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Introducing malaria rapid diagnostic tests in private medicine retail outlets: A systematic literature review

  • Theodoor Visser ,

    tvisser@clintonhealthaccess.org

    Affiliation Clinton Health Access Initiative, Boston, Massachusetts, United States of America

  • Katia Bruxvoort,

    Affiliation Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Kathleen Maloney,

    Affiliation Bill and Melinda Gates Foundation, Seattle, Washington, United States of America

  • Toby Leslie,

    Affiliation Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Lawrence M. Barat,

    Affiliation US President’s Malaria Initiative, United States Agency for International Development, Washington DC, United States of America

  • Richard Allan,

    Affiliation Mentor Initiative, West Sussex, United Kingdom

  • Evelyn K. Ansah,

    Affiliation Research & Development Division, Ghana Health Service, Accra, Ghana

  • Jennifer Anyanti,

    Affiliation Society for Family Health, Abuja, Nigeria

  • Ian Boulton,

    Affiliation TropMed Pharma Consulting, Lower Shiplake, Oxfordshire, United Kingdom

  • Siân E. Clarke,

    Affiliation Department of Disease Control, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Jessica L. Cohen,

    Affiliation Harvard T.H. Chan School of Public Health, Boston, United States of America

  • Justin M. Cohen,

    Affiliation Clinton Health Access Initiative, Boston, Massachusetts, United States of America

  • Andrea Cutherell,

    Affiliation Population Services International, Nairobi, Kenya

  • Caitlin Dolkart,

    Affiliation Clinton Health Access Initiative, Boston, Massachusetts, United States of America

  • Katie Eves,

    Affiliation Mentor Initiative, West Sussex, United Kingdom

  • Günther Fink,

    Affiliation Harvard T.H. Chan School of Public Health, Boston, United States of America

  • Catherine Goodman,

    Affiliation Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Eleanor Hutchinson,

    Affiliation Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Sham Lal,

    Affiliation Department of Disease Control, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Anthony Mbonye,

    Affiliation Ministry of Health, Kampala, Uganda

  • Obinna Onwujekwe,

    Affiliation University of Enugu, Agbani, Enugu State, Nigeria

  • Nora Petty,

    Affiliation Clinton Health Access Initiative, Boston, Massachusetts, United States of America

  • Julie Pontarollo,

    Affiliation Mentor Initiative, West Sussex, United Kingdom

  • Stephen Poyer,

    Affiliation Population Services International, Nairobi, Kenya

  • David Schellenberg,

    Affiliation Department of Disease Control, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Elizabeth Streat,

    Affiliation Malaria Consortium, London, United Kingdom

  • Abigail Ward,

    Affiliation Clinton Health Access Initiative, Boston, Massachusetts, United States of America

  • Virginia Wiseman,

    Affiliations Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom, School of Public Health and Community Medicine, University of New South Wales, UNSW, Sydney, Australia

  • Christopher J. M. Whitty,

    Affiliation Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Shunmay Yeung,

    Affiliations Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom, Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • Jane Cunningham,

    Affiliation Global Malaria Program, World Health Organization, Geneva, Switzerland

  •  [ ... ],
  • Clare I. R. Chandler

    Affiliation Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, United Kingdom

  • [ view all ]
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Introducing malaria rapid diagnostic tests in private medicine retail outlets: A systematic literature review

  • Theodoor Visser, 
  • Katia Bruxvoort, 
  • Kathleen Maloney, 
  • Toby Leslie, 
  • Lawrence M. Barat, 
  • Richard Allan, 
  • Evelyn K. Ansah, 
  • Jennifer Anyanti, 
  • Ian Boulton, 
  • Siân E. Clarke
PLOS
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Abstract

Background

Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs. To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures. This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions.

Methods

Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed. Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings. Outcomes were extracted from publications or provided by principal investigators.

Results

Six published and six unpublished studies were found. Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies. None of the studies assessed large-scale implementation in PMRs. RDT uptake varied widely from 8%-100%. Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies. Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies. Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results. Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges.

Conclusions

Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials. However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.

Background

Provision of artemisinin-based combination therapies (ACTs) and other antimalarials to patients without confirmed malaria frequently results in overtreatment, potentially delaying diagnosis and treatment of other causes of illness and reducing availability of ACTs for true malaria cases [1, 2]. Overuse of antimalarials by patients without malaria has been estimated to be half of global demand [3].

