Poor quality vital anti-malarials in Africa - an urgent neglected public health priority.

BACKGROUND: Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. METHODS: Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. RESULTS: Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. CONCLUSIONS: Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

Evaluating different dimensions of programme effectiveness for private medicine retailer malaria control interventions in Kenya.

BACKGROUND: Private medicine retailers (PMRs) are key partners in the home management of fevers in many settings. Current evidence on effectiveness for PMR interventions at scale is limited. This study presents evaluation findings of two different programs implemented at moderate scale targeting PMRs for malaria control in the Kisii and Kwale districts of Kenya. Key components of this evaluation were measurement of program performance, including coverage, PMR knowledge, practices, and utilization based on spatial analysis. METHODOLOGY/PRINCIPAL FINDINGS: The study utilized mixed quantitative methods including retail audits and surrogate client surveys based on post-intervention cross-sectional surveys in intervention and control areas and mapping of intervention outlets. There was a large and significant impact on PMR knowledge and practices of the program in Kisii, with 60.5% of trained PMRs selling amodiaquine medicines in adequate doses compared to 2.8% of untrained ones (OR; 53.5: 95% CI 6.7, 428.3), a program coverage of 69.7% targeted outlets, and a potential utilization of about 30,000 children under five. The evaluation in Kwale also indicates a significant impact with 18.8% and 2.3% intervention and control PMRs selling amodiaquine with correct advice, respectively (OR; 9.4: 95% CI 1.1, 83.7), a program coverage of 25.3% targeted outlets, and a potential utilization of about 48,000 children under five. A provisional benchmark of 7.5 km was a reasonable threshold distance for households to access PMR services. CONCLUSIONS/SIGNIFICANCE: This evaluation show that PMR interventions operationalized in the district level settings are likely to impact PMR knowledge and practices and lead to increased coverage of appropriate treatment to target populations. There is value of evaluating different dimensions of public health programs, including quality, spatial access, and implementation practice. This approach strengthens the potential contribution of pragmatic study designs to evaluating public health programs in the real world.

The use of artemether-lumefantrine by febrile children following national implementation of a revised drug policy in Kenya.

OBJECTIVES: To examine access to, timing and use of artemisinin-based combination therapy among rural Kenyan febrile children before and following the introduction of artemether-lumefantrine (AL) as first-line antimalarial drug policy. METHODS: In August 2006, a cohort was established within 72 rural clusters in four sentinel districts to monitor the period prevalence of fever and treatment in children aged 0-4 years through four repeat cross-sectional surveys (one prior to introduction of AL and three post-AL introduction: January-June 2007). Mothers/guardians of children were asked about fever in the last 14 days and related treatment actions including the timing, drugs used, dosing and adherence supported by visual aids of commonly available drug products. RESULTS: A total of 2526 child-observations were recorded during the four survey rounds. The period prevalence of fever was between 20% and 26% with little variation between survey rounds. The overall proportion of children with fever receiving antimalarial drugs for their fever was 31 % (95% CI, 26-36%) and the proportion of febrile children receiving antimalarial drugs within 48 h was 23.3% (95% CI, 18.6-28.0%). The proportion of febrile children who received first-line recommended AL within 48 h was 10.2% (95% CI, 7.0-13.4%), compared to only 4.6% (95% CI, 3.8-5.4%) of children receiving sulphadoxine-pyrimethamine first-line therapy in 2001. CONCLUSIONS: Although Kenya was less than a year into the new policy implementation and AL is restricted to the public formal sector, access to antimalarial drugs among children within 48 h and to the first-line therapy has improved. But it remains well below national and international targets. The continued use of amodiaquine and artemisinin monotherapies constrains effective implementation of artemisinin-based combination therapy policy in Kenya.

Increasing coverage and decreasing inequity in insecticide-treated bed net use among rural Kenyan children.

