COVID-19 Therapeutics for Low- and Middle-Income Countries: A Review of Candidate Agents with Potential for Near-Term Use and Impact.

Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States (US), European Union (EU), and World Health Organization (WHO) clinical trial registries, we reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism and with at least five registered trials. The search yielded 1,001, 203, and 1,128 trials, in the US, EU, and WHO trial registers, respectively. These trials covered 13 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics with established safety profiles. The available evidence regarding proposed mechanisms of action, potential limitations, and trial status is summarized. The results of the search demonstrate few published studies of high quality, a low proportion of trials completed, and the vast majority with negative results. These findings reflect limited investment in COVID-19 therapeutics development compared with vaccines. We also identified the need for better coordination of trials of accessible agents and their combinations in LMICs. To prevent COVID-19 from becoming a neglected tropical disease, there is a critical need for rapid and coordinated efforts in the evaluation and deployment of those agents found to be efficacious.

Price subsidies increase the use of private sector ACTs: evidence from a systematic review.

BACKGROUND: Although artemisinin combination therapies (ACTs) are the recommended first-line treatment for uncomplicated malaria in most endemic countries, they have been prohibitively expensive in the retail sector where many suspected malaria cases purchase treatment. ACT subsidies seek to stimulate consumer demand for the drugs over cheaper but often ineffective alternatives by reducing their prices. Recent evidence from eight regions implementing such subsidies suggests that they are generally successful in improving availability of the drugs and decreasing their retail prices, but it remains unclear whether these outcomes translate to improved use by patients with suspected malaria. METHODS: A systematic literature review was conducted to identify reports of experimental or programmatic ACT subsidies to assess the impact of subsidies on consumer use. Relationships between price, use and potential confounding factors were examined using logistic and repeated measures binomial regression models, and approximate magnitudes of associations were assessed with linear regression. In total, 40 studies, 14 peer-reviewed and 26 non-peer-reviewed, were eligible for inclusion in the analysis. The reviewed studies found a substantial increase in private sector ACT use following the introduction of a subsidy. Overall, each $1 decrease in price was linked to a 24 percentage point increase in the fraction of suspected malaria cases purchasing ACTs (R(2) = 0.302). No significant differences were evident in this relationship when comparing the poorest and richest groups, rural vs urban populations or children vs adults. CONCLUSIONS: These findings suggest that ACT price reductions can increase their use for suspected malaria, even within poorer, more remote populations that may be most at risk of malaria mortality. Whether a subsidy is appropriate will depend upon local context, including treatment-seeking behaviours and malaria prevalence. This review provides an initial foundation for policymakers to make evidence-based decisions regarding ACT price reductions to increase use of potentially life-saving drugs.

Diffusion of subsidized ACTs in accredited drug shops in Tanzania: determinants of stocking and characteristics of early and late adopters.

BACKGROUND: Many households in sub-Saharan Africa utilize the private sector as a primary source of treatment for malaria episodes. Expanding access to effective treatment in private drug shops may help reduce incidence of severe disease and mortality. This research leveraged a longitudinal survey of stocking of subsidized artemisinin combination therapies (ACTs), an effective anti-malarial, in Accredited Drug Dispensing Outlets (ADDOs) in two regions of Tanzania. This provided a unique opportunity to explore shop and market level determinants of product diffusion in a developing country retail market. METHODS: 356 ADDOs in the Rukwa and Mtwara regions of Tanzania were surveyed at seven points between Feb 2011 and May 2012. Shop level audits were used to measure the availability of subsidized ACTs at each shop. Data on market and shop level factors were collected during the survey and also extracted from GIS layers. Regression and network based methodologies were used. Shops classified as early and late adopters, following Rogers' model of product diffusion, were compared. The Bass model of product diffusion was applied to determine whether shops stocked ACTs out of a need to imitate market competitors or a desire to satisfy customer needs. RESULTS: Following the introduction of a subsidy for ACTs, stocking increased from 12% to nearly 80% over the seven survey rounds. Stocking was influenced by higher numbers of proximal shops and clinics, larger customer traffic and the presence of a licensed pharmacist. Early adopters were characterized by a larger percentage of customers seeking care for malaria, a larger catchment and sourcing from specific wholesalers/suppliers. The Bass model of product diffusion indicated that shops were adopting products in response to competitor behavior, rather than customer demand. CONCLUSIONS: Decisions to stock new pharmaceutical products in Tanzanian ADDOs are influenced by a combination of factors related to both market competition and customer demand, but are particularly influenced by the behavior of competing shops. Efforts to expand access to new pharmaceutical products in developing country markets could benefit from initial targeting of high profile shops in competitive markets and wholesale suppliers to encourage faster product diffusion across all drug retailers.

