Using Health Systems and Policy Research to Achieve Universal Health Coverage in Ghana.

Ghana is positioned to become the first country in sub-Saharan Africa to implement universal health coverage based on nationwide expansion of geographic access through the Community-based Health Planning and Services initiative. This achievement is the outcome of 3 decades of implementation research that health authorities have used for guiding the development of its primary health care program. This implementation research process has comprised Ghana's official endorsement of the 1978 Alma Ata Declaration, leading to the institutionalization of evidence relevant to the strategic design of primary health care and national health insurance policies and services. Rather than relying solely upon the dissemination of project results, Ghana has embraced a continuous and systemic process of knowledge capture, curation, and utilization of evidence in expanding geographic access by a massive expansion in the number of community health service points that has taken decades. A multisectoral approach has been pursued that has involved the creation of systematic partnerships that included all levels of the political system, local development officials, community groups and social networks, multiple university-based disciplines, external development partners, and donors. However, efforts to achieve high levels of financial access through the roll-out of the National Health Insurance Scheme have proceeded at a less consistent pace and been fraught with many challenges. As a result, financial access has been less comprehensive than geographical access despite sequential reforms having been made to both programs. The legacy of activities and current research on primary health care and national health insurance are reviewed together with unaddressed priorities that merit attention in the future. Factors that have facilitated or impeded progress with research utilization are reviewed and implications for health systems strengthening in Ghana and elsewhere in Africa and globally are discussed.

A Roadmap for the Development of Ivermectin as a Complementary Malaria Vector Control Tool.

In the context of stalling progress against malaria, resistance of mosquitoes to insecticides, and residual transmission, mass drug administration (MDA) of ivermectin, an endectocide used for neglected tropical diseases (NTDs), has emerged as a promising complementary vector control method. Ivermectin reduces the life span of Anopheles mosquitoes that feed on treated humans and/or livestock, potentially decreasing malaria parasite transmission when administered at the community level. Following the publication by WHO of the preferred product characteristics for endectocides as vector control tools, this roadmap provides a comprehensive view of processes needed to make ivermectin available as a vector control tool by 2024 with a completely novel mechanism of action. The roadmap covers various aspects, which include 1) the definition of optimal dosage/regimens for ivermectin MDA in both humans and livestock, 2) the risk of resistance to the drug and environmental impact, 3) ethical issues, 4) political and community engagement, 5) translation of evidence into policy, and 6) operational aspects of large-scale deployment of the drug, all in the context of a drug given as a prevention tool acting at the community level. The roadmap reflects the insights of a multidisciplinary group of global health experts who worked together to elucidate the path to inclusion of ivermectin in the toolbox against malaria, to address residual transmission, counteract insecticide resistance, and contribute to the end of this deadly disease.

Simulations Show Diagnostic Testing For Malaria In Young African Children Can Be Cost-Saving Or Cost-Effective.

Malaria imposes a substantial global disease burden. It disproportionately affects sub-Saharan Africans, particularly young children. In an effort to improve disease management, the World Health Organization (WHO) recommended in 2010 that countries test children younger than age five who present with suspected malaria fever to confirm the diagnosis instead of treating them presumptively with antimalarial drugs. Costs and concerns about the overall health impact of such diagnostic testing for malaria in children remain barriers to full implementation. Using data from national Malaria Indicator Surveys, we estimated two-stage microsimulation models for Angola, Tanzania, and Uganda to assess the policy's cost-effectiveness. We found that diagnostic testing for malaria in children younger than five is cost-saving in Angola. In Tanzania and Uganda the cost per life-year gained is $5.54 and $94.28, respectively. The costs projected for Tanzania and Uganda are less than the WHO standard of $150 per life-year gained. Our results were robust under varying assumptions about cost, prevalence of malaria, and behavior, and they strongly suggest the pursuit of policies that facilitate full implementation of testing for malaria in children younger than five.

Selection and spread of artemisinin-resistant alleles in Thailand prior to the global artemisinin resistance containment campaign.