Prompted by recommendations from the World Health Organization in 2010 [4], national malaria programs in most endemic countries revised their diagnosis and treatment guidelines to emphasize the use of parasite-based diagnosis of malaria before treatment for all suspected malaria cases [5, 6]. Since then, procurement of malaria rapid diagnostic tests (RDTs) has increased significantly in the public health care sector across much of sub-Saharan Africa [5, 7]. In contrast, availability and use of diagnostic testing in the private medicine retail sector has remained low. Efforts to improve or expand malaria case management in the private sector, as demonstrated in the Affordable Medicines Facility- malaria (AMFm) pilot, focused on treatment delivery, but did not promote the use of diagnostic testing [8]. Evidence shows that RDTs or microscopy are available in less than 20% of pharmacies and drug shops selling antimalarials in six out of eight sub-Saharan African countries surveyed in 2013 or 2014 [9]. Though treatment-seeking practices vary greatly between countries, overall approximately one-third of febrile children obtaining malaria drugs are treated by private providers with limited access to malaria diagnostic services [3].

The private health care sector consists of private not-for-profit and private for-profit health providers, with the latter including private health facilities, diagnostic centers, private medicine retailers and informal practitioners [10]. Private medicine retail outlets (PMRs), a large category of for-profit private health providers in many countries [11], include outlets that specialize in medicines such as pharmacies and drug stores, as well as general stores or itinerant vendors that sell medicines along with other household merchandise [12]. In many countries, PMRs play a dominant role in the distribution and sale of antimalarials [9]. Typically, the outlets that specialize in selling medicines have storefronts, product displays, and a counter. Some may have a small room in the back, separated by a curtain or door, for examinations and treatment. Skills and qualifications vary among staff working in these outlets and include physicians, pharmacists, nurses and drug sellers with little to no formal health training [13]. PMRs are allowed to only carry over the counter drugs and in some cases a limited number of prescription drugs such as antimalarials and certain antibiotics. They are typically not allowed to perform diagnostic services, but government regulations vary amongst countries and are often poorly enforced [1416].

Given the importance of PMRs as a first source of care and antimalarial treatment, several endemic countries in sub-Saharan Africa and Southeast Asia are considering introducing and scaling up RDTs in these outlets to achieve universal access to prompt parasite based diagnosis prior to treatment [17]. Introducing blood-testing in these outlets is not without controversy, and evidence to guide decisions on how and where to scale up RDTs amongst PMRs is currently lacking [18]. PMRs are often poorly supervised, rarely report into health information systems and are not equipped to manage severe illnesses [12]. Although the procedure to perform RDTs does not require specialized training, operators are required to draw and transfer an exact quantity of blood, apply a specific number of buffer drops, wait the required time before a result can be read (i.e. 15 or 20 minutes) and appropriately dispose of the hazardous infectious waste. Without adequate oversight, public health officials fear that PMRs may misdiagnose patients or not treat patients according to malaria guidelines, providing antimalarials or antibiotics to patients that test negative for malaria [19]. PMRs may also use substandard RDTs, affecting the trust in the result of the test and hence adherence to its results [20]. There is also a concern that improper handling of hazardous waste may lead to the spread of other infectious illnesses [21].

This review identifies and synthesizes available evidence and explores how it can help inform decisions about scaling up RDTs in PMRs.

Objectives

We undertook a systematic review of published and unpublished intervention studies to evaluate available evidence of the implementation and impact of RDT introduction in PMRs (pharmacies, drug stores, general stores, and/or itinerant vendors that sell medicines along with other household merchandise). The review aimed to:

  1. Examine outcomes pertaining to RDT uptake, provider adherence to test results, referral, cost and safety.
  2. Review characteristics of each intervention to introduce RDT use (e.g. the length and content of trainings, supervision frequency, referral guidelines, demand generation activities and retail price of RDTs) to explore factors that are associated with RDT uptake and provider adherence to test results.

