before the acquisition of a new net, hence not a priority in a busy household. Inconsistencies were observed between reported intentions to repair mosquito nets and current net condition. Targeted education through health facilities and community change agents are potential means to overcome barriers to net care and repair.

Design, Implementation, and Evaluation of a School Insecticide-Treated Net Distribution Program in Cross River State, Nigeria.

BACKGROUND: In 2013, the World Health Organization recommended distribution through schools, health facilities, community health workers, and mass campaigns to maintain coverage with insecticide-treated nets (ITNs). We piloted school distribution in 3 local government areas (LGAs) of Cross River State, Nigeria. METHODS: From January to March 2011, all 3 study sites participated in a mass ITN campaign. Baseline data were collected in June 2012 (N=753 households) and school distribution began afterward. One ITN per student was distributed to 4 grades once a year in public schools. Obubra LGA distributed ITNs in 2012, 2013, and 2014 and Ogoja LGA in 2013 and 2014 while Ikom LGA served as a comparison site. Pregnant women in all sites were eligible to receive ITNs through standard antenatal care (ANC). Endline survey data (N=1,450 households) were collected in March 2014. Data on ITN ownership, population access to an ITN, and ITN use were gathered and analyzed. Statistical analysis used contingency tables and chi-squared tests for univariate analysis, and a concentration index was calculated to assess equity in ITN ownership. RESULTS: Between baseline and endline, household ownership of at least 1 ITN increased in the intervention sites, from 50% (95% confidence interval [CI]: 44.7, 54.3) to 76% (95% CI: 71.2, 81.0) in Ogoja and from 51% (95% CI: 35.3, 66.7) to 78% (95% CI: 71.5, 83.1) in Obubra, as did population access to ITN, from 36% (95% CI: 32.0, 39.5) to 53% (95% CI: 48.0, 58.0) in Ogoja and from 34% (95% CI: 23.2, 45.6) to 55% in Obubra (95% CI: 48.4, 60.9). In contrast, ITN ownership declined in the comparison site, from 64% (95% CI: 56.4, 70.8) to 43% (95% CI: 37.4, 49.4), as did population ITN access, from 47% (95% CI: 40.0, 53.7) to 26% (95% CI: 21.9, 29.9). Ownership of school ITNs was nearly as equitable (concentration index 0.06 [95% CI: 0.02, 0.11]) as for campaign ITNs (-0.03 [95% CI: -0.08, 0.02]), and there was no significant oversupply or undersupply among households with ITNs. Schools were the most common source of ITNs at endline and very few households (<2%) had nets from both school and ANC. CONCLUSION: ITN distribution through schools and ANC provide complementary reach and can play an effective role in achieving and maintaining universal coverage. More research is needed to evaluate the cost-effectiveness of such continuous distribution channels in combination with, or as a potential replacement for, subsequent mass campaigns.

Multiple insecticide resistance in Anopheles gambiae from Tanzania: a major concern for malaria vector control.

BACKGROUND: Malaria vector control in Tanzania is based on use of long-lasting insecticide treated nets (LLINs) and indoor residual spraying (IRS), which both rely on the use of chemical insecticides. The effectiveness of these control tools is endangered by the development of insecticide resistance in the major malaria vectors. This study was carried out to monitor the susceptibility status of major malaria vectors to insecticides used for IRS and LLINs in mainland Tanzania. METHODS: Mosquito larvae were collected in 20 sites of Tanzania mainland in 2015. Phenotypic resistance was determined using standard WHO susceptibility tests. Molecular assay were used to determine distribution of Anopheles gambiae sub-species. A microplate assay approach was used for identifying enzyme levels on single mosquitoes from each sites compared with a susceptible reference strain, An. gambiae sensu stricto (s.s.) Kisumu strain. RESULTS: Anopheles arabiensis was the dominant malaria specie in the country, accounting for 52% of the sibling species identified, while An. gambiae s.s. represented 48%. In Arumeru site, the dominant species was An. arabiensis, which was resistant to both pyrethroids (permethrin and deltamethrin), and pirimiphos-methyl, and had significant elevated levels of GSTs, non-specific esterases, and oxidase enzymes. An. arabiensis was also a dominant species in Kilombero and Kondoa sites, both were resistant to permethrin and deltamethrin with significant activity levels of oxidase enzymes. Resistance to bendiocarb was recorded in Ngara site where specie composition is evenly distributed between An. gambiae s.s. and An.arabiensis. Also bendiocarb resistance was recorded in Mbozi site, where An. gambiae s.s. is the dominant species. CONCLUSIONS: Overall, this study confirmed resistance to all four insecticide classes in An. gambiae sensu lato in selected locations in Tanzania. Results are discussed in relation to resistance mechanisms and the optimization of resistance management strategies.

Evaluation of a continuous community-based ITN distribution pilot in Lainya County, South Sudan 2012-2013.