Do price subsidies on artemisinin combination therapy for malaria increase household use? Evidence from a repeated cross-sectional study in remote regions of Tanzania.

BACKGROUND: The Affordable Medicines Facility-malaria (AMFm) is a pilot program that uses price subsidies to increase access to Artemisinin Combination Therapies (ACTs), currently the most effective malaria treatment. Recent evidence suggests that availability and affordability of ACTs in retail sector drug shops (where many people treat malaria) has increased under the AMFm, but it is unclear whether household level ACT use has increased. METHODS AND FINDINGS: household surveys were conducted in two remote regions of Tanzania (Mtwara and Rukwa) in three waves: March 2011, December 2011 and March 2012, corresponding to 3, 13 and 16 months into the AMFm implementation respectively. Information about suspected malaria episodes including treatment location and medications taken was collected. Respondents were also asked about antimalarial preferences and perceptions about the availability of these medications. Significant increases in ACT use, preference and perceived availability were found between Rounds 1 and 3 though not for all measures between Rounds 1 and 2. ACT use among suspected malaria episodes was 51.1% in March 2011 and increased by 10.9 percentage points by Round 3 (p = .017). The greatest increase was among retail sector patients, where ACT use increased from 31% in Round 1 to 49% in Round 2 (p = .037) and to 61% (p<.0001) by Round 3. The fraction of suspected malaria episodes treated in the retail sector increased from 30.2% in Round 1 to 46.7% in Round 3 (p = .0009), mostly due to a decrease in patients who sought no treatment at all. No significant changes in public sector treatment seeking were found. CONCLUSIONS: The AMFm has led to significant increases in ACT use for suspected malaria, especially in the retail sector. No evidence is found supporting the concerns that the AMFm would crowd out public sector treatment or neglect patients in remote areas and from low SES groups.

Trends in availability and prices of subsidized ACT over the first year of the AMFm: evidence from remote regions of Tanzania.

BACKGROUND: The Affordable Medicines Facility for malaria (AMFm) is a pilot supra-national subsidy program that aims to increase access and affordability of artemisinin combination therapy (ACT) in public sector clinics and private retail shops. It is unclear to what extent the AMFm model will translate into wide scale availability and price reductions in ACT, particularly for rural, remote areas where disparities in access to medicines often exist. This study is the first to rigorously examine the availability and price of subsidized ACT during the first year of the AMFm, measured through retail audits in remote regions of Tanzania. METHODS: Periodic retail audits of Accredited Drug Dispensing Outlets (ADDOs) were conducted in two remote regions of Tanzania (Mtwara and Rukwa). Temporal and spatial variation in ACT availability and pricing were explored. A composite measure of ADDO remoteness, using variables, such as distance to suppliers and towns, altitude and population density, was used to explore whether ACT availability and price vary systematically with remoteness. RESULTS: Between February 2011 and January 2012, the fraction of ADDOs stocking AMFm-ACT increased from 25% to 88% in Mtwara and from 3% to 62% in Rukwa. Availability was widespread, though diffusion throughout the region was achieved more quickly in Mtwara. No significant relationship was found between ACT availability and remoteness. Adult doses of AMFm-ACT were much more widely available than any other age/weight band. Average prices fell from 1529 TZS (1.03 USD) to 1272 TZS (0.81 USD) over the study period, with prices in Rukwa higher than Mtwara. The government recommended retail price for AMFm- ACT is 1,000 TZS ($0.64 USD). The median retail ACT price in the final round of data collection was 1,000 TZS. CONCLUSIONS: The AMFm led to large increases in availability of low priced ACT in Tanzania, with no significant variation in availability based on remoteness. Availability did remain lower and prices remained higher in Rukwa, which is a more remote region overall. Low availability of child and adolescent ACT doses could be due in part to lower quantities of non-adult packs imported into Tanzania. Future research will explore whether increased availability and affordability persists and whether it translates into higher ACT use in Tanzania.

Malaria resurgence: a systematic review and assessment of its causes.