The recent emergence of artemisinin resistance in the Greater Mekong Subregion poses a major threat to the global effort to control malaria. Tracking the spread and evolution of artemisinin-resistant parasites is critical in aiding efforts to contain the spread of resistance. A total of 417 patient samples from the year 2007, collected during malaria surveillance studies across ten provinces in Thailand, were genotyped for the candidate Plasmodium falciparum molecular marker of artemisinin resistance K13. Parasite genotypes were examined for K13 propeller mutations associated with artemisinin resistance, signatures of positive selection, and for evidence of whether artemisinin-resistant alleles arose independently across Thailand. A total of seven K13 mutant alleles were found (N458Y, R539T, E556D, P574L, R575K, C580Y, S621F). Notably, the R575K and S621F mutations have previously not been reported in Thailand. The most prevalent artemisinin resistance-associated K13 mutation, C580Y, carried two distinct haplotype profiles that were separated based on geography, along the Thai-Cambodia and Thai-Myanmar borders. It appears these two haplotypes may have independent evolutionary origins. In summary, parasites with K13 propeller mutations associated with artemisinin resistance were widely present along the Thai-Cambodia and Thai-Myanmar borders prior to the implementation of the artemisinin resistance containment project in the region.

Field trial evaluation of the performances of point-of-care tests for screening G6PD deficiency in Cambodia.

BACKGROUND: User-friendly, accurate, point-of-care rapid tests to detect glucose-6-phosphate dehydrogenase deficiency (G6PDd) are urgently needed at peripheral level to safely recommend primaquine for malaria elimination. METHODS: The CareStart G6PD RDT (AccessBio, New Jersey, USA), a novel rapid diagnostic test and the most commonly used test, the fluorescent spot test (FST) were assessed against the quantitatively measured G6PD enzyme activity for detecting G6PDd. Subjects were healthy males and non-pregnant females aged 18 years or older residing in six villages in Pailin Province, western Cambodia. FINDINGS: Of the 938 subjects recruited, 74 (7.9%) were severe and moderately severe G6PD deficient (enzyme activity <30%), mostly in male population; population median G6PD activity was 12.0 UI/g Hb. The performances of the CareStart G6PD RDT and the FST, according to different cut-off values used to define G6PDd were very similar. For the detection of severe and moderately severe G6PDd (enzyme activity < 30%, < 3.6 UI/g Hb) in males and females, sensitivity and negative (normal status) predictive value were 100% for both point-of-care tools. When the G6PDd cut-off value increased (from < 40% to < 60%), the sensitivity for both PoCs decreased: 93.3% to 71.7% (CareStart G6PD RDT, p = 10(-6)) and 95.5% to 73.2% (FST, p = 10(-6)) while the specificity for both PoCs remained similar: 97.4% to 98.3% (CareStart G6PD RDT, p = 0.23) and 98.7% to 99.6% (FST, p = 0.06). The cut-off values for classifying individuals as normal were 4.0 UI/g Hb and 4.3 UI/g Hb for the CareStart G6PD RDT and the FST, respectively. CONCLUSIONS: The CareStart G6PD RDT reliably detected moderate and severe G6PD deficient individuals (enzyme activity <30%), suggesting that this novel point-of-care is a promising tool for tailoring appropriate primaquine treatment for malaria elimination by excluding individuals with severe G6PDd for primaquine treatment.

The evolution of pyrimethamine resistant dhfr in Plasmodium falciparum of south-eastern Tanzania: comparing selection under SP alone vs SP+artesunate combination.

