A comparative field evaluation of six medicine quality screening devices in Laos

BackgroundMedicine quality screening devices hold great promise for post-market surveillance (PMS). However, there is little independent evidence on their field utility and usability to inform policy decisions. This pilot study in the Lao PDR tested six devices’ utility and usability in detecting substandard and falsified (SF) medicines.Methodology/principal findingsObservational time and motion studies of the inspections by 16 Lao medicine inspectors of 1) the stock of an Evaluation Pharmacy (EP), constructed to resemble a Lao pharmacy, and 2) a sample set of medicines (SSM); were conducted without and with six devices: four handheld spectrometers (two near infrared: MicroPHAZIR RX, NIR-S-G1 & two Raman: Progeny, Truscan RM); one portable mid-infrared spectrometer (4500a), and single-use paper analytical devices (PAD). User experiences were documented by interviews and focus group discussions.Significantly more samples were wrongly categorised as pass/fail with the PAD compared to the other devices in EP inspections (p<0.05). The numbers of samples wrongly classified in EP inspections were significantly lower than in initial visual inspections without devices for 3/6 devices (NIR-S-G1, MicroPHAZIR RX, 4500a). The NIR-S-G1 had the fastest testing time per sample (median 93.5 sec, p<0.001). The time spent on EP visual inspection was significantly shorter when using a device than for inspections without devices, except with the 4500a, risking missing visual clues of samples being SF. The main user errors were the selection of wrong spectrometer reference libraries and wrong user interpretation of PAD results. Limitations included repeated inspections of the EP by the same inspectors with different devices and the small sample size of SF medicines.Conclusions/significanceThis pilot study suggests policy makers wishing to implement portable screening devices in PMS should be aware that overconfidence in devices may cause harm by reducing inspectors’ investment in visual inspection. It also provides insight into the advantages/limitations of diverse screening devices in the hands of end-users.     

Laboratory evaluation of twelve portable devices for medicine quality screening

BackgroundPost-market surveillance is a key regulatory function to prevent substandard and falsified (SF) medicines from being consumed by patients. Field deployable technologies offer the potential for rapid objective screening for SF medicines.Methods and findingsWe evaluated twelve devices: three near infrared spectrometers (MicroPHAZIR RX, NIR-S-G1, Neospectra 2.5), two Raman spectrometers (Progeny, TruScan RM), one mid-infrared spectrometer (4500a), one disposable colorimetric assay (Paper Analytical Devices, PAD), one disposable immunoassay (Rapid Diagnostic Test, RDT), one portable liquid chromatograph (C-Vue), one microfluidic system (PharmaChk), one mass spectrometer (QDa), and one thin layer chromatography kit (GPHF-Minilab). Each device was tested with a series of field collected medicines (FCM) along with simulated medicines (SIM) formulated in a laboratory. The FCM and SIM ranged from samples with good quality active pharmaceutical ingredient (API) concentrations, reduced concentrations of API (80% and 50% of the API), no API, and the wrong API. All the devices had high sensitivities (91.5 to 100.0%) detecting medicines with no API or the wrong API. However, the sensitivities of each device towards samples with 50% and 80% API varied greatly, from 0% to 100%. The infrared and Raman spectrometers had variable sensitivities for detecting samples with 50% and 80% API (from 5.6% to 50.0%). The devices with the ability to quantitate API (C-Vue, PharmaChk, QDa) had sensitivities ranging from 91.7% to 100% to detect all poor quality samples. The specificity was lower for the quantitative C-Vue, PharmaChk, & QDa (50.0% to 91.7%) than for all the other devices in this study (95.5% to 100%).ConclusionsThe twelve devices evaluated could detect medicines with the wrong or none of the APIs, consistent with falsified medicines, with high accuracy. However, API quantitation to detect formulations similar to those commonly found in substandards proved more difficult, requiring further technological innovation.     