Methods

Registration and eligibility criteria

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (http://www.prisma-statement.org/) and registered with PROSPERO (2013:CRD42013006146). We used the following inclusion criteria:

  • Participants: Any PMR providers and their patients
  • Interventions: Any introduction of RDTs with or without supporting interventions, where RDTs were performed by PMR staff
  • Comparisons: Studies were included whether or not there was a comparison group, and whether or not the comparison group was randomly allocated
  • Outcomes: Any measurement of the impact of an intervention to introduce RDTs, such as RDT uptake, provider adherence to test results, recommended retail price or safety protocols

We excluded studies that took place outside of PMRs among other private for-profit, private not-for-profit, and public health care providers (e.g., private health facilities, mission or non-governmental facilities, community health workers, and public health facilities); that reported only on the accuracy of RDTs (such as laboratory-based performance comparisons); where RDTs were not introduced into routine practice (if not performed by outlet staff or used only for reference by a research team); that evaluated the use, presence or proportion of outlets stocking RDTs without implementing any interventions to introduce RDTs; and studies based on hypothetical scenarios or modeling. To increase the evidence base, recent studies yet to be published at the time of the search were also included in the review. Principal investigators from unpublished studies were asked to extract specific testing and treatment outcome data to enable analysis across studies. Principal investigators of published studies were also asked to provide clarifications and data on additional outcomes not reported in the publication.

Search methods

We performed a systematic literature search of electronic databases on November 16, 2016, including PubMed/Medline, Cochrane Library Online, WHOLIS internet databases, IBSS, Web of Science and Ovid (EMBASE, Global Health, and Journals at Ovid). Studies which were yet to be published were identified at a Roll Back Malaria (RBM) Case Management Working Group, Informal Private Sector Task Force meeting in April 2013 [22] and a consultative working meeting on fever case management in the private health care sector in Africa, organized by ACT Consortium in October 2015 [17].

Search terms.

Literature searches used synonyms and MESH terms for three concepts (i) ‘malaria’ (ii) ‘rapid diagnostic test’ and (iii) ‘private sector’. No search terms or filters for methods were included. Table 1 provides an overview of the search terms.

Study selection.

For published studies the resulting titles and abstracts were reviewed independently by two authors (TV and KB) to select papers or reports to read in full text. Discrepancies were resolved by a third author (KM). Papers that were clearly irrelevant were excluded after reading title and abstract. The remaining papers were read in full and excluded if they did not match the inclusion criteria after agreement between TV, KB and KM. Remaining papers were included in the systematic review.

For inclusion of unpublished studies, investigators were contacted initially to ascertain whether studies met the eligibility criteria, whether data would be available and/or computed within a given time frame and to reach agreement with investigators to include their unpublished findings in the review. Studies that met each of these criteria were subsequently included in the review and investigators asked to contribute results from their studies.

Data outcomes and extraction

Data extraction tables were used to collate information from both published and unpublished studies. The following diagnosis and treatment outcomes were compared across studies:

  1. Uptake: the proportion of patients seeking treatment for fever or suspected malaria who were tested with an RDT
  2. RDT positivity: the proportion of patients receiving a positive RDT result
  3. ACT provision: the proportion of patients seeking treatment for fever or suspected malaria who were sold ACTs, regardless of whether or not they were tested
  4. Adherence to negative or positive test results: the proportion of patients that were sold ACTs in the presence of a positive RDT result or the proportion of patients that that were not sold ACTs or other antimalarials in the presence of a negative RDT result
  5. Antibiotic provision: the proportion of patients who were sold antibiotics in the presence of a positive RDT result; or the proportion of patients who were sold antibiotics in the presence of a negative RDT result
  6. Referrals: the proportion of patients referred to a public facility by the provider for further care
  7. Accuracy and safety: the proportion of PMR providers who accurately performed the RDT, read the result, and adequately disposed of the infectious hazardous waste
  8. Median retail price of a RDT

We reported outcomes as proportions with comparable denominators where possible. In studies that provided cluster and individual level outcomes, we chose to use individual outcomes to enable comparison across studies. Where the same outcome was reported by more than one method of data collection, we chose the most complete data set, or presented neither if results for an outcome substantially differed between methods. To explore factors that appear to have supported RDT uptake and provider adherence to test results, outcomes across study arms were reviewed in terms of the characteristics of each intervention (length and content of trainings, supervision frequency, demand generation activities, recommended RDT retail price and referral policy). We did not make statistical comparisons between studies because of the different methodologies and outcomes used.