BACKGROUND: Sulphadoxine-pyrimethamine (SP) resistance is now widespread throughout east and southern Africa and artemisinin compounds in combination with synthetic drugs (ACT) are recommended as replacement treatments by the World Health Organization (WHO). As well as high cure rates, ACT has been shown to slow the development of resistance to the partner drug in areas of low to moderate transmission. This study looked for evidence of protection of the partner drug in a high transmission African context. The evaluation was part of large combination therapy pilot implementation programme in Tanzania, the Interdisciplinary Monitoring Programme for Antimalarial Combination Therapy (IMPACT-TZ) METHODS: The growth of resistant dhfr in a parasite population where SP Monotherapy was the first-line treatment was measured for four years (2002-2006), and compared with the development of resistant dhfr in a neighbouring population where SP + artesunate (SP+AS) was used as the first-line treatment during the same interval. The effect of the differing treatment regimes on the emergence of resistance was addressed in three ways. First, by looking at the rate of increase in frequency of pre-existing mutant dhfr alleles under monotherapy and combination therapy. Second, by examining whether de-novo mutant alleles emerged under either treatment. Finally, by measuring diversity at three dhfr flanking microsatellite loci upstream of the dhfr gene. RESULTS: The reduction in SP selection pressure resulting from the adoption of ACT slowed the rate of increase in the frequency of the triple mutant resistant dhfr allele. Comparing between the two populations, the higher levels of genetic diversity in sequence flanking the dhfr triple mutant allele in the population where the ACT regimen had been used indicates the reduction in SP selection pressure arising from combination therapy. CONCLUSION: The study demonstrated that, alleles containing two mutations at the dhfr have arisen at least four times independently while those containing triple mutant dhfr arose only once, and were found carrying a single unique Asian-type flanking sequence, which apparently drives the spread of pyrimethamine resistance associated dhfr alleles in east Africa. SP+AS is not recommended for use in areas where SP cure rates are less than 80% but this study reports an observed principle of combination protection from an area where pyrimethamine resistance was already high.

Media, health workers, and policy makers' relationship and their impact on antimalarial policy adoption: a population genetics perspective.

Drug resistance negatively impacts malaria treatments, making treatment policy revision unavoidable. So far, studies relating sociopolitical and technical issues on policy change with malaria parasite genetic change are lacking. We have quantified the effect of malaria treatment policy on drug pressure and the influence of the media, policy makers, and health worker relationship on parasite population genetic change in Kilombro/Ulanga district. Cross-sectional surveys of asymptomatic infections conducted before, during and after the switch from chloroquine to sulphadoxine/pyrimethamine were used for genetic analysis of SP resistance genes in 4,513 asymptomatic infections identified, and their frequency change was compared with retrospective study of the documented process of policy change. Highly significant changes of dhfr and dhps resistance alleles occurred within one year of switch to SP first line, followed by a decline of their rate of selection caused by reduction of SP usage, as a result of negative media reports on SP usage and lack of adequate preparations.

Drug coverage in treatment of malaria and the consequences for resistance evolution--evidence from the use of sulphadoxine/pyrimethamine.

BACKGROUND: It is argued that, the efficacy of anti-malarials could be prolonged through policy-mediated reductions in drug pressure, but gathering evidence of the relationship between policy, treatment practice, drug pressure and the evolution of resistance in the field is challenging. Mathematical models indicate that drug coverage is the primary determinant of drug pressure and the driving force behind the evolution of drug resistance. These models show that where the basis of resistance is multigenic, the effects of selection can be moderated by high recombination rates, which disrupt the associations between co-selected resistance genes. METHODS: To test these predictions, dhfr and dhps frequency changes were measured during 2000-2001 while SP was the second-line treatment and contrasted these with changes during 2001-2002 when SP was used for first-line therapy. Annual cross sectional community surveys carried out before, during and after the policy switch in 2001 were used to collect samples. Genetic analysis of SP resistance genes was carried out on 4,950 Plasmodium falciparum infections and the selection pressure under the two policies compared. RESULTS: The influence of policy on the parasite reservoir was profound. The frequency of dhfr and dhps resistance alleles did not change significantly while SP was the recommended second-line treatment, but highly significant changes occurred during the subsequent year after the switch to first line SP. The frequency of the triple mutant dhfr (N51I,C59R,S108N) allele (conferring pyrimethamine resistance) increased by 37% - 63% and the frequency of the double A437G, K540E mutant dhps allele (conferring sulphadoxine resistance) increased 200%-300%. A strong association between these unlinked alleles also emerged, confirming that they are co-selected by SP. CONCLUSION: The national policy change brought about a shift in treatment practice and the resulting increase in coverage had a substantial impact on drug pressure. The selection applied by first-line use is strong enough to overcome recombination pressure and create significant linkage disequilibrium between the unlinked genetic determinants of pyrimethamine and sulphadoxine resistance, showing that recombination is no barrier to the emergence of resistance to combination treatments when they are used as the first-line malaria therapy.