BACKGROUND: Inexpensive and efficacious interventions that avert childhood deaths in sub-Saharan Africa have failed to reach effective coverage, especially among the poorest rural sectors. One particular example is insecticide-treated bed nets (ITNs). In this study, we present repeat observations of ITN coverage among rural Kenyan homesteads exposed at different times to a range of delivery models, and assess changes in coverage across socioeconomic groups. METHODS AND FINDINGS: We undertook a study of annual changes in ITN coverage among a cohort of 3,700 children aged 0-4 y in four districts of Kenya (Bondo, Greater Kisii, Kwale, and Makueni) annually between 2004 and 2006. Cross-sectional surveys of ITN coverage were undertaken coincidentally with the incremental availability of commercial sector nets (2004), the introduction of heavily subsidized nets through clinics (2005), and the introduction of free mass distributed ITNs (2006). The changing prevalence of ITN coverage was examined with special reference to the degree of equity in each delivery approach. ITN coverage was only 7.1% in 2004 when the predominant source of nets was the commercial retail sector. By the end of 2005, following the expansion of heavily subsidized clinic distribution system, ITN coverage rose to 23.5%. In 2006 a large-scale mass distribution of ITNs was mounted providing nets free of charge to children, resulting in a dramatic increase in ITN coverage to 67.3%. With each subsequent survey socioeconomic inequity in net coverage sequentially decreased: 2004 (most poor [2.9%] versus least poor [15.6%]; concentration index 0.281); 2005 (most poor [17.5%] versus least poor [37.9%]; concentration index 0.131), and 2006 with near-perfect equality (most poor [66.3%] versus least poor [66.6%]; concentration index 0.000). The free mass distribution method achieved highest coverage among the poorest children, the highly subsidised clinic nets programme was marginally in favour of the least poor, and the commercial social marketing favoured the least poor. CONCLUSIONS: Rapid scaling up of ITN coverage among Africa's poorest rural children can be achieved through mass distribution campaigns. These efforts must form an important adjunct to regular, routine access to ITNs through clinics, and each complimentary approach should aim to make this intervention free to clients to ensure equitable access among those least able to afford even the cost of a heavily subsidized net.

The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya.

BACKGROUND: Sulphadoxine/sulphalene-pyrimethamine (SP) was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT) in Africa are less well documented. METHODS: A narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy. RESULTS: Following a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL) as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data between AL and amodiaquine-based alternatives, a poor dialogue with pharmaceutical companies with a national interest in antimalarial drug supply versus the single sourcing of AL and complex drug ordering, tendering and procurement procedures. CONCLUSION: Decisions to abandon failing monotherapy in favour of ACT for the treatment of malaria can be achieved relatively quickly. Future policy changes in Africa should be carefully prepared for a myriad of financial, political and legislative issues that might limit the rapid translation of drug policy change into action.

Modelling distances travelled to government health services in Kenya.

OBJECTIVE: To systematically evaluate descriptive measures of spatial access to medical treatment, as part of the millennium development goals to reduce the burden of HIV/AIDS, tuberculosis and malaria. METHODS: We obtained high-resolution spatial and epidemiological data on health services, population, transport network, topography, land cover and paediatric fever treatment in four Kenyan districts to develop access and use models for government health services in Kenya. Community survey data were used to model use of government health services by febrile children. A model based on the transport network was then implemented and adjusted for actual use patterns. We compared the predictive accuracy of this refined model to that of Euclidean distance metrics. RESULTS Higher-order facilities were more attractive to patients (54%, 58% and 60% in three scenarios) than lower-order ones. The transport network model, adjusted for competition between facilities, was most accurate and selected as the best-fit model. It estimated that 63% of the population of the study districts were within the 1 h national access benchmark, against 82% estimated by the Euclidean model. CONCLUSIONS: Extrapolating the results from the best-fit model in study districts to the national level shows that approximately six million people are currently incorrectly estimated to have access to government health services within 1 h. Simple Euclidean distance assumptions, which underpin needs assessments and against which millennium development goals are evaluated, thus require reconsideration.

Wealth, mother's education and physical access as determinants of retail sector net use in rural Kenya.

