Operational guidance for priority interventions post COVID-19 Test and Treat: Integration of COVID-19 services into Primary Health Care Prepared by: Emily Wroe, Anne Moller, Paul Sonenthal, and KJ Seung Partners In Health September 2023 Table of Contents Situation Overview.........................................................................- 3 - Early Lessons Learned...................................................................- 5 - What is Test & Treat.......................................................................- 6 - Importance of Test & Treat.............................................................- 8 - Existing work on Test & Treat.......................................................- 11 - Implementation of Test & Treat..............................................- 13 - 14 - Monitoring & Evaluation.........................................................- 20 - 21 - Resources.............................................................................- 22 - 23 - Acknowledgements...............................................................- 23 - 24 - References............................................................................- 24 - 25 - 2 Situation Overview The COVID-19 pandemic underlined, exposed, and exacerbated vast global inequity in health care. Health systems and access to health that was already fragile or precarious was worsened, and existing global dynamics in access to commodities were magnified. In addition to global vaccine apartheid, access to COVID-19 tests, therapeutics, and other medical interventions that could alter the course of the disease and save lives was severely hampered among most of the world living in marginalized or poor countries and communities. Globally, as of September 14th, 2023, there have been 770,563,467 confirmed cases of COVID-19, including 6,957,216 deaths, reported to WHO.1 These numbers are staggering and unprecedented, but as we examine testing and treatment as core interventions for combatting COVID-19, there are additional numbers to consider as well. Remarkably, between March 2020 and April 2023, only 0.4% of the estimated more than 6 billion COVID-19 tests performed globally were in low-in- come countries and 20% of tests in lower middle-income countries, despite these countries comprising 50.6% of the global population.2 (Figure 1) By the end of 2021, the World Health Organization (WHO) was estimating that 6 out of every 7 cases in Africa was going undetected.3 The need for Test & Treat programs is striking, and while substantial attention is needed thera- peutics, it is imperative to remember that robust testing programs are a critical ingredient. Figure 1. Global testing rates for COVID-19 Source: FIND Test Tracker (finddx.org/covid-19/test-tracker) Treatment numbers are even harder to come by given the limited availability and accessibility of therapeutics. In the early months of the pandemic, there were limited therapeutics available. Lat- er, access to therapeutics was plagued by several barriers including regulatory, intellectual prop- erty, and price. The first therapeutic available, Gilead’s remdesivir, was expensive and given by intravenous infusion, and had limited widespread availability.4 Monoclonal antibodies were next 3 on the scene, though they were also given intravenously and there was not enough supply for them to be meaningfully available to the general population. Intellectual property barriers and use restrictions also plagued the monoclonal antibody therapies as the answer to treatment needed by much of the world. It was therefore toward the end of 2021 when the conversation started to change around out- patient therapies for COVID-19, with the arrival of Merck’s molnupiravir and Pfizer’s PaxlovidTM (nirmatrelvir/ ritonavir).5,6 However, while this is when these medications became available in high-income countries, to this day they are not widely available in low- or even middle-income countries. With strong evidence from previous pandemics and management of infectious diseases, and with advocacy efforts from civil society, a global advocacy movement and conversation was start- ed around the need for robust COVID-19 Test & Treat programs to be integrated within primary and community care systems everywhere.4 However, despite the emergence of consortia, a limited amount of funding, and small pilot programs, Test & Treat for COVID-19 has not garnered the momentum and widespread availability that is needed – both to address ongoing COVID-19 infections as well as to set up robust and nimble systems to adjust Test & Treat programming for future emerging pathogens. 4 Photo: Ezra Acayan / World Bank Early Lessons Learned This operational guidance will delve into the doses. (2) But demand for Paxlovid from some definitions of Test & Treat programs and the LMICs lagged too. Low demand was attributed different approaches and implementation to complicated eligibility requirements, reduced components that are contained within this testing, and potential for drug interactions (1) important piece of responding to pandemics. by several international press articles, but doc- But first, it is important to reflect on where we tors and nurses in several rural communities, are and where we’ve come – both on prog- including in Haiti, Nigeria, and Madagascar, ress made and ongoing limitations and weak- reported never having heard of Paxlovid and nesses. Test & Treat in particular faced some novel antivirals for COVID-19 (2). Demand for substantial barriers and challenges during the therapeutics simply cannot exist without knowl- COVID-19 pandemic – things we can learn edge of the drugs. from as we continue to respond to COVID-19 and strengthen systems for future pandem- ics. It is not a stretch to say that largely Test & Overall the following represent some of the Treat for COVID-19 failed to be implemented severe weaknesses and limitations in global everywhere, with the exception of high-income systems for successful and widespread imple- countries, despite the fact that it is a critical mentation of Test & Treat: model in the response with significant potential for impact.7 However, some lessons are critical in order to move forward successfully with Test  Testing was not widely accessible nor in the & Treat programs. numbers needed.  