Results

Study selection

A total of 1645 titles from published studies were identified through the search strategy (Fig 1). After removing duplicates, 904 titles and abstracts were screened and 136 publications were reviewed in detail. Of these, two studies focused on Cambodia [23, 24], where RDTs had been scaled-up for over a decade. However, these studies did not directly evaluate the impact of implementation of RDTs on any outcomes comparable with other studies. Two other studies (Cohen et al. 2012 and Awor et al. 2014) published initial data followed by more recent publications with additional data from the same studies (Cohen et al. 2015 and Awor et al. 2015). Each of these pairs are presented together and counted as one study. In addition, eight unpublished studies were identified. Two of these, a study in Madagascar and a study in Angola, were excluded, as data were not available at the time of this review. In all, six published [2532] and six unpublished studies (please refer to the supporting information file S2 File) were included in the review, for a total of 12 studies.

Study design and characteristics

Table 2 provides characteristics of the included studies. Most were trials of pilot interventions to introduce RDTs in PMRs specialized in selling drugs (e.g., drug shops or pharmacies) in sub-Saharan Africa, with one trial in Myanmar (Aung et al. 2015). Four studies had a control group without RDTs (Ansah et al. 2015; Awor et al. 2013; Maloney et al. under review; Mbonye et al. 2015) and three studies had multiple RDT intervention arms (Aung et al. 2015; Maloney et al. under review; Onwujekwe et al. 2015). The studies took place in areas of medium to high malaria transmission [33] and in rural, peri-urban, and urban settings. Outcomes were assessed using various data collection methods: provider records, exit interviews, mystery shoppers, direct observation, supervision visits, and household surveys (Table 3). Regulations in all study countries except Myanmar did not permit RDTs to be performed by providers in PMRs; studies were granted waivers or special permission from governments. The length of the studies ranged from six months (Onwujekwe et al. 2015) to 27 months (Allan et al. unpublished data). The number of outlets where RDTs were introduced varied from 29 to over 600 outlets in the intervention arm in Uganda and Myanmar, respectively (Mbonye et al. 2015, Aung et al. 2015).

RDTs were either free to patients (Ansah et al. 2015; Awor et al. 2014, 2015) or heavily subsidized by implementers. Subsidies ranged from US$0.26 to US$0.8 per RDT (Mbonye et al. 2015; Aung et al. 2015; Streat et al. Zambia unpublished data; Streat et al. Ug unpublished data; Streat et al. Nigeria unpublished data; Allan et al. unpublished data; Onwujekwe et al. 2015; Cohen et al. 2012, 2015), except in a study in Kenya (Poyer et al. unpublished results) and one arm of a study in Tanzania (Maloney et al. under review), where RDTs were not subsidized. Gloves and infectious hazardous waste disposal units (i.e. a sharp box) were provided free of cost in most studies. RDTs were distributed either directly to a participating provider from a research warehouse or through a pre-selected wholesaler, importer or government entity. The length of the training varied from half a day to five days and often combined lectures and practice in performing the RDTs. Training content typically covered the symptoms of malaria and the recommended policies on antimalarial treatment and safety. In most intervention arms, training emphasized adherence to test results, including guidance on referral to nearby public health facilities for patients with signs of severe disease. Most studies also recommended referral when patients tested negative. Exceptions included a study in Uganda, where providers were trained on ACTs as first-line malaria treatment and how to perform RDTs but were not given specific algorithms on when to use RDTs or how to manage positive and negative results (Cohen et al. 2012, 2015). In another study in Uganda, the RDT introduction was part of a five day integrated community case management (iCCM) training that included treatment of malaria, pneumonia, and diarrhoea (Awor et al. 2014, 2015). In one arm of a study in Nigeria, training focused only on how to perform RDTs (Onwujekwe et al. 2015). The frequency of supportive supervision also differed, but in most studies research staff visited participating facilities monthly or quarterly to evaluate stock management, waste management practices and how RDTs were performed, stored, and priced (through direct observation using a checklist). In a study in Kenya, outlet supervision visits were conducted based on febrile client volume and quality of care, prioritizing high volume and under-performing outlets (Poyer et al. unpublished data). In studies in Nigeria and Uganda, professional associations and medical retailers were contracted to perform the supervision (Streat et al. Nigeria unpublished data; Streat et al. Uganda unpublished data). Activities to raise awareness of RDTs included organizing community meetings and door to door visits using volunteer health promotors (Allan et al. unpublished data, Mbonye et al. 2015), community films (Ansah et al. 2015) conducting small group communication sessions and household visits (Poyer et al. unpublished data), school-based activities (Onwujekwe et al. 2015) and national or regional media campaigns promoting the use of RDTs (Cohen et al. 2012, 2015; Maloney et al. under review; Poyer et al. unpublished data; Streat et al. Nigeria unpublished data; Streat et al. Uganda unpublished data).

