Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries

BACKGROUND: Artemisinin-based combination therapy (ACT) is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia. METHODS: Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. RESULTS: 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets) as compared to first-line quality-assured ACT (< 25%). In the public/not-for-profit sector, first-line quality-assured ACT was available for free in all countries except Benin and the DRC (US$1.29 [Inter Quartile Range (IQR):$1.29-$1.29] and$0.52[IQR: $0.00-$1.29] per adult equivalent dose respectively). In the private sector, first-line quality-assured ACT was 5-24 times more expensive than non-artemisinin therapies. The exception was Madagascar where, due to national social marketing of subsidized ACT, the price of first-line quality-assured ACT ($0.14 [IQR:$0.10, $0.57]) was significantly lower than the most popular treatment (chloroquine,$0.36 [IQR: $0.36,$0.36]). Quality-assured ACT accounted for less than 25% of total anti-malarial volumes; private-sector quality-assured ACT volumes represented less than 6% of the total market share. Most anti-malarials were distributed through the private sector, but often comprised non-artemisinin therapies, and in the DRC and Nigeria, oral artemisinin monotherapies. Provider knowledge of the first-line treatment was significantly lower in the private sector than in the public/not-for-profit sector. CONCLUSIONS: These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria

The Malaria Testing and Treatment Market in Kinshasa, Democratic Republic of the Congo, 2013

Background The Democratic Republic of Congo (DRC) is one of the two most leading contributors to the global burden of disease due to malaria. This paper describes the malaria testing and treatment market in the nation’s capital province of Kinshasa, including availability of malaria testing and treatment and relative anti-malarial market share for the public and private sector. Methods A malaria medicine outlet survey was conducted in Kinshasa province in 2013. Stratified multi-staged sampling was used to select areas for the survey. Within sampled areas, all outlets with the potential to sell or distribute anti-malarials in the public and private sector were screened for eligibility. Among outlets with anti-malarials or malaria rapid diagnostic tests (RDT) in stock, a full audit of all available products was conducted. Information collected included product information (e.g. active ingredients, brand name), amount reportedly distributed to patients in the past week, and retail price. Results In total, 3364 outlets were screened for inclusion across Kinshasa and 1118 outlets were eligible for the study. Among all screened outlets in the private sector only about one in ten (12.1%) were stocking quality-assured Artemisinin-based Combination Therapy (ACT) medicines. Among all screened public sector facilities, 24.5% had both confirmatory testing and quality-assured ACT available, and 20.2% had sulfadoxine-pyrimethamine (SP) available for intermittent preventive therapy during pregnancy (IPTp). The private sector distributed the majority of anti-malarials in Kinshasa (96.7%), typically through drug stores (89.1% of the total anti-malarial market). Non-artemisinin therapies were the most commonly distributed anti-malarial (50.1% of the total market), followed by non quality-assured ACT medicines (38.5%). The median price of an adult quality-assured ACT was $6.59, and more expensive than non quality-assured ACT ($3.71) and SP ($0.44). Confirmatory testing was largely not available in the private sector (1.1%). Conclusions While the vast majority of anti-malarial medicines distributed to patients in Kinshasa province are sold within the private sector, availability of malaria testing and appropriate treatment for malaria is alarmingly low. There is a critical need to improve access to confirmatory testing and quality-assured ACT in the private sector. Widespread availability and distribution of non quality-assured ACT and non-artemisinin therapies must be addressed to ensure effective malaria case management

Monitoring fever treatment behaviour and equitable access to effective medicines in the context of initiatives to improve ACT access: baseline results and implications for programming in six African countries