In particular, rapid scale up of Antigen rapid Testing systems remained weak throughout diagnostic tests (Ag RDTs) was limited due the pandemic in some places, particularly in to supply, cost, and a delay and lack of clari- more rural and impoverished settings, where ty in use-case guidance.4 The early months testing rates remained meager. Therapeutics or even years of the pandemic prioritized also struggled, notably in a way that vaccines PCR testing over rapid tests which placed did not, lacking the projections, funding, and all emphasis on accuracy and sensitivity of coordination of global supply chain through tests without consideration of accessibility COVAX and GAVI that were applied to vac- and ease of testing scale up. Some coun- cines. As we examine Test & Treat programs, tries also struggled with regulations that it is therefore important to recognize some of stipulated higher level staff was needed to the specific challenges and lessons learned for perform the Ag RDTs, and sometimes these a variety of issues that collectively limited Test staff were not available at primary care level. & Treat programs worldwide.4,7,8,9  Self-testing with Ag RDTs, a proven strategy with other conditions, was significantly de- Limited supply of Paxlovid was a known chal- layed, and research was required for accept- lenge for low- and middle-income countries. ability. This not only delayed approval, but it should be noted that research for self-test- For example, Somalia, a country of 15 million ing was not required for this widespread use people, received only 300 of 3000 requested case in high-income countries. Furthermore, 5 research should include considerations sons to be hopeful that renewed energy around how to link self-tests to availabltreat- around Test & Treat can be successful and ment. these efforts can be synergistic for health sys- tems strengthening:  Implementation studies were also called for on Test & Treat programs themselves, but  Test & Treat already exists and has been this was not possible given there were no very successful for some conditions such as therapeutics or products available. Generics HIV, malaria, TB. and pre-qualification both experienced signif- icant delays.  Building capability and capacity for Test & Treat for one system is repeatable and can  Manufacturing of diagnostics is largely con- be applied to other conditions, new and ex- centrated in a few countries, but this must isting. change in the future with expanded manu- facturing in low- and middle-income regions,  Test & Treat offers opportunity to system- including resources, technology transfer, and atize and integrate policy guidelines, techni- technical support as well as faster regulato- cal working groups, clinical guidelines, sup- ry approval and improved distribution mech- ply chain systems, workforce development, anisms.4 and data systems within existing efforts.  The Medicine Patents Pool (MPP) agree-  Self-testing has been approved by WHO and ments for voluntary licensing, signed in late has also been successful in other conditions 2021 for generic manufacturers to provide and is an opportunity for early case finding nirmatrelvir/ritonavir and molnupiravir made and community engagement, as well as re- generic pricing available for around 100 ducing barriers in access to care. countries but did not include middle-income  Ministries of Health are well positioned to countries, some with huge populations – deliver Test & Treat systems provided that including large populations living in pover- commodities are accessible; modifications ty – and high disease burden (e.g. Brazil, of existing delivery systems are quite possi- Thailand, Malaysia, Peru, etc)7 Lack of price ble, even for new or specialized commodi- transparency also limited countries’ negoti- ties. ating power, particularly for these countries excluded from MPP agreements.  Attention to Test & Treat was not elevated to What is Test & Treat similar levels as vaccination, though robust response to new pathogens requires both – vaccinating the general population while Test & Treat is a combined strategy that inten- continuing to test and treat those who are tionally emphasizes both testing and treatment. affected. When someone tests negative, that One alone is not enough – not only do suc- is also an opportunity for vaccination. cessful programs need access to both testing and therapies, they need to include a high de-  Much of the strategy for community out- gree of quality, integration within primary care reach centered around “risk communication”, and community systems, and community out- though this inherently is framed in a negative reach and trust. light without discussion of the benefits of early testing and treatment. Despite these limitations, there are also rea- Fortunately, test & treat is not new. In fact, it’s 6 a reliable and proven approach used in count- Test and Treat IS less primary care strategies to reduce poor outcomes from infections both for individuals  A tried-and-true approach (such as severe illness or death) and for com-  Treatment agnostic munities (such as transmission and increased  Rooted in equity cases).10 (Box 1) Programs such as malaria  Person-centered and HIV highlight Test & Treat as core pillars of  Integrated into existing systems their strategy. Box 2 provides additional over- arching characteristics of a successful Test & Treat program. Test and Treat is NOT Box 1. Test & Treat  A new idea  Short term  A standalone or vertical system Test & Treat is a proven ap-  Based on specific medications proach in which  An urban or central or referral hospital program • Access to early diagnosis • Outpatient treatment and