BACKGROUND: Insecticide-treated bed nets (ITN) provide real hope for the reduction of the malaria burden across Africa. Understanding factors that determine access to ITN is crucial to debates surrounding the optimal delivery systems. The influence of homestead wealth on use of nets purchased from the retail sector is well documented, however, the competing influence of mother's education and physical access to net providers is less well understood. METHODS: Between December 2004 and January 2005, a random sample of 72 rural communities was selected across four Kenyan districts. Demographic, assets, education and net use data were collected at homestead, mother and child (aged < 5 years) levels. An assets-based wealth index was developed using principal components analysis, travel time to net sources was modelled using geographic information systems, and factors influencing the use of retail sector nets explored using a multivariable logistic regression model. RESULTS: Homestead heads and guardians of 3,755 children < 5 years of age were interviewed. Approximately 15% (562) of children slept under a net the night before the interview; 58% (327) of the nets used were purchased from the retail sector. Homestead wealth (adjusted OR = 10.17, 95% CI = 5.45-18.98), travel time to nearest market centres (adjusted OR = 0.51, 95% CI = 0.37-0.72) and mother's education (adjusted OR = 2.92, 95% CI = 1.93-4.41) were significantly associated with use of retail sector nets by children aged less than 5 years. CONCLUSION: Approaches to promoting access to nets through the retail sector disadvantage poor and remote communities where mothers are less well educated.

The cost of uncomplicated childhood fevers to Kenyan households: implications for reaching international access targets.

BACKGROUND: Fever is the clinical hallmark of malaria disease. The Roll Back Malaria (RBM) movement promotes prompt, effective treatment of childhood fevers as a key component to achieving its optimistic mortality reduction goals by 2010. A neglected concern is how communities will access these new medicines promptly and the costs to poor households when they are located in rural areas distant to health services. METHODS: We assemble data developed between 2001 and 2002 in Kenya to describe treatment choices made by rural households to treat a child's fever and the related costs to households. Using a cost-of-illness approach, we estimate the expected cost of a childhood fever to Kenyan households in 2002. We develop two scenarios to explore how expected costs to households would change if more children were treated at a health care facility with an effective antimalarial within 48 hours of fever onset. RESULTS: 30% of uncomplicated fevers were managed at home with modern medicines, 38% were taken to a health care facility (HCF), and 32% were managed at home without the use of modern medicines. Direct household cash expenditures were estimated at $0.44 per fever, while the total expected cost to households (cash and time) of an uncomplicated childhood fever is estimated to be $1.91. An estimated mean of 1.42 days of caretaker time devoted to each fever accounts for the majority of household costs of managing fevers. The aggregate cost to Kenyan households of managing uncomplicated childhood fevers was at least $96 million in 2002, equivalent to 1.00% of the Kenyan GDP. Fewer than 8% of all fevers were treated with an antimalarial drug within 24 hours of fever onset, while 17.5% were treated within 48 hours at a HCF. To achieve an increase from 17.5% to 33% of fevers treated with an antimalarial drug within 48 hours at a HCF (Scenario 1), children already being taken to a HCF would need to be taken earlier. Under this scenario, direct cash expenditures would not change, and total household costs would fall slightly to $1.86 because caretakers also save time with prompt treatment if the child has malaria. CONCLUSION: The management of uncomplicated childhood fevers imposes substantial costs on Kenyan households. Achieving substantial improvements in the numbers of fevers treated within 48 hours at a HCF with an effective antimalarial drug (Scenario 1) will not impose additional costs on households. Achieving additional improvements in fevers treated promptly at a HCF (Scenario 2) will impose additional costs on some households roughly equal to average cash expenses for transportation to a HCF. Additional financing mechanisms that further reduce the costs of accessing care at a HCF and/or that make artemisinin-based combination therapies (ACTs) accessible for home management need to be developed and evaluated as a top priority.

Brands, costs and registration status of antimalarial drugs in the Kenyan retail sector.