In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes

Plasmodium falciparum resistance to the former first-line antimalarials chloroquine and sulfadoxine/pyrimethamine has reached critically high levels in many malaria-endemic regions. This has spurred the introduction of several new artemisinin-based combination therapies (ACTs) that display excellent potency in treating drug-resistant malaria. Monitoring for the emergence of drug resistant P. falciparum is important for maximising the clinically effective lifespan of ACTs. Here, we provide a commentary on the article by Kaddouri et al., published in this issue of the International Journal of Parasitology, which documents the levels of susceptibility to ACT drugs and chloroquine in P. falciparum isolates from Mali. These authors report that some isolates approached a proposed in vitro threshold of resistance to monodesethyl-amodiaquine (the principal effective metabolite of amodiaquine, an important ACT partner drug), and establish baseline levels of susceptibility to the ACT drugs dihydroartemisinin and lumefantrine. The majority of clinical isolates manifested in vitro resistance to chloroquine. The authors also show good concordance between field-based assays employing a non-radioactive lactate dehydrogenase-based method of determining in vitro drug IC₅₀ values and the well-established [³H]hypoxanthine-based radioactive method. This work illustrates a good example of drug resistance surveillance, whose global coordination is being championed by the World Antimalarial Resistance Network. Our current opinion also more generally discusses the complexities inherent to conducting in vitro investigations with P. falciparum patient isolates and correlating these findings with treatment outcome data.     

Evaluation of portable devices for medicine quality screening: Lessons learnt,recommendations for implementation,and future priorities

Céline Caillet and co-authors discuss a Collection on use of portable devices for the evaluation of medicine quality and legitimacy.

Summary points

• Portable devices able to detect substandard and falsified medicines are vital innovations for enhancing the inspection of medicines in pharmaceutical supply chains and for timely action before they reach patients. Such devices exist, but there has been little to no independent scientific evidence of their accuracy and cost-effectiveness to guide regulatory authorities in choosing appropriate devices for their settings.
• We tested 12 portable devices, evaluated their diagnostic performances and the resources required to use each device in a laboratory.
• We then assessed the utility and usability of the devices in medicine inspectors’ hands in a pharmacy mimicking a real-life Lao pharmacy.
• We then assessed the health and economic benefits of using portable devices compared to not using them in a low- to middle-income setting.
• Here, we discuss the conclusions and practical implications of the multiphase study discussed in this Collection. We discuss the results, highlight the evidence gaps, and provide recommendations on the key aspects to consider in the implementation of portable devices and their main advantages and limitations.

Global concerns over the quality of medicines, especially in low- and middle-income countries (LMICs) are exacerbated by the Coronavirus Disease 2019 (COVID-19) pandemic [1,2]. The World Health Organisation (WHO) estimated that 10.5% of medicines in LMICs may be substandard or falsified (SF) [3]. “Prevention, detection, and response” to SF medical products are strategic priorities of WHO to contribute to effective and efficient regulatory systems [4]. Numerous portable medicine screening devices are available on the market, holding great hope for detection of SF medicines in an efficient and timely manner, and, therefore, might serve as key detection tools to inform prevention and response [5,6]. Screening devices have the potential to rapidly identify suspected SF medical products, giving more objective selection for reference assays, reducing the financial and technical burden. However, little is known regarding how well the existing devices fulfil their functions and how they could be deployed within risk-based postmarketing surveillance (rb-PMS) systems [5–7].We conducted, during 2016 to 2018, a collaborative multiphase exploratory study aimed at comparing portable screening devices. This paper accompanies 4 papers in this PLOS Collection “A multiphase evaluation of portable screening devices to assess medicines quality for national Medicines Regulatory Authorities.” The first article introduced the multiphase study [8]. In brief, 12 devices (S1 Table) were first evaluated in a laboratory setting [9], to select the most field-suitable devices for further evaluation of their utility/usability by Lao medicines inspectors [10]. Cost-effectiveness analysis of their implementation for rb-PMS in Laos was also conducted [11]. The results of these 3 phases were discussed in a multistakeholder meeting in 2018 in Vientiane, Lao PDR (S1 Text). The advantages/disadvantages, cost-effectiveness, and optimal use of screening devices in medicine supply chains were discussed to develop policy recommendations for medicines regulatory authorities (MRAs) and other institutions who wish to implement screening technologies. A summary of the main results of the multiphase study is presented in S2 Table.As far as we are aware, this is the first independent investigation comparing the accuracy and practical use from a public health perspective, of a diverse set of portable medicine quality screening devices. The specific objective(s) for which the portable screening technologies are implemented, their advantages/limitations, costs and logistics, and the development of detailed standard operating procedures and training programmes are key points to be carefully addressed when considering selection and deployment of screening technologies within specific rb-PMS systems (Fig 1).Open in a separate windowFig 1Major proposed considerations for the selection and implementation of medicine quality screening device.Each circle represents a key consideration when purchasing a screening device, grouped by themes (represented by heptagons). When the shapes overlap, the considerations are connected. For example, standard operating procedures are needed for the implementation of devices and should include measures for user safety. The circle diameters are illustrative.Here, we utilise this research and related literature to discuss the evidence, gaps, and recommendations, complementary to those recently published by the US Pharmacopeial Convention [12]. These discussions can inform policy makers, non-governmental organisations, wholesalers/distributors, and hospital pharmacies considering the implementation of such screening devices. We discuss unanswered research questions that require attention to ensure that the promise these devices hold is realised.     