follow-up reduces or prevents Test & Treat is positioned within broader health systems strategies to combat infections and • Disease progression & epidemics. Figure 2 depicts that a successful complications, and equitable global COVID-19 response in- • Death cludes Test & Treat, which sits within a broader • Transmission strategy of interventions that address the con- tinuum of care from prevention (vaccines) to outpatient measures (Test & Treat) to hospital care for those severely ill.11 Box 2. Test & Treat characteristics Figure 2. Components of an equitable global strategy for COVID-19 7 Importance of Test & Treat incorporation of recognizing, diagnosing, and treating COVID-19 as part of our routine There are several reasons why a robust Test models of care at the primary health care & Treat strategy for COVID-19 – and for any level and in the community. future surges, new pathogens, epidemics or pandemics: Possible Impact of Test & Treat  As above, Test & Treat is a proven and com- monly used strategy with other infectious diseases to reduce disease progression and community transmission. Any strong and Many advocates, members of civil society and ongoing epidemic response needs to tend to community forums, researchers, and policy- the entire spectrum of the public health and makers have written about the potential impact medical system – including in between surg- of test and treat, and they all highlight a similar es, in an interpandemic phase, or even when set of benefits and impact:4,7,8,10,12,13 the offending pathogen has become part of routine circulating seasonal viruses. Luckily, there are good tests and outpatient treat- Reduce hospital admissions and save lives. ment for COVID-19 in order deploy a robust This is the most important reason to implement Test & Treat strategy. Test & Treat programs for COVID-19, and for any future pathogens we may face. If people  For COVID-19, the vast majority of people are connected to diagnosis and care early, it is affected can be supported in the outpatient an opportunity to reduce their risk of disease setting. It is critical to derive strategies that progression, complications, and hospitaliza- address infection and illness in the majority tion. of those affected. While strong systems for inpatient and critical care are paramount for reducing mortality, these are complemented by a strong strategy that focuses on outpa- Protect those at risk and/or marginalized. tients, primary care, and communities. At their core, a Test & Treat programs work to fight against structural inequities and improve  During an outbreak or pandemic, evidence outcomes for those who are most at risk – and therapeutics change rapidly. Starting in medically, socially, economically, or otherwise. 2021, we saw a rapidly shifting landscape By focusing on primary care systems and in therapeutics for COVID-19, and robust communities, Test & Treat programs empha- test & treat systems can be designed to be size equity – bringing services closer to peo- agnostic to which treatment and be ready ple’s homes. By increasing access – to tests, for any and all treatments that are shown treatments, information, and care – Test & Treat to have impact. System readiness at the can help focus on communities at risk of being primary care level and community level is most affected. Additionally, as in COVID-19, paramount. outpatient therapies often target those most  COVID-19 is not going away. While globally at risk of poor outcomes. Guidelines and ini- we are not in pandemic mode anymore and tiatives for Test & Treat for COVID-19 focus on outbreaks and news cycles have slowed enabling access to anti-viral therapy to those down, the virus is still in circulation. Just as at risk from COVID-19 from their age, comor- Test & Treat programs for other infections bidities, or other circumstances. But addition- are part and parcel of primary care and ally, by allowing people to get tested and know community systems, we need to focus on 8 if they are infected, it also enables people to early in their course of illness, it is also an op- protect their communities, such as isolating or portunity to identify anyone who may be high quarantining from someone at high risk. risk, or may be worsening or experiencing se- vere illness, in order to connect them to needs for hospitalization or more advanced care as Build Community Trust. All Test & Treat pro- soon as possible. grams interact intimately with community trust. Many health conditions have taught us that rapid access to treatment increases the de- Identify and contain outbreaks. COVID-19 is mand for testing – people are more motivated a clustering disease.14 This means that it tends to test if they know they can do something to occur in outbreaks, which was something about a positive result. (Figure 3) Additionally, we recognized early in the onset of the pan- there are social and economic benefits to treat- demic with the stories of ‘super spreaders’, a ment in addition to feeling better – people can term that may not have a specific definition but return to work earlier, care for their children, definitely has scientific merit. This illness does fulfil their obligations. This can reduce the so- not spread evenly but rather a small proportion cial and economic disruptions and hardships of the cases can be responsible for a sub- that individuals and communities impacted by stantial portion of the impact. However, we do COVID-19 can face.4 not know which cases these may be. If Test & Treat programs can successfully identify peo- ple infected early and put them on therapy, this can help. Early therapy with drugs that target the virus itself can lower the viral load and can shorten the period of active infection.4 As an integrated strategy, if Test & Treat is embedded with the primary care and public health system, it can be linked with several activities that can contain spread:  Isolation of infected cases in order to pro- tect family and communities from further spread  