BACKGROUND: Although an important source of treatment for fevers, little is known about the structure of the retail sector in Africa with regard to antimalarial drugs. This study aimed to assess the range, costs, sources and registration of antimalarial drugs in the Kenyan retail sector. METHODS: In 2002, antimalarial drug registration and trade prices were established by triangulating national registration lists, government gazettes and trade price indices. Data on registration status and trade prices were compared with similar data generated through a retail audit undertaken among 880 randomly sampled retailers in four districts of Kenya. RESULTS: Two hundred and eighteen antimalarial drugs were in circulation in Kenya in 2002. These included 65 "sulfur"-pyrimethamine (sulfadoxine-pyrimethamine and sulfalene-pyrimethamine (SP), the first-line recommended drug in 2002) and 33 amodiaquine (AQ, the second-line recommended drug) preparations. Only half of SP and AQ products were registered with the Pharmacy and Poisons Board. Of SP and AQ brands at district level, 40% and 44% were officially within legal registration requirements. 29% of retailers at district level stocked SP and 95% stocked AQ. The retail price of adult doses of SP and AQ were on average 0.38 and 0.76 US dollars, 100% and 347% higher than trade prices from manufacturers and importers. Artemether-lumefantrine, the newly announced first-line recommended antimalarial drug in 2004, was found in less than 1% of all retail outlets at a median cost of 7.6 US dollars. CONCLUSION: There is a need to ensure that all antimalarial drugs are registered with the Pharmacy and Poisons Board to facilitate a more stringent post-marketing surveillance system to ensure drugs are safe and of good quality post-registration.

The difference between effectiveness and efficacy of antimalarial drugs in Kenya.

OBJECTIVE: To demonstrate the difference between effectiveness and efficacy of antimalarial (AM) drugs in Kenya. METHODS: We undertook a series of linked surveys in four districts of Kenya between 2001 and 2002 on (i) community usage of nationally recommended first- and second-line AM drugs; (ii) commonly stocked AM products in the retail and wholesale sectors; and (iii) quality of the most commonly available first- and second-line AM products. These were combined with estimates of adherence and clinical efficacy to derive overall drug effectiveness. RESULTS: The overall modelled effectiveness for sulphadoxine-pyrimethamine (SP) was estimated to be 62% compared with 85% for reported SP clinical efficacy. For amodiaquine the modelled effectiveness was 48% compared with 99% reported efficacy during the same time period. CONCLUSIONS: The quality of AM products and patient adherence to dosage regimens are important determinants of drug effectiveness, and should be measured alongside clinical efficacy. Post-registration measures to regulate drug quality and improve patient adherence would contribute significantly to AM drug performance.

The use of formal and informal curative services in the management of paediatric fevers in four districts in Kenya.

OBJECTIVE: To assess the sources, costs, timing and types of treatment for fevers among children under 5 years of age in four ecologically distinct districts of Kenya. METHODS: Structured questionnaires were administered to caretakers of one randomly selected child aged <5 years per homestead to establish whether the child had had a fever within the last 14 days and the types, sources, costs, and timing of treatment. Drug charts of common proprietary anti-malarial and antipyretic drugs in Kenya were used as visual aids. RESULTS: A total of 2655 fevers were reported among 6287 (42.2%) children with significant differences between the four districts (P<0.01). A substantial number of fevers remained untreated (28.1%) across all districts and more fevers were treated in Greater Kisii than any other district (P<0.01). The median delay to any treatment was 2 days [inter-quartile range (IQR): 2, 4]. The informal retail sector had no transport costs associated with it and charged less for drugs than all the other sectors. Most antimalarial treated fevers occurred in the formal public sector (52.6%). Only 2.3% of fevers were treated within 24 h of onset with a sulphur-pyrimethamine drug, the nationally recommended first-line drug for the management of uncomplicated malaria. CONCLUSIONS: The Abuja target of ensuring that 60% of childhood fevers are treated with appropriate antimalarial drugs within 24 h of onset by 2010 is largely unmet and a major investment in improving prompt access to antimalarial drugs will be required to achieve this.