Prevalence of malaria parasitemia and accuracy of microscopic diagnosis in Haiti, October 1995

In October 1995 the Ministry of Public Health and Population in Haiti surveyed 42 health facilities for the prevalence and distribution of malaria infection. They examined 1.083 peripheral blood smears from patients with suspected malaria; the overall slide positivity rate was 4.0 por cent (range, 0.0 por cent to 14.3 por cent). The rate was lowest among 1-to 4-year-old children (1.6 por cent) and highest among persons aged 15 and older (5.5 por cent). Clinical and microscopic diagnoses of malaria were unreliable; the overall sensitivity of microscopic diagnosis was 83.6 por cent, specificity was 88.6 por cent, and the predictive value of a positive slide was 22.2 por cent. Microscopic diagnoses need to be improved, and adequate surveillance must be reestablished to identify areas where transmission is most intense. The generally low level of malaria is encouraging and suggests that intensified control efforts targeted to the areas of highest prevalence could furhter diminish the effect of malaria in Haiti

Prevalence of malaria parasitemia and accuracy of microscopic diagnosis in Haiti, October 1995 / Prevalencia de parasitemia por malaria y precisión del diagnóstico microscópico en Haití, octubre de 1995

In October 1995 the Ministry of Public Health and Population in Haiti surveyed 42 health facilities for the prevalence and distribution of malaria infection. They examined 1.083 peripheral blood smears from patients with suspected malaria; the overall slide positivity rate was 4.0 por cent (range, 0.0 por cent to 14.3 por cent). The rate was lowest among 1-to 4-year-old children (1.6 por cent) and highest among persons aged 15 and older (5.5 por cent). Clinical and microscopic diagnoses of malaria were unreliable; the overall sensitivity of microscopic diagnosis was 83.6 por cent, specificity was 88.6 por cent, and the predictive value of a positive slide was 22.2 por cent. Microscopic diagnoses need to be improved, and adequate surveillance must be reestablished to identify areas where transmission is most intense. The generally low level of malaria is encouraging and suggests that intensified control efforts targeted to the areas of highest prevalence could furhter diminish the effect of malaria in Haiti

En octubre de 1995 el Ministerio de Salud Pública y Población de Haití inspeccionó 42 establecimientos de salud para determinar la prevalencia y distribución de la infección por malaria. Se examinaron 1 803 frotis de sangre periférica obtenidos de pacientes con sospecha de tener esa enfermedad; la tasa general de positividad de los frotis fue de 4,0% (con un recorrido de 0,0 a 14,3%). La tasa más baja (1,6%) se observó en el grupo de niños de 1 a 4 años y la más alta en personas de 15 años de edad o mayores (5,5%). Los diagnósticos clínico y microscópico de la malaria fueron poco confiables; la sensibilidad general del diagnóstico microscópico fue de 83,6% y su especificidad de 88,6%, y el valor predictivo de un frotis positivo fue de 22,2%. Es preciso mejorar los diagnósticos microscópicos y reestablecer una vigilancia adecuada a fin de identificar las zonas donde la transmisión es más intensa. La frecuencia relativamente baja de la malaria es un dato alentador y sugiere que el refuerzo de las iniciativas de control dirigidas a las zonas de mayor prevalencia podría mitigar aun más el efecto de la malaria en Haití