BACKGROUND: Considerable declines in malaria have accompanied increased funding for control since the year 2000, but historical failures to maintain gains against the disease underscore the fragility of these successes. Although malaria transmission can be suppressed by effective control measures, in the absence of active intervention malaria will return to an intrinsic equilibrium determined by factors related to ecology, efficiency of mosquito vectors, and socioeconomic characteristics. Understanding where and why resurgence has occurred historically can help current and future malaria control programmes avoid the mistakes of the past. METHODS: A systematic review of the literature was conducted to identify historical malaria resurgence events. All suggested causes of these events were categorized according to whether they were related to weakened malaria control programmes, increased potential for malaria transmission, or technical obstacles like resistance. RESULTS: The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s. Almost all resurgence events (68/75 = 91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68 = 57%). Over half of the events (44/75 = 59%) were attributed in part to increases in the intrinsic potential for malaria transmission, while only 24/75 (32%) were attributed to vector or drug resistance. CONCLUSIONS: Given that most malaria resurgences have been linked to weakening of control programmes, there is an urgent need to develop practical solutions to the financial and operational threats to effectively sustaining today's successful malaria control programmes.

Do patients adhere to over-the-counter artemisinin combination therapy for malaria? evidence from an intervention study in Uganda.

BACKGROUND: Increasing affordability of artemisinin combination therapy (ACT) in the African retail sector could be critical to expanding access to effective malaria treatment, but must be balanced by efforts to protect the efficacy of these drugs. Previous research estimates ACT adherence rates among public sector patients, but adherence among retail sector purchasers could differ substantially. This study aimed to estimate adherence rates to subsidized, over-the-counter ACT in rural Uganda. METHODS: An intervention study was conducted with four licensed drug shops in Eastern Uganda in December 2009. Artemether-lumefantrine (AL) was made available for sale at a 95% subsidy over-the counter. Customers completed a brief survey at the time of purchase and then were randomly assigned to one of three study arms: no follow-up, follow-up after two days or follow-up after three days. Surveyors recorded the number of pills remaining through blister pack observation or through self-report if the pack was unavailable. The purpose of the three-day follow-up arm was to capture non-adherence in the sense of an incomplete treatment course ("under-dosing"). The purpose of the two-day follow-up arm was to capture whether participants completed the full course too soon ("over-dosing"). RESULTS: Of the 106 patients in the two-day follow-up sample, 14 (13.2%) had finished the entire treatment course by the second day. Of the 152 patients in the three-day follow-up sample, 49 (32.2%) were definitely non-adherent, three (2%) were probably non-adherent and 100 (65.8%) were probably adherent. Among the 52 who were non-adherent, 31 (59.6%) had more than a full day of treatment remaining. CONCLUSIONS: Overall, adherence to subsidized ACT purchased over-the-counter was found to be moderate. Further, a non-trivial fraction of those who complete treatment are taking the full course too quickly. Strategies to increase adherence in the retail sector are needed in the context of increasing availability and affordability of ACT in this sector.

Preventing the reintroduction of malaria in Mauritius: a programmatic and financial assessment.

Sustaining elimination of malaria in areas with high receptivity and vulnerability will require effective strategies to prevent reestablishment of local transmission, yet there is a dearth of evidence about this phase. Mauritius offers a uniquely informative history, with elimination of local transmission in 1969, re-emergence in 1975, and second elimination in 1998. Towards this end, Mauritius's elimination and prevention of reintroduction (POR) programs were analyzed via a comprehensive review of literature and government documents, supplemented by program observation and interviews with policy makers and program personnel. The impact of the country's most costly intervention, a passenger screening program, was assessed quantitatively using simulation modeling.On average, Mauritius spent $4.43 per capita per year (pcpy) during its second elimination campaign from 1982 to 1988. The country currently spends $2.06 pcpy on its POR program that includes robust surveillance, routine vector control, and prompt and effective treatment and response. Thirty-five percent of POR costs are for a passenger screening program. Modeling suggests that the estimated 14% of imported malaria infections identified by this program reduces the annual risk of indigenous transmission by approximately 2%. Of cases missed by the initial passenger screening program, 49% were estimated to be identified by passive or reactive case detection, leaving an estimated 3.1 unidentified imported infections per 100,000 inhabitants per year.The Mauritius experience indicates that ongoing intervention, strong leadership, and substantial predictable funding are critical to consistently prevent the reestablishment of malaria. Sustained vigilance is critical considering Mauritius's enabling conditions. Although the cost of POR is below that of elimination, annual per capita spending remains at levels that are likely infeasible for countries with lower overall health spending. Countries currently embarking on elimination should quantify and plan for potentially similar POR operations and costs.