Testing and treatment outcomes

Table 4 provides the diagnosis and treatment outcomes included in the review. Table 5 provides a summary of diagnosis and treatment outcomes by study arm alongside a summary of the supporting interventions implemented, ordered by RDT uptake (high to low).

Uptake of RDTs.

All studies reported on uptake (the proportion of eligible patients for whom an RDT was undertaken), which ranged from 8% (96/1279, exit interviews) in the provider and school-based intervention arm of a study in Nigeria (Onwujekwe et al. 2015) to 100% (2719/2719, provider records) in a study in Ghana (Ansah et al. 2015). Five studies reported uptake below 50% (Cohen et al. 2013, 2015; Streat et al. Uganda unpublished data; Allan et al. unpublished data; Onwujekwe et al. 2015; Poyer et al. unpublished), three studies reported uptake between 50% and 80% (Aung et al. 2015; Maloney et al. under review; Streat et al. Zambia unpublished data) and three studies reported uptake above 80% (Mbonye et al. 2015; Ansah et al. 2015; Awor et al. 2014, 2015).

ACT provision and RDT positivity.

Eight studies reported on ACT provision among all patients seeking treatment for fever or suspected malaria. ACT provision ranged from 30% to 60% in six studies (Allan et al. unpublished data; Ansah et al. 2015; Maloney et al. under review; Mbonye et al. 2015; Onwujekwe et al. 2015; Poyer et al. unpublished data). Both the highest ACT provision (81%, 393/487, exit interviews) and the lowest (29%, 840/2868, household surveys) were reported in studies in Uganda (Awor et al. 2014, 2015 and Cohen et al. 2012, 2015, respectively).

ACT provision was compared between intervention and control (no RDT intervention) arms in four studies: in Uganda (Mbonye et al. 2015; Awor et al. 2014, 2015), Ghana (Ansah et al. 2015), and Tanzania (Maloney et al. under review). In three of these studies, 10 to 40 percentage points fewer patients in the RDT intervention arms compared to the control arms obtained ACTs (Mbonye et al. 2015, Ansah et al. 2015; Maloney et al. under review). RDT positivity in these studies was approximately 50% to 60%. In Awor et al. (2014, 2015), 20 percentage points more patients in the intervention arm compared to the control arm obtained ACTs. In this study, RDT positivity and ACT provision were both high (75% and 81%, respectively). Four other studies also reported similarly high RDT positivity (Streat et al. Uganda, unpublished data; Streat et al. Zambia, unpublished data; Onwujekwe et al. 2015; Cohen et al. 2012, 2015), while RDT positivity in the remaining studies ranged from 33% to 50% (Ansah et al. 2015; Mbonye et al. 2015; Onwujekwe et al. 2015; Allan et al. unpublished data).

Adherence to RDT results.

All studies reported adherence to RDT results. Overall, antimalarials were less commonly provided to RDT-negative patients than to RDT-positive and untested patients. In eight studies, the percentage of RDT-negative patients who received an unnecessary antimalarial was at or below 20% (Ansah et al. 2015; Awor et al. 2014, 2015; Aung et al. 2015; Maloney et al. under review; Mbonye et al. 2015; Poyer et al. unpublished data; Streat et al. Nigeria unpublished data; Streat et al. Uganda unpublished data). However, high adherence was not universal. A study in Uganda (Cohen et al. 2013, 2015) found relatively low adherence, with 41% of patients testing negative receiving an antimalarial (22/54 household members reporting getting an RDT at a drug shop). In addition, all three intervention arms in a study in Nigeria (Onwujekwe et al. 2015) found very low adherence, with over 50% of those testing negative receiving an antimalarial.

The proportions of RDT-positive patients receiving ACTs exceeded 85% in six studies (Ansah et al. 2015; Awor et al. 2014, 2015; Maloney et al. under review; Mbonye et al. 2015; Poyer et al. unpublished data; Streat et al. Zambia unpublished data). In four studies, ACT provision ranged between 65% and 85% (Allan et al. unpublished data; one intervention arm of Maloney et al. under review; Streat et al. Uganda unpublished data; Onwujekwe et al. 2015). The lowest adherence to positive results (30%, 128/421, household surveys) was found in a study in Uganda that also found relatively poor uptake and adherence to negative test results (Cohen et al. 2012, 2015).

