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.

Costs and cost-effectiveness of malaria reactive case detection using loop-mediated isothermal amplification compared to microscopy in the low transmission setting of Aceh Province, Indonesia.

BACKGROUND: Reactive case detection (RACD) is an active case finding strategy where households and neighbours of a passively identified case (index case) are screened to identify and treat additional malaria infections with the goal of gathering surveillance information and potentially reducing further transmission. Although it is widely considered a key strategy in low burden settings, little is known about the costs and the cost-effectiveness of different diagnostic methods used for RACD. The aims of this study were to measure the cost of conducting RACD and compare the cost-effectiveness of microscopy to the more sensitive diagnostic method loop-mediated isothermal amplification (LAMP). METHODS: The study was conducted in RACD surveillance sites in five sub-districts in Aceh Besar, Indonesia. The cost inputs and yield of implementing RACD with microscopy and/or LAMP were collected prospectively over a 20 months study period between May 2014 and December 2015. Costs and cost-effectiveness (USD) of the different strategies were examined. The main cost measures were cost per RACD event, per person screened, per population at risk (PAR); defined as total population in each sub-district, and per infection found. The main cost-effectiveness measure was incremental cost-effectiveness ratio (ICER), expressed as cost per malaria infection detected by LAMP versus microscopy. The effects of varying test positivity rate or diagnostic yield on cost per infection identified and ICER were also assessed. RESULTS: Among 1495 household members and neighbours screened in 36 RACD events, two infections were detected by microscopy and confirmed by LAMP, and four infections were missed by microscopy but detected by LAMP. The average total cost of conducting RACD using microscopy and LAMP was $1178 per event with LAMP-specific consumables and personnel being the main cost drivers. The average cost of screening one individual during RACD was $11, with an additional cost of diagnostics at $0.62 and $16 per person for microscopy and LAMP, respectively. As a public health intervention, RACD using both diagnostics cost an average of $0.42 per PAR per year. Comparing RACD using microscopy only versus RACD using LAMP only, the cost per infection found was $8930 and $6915, respectively. To add LAMP as an additional intervention accompanying RACD would cost $9 per individual screened annually in this setting. The ICER was estimated to be $5907 per additional malaria infection detected by LAMP versus microscopy. Cost per infection identified and ICER declined with increasing test positivity rate and increasing diagnostic yield. CONCLUSIONS: This study provides the first estimates on the cost and cost-effectiveness of RACD from a low transmission setting. Costs per individual screened were high, though costs per PAR were low. Compared to microscopy, the use of LAMP in RACD was more costly but more cost-effective for the detection of infections, with diminishing returns observed when findings were extrapolated to scenarios with higher prevalence of infection using more sensitive diagnostics. As malaria programmes consider active case detection and the integration of more sensitive diagnostics, these findings may inform strategic and budgetary planning.

Eliminating malaria in Malaysia: the role of partnerships between the public and commercial sectors in Sabah.

BACKGROUND: Countries in the Asia Pacific region have made great progress in the fight against malaria; several are rapidly approaching elimination. However, malaria control programmes operating in elimination settings face substantial challenges, particularly around mobile migrant populations, access to remote areas and the diversity of vectors with varying biting and breeding behaviours. These challenges can be addressed through subnational collaborations with commercial partners, such as mining or plantation companies, that can conduct or support malaria control activities to cover employees. Such partnerships can be a useful tool for accessing high-risk populations and supporting malaria elimination goals. METHODS: This observational qualitative case study employed semi-structured key informant interviews to describe partnerships between the Malaysian Malaria Control Programme (MCP), and private palm oil, rubber and acacia plantations in the state of Sabah. Semi-structured interview guides were used to examine resource commitments, incentives, challenges, and successes of the collaborations. RESULTS: Interviews with workers from private plantations and the state of Sabah MCP indicated that partnerships with the commercial sector had contributed to decreases in incidence at plantation sites since 1991. Several plantations contribute financial and human resources toward malaria control efforts and all plantations frequently communicate with the MCP to help monitor the malaria situation on-site. Management of partnerships between private corporations and government entities can be challenging, as prioritization of malaria control may change with annual profits or arrival of new management. CONCLUSIONS: Partnering with the commercial sector has been an essential operational strategy to support malaria elimination in Sabah. The successes of these partnerships rely on a common understanding that elimination will be a mutually beneficial outcome for employers and the general public. Best practices included consistent communication, developing government-staffed subsector offices for malaria control on-site, engaging commercial plantations to provide financial and human resources for malaria control activities, and the development of new worker screening programmes. The successes and challenges associated with partnerships between the public and commercial sector can serve as an example for other malaria-eliminating countries with large plantation sectors, and may also be applied to other sectors that employ migrant workers or have commercial enterprises in hard to reach areas.

Active case detection for malaria elimination: a survey among Asia Pacific countries.

BACKGROUND: Moving from malaria control to elimination requires national malaria control programmes to implement strategies to detect both symptomatic and asymptomatic cases in the community. In order to do this, malaria elimination programmes follow up malaria cases reported by health facilities to carry out case investigations that will determine the origin of the infection, whether it has been imported or is due to local malaria transmission. If necessary, the malaria programme will also carry out active surveillance to find additional malaria cases in the locality to prevent further transmission. To understand current practices and share information on malaria elimination strategies, a survey specifically addressing country policies on case investigation and reactive case detection was carried out among fourteen countries of the Asia Pacific Malaria Elimination Network (APMEN). METHODS: A questionnaire was distributed to the malaria control programme managers amongst 14 countries in the Asia Pacific who have national or sub-national malaria elimination goals. RESULTS: Results indicate that there are a wide variety of case investigation and active case detection activities employed by the 13 countries that responded to the survey. All respondents report conducting case investigation as part of surveillance activities. More than half of these countries conduct investigations for each case. Over half aim to accomplish the investigation within one to two days of a case report. Programmes collect a broad array of demographic data during investigation procedures and definitions for imported cases are varied across respondents. Some countries report intra-national (from a different province or district) importation while others report only international importation (from a different country). Reactive case detection in respondent countries is defined as screening households within a pre-determined radius in order to identify other locally acquired infections, whether symptomatic or asymptomatic. Respondents report that reactive case detection can be triggered in different ways, in some cases with only a single case report and in others if a defined threshold of multiple cases occurs. The spatial range of screening conducted varies from a certain number of households to an entire administrative unit (e g, village). Some countries target symptomatic people whereas others target all people in order to detect asymptomatic infections. The majority of respondent programmes collect a range of information from those screened for malaria, similar to the range of information collected during case investigation. CONCLUSION: Case investigation and reactive case detection are implemented in the malaria elimination programmes in the Asia Pacific, however practices vary widely from country to country. There is little evidence available to support countries in deciding which methods to maintain, change or adopt for improved effectiveness and efficiency. The development and use of common evaluation metrics for these activities will allow malaria programmes to assess performance and results of resource-intensive surveillance measures and may benefit other countries that are considering implementing these activities.