Source investigation and contact tracing can help identify where someone got in- Figure 3. Interplay between testing, treat- fected and thus identify possible clusters ment, and community trust. or outbreaks which can be responded to which additional public health measures Maximize spillover benefits to other health such as testing, environmental mitigation, interventions. Health systems and communi- and identification of groups who may not ties are not operating in isolation. If Test & Treat yet be vaccinated. programs can increase the number of people  Counseling and education being tested, anyone testing negative can be offered a vaccine if they have not yet been  Surveillance of outbreaks or new variants vaccinated. Once people who do test positive emerging recover, they are also connected to care and can be offered the vaccine. By seeing people 9 Reduce long-term sequelae. There exist many infectious diseases in which prompt access to therapy can reduce long-term sequelae beyond the immediate benefits of reducing severe ill- ness or hospitalization. For example, early detection of several viruses with available therapy can reduce long-term complications including Hepatitis B, Hepatitis C, Human Papilloma Virus (HPV), HIV, and more. We are still learning about COVID-19, but we do know that long COVID is an im- portant condition and likely affecting many people worldwide – up to as many as 10-20% of peo- ple infected with COVID-19.15 We also know that COVID-19 is associated with several different types of cardiac complications.16 We do not yet know the extent to which early access to treat- ment during COVID-19 infection is poised to reduce these risks, but early evidence suggests that this may well be the case and is within the realm of real possibility.17 Figure 4a depicts what a primary care system for COVID-19 in a rural and impoverished area may look like from the perspective an individual facing COVID-19 infection or the possibility of COVID-19 spread in their community.11 At baseline, it may be very difficult to determine that it is COVID-19 causing someone’s symptoms, limiting their ability to protect their family and commu- nity. Limited testing and treatment at primary care or community level may spur a long journey to a hospital, which may only occur when someone is very ill. Figure 4a. Individual perspective of a lack of Test & Treat 10 Figure 4b depicts what the opportunity is and where a robust Test & Treat program can inter- vene, walking through the available services and activities at each step – in the community, at the primary care system, an opportunity for public health and community response to play a substantial role, and finally, if needed, at the hospital.11 Figure 4b. How indi- vidual perspective can change if Test & Treat is introduced. 11 Existing work on Test & Treat Regarding treatment, WHO therapeutic guide- lines detail the medications recommended for various scenarios for people with COVID-19.20 There is also a set of tools guiding the use of Existing Guidelines nirmatrelvir/ritonavir (Paxlovid), identifying that those who are at high risk and presenting with- in 5 days of symptom onset are eligible for this treatment as an outpatient.21 The definition of World Health Organization high risk in these guidelines casts a wide net, As of September 2023, the World Health Or- including older age and/or a long list and vari- ganization (WHO) does not have comprehen- ety of chronic conditions. WHO also has a tool sive guidelines on Test & Treat programming guiding the use of molnupiravir, highlighting to for COVID-19, though guidelines are under avoid use in pregnant women or those who development. may become pregnant as well as caution in men of reproductive age or those who can im- pregnate.22 Other than these two therapeutics, WHO testing guidelines for national testing the only medication recommended for outpa- strategies (June 2021) highlight the importance tients or non-severe COVID-19 is remdesivir, of national-level testing programs linked to which is an intravenous medication and thus public health action.18 These guidelines high- less practical in most Test & Treat programs.20 light that everyone who meets the case defini- tion of COVID should be tested regardless of their vaccination status or how sick they are. Existing Programs Nucleic Acid Amplification Tests (NAAT) are the reference standard for acute COVID infection; polymerase chain reaction (PCR) fits in to this category. But, countries can use Antigen rapid COVID Treatment QuickStart Consortium diagnostic tests (Ag RDTs) which are simpler This consortium, launched in September 2022, to use and can be used quickly at the point of brings together COVID Collaborative, Duke care.18 These are the most common type of University, the Clinton Health Access Initiatives test in a Test & Treat program at the primary (CHAI), and Americares as implementing part- care or community level. ners. The consortium is funded by the Open Society Foundations, the Conrad N Hilton Foundation, and Pfizer.12 QuickStart Consor- The latest testing guidelines (March 2022) for tium is working with governments to introduce Ag RDTs also highlight that self-testing is rec- access to antiviral therapy for COVID-19, spe- ommended and acceptable as an addition cifically paxlovidTM (nirmatrelvir/ritonavir), through to testing by professional care providers.19 attest-and-treat model. Efforts focus on ensur- Guidelines highlight that self-testing is feasible, ing accessible treatment, preparing for future acceptable, likely to support timely diagnosis surges, and building primary care capacity.23 and good uptake. Self-testing with Ag RDTs The consortium started off with a donation of is approved both for diagnosis for people with medication from Pfizer and is shifting to using symptoms as well as for screening (for people low-cost generics to enable more widespread who do not have symptoms). adoption. As of March 2023, 4 countries had received oral antiviral therapy for COVID in- cluding Laos, Malawi, Rwanda, and Zambia. 