Who Gets Prompt Access to Artemisinin-Based Combination Therapy? A Prospective Community-Based Study in Children from Rural Kilosa,Tanzania

Background

Effective and timely case management remains one of the fundamental pillars for control of malaria. Tanzania introduced artemisinin-combination therapy [ACT] for uncomplicated malaria; however, the policy change is challenged by limited availability of ACTs due to high cost. This study aimed to determine factors influencing prompt access to ACTs among febrile children in rural Kilosa, Tanzania.

Methods and Findings

In a community-based study, 1,235 randomly selected children under five were followed up weekly for six months, in 2008. Using a structured questionnaire, children''s caretakers were asked about the child''s febrile history in the last seven days, and treatment actions including timing, medicines used and source of care. Caretakers'' knowledge about malaria and socioeconomic and demographic data were also obtained. About half of followed-up children had at least one episode of fever. Less than half (44.8%) of febrile children were taken to government facilities. Almost one-third (37.6%; 95% CI 33.1–42.1) of febrile children had prompt access to ACT. Care-seeking from a government facility was the overriding factor, increasing the likelihood of prompt access to an ACT 18 times (OR 17.7; 95% CI 10.55–29.54; adjusted OR 16.9; 95% CI 10.06–28.28). Caretakers from the better-off household (3rd–5th quintiles) were more likely to seek care from government facilities (OR 3.66; 95% CI 2.56–5.24; adjusted OR 1.80; 95% CI 1.18–2.76). The majority of antimalarials accessed by the poor were ineffective [86.0%; 295/343], however, they paid more for them (median Tsh 500) compared to the better-offs (median Tsh 0).

Conclusions

Prompt access to ACT among febrile children was unacceptably low, due mainly to limited availability of subsidised ACT at the location where most caretakers sought care. There is urgent need to accelerate implementation of strategies that will ensure availability of ACT at an affordable price in remote rural areas, where the burden of malaria is highest.     

Has Tanzania Embraced the Green Leaf? Results from Outlet and Household Surveys before and after Implementation of the Affordable Medicines Facility -Malaria

Background

The Affordable Medicines Facility - malaria (AMFm) is primarily an artemisinin combination therapy (ACT) subsidy, aimed at increasing availability, affordability, market share and use of quality-assured ACTs (QAACTs). Mainland Tanzania was one of eight national scale programmes where AMFm was introduced in 2010. Here we present findings from outlet and household surveys before and after AMFm implementation to evaluate its impact from both the supply and demand side.