BACKGROUND: Access to artemisinin-based combination therapy (ACT) remains limited in high malaria-burden countries, and there are concerns that the poorest people are particularly disadvantaged. This paper presents new evidence on household treatment-seeking behaviour in six African countries. These data provide a baseline for monitoring interventions to increase ACT coverage, such as the Affordable Medicines Facility for malaria (AMFm). METHODS: Nationally representative household surveys were conducted in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia between 2008 and 2010. Caregivers responded to questions about management of recent fevers in children under five. Treatment indicators were tabulated across countries, and differences in case management provided by the public versus private sector were examined using chi-square tests. Logistic regression was used to test for association between socioeconomic status and 1) malaria blood testing, and 2) ACT treatment. RESULTS: Fever treatment with an ACT is low in Benin (10%), the DRC (5%), Madagascar (3%) and Nigeria (5%), but higher in Uganda (21%) and Zambia (21%). The wealthiest children are significantly more likely to receive ACT compared to the poorest children in Benin (OR = 2.68, 95% CI = 1.12-6.42); the DRC (OR = 2.18, 95% CI = 1.12-4.24); Madagascar (OR = 5.37, 95% CI = 1.58-18.24); and Nigeria (OR = 6.59, 95% CI = 2.73-15.89). Most caregivers seek treatment outside of the home, and private sector outlets are commonly the sole external source of treatment (except in Zambia). However, children treated in the public sector are significantly more likely to receive ACT treatment than those treated in the private sector (except in Madagascar). Nonetheless, levels of testing and ACT treatment in the public sector are low. Few caregivers name the national first-line drug as most effective for treating malaria in Madagascar (2%), the DRC (2%), Nigeria (4%) and Benin (10%). Awareness is higher in Zambia (49%) and Uganda (33%). CONCLUSIONS: Levels of effective fever treatment are low and inequitable in many contexts. The private sector is frequently accessed however case management practices are relatively poor in comparison with the public sector. Supporting interventions to inform caregiver demand for ACT and to improve provider behaviour in both the public and private sectors are needed to achieve maximum gains in the context of improved access to effective treatment

Methods for implementing a medicine outlet survey: lessons from the anti-malarial market.

BACKGROUND: In recent years an increasing number of public investments and policy changes have been made to improve the availability, affordability and quality of medicines available to consumers in developing countries, including anti-malarials. It is important to monitor the extent to which these interventions are successful in achieving their aims using quantitative data on the supply side of the market. There are a number of challenges related to studying supply, including outlet sampling, gaining provider cooperation and collecting accurate data on medicines. This paper provides guidance on key steps to address these issues when conducting a medicine outlet survey in a developing country context. While the basic principles of good survey design and implementation are important for all surveys, there are a set of specific issues that should be considered when conducting a medicine outlet survey. METHODS: This paper draws on the authors' experience of designing and implementing outlet surveys, including the lessons learnt from ACTwatch outlet surveys on anti-malarial retail supply, and other key studies in the field. Key lessons and points of debate are distilled around the following areas: selecting a sample of outlets; techniques for collecting and analysing data on medicine availability, price and sales volumes; and methods for ensuring high quality data in general. RESULTS AND CONCLUSIONS: The authors first consider the inclusion criteria for outlets, contrasting comprehensive versus more focused approaches. Methods for developing a reliable sampling frame of outlets are then presented, including use of existing lists, key informants and an outlet census. Specific issues in the collection of data on medicine prices and sales volumes are discussed; and approaches for generating comparable price and sales volume data across products using the adult equivalent treatment dose (AETD) are explored. The paper concludes with advice on practical considerations, including questionnaire design, field worker training, and data collection. Survey materials developed by ACTwatch for investigating anti-malarial markets in sub-Saharan Africa and Asia provide a helpful resource for future studies in this area

A Cell-Based High-Throughput Screen Validates the Plasmodial Surface Anion Channel As an Antimalarial Target

The plasmodial surface anion channel (PSAC) is an unusual small-conductance ion channel induced on erythrocytes infected with plasmodia, including parasites responsible for human malaria. Although broadly available inhibitors produce microscopic clearance of parasite cultures at high concentrations and suggest that PSAC is an antimalarial target, they have low affinity for the channel and may interfere with other parasite activities. To address these concerns, we developed a miniaturized assay for PSAC activity and carried out a high-throughput inhibitor screen. Approximately 70,000 compounds from synthetic and natural product libraries were screened, revealing inhibitors from multiple structural classes including two novel and potent heterocyclic scaffolds. Single-channel patch-clamp studies indicated that these compounds act directly on PSAC, further implicating a proposed role in transport of diverse solutes. A statistically significant correlation between channel inhibition and in vitro parasite killing by a family of compounds provided chemical validation of PSAC as a drug target. These new inhibitors should be important research tools and may be starting points for much-needed antimalarial drugs

Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors

<div><p>Malaria parasites increase their host erythrocyte’s permeability to a broad range of ions and organic solutes. The plasmodial surface anion channel (PSAC) mediates this uptake and is an established drug target. Development of therapies targeting this channel is limited by several problems including interactions between known inhibitors and permeating solutes that lead to incomplete channel block. Here, we designed and executed a high-throughput screen to identify a novel class of PSAC inhibitors that overcome this solute-inhibitor interaction. These new inhibitors differ from existing blockers and have distinct effects on channel-mediated transport, supporting a model of two separate routes for solute permeation though PSAC. Combinations of inhibitors specific for the two routes had strong synergistic action against <i>in vitro</i> parasite propagation, whereas combinations acting on a single route produced only additive effects. The magnitude of synergism depended on external nutrient concentrations, consistent with an essential role of the channel in parasite nutrient acquisition. The identified inhibitors will enable a better understanding of the channel’s structure-function and may be starting points for novel combination therapies that produce synergistic parasite killing.</p></div

Synergistic killing by combinations of primary and residual inhibitors, but not by combinations from one class only.

<p>(A) Isobologram showing effect of fixed ratio combinations of the primary component inhibitor cpd <b>1</b> and the residual transport inhibitor PRT1-20. Each symbol represented the <i>IC</i>_<i>50</i> for a fixed ratio of the two inhibitors, determined from a full dose response experiment with replicates. Error bars, shown for single compound <i>IC</i>_<i>50</i> values (symbols on the <i>x</i> and <i>y</i> axes), represent S.E.M. values. Solid line connecting these intercept values is the expected profile for additive parasite killing. Strong synergistic killing was found for this drug combination as the symbols are markedly below the additive line. (B) Isobologram for two primary component inhibitors, showing additive interaction. (C) Isobologram for two residual component inhibitors, showing additive interaction.</p

A PRT-1 derivative with improved potency and specificity.

<p>(A) Structure of PRT1-20. A longer alkoxy side chain distinguishes this compound from PRT-1 (red highlight). (B) Mean ± S.E.M. inhibitor <i>K</i>_{<i>0</i>.<i>5</i>} values in PhTMA⁺ + 200 μM furosemide (red bars) and sorbitol (black). When compared to PRT-1, PRT1-20 has improved greater potency against residual transport and reduced activity against the primary mechanism.</p

Hits act against residual transport and differ from known PSAC inhibitors.

<p>(A) Osmotic lysis kinetics in PhTMA lysis solution without (black trace) or with 200 μM furosemide (green or red traces). Addition of 0.1, 0.3, or 1 μM PRT-1 (top to bottom red traces, respectively) inhibits residual lysis. (B) Dose responses for inhibition of residual permeability (<i>P</i>) of PhTMA⁺ or proline (red and blue circles, respectively; mean ± S.E.M. of up to 10 trials each). (C) Inhibitor concentrations that block uptake by 50% (<i>K</i>_{<i>0</i>.<i>5</i>}). Mean ± S.E.M. for inhibition of residual transport in PhTMA⁺ + 200 μM furosemide or primary transport in sorbitol are shown on a logarithmic scale as black and red bars, respectively. While ISG-21 and TP-52 have higher affinities against primary transport, PRT inhibitors have comparable or greater activity against residual transport. (D) Dose responses for PRT-1 inhibition of residual <i>P</i> in PhTMA⁺ plus either 100 nM ISG-21 or 2 μM TP-52 (blue and green triangles, respectively; mean ± S.E.M. of up to 3 trials each). Solid lines in panels (B) and (D) represent the best fits to the sum of two Langmuir isotherms [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0149214#pone.0149214.ref011" target="_blank">11</a>].</p

Effect of external nutrient levels on synergistic killing.

<p>(A) Isobologram for ISG-21 and PRT-1 interactions in PGIM. Note that synergistic action is lost in this medium. (B) Isobologram for an identical growth experiments after increasing the culture medium isoleucine concentration to 34 μM, showing restored synergy. The ISG-21 <i>IC</i>_<i>50</i> values in (A) and (B)—17.3 ± 1 nM and 1.25 ± 0.1 μM, <i>x</i> axis intercepts—differ markedly because extracellular nutrient levels affect killing by primary component blockers.</p