12 By August 2023, Ghana, Kenya, Nigeria, and Unitaid, Global Fund, & FIND Uganda had also received medications. A complete list of the 10 partner countries in- This program was announced in May 2022, cludes: Ghana, Kenya, Laos, Malawi, Nigeria, where the Global Fund, United States, and Rwanda, South Africa, Uganda, Zambia, and Unitaid announced a program in partnership Zimbabwe.23 Results and research efforts from with FIND and other Act-Accelerator partners this Consortium are anticipated by the end of to support countries in implementing Test & 2023. Treat programs. 26 This announcement built upon some ongoing Unitaid-FIND early adop- tion programs that represented some of the first efforts in Test & Treat for COVID-19, start- USAID Program ing from late 2021. The program highlights the USAID also announced in September 2022 potential of Test & Treat programs to save lives plans to support Test & Treat programs (called and reduce global inequities in access to com- “Test-To-Treat”). Several partners work on this modities for COVID-19, aiming to expand the with them including University of California San introduction of new treatments in over 20 low- Francisco (UCSF), STAR, RISE, and EpiC. Fo- and middle-income countries.27 cusing on populations at high risk of severe illness, the program announced it would begin in ten countries including Bangladesh, Botswa- na, Côte d’Ivoire, El Salvador, Ghana, Lesotho, Malawi, Mozambique, Rwanda, and Senegal.24 Through this work, there are several resources available, including an algorithm for outpatient antiviral treatment as well as an implementation guide.25 (See Section on Resources below). More results and details are anticipated to become available in coming months from this program. 13 Implementation of Test & Treat Key Features of Test & Treat Programs Table 1 shows key features of successful Test & Treat Programs derived from best practices and lessons learned from existing programs.4,11,23,25 Table 1. Features of successful Test & Treat Programs Overall Program  Focus on primary care and rural systems where the population lives (don’t focus only on urban centers or referral hospitals)  Community outreach and trust is critical*. Use many channels to get the word out as soon as testing and/or treatment: mass media campaigns, Community Health Workers, local advocates, etc. Plan for questions and discussion with community members.23  Track basic indicators and share data early* – with policymakers, health care workers, and the community Testing Treatment  Free and routine  Available at primary care and in the com-  Initiate rapid access to treatment in the same munity – decentralize testing as quickly encounter and as much as possible*  Design the system to adapt for new ther-  Enable access to self-testing whenever apeutics and include all possible effective possible, with linkage to care outpatient treatments  Integrate testing* within existing programs  Leverage the visit provide education and in health systems, e.g. incorporate test- counseling ing in routine visits for HIV, TB, NCDs,  Pair with public health services: support for maternal health, etc in addition to acute home isolation, source and outbreak investi- care visits in the outpatient department gation  Focus on reaching high-risk populations*  Link to higher levels of care if needed *one of 5 key testing themes from QuickStart23 Testing Who to test? There are several possible approaches to testing for COVID-19 that are recommended by differ- ent stakeholders and programs. 14 Symptomatic Testing is the most common Testing of Exposed Contacts is also an im- type of testing for Test & Treat programs. It re- portant screening question (Box 3) and should quires casting a wide net for people presenting be included in all Test & Treat programs. to different types of health facilities with a va- riety of different symptoms given the variable presentation of COVID-19. (Box 3) Identifying people with symptoms and/or those who have been exposed to COVID-19 can Box 3. Screening questions for COVID-19 be integrated into a variety of clinical settings Testing including outpatient departments, chronic dis- Sample Screening Questions ease clinics such as HIV, TB, and Non-Com- municable Diseases, Maternal & Child Health • Do you have any of the follow- Services, and more. Several priorities merge in ing new symptoms? these settings so it is important to consider the • Fever approach from a healthcare worker perspec- tive, not as a vertical testing program. Some- • Cough one coming in with cough for example, also • Shortness of Breath may need evaluation for possible tuberculosis. • Muscle Aches Figure 5 is one approach that our team de- • Sore Throat vised for clinical staff at outpatient departments to quickly identify those needing a variety of • Runny Nose types of testing, keeping in mind that someone • Loss of Smell or may present with more than one condition at a Taste time.11 • In the last 14 days have you spent any time near someone with COVID-19 or symptoms of Figure 5. An example of a testing algorithm COVID?  at a primary care clinic. 15 Photo: Ezra Acayan / World Bank Routine testing has also been advocated for, which can be done a variety of ways and demon- strates the potential to link Test & Treat programs with surveillance efforts.  