Costs and financial feasibility of malaria elimination.

The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework-potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed.

Shrinking the malaria map: progress and prospects.

In the past 150 years, roughly half of the countries in the world eliminated malaria. Nowadays, there are 99 endemic countries-67 are controlling malaria and 32 are pursuing an elimination strategy. This four-part Series presents evidence about the technical, operational, and financial dimensions of malaria elimination. The first paper in this Series reviews definitions of elimination and the state that precedes it: controlled low-endemic malaria. Feasibility assessments are described as a crucial step for a country transitioning from controlled low-endemic malaria to elimination. Characteristics of the 32 malaria-eliminating countries are presented, and contrasted with countries that pursued elimination in the past. Challenges and risks of elimination are presented, including Plasmodium vivax, resistance in the parasite and mosquito populations, and potential resurgence if investment and vigilance decrease. The benefits of elimination are outlined, specifically elimination as a regional and global public good. Priorities for the next decade are described.

A framework for assessing the feasibility of malaria elimination.

The recent scale-up of malaria interventions, the ensuing reductions in the malaria burden, and reinvigorated discussions about global eradication have led many countries to consider malaria elimination as an alternative to maintaining control measures indefinitely. Evidence-based guidance to help countries weigh their options is thus urgently needed. A quantitative feasibility assessment that balances the epidemiological situation in a region, the strength of the public health system, the resource constraints, and the status of malaria control in neighboring areas can serve as the basis for robust, long-term strategic planning. Such a malaria elimination feasibility assessment was recently prepared for the Minister of Health in Zanzibar. Based on the Zanzibar experience, a framework is proposed along three axes that assess the technical requirements to achieve and maintain elimination, the operational capacity of the malaria programme and the public health system to meet those requirements, and the feasibility of funding the necessary programmes over time. Key quantitative and qualitative metrics related to each component of the assessment are described here along with the process of collecting data and interpreting the results. Although further field testing, validation, and methodological improvements will be required to ensure applicability in different epidemiological settings, the result is a flexible, rational methodology for weighing different strategic options that can be applied in a variety of contexts to establish data-driven strategic plans.

A pharmacy too far? Equity and spatial distribution of outcomes in the delivery of subsidized artemisinin-based combination therapies through private drug shops.

BACKGROUND: Millions of individuals with malaria-like fevers purchase drugs from private retailers, but artemisinin-based combination therapies (ACTs), the only effective treatment in regions with high levels of resistance to older drugs, are rarely obtained through these outlets due to their relatively high cost. To encourage scale up of ACTs, the Affordable Medicines Facility--malaria is being launched to subsidize their price. The Government of Tanzania and the Clinton Foundation piloted this subsidized distribution model in two Tanzanian districts to examine concerns about whether the intervention will successfully reach poor, rural communities. METHODS: Stocking of ACTs and other antimalarial drugs in all retail shops was observed at baseline and in four subsequent surveys over 15 months. Exit interviews were conducted with antimalarial drug customers during each survey period. All shops and facilities were georeferenced, and variables related to population density and proximity to distribution hubs, roads, and other facilities were calculated. To understand the equity of impact, shops stocking ACTs and consumers buying them were compared to those that did not, according to geographic and socioeconomic variables. Patterning in ACT stocking and sales was evaluated against that of other common antimalarials to identify factors that may have impacted access. Qualitative data were used to assess motivations underlying stocking, distribution, and buying disparities. RESULTS: Results indicated that although total ACT purchases rose from negligible levels to nearly half of total antimalarial sales over the course of the pilot, considerable geographic variation in stocking and sales persisted and was related to a variety of socio-spatial factors; ACTs were stocked more often in shops located closer to district towns (p<0.01) and major roads (p<0.01) and frequented by individuals of higher socioeconomic status (p<0.01). However, other antimalarial drugs displayed similar patterning, indicating the existence of underlying disparities in access to antimalarial drugs in general in these districts. CONCLUSIONS: As this subsidy model is scaled up across multiple countries, these results confirm the potential for increased ACT usage but suggest that additional efforts to increase access in remote areas will be needed for the scale-up to have equitable impact. TRIAL REGISTRATION: Current Controlled Trials ISRCTN39125414.