Methods

Outlet surveys were conducted in 49 randomly selected wards throughout mainland Tanzania in 2010 and 2011, and data on outlet characteristics and stocking patterns were collected from outlets stocking antimalarials. Household surveys were conducted in 240 randomly selected enumeration areas in three regions in 2010 and 2012. Questions about treatment seeking for fever and drugs obtained were asked of individuals reporting fever in the previous two weeks.

Results

The availability of QAACTs increased from 25.5% to 69.5% among all outlet types, with the greatest increase among pharmacies and drug stores, together termed specialised drug sellers (SDSs), where the median QAACT price fell from $5.63 to $0.94. The market share of QAACTs increased from 26.2% to 42.2%, again with the greatest increase in SDSs. Household survey results showed a shift in treatment seeking away from the public sector towards SDSs. Overall, there was no change in the proportion of people with fever obtaining an antimalarial or ACT from baseline to endline. However, when broken down by treatment source, ACT use increased significantly among clients visiting SDSs.

Discussion

Unchanged ACT use overall, despite increases in QAACT availability, affordability and market share in the private sector, reflected a shift in treatment seeking towards private providers. The reasons for this shift are unclear, but likely reflect both persistent stockouts in public facilities, and the increased availability of subsidised ACTs in the private sector.     

Cost-effectiveness of opportunistic screening and minimal contact psychotherapy to prevent depression in primary care patients

Background

Depression causes a large burden of disease worldwide. Effective prevention has the potential to reduce that burden considerably. This study aimed to investigate the cost-effectiveness of minimal contact psychotherapy, based on Lewinsohn''s ‘Coping with depression’ course, targeted at opportunistically screened individuals with sub-threshold depression.

Methods and Results

Using a Markov model, future health effects and costs of an intervention scenario and a current practice scenario were estimated. The time horizon was five years. Incremental cost-effectiveness ratios were expressed in euro per Disability Adjusted Life Year (DALY) averted. Probabilistic sensitivity analysis was employed to study the effect of uncertainty in the model parameters. From the health care perspective the incremental cost-effectiveness ratio was € 1,400 per DALY, and from the societal perspective the intervention was cost-saving. Although the estimated incremental costs and effects were surrounded with large uncertainty, given a willingness to pay of € 20,000 per DALY, the probability that the intervention is cost-effective was around 80%.

Conclusion

This modelling study showed that opportunistic screening in primary care for sub-threshold depression in combination with minimal contact psychotherapy may be cost-effective in the prevention of major depression.     

The lineage and diversity of putative amino acid sensor ACR proteins in plants

Amino acid metabolic enzymes often contain a regulatory ACT domain, named for aspartate kinase, chorismate mutase, and TyrA (prephenate dehydrogenase). Arabidopsis encodes 12 putative amino acid sensor ACT repeat (ACR) proteins, all containing ACT repeats but no identifiable catalytic domain. Arabidopsis ACRs comprise three groups based on domain composition and sequence: group I and II ACRs contain four ACTs each, and group III ACRs contain two ACTs. Previously, all three groups had been documented only in Arabidopsis. Here, we extended this to algae and land plants, showing that all three groups of ACRs are present in most, if not all, land plants, whereas among algal ACRs, although quite diverse, only group III is conserved. The appearance of canonical group I and II ACRs thus accompanied the evolution of plants from living in water to living on land. Alignment of ACTs from plant ACRs revealed a conserved motif, DRPGLL, at the putative ligand-binding site. Notably, the unique features of the DRPGLL motifs in each ACT domain are conserved in ACRs from algae to land plants. The conservation of plant ACRs is reminiscent of that of human cellular arginine sensor for mTORC1 (CASTOR1), a member of a small protein family highly conserved in animals. CASTOR proteins also have four ACT domains, although the sequence identities between ACRs and CASTORs are very low. Thus, plant ACRs and animal CASTORs may have adapted the regulatory ACT domains from a more ancient metabolic enzyme, and then evolved independently.     