BACKGROUND: Continuous distribution of insecticide-treated nets (ITNs) has now been accepted as one way of sustaining ITN universal coverage. Community-based channels offer an interesting means of delivering ITNs to households to sustain universal ITN coverage. The objective of this study was to provide proof of concept for this channel. METHODS: A 9-month, community-based, distribution pilot was implemented beginning 1 year after a mass campaign in Lainya County, South Sudan from 2012 to 2013. Following social mobilization, community members could request an ITN from a net coupon holder. Eligibility criteria included having lost an ITN, giving birth outside of the health facility, or not having enough ITNs for all household members. After verification, households could exchange the coupon for an ITN at a distribution point. The evaluation was a pre/post design using representative household surveys with two-stage cluster sampling and a sample size of 600 households per survey. RESULTS: At endline, 78% of respondents were aware of the scheme and 89% of those also received an ITN through community-based distribution. Population access to ITNs nearly doubled, from 38% at baseline to 66% after the pilot. Household ownership of any ITN and enough ITNs (1 for 2 people) also increased significantly, from 66 to 82% and 19 to 46%, respectively. Community-based distribution was the only source of ITNs for 53.4% of households. The proportion of the population using an ITN last night increased from 22.7% at baseline to 53.9% at endline. A logistic regression model indicates that although behaviour change communication was positively associated with an increase in ITN use, access to enough nets was the greatest determinant of use. CONCLUSIONS: ITN access and use improved significantly in the study area during the pilot, coming close to universal coverage targets. This pilot serves as proof of concept for the community-based distribution methodology implemented as a mechanism to sustain ITN universal coverage. Longer periods of implementation should be evaluated to determine whether community-based distribution can successfully maintain ITN coverage beyond the short term, and reach all wealth quintiles equitably.

School Distribution as Keep-Up Strategy to Maintain Universal Coverage of Long-Lasting Insecticidal Nets: Implementation and Results of a Program in Southern Tanzania.

Tanzania successfully scaled up coverage of long-lasting insecticidal nets (LLINs) through mass campaigns. To sustain these gains, a school-based approach was piloted in the country's Southern Zone starting in 2013, called the School Net Program 1 (SNP1). We report on the design, implementation, monitoring, and outputs of the second round (SNP2) undertaken in 2014. SNP2 was conducted in all schools in Lindi, Mtwara, and Ruvuma regions, targeting students in primary (Standards 1, 3, 5, and 7) and secondary (Forms 2 and 4) schools and all teachers. In Lindi region, 2 additional classes (Standards 2 and 4) were targeted. LLIN distribution data were managed using an Android software application called SchoolNet. SNP2 included 2,337 schools, 473,700 students, and 25,269 teachers. A total of 5,070 people were trained in LLIN distribution (487 trainers and 4,583 distributors), and 4,392 (434 ward and 3,958 village) community change agents undertook sensitization and mobilization. A total of 507,775 LLINs were distributed to schools, with 464,510 (97.9% of those registered) students and 24,206 (95.8% of those registered) school teachers receiving LLINs. LLIN ownership and use is expected to have increased, potentially further reducing the burden of malaria in the Southern Zone of Tanzania.

Efficacy, persistence and vector susceptibility to pirimiphos-methyl (Actellic 300CS) insecticide for indoor residual spraying in Zanzibar.

BACKGROUND: Indoor residual spraying (IRS) of households with insecticide is a principal malaria vector control intervention in Zanzibar. In 2006, IRS using the pyrethroid lambda-cyhalothrine was introduced in Zanzibar. Following detection of pyrethroid resistance in 2010, an insecticide resistance management plan was proposed, and IRS using bendiocarb was started in 2011. In 2014, bendiocarb was replaced by pirimiphos methyl. This study investigated the residual efficacy of pirimiphos methyl (Actellic 300CS) sprayed on common surfaces of human dwellings in Zanzibar. METHODS: The residual activity of Actellic 300CS was determined over 9 months through bioassay tests that measured the mortality of female Anopheles mosquitoes, exposed to sprayed surfaces under a WHO cone. The wall surfaces included; mud wall, oil or water painted walls, lime washed wall, un-plastered cement block wall and stone blocks. Insecticide susceptibility testing was done to investigate the resistance status of local malaria vectors against Actellic 300CS using WHO protocols; Anopheline species were identified using PCR methods. RESULTS: Baseline tests conducted one-day post-IRS revealed 100% mortality on all sprayed surfaces. The residual efficacy of Actellic 300CS was maintained on all sprayed surfaces up to 8 months post-IRS. However, the bioassay test conducted 9 months post-IRS showed the 24 h mortality rate to be ≤80% for lime wash, mud wall, water paint and stone block surfaces. Only oil paint surface retained the recommended residual efficacy beyond 9 months post-IRS, with mortality maintained at ≥97 %. Results of susceptibility tests showed that malaria vectors in Zanzibar were fully (100%) susceptible to Actellic 300CS. The predominant mosquito vector species was An. arabiensis (76.0%) in Pemba and An. gambiae (83.5%) in Unguja. CONCLUSION: The microencapsulated formulation of pirimiphos methyl (Actellic 300CS) is a highly effective and appropriate insecticide for IRS use in Zanzibar as it showed a relatively prolonged residual activity compared to other products used for the same purpose. The insecticide extends the residual effect of IRS thereby making it possible to effectively protect communities with a single annual spray round reducing overall costs. The insecticide proved to be a useful alternative in insecticide resistance management plans.