General Population routine testing may be recommended during surges or in places with high rates of COVID-19. Because people infected with the virus can be infectious before they become symptomatic, these approaches have the added advantage of identifying people early in the course of their illness, giving time and opportunity to protect their households and communities. Places where routine testing has been deployed include schools, high risk places of employment or other locations where exposures may be repeated and high in volume.4  High Risk Groups undergoing routine testing is a possible alternative and one that may be lower in cost than routine testing in the general population. This approach would focus on places with high-risk individuals such as those with older age or comorbidities or in high risk settings such as crowded housing. (Box 4) Box 4. Risk factors for severe COVID-19 Risk Factors for severe disease from COVID-19:  Age ≥65 years  HIV  Primary immunodeficiencies  Cancer  Mental health disor-  Smoking (current and for-  Cerebrovascular disease mer) ders   Children with certain  Sickle cell disease underlying conditions,   Neurologic condi-  Solid organ or blood stem  Chronic kidney disease,  tions(dementia) cell transplantation  Chronic lung disease,   Obesity (BMI ≥30 kg/  Substance use disorders  Chronic liver disease,  m2) and overweight  Tuberculosis  Cystic fibrosis,  (BMI 25 to 29 kg/m2)  Use of corticosteroids or  Diabetes mellitus, type 1  Physical inactivity other immunosuppressive and type 2  Pregnancy or recent medications  Heart conditions pregnancy 16 Where should testing occur? mission since it would only mean testing part of the population every year.4,29 Even so, most impoverished countries did not come close to this target.2 As above, there are several locations within a health facility where symptom screening and testing should be integrated into routine ser- vices. The main goal of Test & Treat programs Going forward, Test & Treat programs should is to make testing as accessible as early as monitor the positivity rate closely so that the possible. Advocates and civil society have program can be dynamic to changes in rates contributed considerable voice to this move- of transmission in the community. This would ment, collectively pointing out the need for mean, for example, if 1 out of ever 3 or even 5 community-based testing as early as possible tests were positive, that more people needed in a pandemic – an ongoing community testing to be testing and testing strategy could shift to for COVID-19.4 As soon as possible, addition- become more aggressive. During times of low- al cadres should be trained and permitted to er transmission, when for example 1 test might provide and conduct Antigen Rapid Diagnostic be positive out of every 20-30 tested, lower Tests (Ag RDTs) in order to increase access total testing numbers would work until the pos- and availability. This includes Community itivity rate started to rise again. Health Workers and other workers based in communities, and careful attention should also be paid to staff at health centers who routinely Approach to testing in Test & Treat perform other types of rapid tests (e.g. malaria) Programs – often these personnel are not formal labora- tory technicians but are critical team members in diagnostic testing at primary care level. Test & Treat programs, with a focus on access Self-testing should also be highly recommend- in primary care and community settings, will ed and implemented wherever possible.4,13,28 rely primarily on Ag RDTs. There are a few key This approach has been used in a variety of challenges with Ag RDTs that need to be ad- other conditions including HIV and malaria, dressed at different levels – global, national, and can be adapted for conditions such as and local: COVID-19. • Adequate supply is critical – it has been too low in the past.4 This comprises a variety How much testing is enough? of factors: o Setting testing targets is import- ant that can adjust over time Testing rates, particularly in low- and middle-in- based on the positivity rate and come countries never achieved adequate community rates of infection is rates during the entirety of the COVID-19 pan- important. Past testing targets demic. At the height of the pandemic, rates in have both been too low but still low-income settings were up to 10 times times have not been met in the majori- lower than in the United States and Europe.2 ty of the world. In May 2020 , a global target was set of 1 test o Expanded settings need to be per 1000 people per day, but even this was equipped for testing as dis- likely not adequate in places with high trans- cussed above, including primary 17 care as well as community ven- ues and self-testing. Treatment o Manufacturing has been primar- ily centered in a few countries during much of the pandemic, Who to treat but efforts should continue and be augmented to expand manu- Timing of Treatment is very important, thus link- facturing to more low- and mid- ing treatment to a robust testing program and dle- income countries. offering same day linkage to treatment is very • The cost of testing has been too high. The important. The most common type of outpa- cost of testing needs to decline (reports tient treatment, PaxlovidTM (nirmatrelvir/ ritonavir, cite that reported costs in some European is recommended to be initiated within 5 days contexts are as low as $1 USD per test, of symptom onset.20,21 but prices remain higher in much of the High Risk: In general, most guidelines and tools world.4 The civil society report from ACT-A that guide outpatient therapy for COVID-19 urges a common goal of $1 USD /test or to be guided by identifying individuals at risk less.4 of progression to severe disease (see Box 4 • Who bears the cost is also critical – testing above). Most treatment guidelines simply the for a community member or patient should definition of high risk to the following conditions be provided free of charge as even nom- in order to prioritize who is eligible for treat- inal costs can be prohibitive particularly ment:23,25 when there are competing priorities for people.  