Modelling the Impact of Artemisinin Combination Therapy and Long-Acting Treatments on Malaria Transmission Intensity

Background

Artemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite. With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue. This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas.

Methods and Findings

We developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania. We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data. Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%). Estimated percentage reductions in incidence of clinical episodes were similar. The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area. High coverage was important. Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission. An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting.

Conclusions

Our results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings. ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.     

An Economic Evaluation of Home Management of Malaria in Uganda: An Interactive Markov Model

Background

Home management of malaria (HMM), promoting presumptive treatment of febrile children in the community, is advocated to improve prompt appropriate treatment of malaria in Africa. The cost-effectiveness of HMM is likely to vary widely in different settings and with the antimalarial drugs used. However, no data on the cost-effectiveness of HMM programmes are available.

Methods/Principal Findings

A Markov model was constructed to estimate the cost-effectiveness of HMM as compared to conventional care for febrile illnesses in children without HMM. The model was populated with data from Uganda, but is designed to be interactive, allowing the user to adjust certain parameters, including the antimalarials distributed. The model calculates the cost per disability adjusted life year averted and presents the incremental cost-effectiveness ratio compared to a threshold value. Model output is stratified by level of malaria transmission and the probability that a child would receive appropriate care from a health facility, to indicate the circumstances in which HMM is likely to be cost-effective. The model output suggests that the cost-effectiveness of HMM varies with malaria transmission, the probability of appropriate care, and the drug distributed. Where transmission is high and the probability of appropriate care is limited, HMM is likely to be cost-effective from a provider perspective. Even with the most effective antimalarials, HMM remains an attractive intervention only in areas of high malaria transmission and in medium transmission areas with a lower probability of appropriate care. HMM is generally not cost-effective in low transmission areas, regardless of which antimalarial is distributed. Considering the analysis from the societal perspective decreases the attractiveness of HMM.

Conclusion

Syndromic HMM for children with fever may be a useful strategy for higher transmission settings with limited health care and diagnosis, but is not appropriate for all settings. HMM may need to be tailored to specific settings, accounting for local malaria transmission intensity and availability of health services.     

Electrocardiographic Screening for Prolonged QT Interval to Reduce Sudden Cardiac Death in Psychiatric Patients: A Cost-Effectiveness Analysis

ImportanceSudden cardiac death is a leading cause of mortality in psychiatric patients. Long QT (LQT) is common in this population and predisposes to Torsades-de-Pointes (TdP) and subsequent mortality.ObjectiveTo estimate the cost-effectiveness of electrocardiographic screening to detect LQT in psychiatric inpatients.ResultsIn the base-case scenario, the numbers of patients needed to screen were 1128 and 2817 to avoid one TdP and one death, respectively. The ICER of systematic ECG screening was $8644 (95%CI, 3144-82 498) per QALY. The probability of cost-effectiveness was 96% at a willingness-to-pay of $50 000 for one QALY. In sensitivity analyses, results were sensitive to the case-fatality of TdP episodes and to the TdP reduction following the diagnosis of LQT.

Conclusion and Relevance

In psychiatric hospitals, performing systematic ECG screening at admission help reduce the number of sudden cardiac deaths in a cost-effective fashion.     

Searching distant homologs of the regulatory ACT domain in phenylalanine hydroxylase

High sequence divergence, evolutionary mobility, and superfold topology characterize the ACT domain. Frequently found in multidomain proteins, these domains induce allosteric effects by binding a regulatory ligand usually to an ACT domain dimer interface. In mammalian phenylalanine hydroxylase (PAH), no contacts are formed between ACT domains, and the domain promotes an allosteric effect despite the apparent lack of ligand binding. The increased functional scenario of this abundant domain encouraged us to search for distant homologs, aiming to enhance the understanding of the ACT domain in general and the ACT domain of PAH in particular. The PDB was searched using the FATCAT server with the ACT domain of PAH as a query. The hits that were confirmed by the SSAP algorithm were divided into known ACT domains (KADs) and potential ACT domains (PADs). The FATCAT/SSAP procedure recognized most of the established KADs, as well 18 so far unrecognized non-redundant PADs with extremely low sequence identities and high divergence in functionality and oligomerization. However, analysis of the structural similarity provides remarkable clustering of the proteins according to similarities in ligand binding. Despite enormous sequence divergence and high functional variability, there is a common regulatory theme among these domains. The results reveal the close relationships of the ACT domain of PAH with amino acid binding and metallobinding ACT domains and with acylphosphatase.     

