Safety, tolerability and efficacy of repeated doses of dihydroartemisinin-piperaquine for the prevention and treatment of malaria: A systematic review and meta-analysis

Background Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to determine the efficacy and safety of repeated treatment with DP. Methods Following PRISMA guidelines, we searched multiple databases on September 1, 2016 with the terms: “human” AND “dihydroartemisinin-piperaquine” OR “DHA-PPQ.”. Prospective studies of IPT-DP or repeat DP courses for case-management were eligible. Random effects models were used. Findings Eleven studies were included: two repeat treatment studies (one in children <5y and one in pregnant women), and nine IPT trials (five in children <5y; one in schoolchildren; one in adults; two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP-amodiaquine, SP-piperaquine, SP-chloroquine, and trimethoprim-sulfamethoxazole. Of 14,628 participants, 3,935 received multiple DP courses (2-18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared to placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily trimethoprim-sulfamethoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women), all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP. Interpretation Monthly DP appears well-tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing. Funding Source Bill & Melinda Gates Foundation and NI

Barriers and facilitators to antenatal and delivery care in western Kenya: a qualitative study

Background In western Kenya, maternal mortality is a major public health problem estimated at 730/100,000 live births, higher than the Kenyan national average of 488/ 100,000 women. Many women do not attend antenatal care (ANC) in the first trimester, half do not receive 4 ANC visits. A high proportion use traditional birth attendants (TBA) for delivery and 1 in five deliver unassisted. The present study was carried out to ascertain why women do not fully utilise health facility ANC and delivery services. Methods A qualitative study using 8 focus group discussions each consisting of 8–10 women, aged 15–49 years. Thematic analysis identified the main barriers and facilitators to health facility based ANC and delivery. Results Attending health facility for ANC was viewed positively. Three elements of care were important; testing for disease including HIV, checking the position of the foetus, and receiving injections and / or medications. Receiving a bed net and obtaining a registration card were also valuable. Four barriers to attending a health facility for ANC were evident; attitudes of clinic staff, long clinic waiting times, HIV testing and cost, although not all women felt the cost was prohibitive being worth it for the health of the child. Most women preferred to deliver in a health facility due to better management of complications. However cost was a barrier, and a reason to visit a TBA because of flexible payment. Other barriers were unpredictable labour and transport, staff attitudes and husbands’ preference. Conclusions Our findings suggest that women in western Kenya are amenable to ANC and would be willing and even prefer to deliver in a healthcare facility, if it were affordable and accessible to them. However for this to happen there needs to be investment in health promotion, and transport, as well as reducing or removing all fees associated with antenatal and delivery care. Yet creating demand for service will need to go alongside investment in antenatal services at organisational, staffing and facility level in order to meet both current and future increase in demand

Global estimates of the number of pregnancies at risk of malaria from 2007 to 2020: a demographic study

Background: This study estimates the global distribution of pregnancies at risk of malaria for 2020 and shows trends since 2007. Rationale: This study aims to provide data on the global distribution of pregnancies at risk to inform global malaria prevention and control efforts. Methods: We used estimates from the Malaria-Atlas-Project on the total population living within areas of Plasmodium falciparum and P. vivax transmission, combined with country-specific demographic data on women of reproductive age, fertility rates, induced abortions, and stillbirths to derive the annual number of pregnancies overall and by parasite species and endemicity strata from 2007-to-2020. Results: In 2020, 122 million pregnancies occurred in malaria transmission areas, resulting in an estimated 71m live-births, including 53, 5, 46, 11, and 7 million pregnancies in the countries falling under the World Health Organization regional offices for South-East-Asia (SEARO), Western-Pacific (WPRO), Africa (AFRO), Eastern-Mediterranean (EMRO), and Americas (AMRO). Between 2007 and 2020, pregnancies in P. falciparum transmission areas fell by 11.4% globally despite an overall 7.0% increase in pregnancies by 2020, representing a decrease of 100%, 52.6%, 51.5%, 23.9% and 17.2% in EURO, WPRO, AMRO, EMRO and SEARO, but a 25.4% increase in AFRO. Those in P. vivax transmission areas fell by 42.8%, representing a decrease of 100.0%, 89.8%, 48.4%, 32.4% and 10% in EURO, WPRO, AMRO, EMRO and SEARO, but a 25.8% increase in AFRO. Our sensitivity analysis suggests that the number of pregnancies at risk of P.vivax could be 7-fold higher for AFRO if the whole of sub-Saharan Africa is considered endemic, which could be confirmed once more sensitive diagnostics and data are available. Conclusion: Between 2007 and 2020, substantial declines in the number of pregnancies at risk of malaria were seen globally. In AFRO, 25% more pregnancies are at risk of P. falciparum and P.vivax malaria than in 2007. This increase in the numbers at risk comes despite the decline in malaria rates due to the rapidly rising population and the number of pregnancies in endemic areas. These estimates should guide priority setting for resource allocation to control malaria in pregnancy. Funding: Gates Foundation and Telethon Trus

Pharmacokinetics of mefloquine and its effect on sulfamethoxazole and trimethoprim steady-state blood levels in intermittent preventive treatment (IPTp) of pregnant HIV-infected women in Kenya..