HIV or other immunosuppression  Older age (> 50 years)  Obesity (BMI > 30) While Test & Treat programs focus on Ag  Diabetes RDTs, there are roles for additional and more  Chronic conditions such as chronic kidney sophisticated types of testing. For example, disease, heart disease, or chronic lung dis- polymerase chain reaction (PCR) can sup- ease plement when higher level labs are available  Note that Pregnancy is considered high risk such as testing at referral hospitals. Some PCR but guidelines differ on some of the medi- systems can run higher volume of tests, such cations and should be addressed per local as in a large screening program in a school or guidelines.23 at risk workplace. Of course, it is also important to mention that Additionally, PCR laboratories are important in clinical judgment based on the individual cir- linking COVID-19 testing programs to surveil- cumstances is also important to consider when lance programs for new variants. Utilizing PCR designing Test & Treat programs as these algo- labs with the capacity to perform COVID-19 rithms, while incredibly powerful, may neglect sequencing as part of Test & Treat programs specific clinical scenarios where an individual can help detect new or emerging variants. may benefit from outpatient treatment. These programs can be linked in a variety of ways – for example, sending a subset of sam- ples from people with positive Ag RDTs for Triage is also important to implement when PCR and sequencing, or using this approach evaluating people for outpatient therapy for large scale screening programs. through Test & Treat programs. Training should include how to recognize and identify danger 18 signs or circumstances where hospitalization symptoms again after completion of Pax- and/or referral to a higher level of care is war- lovid. During this time period they can also ranted. be infectious to others again. The exact risk of rebound is uncertain, but some reports cite as high as 15% occurrence of rebound Outpatient treatment options following Paxlovid treatment. Rebound tends to be mild and can occur in both vaccinated • Paxlovid TM (nirmatrelvir/ ritonavir) and unvaccinated individuals.32,33 In November 2021, Pfizer’s antiviral Paxlovid was announced as a treatment candidate.5 Paxlovid is an antiviral that blocks an enzyme • Molnupiravir needed for viral replication. Preliminary analysis Molnupiravir, made by Merck, is another an- in at study called EPIC_HR showed that the tiviral for COVID-19. While it received some risk of hospitalization or death was reduced initial positive attention, it has fallen out of favor by 89% in high-risk adults who were taking to some extent because while it can reduce Paxlovid compared to placebo. Final results of recovery time, research does not demonstrate this study showed that the risk of hospitaliza- strong reductions in hospitalizations and death. tion from COVID-19 or death from any cause The evidence is a little conflicting for molnupira- during 28 days of follow up was 0.2% in high- vir, but in general it likely does not have signif- risk patients treated with Paxlovid compared to icant effect. One randomized-trial of 25,000 1.7% of those receiving placebo.30 Emergen- outpatients did not show a reduction in risk of cy Use Authorization was originally granted in hospitalization or death but did reduce the re- 2021, and the FDA approved Paxlovid in May covery time.34 There is other data that suggest- 2023.31 ed severe disease is reduced including a ran- domized trial of 1,433 outpatients, where 6.8% on molnupiravir experienced hospitalization or At present, Paxlovid is widely accepted to be death versus 9.7% on placebo, though these the preferred therapy for COVID-19 for peo- results did not reach statistical significance.35 ple at risk for progression to severe disease. Molnupiravir also needs to be taken within 5 Important things to note about this medication days of symptom onset, and the dose does include: not be adjusted for kidney or liver function. It is not recommended in people under 18 years  It should be started within 5 days of symp- tom onset. old or who are pregnant or lactating.  Patients take the medication twice a day for 5 days (though this could change in the fu- ture to be a longer course). • Metformin  There is a substantial and long list of drug- Metformin was investigated as a possible drug interactions, so prescribers must exer- therapeutic for COVID-19 later in the pan- cise caution in reviewing medication lists for demic given its anti-inflammatory properties, patients. specifically to interrogate whether it could help  Dosing needs to be adjusted for patients prevent long COVID. In a phase 3 randomized with impaired kidney function. trial that also investigated fluvoxamine and iver-  There are many reports of “rebound” fol- lowing Paxlovid therapy, meaning that mectin, metformin showed significant promise someone who seems to have recovered in the prevention of long covid. Treatment with from COVID-19 infection can experience metformin reduced the incidence of long covid 19 by about 40% compared with placebo. These promise.40,41 As with any new pathogen, de- results were strongest when participants start- signing robust systems that are able to adapt ed metformin within 3 days of symptoms start- with changing evidence and recommendations ing.36 This drug is important to note because it remains important for both COVID-19 as well is globally available, low-cost, and generally a as future pandemics. very safe medication. (The other drugs in the trial, fluvoxamine and ivermectin, did not show any benefits for long COVID). Examples of algorithms for Test & Treat • Other therapies and a changing landscape Figure 6 shows an overall pathway that can Since the onset of the pandemic, a number of be applied to someone at risk of COVID-19 or studies have investigated other therapeutics to presenting with symptoms, and Figure 7 is an be used on an outpatient basis. Some of them, example of a Test & Treat algorithm from the such as the generic anti-depressant fluvoxam- USAID funded program.42 ine, or inhaled corticosteroids like those used in asthma, showed some initial promise but to date are not recommended given a dearth of evidence in stronger clinical trials.37-39 Still oth- ers were widely touted by the media and oth- ers, such as ivermectin, but never showed any Figure 6. An example of a patient pathway in a Test & Treat program. 