Characterizing the response of calcium signal transducers to generated calcium transients

Cellular Ca2+ transients and Ca2+-binding proteins regulate physiological phenomena as diverse as muscle contraction, neurosecretion, and cell division. When Ca2+ is rapidly mixed with slow Ca2+ chelators, EGTA, or Mg2+/EDTA, artificial Ca2+ transients (ACTs) of varying duration (0.1-50 ms half-widths (hws)) and amplitude can be generated. We have exposed several Ca2+ indicators, Ca2+-binding proteins, and a Ca2+-dependent enzyme to ACTs of various durations and observed their transient binding of Ca2+, complex formation, and/or activation. A 0.1 ms hw ACT transiently occupied approximately 70% of the N-terminal regulatory sites of troponin C consistent with their rapid Ca2+ on-rate (8.7 +/- 2.0 x 10(7) M-1 s-1). A 1.1 ms hw ACT produced approximately 90% transient binding of the N-terminal of calmodulin (CaM) to the RS-20 peptide, but little binding of CaM's C-terminal to RS-20. A 0.6 ms hw ACT was sufficient for the N-terminal of CaM to transiently bind approximately 60% of myosin light chain kinase (MLCK), while a 1.8 ms hw ACT produced approximately 22% transient activation of the sarcoplasmic reticulum (SR) Ca2+/ATPase. In both cases, the ACT had fallen back to baseline approximately 10-30 ms before maximal binding of CaM to MLCK or SR Ca2+/ATPase activation occurred and binding and enzyme activation persisted long after the Ca transient had subsided. The use of ACTs has allowed us to visualize how the Ca2+-exchange rates of Ca2+-binding proteins dictate their Ca2+-induced conformational changes, Ca2+-induced protein/peptide and protein/protein interactions, and enzyme activation and inactivation, in response to Ca2+ transients of various amplitude and duration. By characterizing the response of these proteins to ACTs, we can predict with greater certainty how they would respond to natural Ca2+ transients to regulate cellular phenomena.     

Prevalence of Malaria Parasitemia and Purchase of Artemisinin-Based Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies

Background

Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program.

Method and Findings

A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6–18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was <5 years old (aOR: 6.6; 95% CI: 3.9–11.0) or the shop attendant had >5 years, experience (aOR: 2.8; 95% CI: 1.2–6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5–7.4).

Conclusion

Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops.     

Is Adding HCV Screening to the Antenatal National Screening Program in Amsterdam,The Netherlands,Cost-Effective?

Introduction

Hepatitis C virus (HCV) infection can lead to severe liver disease. Pregnant women are already routinely screened for several infectious diseases, but not yet for HCV infection. Here we examine whether adding HCV screening to routine screening is cost-effective.

Methods

To estimate the cost-effectiveness of implementing HCV screening of all pregnant women and HCV screening of first-generation non-Western pregnant women as compared to no screening, we developed a Markov model. For the parameters of the model, we used prevalence data from pregnant women retrospectively tested for HCV in Amsterdam, the Netherlands, and from literature sources. In addition, we estimated the effect of possible treatment improvement in the future.

Results

The incremental costs per woman screened was €41 and 0.0008 life-years were gained. The incremental cost-effectiveness ratio (ICER) was €52,473 which is above the cost-effectiveness threshold of €50,000. For screening first-generation non-Western migrants, the ICER was €47,113. Best-case analysis for both scenarios showed ICERs of respectively €19,505 and €17,533. We estimated that if costs per treatment were to decline to €3,750 (a reduction in price of €31,000), screening all pregnant women would be cost-effective.