Abstract Background Intermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine is contra-indicated in HIV-positive pregnant women receiving sulfamethoxazole/trimethoprim prophylaxis. Since mefloquine is being considered as a replacement for sulfadoxine/pyrimethamine in this vulnerable population, an investigation on the pharmacokinetic interactions of mefloquine, sulfamethoxazole and trimethoprim in pregnant, HIV-infected women was performed. Methods A double-blinded, placebo-controlled study was conducted with 124 HIV-infected, pregnant women on a standard regimen of sulfamethoxazole/trimethoprim prophylaxis. Seventy-two subjects received three doses of mefloquine (15 mg/kg) at monthly intervals. Dried blood spots were collected from both placebo and mefloquine arms four to 672 h post-administration and on day 7 following a second monthly dose of mefloquine. A novel high-performance liquid chromatographic method was developed to simultaneously measure mefloquine, sulfamethoxazole and trimethoprim from each blood spot. Non-compartmental methods using a naïve-pooled data approach were used to determine mefloquine pharmacokinetic parameters. Results Sulfamethoxazole/trimethoprim prophylaxis did not noticeably influence mefloquine pharmacokinetics relative to reported values. The mefloquine half-life, observed clearance (CL/f), and area-under-the-curve (AUC0→∞) were 12.0 days, 0.035 l/h/kg and 431 µg-h/ml, respectively. Although trimethoprim steady-state levels were not significantly different between arms, sulfamethoxazole levels showed a significant 53 % decrease after mefloquine administration relative to the placebo group and returning to pre-dose levels at 28 days. Conclusions Although a transient decrease in sulfamethoxazole levels was observed, there was no change in hospital admissions due to secondary bacterial infections, implying that mefloquine may have provided antimicrobial protection

Rapid Diagnostic Test Performance Assessed Using Latent Class Analysis for the Diagnosis of Plasmodium falciparum Placental Malaria.

Placental malaria causes low birth weight and neonatal mortality in malaria-endemic areas. The diagnosis of placental malaria is important for program evaluation and clinical care, but is compromised by the suboptimal performance of current diagnostics. Using placental and peripheral blood specimens collected from delivering women in Malawi, we compared estimation of the operating characteristics of microscopy, rapid diagnostic test (RDT), polymerase chain reaction, and histopathology using both a traditional contingency table and a latent class analysis (LCA) approach. The prevalence of placental malaria by histopathology was 13.8%; concordance between tests was generally poor. Relative to histopathology, RDT sensitivity was 79.5% in peripheral and 66.2% in placental blood; using LCA, RDT sensitivities increased to 93.7% and 80.2%, respectively. Our results, if replicated in other cohorts, indicate that RDT testing of peripheral or placental blood may be suitable approaches to detect placental malaria for surveillance programs, including areas where intermittent preventive therapy in pregnancy is not used

Integrating HIV, syphilis, malaria and anaemia point-of-care testing (POCT) for antenatal care at dispensaries in western Kenya: discrete-event simulation modelling of operational impact

Background Despite WHO advocating for an integrated approach to antenatal care (ANC), testing coverage for conditions other than HIV remains low and women are referred to distant laboratories for testing. Using point-of-care tests (POCTs) at peripheral dispensaries could improve access to testing and timely treatment. However, the effect of providing additional services on nurse workload and client wait times are unknown. We use discrete-event simulation (DES) modelling to understand the effect of providing four point-of-care tests for ANC on nurse utilization and wait times for women seeking maternal and child health (MCH) services. Methods We collected detailed time-motion data over 20 days from one high volume dispensary in western Kenya during the 8-month implementation period (2014–2015) of the intervention. We constructed a simulation model using empirical arrival distributions, activity durations and client pathways of women seeking MCH services. We removed the intervention from the model to obtain wait times, length-of-stay and nurse utilization rates for the baseline scenario where only HIV testing was offered for ANC. Additionally, we modelled a scenario where nurse consultations were set to have minimum durations for sufficient delivery of all WHO-recommended services. Results A total of 183 women visited the dispensary for MCH services and 14 of these women received point-of-care testing (POCT). The mean difference in total waiting time was 2 min (95%CI: < 1–4 min, p = 0.026) for MCH women when integrated POCT was given, and 9 min (95%CI: 4–14 min, p < 0.001) when integrated POCT with adequate ANC consult times was given compared to the baseline scenario. Mean length-of-stay increased by 2 min (95%CI: < 1–4 min, p = 0.015) with integrated POCT and by 16 min (95%CI: 10–21 min, p < 0.001) with integrated POCT and adequate consult times compared to the baseline scenario. The two nurses’ overall daily utilization in the scenario with sufficient minimum consult durations were 72 and 75%. Conclusion The intervention had a modest overall impact on wait times and length-of-stay for women seeking MCH services while ensuring pregnant women received essential diagnostic testing. Nurse utilization rates fluctuated among days: nurses experienced spikes in workload on some days but were under-utilized on the majority of days. Overall, our model suggests there was sufficient time to deliver all WHO’s required ANC activities and offer integrated testing for ANC first and re-visits with the current number of healthcare staff. Further investigations on improving healthcare worker, availability, performance and quality of care are needed. Delivering four point-of-care tests together for ANC at dispensary level would be a low burden strategy to improve ANC