20 Figure 7. An example of an algorithm from the USAID funded Test & Treat measures. Source: https://opencriticalcare.org/wp-content/uploads/2023/01/COVID-19-Test-to- Treat-Algorithm-v1.6-2i6fgm.pdf Monitoring & Evaluation Table 2 is a list of suggested indicators to track during a Test & Treat program for COVID-19. Ear- ly in such programs, even simple statistics about testing numbers, positivity rates, and treatment completion can help policymakers and implementers learn a lot about how a program is best serving the needs of a population, learn lessons about supply chain needs, and adjust things early on for improvement. Over time, indicators can be incorporated into national health informa- tion systems to track COVID-19 over time. 21 Table 2. Suggested Indicators for Test & Treat Programs Indicator Suggested Measure(s) Considerations # people tested  # people tested  Population rate can help in  # people tested per 1000 comparing to other settings population and other time points in the pandemic. At the peak, rec- ommendation was at mini- mum 1 per 1000 people per day  Disaggregate tests into type: Ag RDT vs PCR  Positive tests / total # tests  There is not a “good” number Positivity rate of tests defined for this, but trending performed over time can help programs determine if enough testing is occurring.  # of people testing positive  This is also helpful to do for Timeliness: people overall population receiving within 5 days of symptom testing within 5 days testing, regardless of who onset / total # of people of symptom onset tests positive. testing positive People eligible for  # of people testing positive treatment who are eligible for treat- ment / total # of people testing positive Linkage to treatment  # people put on outpatient treatment for COVID-19 Treatment completion  # people completing treat- ment for COVID-19 / total # of people put on treatment for COVID-19  # people with ongoing Long covid symptoms symptoms of COVID-19 6  Disaggregate by who re- months after infection ceived treatment or not  Presence/absence of bud- Budget allocation get for national or subna- tional test & treat program for COVID-19 22 Resources Resource What is it Link WHO guidance on nation- WHO guideline, 25 June https://www.who.int/publications/i/item/WHO-2019-nCoV- al COVID testing 2021 lab-testing-2021.1-eng World Health Organiza- WHO guideline, 9 March tion (WHO) guidance on 2022 https://www.who.int/publications/i/item/WHO-2019-nCoV- COVID self testing Ag-RDTs-Self_testing-2022.1 WHO guidelines on thera- WHO guidelines, 13 Janu- https://www.who.int/publications/i/item/ peutics ary 2023 WHO-2019-nCoV-therapeutics-2023.1 WHO reference tool on WHO reference, 2023 https://www.who.int/publications/i/item/ paxlovid WHO-2019-nCoV-Therapeutics-Nirmatrelvir-ritonavir-Post- er-A-2023.1 WHO reference tool on WHO reference, 2022 https://www.who.int/publications/i/item/ molnupiravir WHO-2019-nCoV-Therapeutics-Molnupiravir-Poster_ B-2022.1 Test-To-Treat implemen- From USAID and partners: https://opencriticalcare.org/wp-content/uploads/2022/06/ tation guide STAR, RISE, EPIC, UCSF, Implementation-Guide-Test-to-Treat-July-2022-ipycid.pdf CHESA Algorithm for oral antivi- From USAID and partners: https://opencriticalcare.org/wp-content/uploads/2023/01/ rals for outpatients STAR, RISE, EPIC, UCSF, COVID-19-Test-to-Treat-Algorithm-v1.6-2i6fgm.pdf CHESA QuickStart Consortium Includes COVID Collab- Learning Network orative, Duke University, the Clinton Health Access Initiatives (CHAI), and https://dukeghic.org/our-work/quick-start/ Americares, funded by the https://www.covidcollaborative.us/initiatives/quick- Open Society Founda- start-consortium tions, the Conrad N Hilton Foundation, and Pfizer QuickStart Consortium Overview: https://dukeghic.org/wp-content/uploads/ webinar “COVID Testing and High sites/20/2023/03/LN-SII-Summary-2.15.23.pdf Risk Populations.”, Febru- ary 2023 Recording: https://www.youtube.com/ watch?v=F2V7BQN6E5w&t=1229s QuickStart Consortium “Speakers discussing the Overview: https://dukeghic.org/wp-content/uploads/ webinar necessity of oral antivirals sites/20/2022/12/7-December-2022-Quick-Start-Ses- to complement continued sion-Summary.pdf access to vaccines for long–term COVID man- Recording: https://www.youtube.com/watch?v=-yMqj2H- agement.”, December 79pU 2022 White paper on Communi- From the Platform for https://covid19advocacy.org/white-paper-on-community- ty based Test & Treat Civil Society & Community based-test-treat/ Representatives for the ACT-Accelerator, Africa CDC COVID-19 Test to Treat https://africacdc.org/download/covid-19-test-to-treat- Guidelines for African guidelines-for-african-union-member-states/ Union Member States Table 3. Resources for more information on Test & Treat for COVID-19 23 Acknowledgements This operational guidance relied heavily on many excellent experiences, writing, and publications from peers and colleagues. Specifically, we are gratefully to the following people and organiza- tions for their invaluable contributions: ACT-Accelerator Civil Society Platform: Brook Baker and colleagues Clinton Health Access Initiative: Sean Regan, Sostena Romano, Zachary Katz, Trevor Peter Duke University: Krishna Udayakumar, Elina Urli Hodges Open Society Foundation: Kiti Kajana Partners In Health: Yerkebulan Algozhin, Afom Andom, Brittany Aryeh, Erick Baganizi, Diego Burga, Emilia Connolly, Friedrich Conrad, Ashley Damewood, Jacob Gomez, Alberto Gonzales Guzman, Marco Antonio Tovar Huamani, Gregory Jerome, Chiyembekezo Kachimanga, Fredrick Kateera, Pranali Koradia, Marta Lado, Wesler Lambert, Fernet Leandre, Jenae Logan, Anatole Manzi, Micheal Mazzi, Cory McMahon, Laura McMeel, Jean Claude Mugunga, Evrard Nahimana, Merab Nyishime, Cate Oswald, Lindsay Palazuelos, Marta Patino, Nestor Ramírez, Ana Rodri- guez, Shada Rouhani, Ralph Ternier, Sterman Toussaint, Joan VanWassenhove-Paetzold, Lauren Viehbacher, Bram Wispelwey 24 References against COVID-19. 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