The use of mobile phone data for the estimation of the travel patterns and imported Plasmodium falciparum rates among Zanzibar residents.

BACKGROUND: Malaria endemicity in Zanzibar has reached historically low levels, and the epidemiology of malaria transmission is in transition. To capitalize on these gains, Zanzibar has commissioned a feasibility assessment to help inform on whether to move to an elimination campaign. Declining local transmission has refocused attention on imported malaria. Recent studies have shown that anonimized mobile phone records provide a valuable data source for characterizing human movements without compromising the privacy of phone users. Such movement data in combination with spatial data on P. falciparum endemicity provide a way of characterizing the patterns of parasite carrier movements and the rates of malaria importation, which have been used as part of the malaria elimination feasibility assessment for the islands of Zanzibar. DATA AND METHODS: Records encompassing three months of complete mobile phone usage for the period October-December 2008 were obtained from the Zanzibar Telecom (Zantel) mobile phone network company, the principal provider on the islands of Zanzibar. The data included the dates of all phone usage by 770,369 individual anonymous users. Each individual call and message was spatially referenced to one of six areas: Zanzibar and five mainland Tanzania regions. Information on the numbers of Zanzibar residents travelling to the mainland, locations visited and lengths of stay were extracted. Spatial and temporal data on P. falciparum transmission intensity and seasonality enabled linkage of this information to endemicity exposure and, motivated by malaria transmission models, estimates of the expected patterns of parasite importation to be made. RESULTS: Over the three month period studied, 88% of users made calls that were routed only through masts on Zanzibar, suggesting that no long distance travel was undertaken by this group. Of those who made calls routed through mainland masts the vast majority of trips were estimated to be of less than five days in length, and to the Dar Es Salaam Zantel-defined region. Though this region covered a wide range of transmission intensities, data on total infection numbers in Zanzibar combined with mathematical models enabled informed estimation of transmission exposure and imported infection numbers. These showed that the majority of trips made posed a relatively low risk for parasite importation, but risk groups visiting higher transmission regions for extended periods of time could be identified. CONCLUSION: Anonymous mobile phone records provide valuable information on human movement patterns in areas that are typically data-sparse. Estimates of human movement patterns from Zanzibar to mainland Tanzania suggest that imported malaria risk from this group is heterogeneously distributed; a few people account for most of the risk for imported malaria. In combination with spatial data on malaria endemicity and transmission models, movement patterns derived from phone records can inform on the likely sources and rates of malaria importation. Such information is important for assessing the feasibility of malaria elimination and planning an elimination campaign.

Piloting the global subsidy: the impact of subsidized artemisinin-based combination therapies distributed through private drug shops in rural Tanzania.

BACKGROUND: WHO estimates that only 3% of fever patients use recommended artemisinin-based combination therapies (ACTs), partly reflecting their high prices in the retail sector from where many patients seek treatment. To overcome this challenge, a global ACT subsidy has been proposed. We tested this proposal through a pilot program in rural Tanzania. METHODS/PRINCIPAL FINDINGS: Three districts were assigned to serve either as a control or to receive the subsidy plus a package of supporting interventions. From October 2007, ACTs were sold at a 90% subsidy through the normal private supply chain to intervention district drug shops. Data were collected at baseline and during intervention using interviews with drug shop customers, retail audits, mystery shoppers, and audits of public and NGO facilities. The proportion of consumers in the intervention districts purchasing ACTs rose from 1% at baseline to 44.2% one year later (p<0.001), and was significantly higher among consumers purchasing for children under 5 than for adults (p = 0.005). No change in ACT usage was observed in the control district. Consumers paid a mean price of $0.58 for ACTs, which did not differ significantly from the price paid for sulphadoxine-pyrimethamine, the most common alternative. Drug shops in population centers were significantly more likely to stock ACTs than those in more remote areas (p<0.001). CONCLUSIONS: A subsidy introduced at the top of the private sector supply chain can significantly increase usage of ACTs and reduce their retail price to the level of common monotherapies. Additional interventions may be needed to ensure access to ACTs in remote areas and for poorer individuals who appear to seek treatment at drug shops less frequently. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN39125414.