Eight studies reported on antibiotic use. The proportion of RDT-negative patients receiving antibiotics ranged from 0.3% (6/1854, exit interviews) in a study in Ghana (Ansah et al. 2015) to 45% (51/113, household survey) in a study in Uganda (Mbonye et al. 2015). Three studies reported antibiotic use exceeding 20% (Cohen et al. 2012, 2015; Mbonye et al. 2015; Poyer et al. unpublished data), with the remaining studies reporting below 20%. Similarly, the proportion of patients with a positive RDT result receiving antibiotics varied from 0% (0/1351, provider records) in Ghana (Ansah et al. 2015) to 31% (129/441, household survey) in a study in Uganda (Cohen et al. 2012, 2015). Studies that reported relatively high provision of antibiotics to RDT-negative patients also reported high provision to RDT positive patients (Cohen et al. 2012, 2015; Mbonye et al. 2015; Poyer et al. unpublished data).

Referrals.

Only five studies reported on the proportion of patients who were referred to public hospitals or clinics. In all of these studies, providers were instructed to refer all RDT negative cases. In a study in Ghana (Ansah et al. 2015), 62% of the 1088 referred patients interviewed by phone reported attendance at the referral facility. The public health facilities had been made well aware of testing going on in the drug shops and accepted the referred patients. In the remaining four studies, referrals were 10% or less of the cases. Reasons given for low rates of referral were explored explicitly in a qualitative component to the study in Uganda (Mbonye et al. 2015), although investigators in other studies reported similar challenges. Providers in the Ugandan study were reluctant to refer except when it was considered medically imperative because of fears that public health workers were unwilling to take patients referred from drug shops or would question the competence of outlet providers, thereby damaging their reputations [34]. Vendors were also concerned that clients might go to another shop rather than to a public facility, and they would lose their clientele. In almost all settings, formal referral systems from private medicine retail outlets to public facilities had not been established. In those studies where providers were encouraged to refer patients with severe illness or if a clear diagnosis could not be made, there was anecdotal evidence of poor or contradictory treatment at the receiving facility.

Safety & accuracy in performing RDTs.

Nine studies provided data on how RDTs were administered using a check list. In general, most providers were able to accurately perform the RDT, read its results and dispose of the hazardous infectious waste appropriately. In six studies where this outcome was recorded, approximately 85% or more of the providers performed the test safely and correctly (Aung et al. 2015; Ansah et al. 2015; Awor et al. 2014, 2015; Cohen et al. 2012, 2015; Maloney et al. under review; Mbonye et al. 2015). In studies in Nigeria (Streat et al. unpublished data) and Uganda (Streat et al. unpublished data) only 75% of providers performed and disposed of the RDT appropriately. A study in Liberia (Allan et al. unpublished data) found that only 39% (15/38, mystery shoppers) performed all nine of the required steps, with the most common omissions being not disposing of sharps in a safety box and not waiting the appropriate amount of time to read the result. Studies in Tanzania (Maloney et al. under review) and Uganda (Cohen et al. 2012, 2015) found that providers would often not wear gloves, in addition to the issue of waiting the required number of minutes and adequate disposal of lancets.

Price of test to patient.

In the seven studies that used a recommended retail price (RRP), actual median retail prices matched the RRP in a study in Tanzania (US$0.67 and US$0.32 in unsubsidized and subsidized arms respectively, Maloney et al. under review) and a study in Uganda (at a subsidized price of $1, Streat et al. Uganda unpublished results). The actual observed median retail prices exceeded the RRP in the other five studies, ranging from US$0.32 (23% above the RRP) in a study in Liberia (Allan et al. unpublished) to US$1.20 (100% above the RRP) in a study in Nigeria (Onwujekwe et al. 2015). In a study in Uganda (Cohen et al. 2012, 2015) that did not use a RRP, most providers priced RDTs to match local microscopy prices at US$0.40. The remaining studies either provided RDTs for free (Ansah et al. 2015; Awor et al. 2014, 2015) or for a fixed price of around $0.20 (Mbonye et al. 2015; Streat et al. Zambia unpublished data).