Conclusions

Currently, adding HCV screening to the already existing screening program for pregnant women is not cost-effective for women in general. However, adding HCV screening for first-generation non-Western women shows a modest cost-effective outcome. Yet, best case analysis shows potentials for an ICER below €20,000 per life-year gained. Treatment options will improve further in the coming years, enhancing cost-effectiveness even more.     

Are Patent Medicine Vendors Effective Agents in Malaria Control? Using Lot Quality Assurance Sampling to Assess Quality of Practice in Jigawa,Nigeria

Background

Patent medicine vendors (PMV) provide antimalarial treatment and care throughout Sub-Saharan Africa, and can play an important role in the fight against malaria. Their close-to-client infrastructure could enable lifesaving artemisinin-based combination therapy (ACT) to reach patients in time. However, systematic assessments of drug sellers’ performance quality are crucial if their role is to be managed within the health system. Lot quality assurance sampling (LQAS) could be an efficient method to monitor and evaluate PMV practice, but has so far never been used for this purpose.

Methods

In support of the Nigeria Malaria Booster Program we assessed PMV practices in three Senatorial Districts (SDs) of Jigawa, Nigeria. A two-stage LQAS assessed whether at least 80% of PMV stores in SDs used national treatment guidelines. Acceptable sampling errors were set in consultation with government officials (alpha and beta <0.10). The hypergeometric formula determined sample sizes and cut-off values for SDs. A structured assessment tool identified high and low performing SDs for quality of care indicators.

Findings

Drug vendors performed poorly in all SDs of Jigawa for all indicators. For example, all SDs failed for stocking and selling first-line antimalarials. PMV sold no longer recommended antimalarials, such as Chloroquine, Sulfadoxine-Pyrimethamine and oral Artesunate monotherapy. Most PMV were ignorant of and lacked training about new treatment guidelines that had endorsed ACTs as first-line treatment for uncomplicated malaria.

Conclusion

There is urgent need to regularly monitor and improve the availability and quality of malaria treatment provided by medicine sellers in Nigeria; the irrational use of antimalarials in the ACT era revealed in this study bears a high risk of economic loss, death and development of drug resistance. LQAS has been shown to be a suitable method for monitoring malaria-related indicators among PMV, and should be applied in Nigeria and elsewhere to improve service delivery.     

Costs and Cost-Effectiveness of Hypertension Screening and Treatment in Adults with Hypertension in Rural Nigeria in the Context of a Health Insurance Program

BackgroundHigh blood pressure is a leading risk factor for death and disability in sub-Saharan Africa (SSA). We evaluated the costs and cost-effectiveness of hypertension care provided within the Kwara State Health Insurance (KSHI) program in rural Nigeria.MethodsA Markov model was developed to assess the costs and cost-effectiveness of population-level hypertension screening and subsequent antihypertensive treatment for the population at-risk of cardiovascular disease (CVD) within the KSHI program. The primary outcome was the incremental cost per disability-adjusted life year (DALY) averted in the KSHI scenario compared to no access to hypertension care. We used setting-specific and empirically-collected data to inform the model. We defined two strategies to assess eligibility for antihypertensive treatment based on 1) presence of hypertension grade 1 and 10-year CVD risk of >20%, or grade 2 hypertension irrespective of 10-year CVD risk (hypertension and risk based strategy) and 2) presence of hypertension in combination with a CVD risk of >20% (risk based strategy). We generated 95% confidence intervals around the primary outcome through probabilistic sensitivity analysis. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the reference scenario.ResultsScreening and treatment for hypertension was potentially cost-effective but the results were sensitive to changes in underlying assumptions with a wide range of uncertainty. The incremental cost-effectiveness ratio for the first and second strategy respectively ranged from US$ 1,406 to US$ 7,815 and US$ 732 to US$ 2,959 per DALY averted, depending on the assumptions on risk reduction after treatment and compared to no access to antihypertensive treatment.ConclusionsHypertension care within a subsidized private health insurance program may be cost-effective in rural Nigeria and public-private partnerships such as the KSHI program may provide opportunities to finance CVD prevention care in SSA.     