PRObiotics and SYNbiotics to improve gut health and growth in infants in western Kenya (PROSYNK Trial): Study protocol for a 4-arm, open-label, randomised, controlled trial

Background Malnutrition amongst under-fives remains common in resource-poor countries and is resistant to current interventions. New opportunities have emerged to target “environmental enteric dysfunction” (EED) that refers to the abnormal gut structure and function that compromises nutrition and growth in early life. EED results from colonisation of the gut with pathogenic microbes. Although the gut microbiome may provide a defence against ingested gut pathogens through colonisation resistance, its development is adversely affected by multiple environmental factors. Dietary supplements of pro- or synbiotics may build the resilience of the gut microbiome against these environmental factors and boost colonisation resistance. We aim to assess whether dietary supplementation of newborns in rural Kenya with pro/synbiotics prevents or ameliorates EED and improves growth. Methods Six hundred newborns less than four days old will be recruited from Homa Bay County Teaching and Referral Hospital, western Kenya. Newborns will be randomly allocated, stratified by HIV exposure, in a 1:1:1:1 ratio to one of 4 study arms to receive either of two synbiotics, a probiotic or no supplement. Supplements will be given daily for ten days and then weekly until six months of age. Participants will be followed until the age of two years. The primary outcome is systemic inflammation at six months assessed by plasma alpha-1-acid glycoprotein. Secondary outcomes include biomarkers of gut health and growth, anthropometric indices, morbidity and mortality. Discussion As dietary supplements with pro- or synbiotics may improve gut health and can be administered in early life, our findings may inform the package of interventions to prevent malnutrition and improve growth in Africa and similar low-resource settings

Performance of four HRP-2/pLDH combination rapid diagnostic tests and field microscopy as screening tests for malaria in pregnancy in Indonesia: a cross-sectional study.

BACKGROUND Malaria in pregnancy poses a major public health problem in Indonesia with an estimated six million pregnancies at risk of Plasmodium falciparum or Plasmodium vivax malaria annually. In 2010, Indonesia introduced a screen and treat policy for the control of malaria in pregnancy at first antenatal visit using microscopy or rapid diagnostic tests (RDTs). A diagnostic study was conducted in Sumba, Indonesia to compare the performance of four different RDTs in predominately asymptomatic pregnant women under field condition. METHODS Women were screened for malaria at antenatal visits using field microscopy and four HRP-2/pLDH combination RDTs (Carestart™, First-Response(®), Parascreen(®) and SD-Bioline(®)). The test results were compared with expert microscopy and nested PCR. End user experience of the RDTs in the field was assessed by questionnaire. RESULTS Overall 950 were recruited and 98.7 % were asymptomatic. The prevalence of malaria was 3.0-3.4 % by RDTs, and 3.6, 5.0 and 6.6 % by field microscopy, expert microscopy and PCR, respectively. The geometric-mean parasite density was low (P. falciparum = 418, P. vivax = 147 parasites/µL). Compared with PCR, the overall sensitivity of the RDTs and field microscopy to detect any species was 24.6-31.1 %; specificities were >98.4 %. Relative to PCR, First-Response(®) had the best diagnostic accuracy (any species): sensitivity = 31.1 %, specificity = 98.9 % and diagnostic odds ratio = 39.0 (DOR). The DOR values for Carestart™, Parascreen(®), SD-Bioline(®), and field microscopy were 23.4, 23.7, 23.5 and 29.2, respectively. The sensitivity of Pan-pLDH bands to detect PCR confirmed P. vivax mono-infection were 8.6-13.0 %. The sensitivity of the HRP-2 band alone to detect PCR confirmed P. falciparum was 10.3-17.9 %. Pan-pLDH detected P. falciparum cases undetected by the HRP-2 band resulting in a better test performance when both bands were combined. First Response(®) was preferred by end-users for the overall practicality. CONCLUSION The diagnostic accuracy to detect malaria among mostly asymptomatic pregnant women and perceived ease of use was slightly better with First-Response(®), but overall, differences between the four RDTs were small and performance comparable to field microscopy. Combination RDTs are a suitable alternative to field microscopy to screen for malaria in pregnancy in rural Indonesia. The clinical relevance of low density malaria infections detected by PCR, but undetected by RDTs or microscopy needs to be determined