Discussion

The introduction of RDTs in PMRs, a primary source of care in many settings, aims to improve case management of febrile illnesses through prompt and appropriate treatment of malaria and a reduction in delays to diagnosis and treatment of other illnesses. This review demonstrates that while RDT introduction can achieve this goal, such outcomes are not guaranteed. Although studies with more intensive interventions generally produced better outcomes, it is unclear whether such efforts could be maintained or scaled up to national level.

The three studies that showed the highest uptake and the highest adherence (Ansah et al. 2015; Mbonye et al. 2015; Awor et al. 2015) included longer trainings (4 or 5 days), close and frequent supervision for an initial period of time (weekly visits by the research team), and low RDT retail prices (US$0.20 or less). These three studies also included the lowest number of outlets compared to the other studies reviewed.

However, there are notable exceptions to these trends. A study in Nigeria (Onwujekwe et al. 2015) compared the uptake of RDTs and adherence to national malaria guidelines under different training scenarios and found that longer and more comprehensive training (two days covering diagnosis and treatment versus one day with only a demonstration on how to use RDTs) did not appear to affect uptake or adherence. In contrast, classroom-based trainings on malaria case management in a study in Myanmar (Aung et al. 2015), were relatively short (only 0.5 days), but uptake and adherence were better than in some studies with longer trainings. Similarly, in a study in Tanzania (Maloney et al. under review), subsidizing the retail price of RDTs by over 50% did not increase uptake compared with an unsubsidized price. Factors that may limit the comparability of outcomes to the intensity of the related interventions include study setting and context (e.g., prior exposure of provider to malaria case management training), the timing of the evaluation (e.g., 3 months vs. 12 months after implementation), the method of data collection (e.g., mystery shopper vs. provider records), the number of outlets included in the studies (e.g., 18 vs. 1502 outlets) or unique events that affected study outcomes (e.g., in a study in Nigeria (Streat et al. Nigeria unpublished data), leakage from public sector into the private sector flooded the market, negatively impacting the uptake`of ‘project’ RDTs).

None of the studies deployed interventions that could be scaled-up easily at the national level. For example, a highly effective intervention in Uganda (Mbonye et al. 2015) included four day trainings, weekly supervision visits for the first two months and a free, continued supply of RDTs, gloves and sharp boxes. Studies that implemented less intense but perhaps more scalable interventions often produced poorer outcomes. For example, in a study in Uganda (Cohen et al. 2012 2015) that showed low RDT uptake and adherence, PMRs were free to choose the price at which the RDTs were sold and free to make treatment recommendations as they wished. Another study, where RDT stock outs were recorded in a study in Tanzania (Maloney et al. under review), chose not to control the supply of RDTs; PMRs were simply informed where they could procure RDTs. Schools in an intervention arm of a study in Nigeria (Onwujekwe et al 2015) were supported to organize malaria events to promote uptake and adherence, but only half of the participating schools did so.

Heterogeneity in outcomes following RDT introduction is not unique to the private sector [3537]. While many public health facilities that increased diagnostic testing for malaria through the use of RDTs also reported reductions in ACT provision, the availability of RDTs alone does not seem sufficient to ensure the appropriate use of ACTs [38, 39]. Public and private providers alike have rationales for providing antimalarials to patients with a negative RDT result. Anxiety over the potential for patients to worsen without being given antimalarials seems paramount [40, 41], just as with antibiotics in other settings [42]. This is accentuated in contexts where antimalarials are expected, or even demanded, by patients or customers [43], and where clients can take their business elsewhere [44]. Overstretched providers may find the time it takes to perform the RDT prohibitive and choose to assist other customers instead of performing the RDT or waiting for its result [45]. In all sectors, behavior change is likely to require sustained efforts.