The Potential Impact of Improving Appropriate Treatment for Fever on Malaria and Non-Malarial Febrile Illness Management in Under-5s: A Decision-Tree Modelling Approach

Background

As international funding for malaria programmes plateaus, limited resources must be rationally managed for malaria and non-malarial febrile illnesses (NMFI). Given widespread unnecessary treatment of NMFI with first-line antimalarial Artemisinin Combination Therapies (ACTs), our aim was to estimate the effect of health-systems factors on rates of appropriate treatment for fever and on use of ACTs.

Methods

A decision-tree tool was developed to investigate the impact of improving aspects of the fever care-pathway and also evaluate the impact in Tanzania of the revised WHO malaria guidelines advocating diagnostic-led management

Results

Model outputs using baseline parameters suggest 49% malaria cases attending a clinic would receive ACTs (95% Uncertainty Interval:40.6–59.2%) but that 44% (95% UI:35–54.8%) NMFI cases would also receive ACTs. Provision of 100% ACT stock predicted a 28.9% increase in malaria cases treated with ACT, but also an increase in overtreatment of NMFI, with 70% NMFI cases (95% UI:56.4–79.2%) projected to receive ACTs, and thus an overall 13% reduction (95% UI:5–21.6%) in correct management of febrile cases. Modelling increased availability or use of diagnostics had little effect on malaria management outputs, but may significantly reduce NMFI overtreatment. The model predicts the early rollout of revised WHO guidelines in Tanzania may have led to a 35% decrease (95% UI:31.2–39.8%) in NMFI overtreatment, but also a 19.5% reduction (95% UI:11–27.2%), in malaria cases receiving ACTs, due to a potential fourfold decrease in cases that were untested or tested false-negative (42.5% vs.8.9%) and so untreated.

Discussion

Modelling multi-pronged intervention strategies proved most effective to improve malaria treatment without increasing NMFI overtreatment. As malaria transmission declines, health system interventions must be guided by whether the management priority is an increase in malaria cases receiving ACTs (reducing the treatment gap), reducing ACT waste through unnecessary treatment of NMFI or expanding appropriate treatment of all febrile illness.     

Characters of aerated compost tea from immature compost that limit colonization of bean leaflets by Botrytis cinerea

Aims: The aim was to produce and characterize an aerated compost tea (ACT) that suppressed growth of the plant pathogen Botrytis cinerea. Methods and Results: Three different open‐windrow composts were sampled weekly from the early secondary mesophilic stage until maturity. Each 10 kg of compost sample was extracted in 30 l of aerated water for 24, 48 or 72 h. Relative to water, all batches of ACT applied to detached bean leaflets reduced lesion development following single‐point inoculations of B. cinerea. There was a significant linear, inverse relationship between the internal windrow temperature of compost (≤51°C) used to prepare ACT and the extent of lesion development. Bacterial diversity in ACTs from one windrow was highest using compost sampled at 48°C. The compost weight‐to‐water volume ratios of 1 : 3, 1 : 10 or 1 : 30, using compost sampled from a fourth windrow at 50°C, also produced ACTs that reduced the growth of B. cinerea on bean leaflets. The ‘1 : 3’ ACT, and to a lesser degree the same ACT filtered to remove micro‐organisms, inhibited the germination of B. cinerea conidia. Conclusions: ACT produced using the methods reported here suppressed the growth of B. cinerea on bean leaflets, with an abundant and diverse microbial community likely to contribute to pathogen suppression. Significance and Impact of the Study: This is the first report of the use of immature compost to produce a pathogen‐suppressive ACT, suggesting that compost stage is an important production variable.