Experience from these studies showed that requirements for introducing RDTs at scale in PMRs should be viewed as the introduction of a comprehensive service, not just another commodity. However, evidence on how to do so remains limited in many operational aspects. First, evidence is needed on how to integrate malaria testing into case management beyond malaria. Where negative cases are expected to be referred, this may be challenging: clients have chosen the retail sector, providers are keen to make a sale, and public sector workers may be unwelcoming to patients referred from PMRs [34]. Guidelines for managing RDT negative adults and children require specific development, based on levels of expertise, resource availability, and local regulations. Second, evidence is needed on how to train and supervise PMRs, given the size and heterogeneity of the sector as well as rapid staff turnover [13]. It may not be feasible or even desirable to train and supervise all PMRs. Some studies experimented with innovative supervision approaches to prioritize certain shops over others based on sales volume or performance [Poyer et al. unpublished data], but little is understood how to find, select or retain these ‘successful’ providers. Some studies in the review [Poyer et al. unpublished data; Streat et al. Nigeria unpublished data; Streat et al. Uganda unpublished data; Maloney et al. under review] aimed to provide more sustainable mechanisms (i.e. having professional associations instead of research team members conduct supervision visits, not subsidizing the RDT or controlling the supply chain) that could be scaled and exist beyond the length of the study, but scale up was not tested. New innovative approaches that build on existing structures and programs in the private sector, rather than building parallel infrastructures, require exploration. Third, evidence is needed on how to deal with hazardous waste from testing at scale in these non-clinical settings. In most studies in this review, research teams were responsible for this. One study in Tanzania (Maloney et al. under review) that instructed providers to visit public health facilities to drop off waste had mixed success; many providers instead chose to bury or burn their waste. A study in Uganda (Streat et al. Uganda unpublished data) contracted a private firm to collect the waste at each of the participating outlets, but poor uptake combined with frequent collection visits caused cost overruns. New innovative approaches to waste disposal require development and evaluation under real world conditions. Finally, additional consideration must also be given to issues beyond malaria control, such as role of PMRs in the wider health system and the legal and regulatory frameworks for in vitro diagnostics. A sustained scale up of RDTs in the private retail sector would require recognition from stakeholders, including regulatory bodies, that PMRs are a viable alternative to public sector provision of quality care for uncomplicated malaria.

Limitations

This review employed a broad search strategy to identify all eligible studies where RDTs were introduced in the private medicine retail sector. We did not include studies that included formal private health facilities such as clinics or hospitals. Since countries are making decisions now about if or how RDTs can be introduced in PMRs, we decided that waiting for more studies to complete the publication process was deemed too much of a delay. While it is possible an eligible but unpublished study could have been missed, this is unlikely given the involvement of extensive contacts identified through the two convened stakeholder meetings in 2013 and 2015 and the large group of authors involved. Some studies did not have data on all the outcomes assessed in the review. The mix of study designs (i.e. differences in intervention and control arm design) and evaluation methods (i.e. mystery shopper or provider records) made formal comparison of point estimates inappropriate. Differences in expectations of RDT positivity and patient demand for diagnosis across studies further limited comparability. The studies included in the review were all small scale trials or pilots with short durations. Most studies evaluated outcomes at a single point in time, which may not be representative of embedded and sustained effects. Finally, studies included in the review did not address the potential regulatory and policy barriers of introducing RDTs to PMRs. All of the studies, except in Myanmar, were provided a waiver to perform RDTs.

Conclusions

Supporting the introduction of malaria rapid diagnostic testing in private medicine retail outlets has the potential to target antimalarial drugs more effectively. This review shows that a range of private providers in different countries can incorporate RDTs into their practice, although with varying degrees of uptake and influence on case management. This review suggests investment in training and supervision may be beneficial to supporting RDT implementation. However, substantial gaps remain in the evidence for systems that will allow for RDT implementation at scale.

Acknowledgments

We acknowledge the contributions of those participating at the RBM Case Management Working Group and the consultative working meeting organized by ACT Consortium but who did not make a direct contribution to this paper. We also acknowledge the Presidents Malaria Initiative and the ACT Consortium in sponsoring the consultative meetings. We would also like to acknowledge the patients and health workers who contributed to each of the studies included in the review.

Author Contributions

  1. Conceptualization: RA LMB KB CIRC JC DS TV.
  2. Data curation: KB CIRC TL TV.
  3. Investigation: EKA JA KB CIRC SEC JLC AC KE GF SL KM AM OO JP SP ES AW VW SY.
  4. Methodology: KB KM CIRC TL TV.
  5. Project administration: TV KB CIRC.
  6. Resources: RA EKA JA SEC JLC AC KE GF SL KM AM OO JP SP ES AW VW SY.
  7. Supervision: LMB CIRC JC DS.
  8. Visualization: KB CIRC TL TV.
  9. Writing – original draft: KB CIRC TL TV.
  10. Writing – review & editing: EKA JA LMB IB KB CIRC SEC JLC JMC AC JC CD KE GF CG EH SL TL KM AM OO NP JP SP ES TV AW CJMW VW SY.

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