Persistent and profound disparity in COVID mortality rates between USA / Western Europe and sub-Saharan Africa

Persistent and profound disparity in COVID mortality rates between USA / Western Europe and sub-Saharan Africa:

Is this explained by crossover efficacy of antimalarial drugs?

Geoff Mitchell, MD, JD, FACEP, Sonya Naryshkin, MD, FIAC, FCAP

Abstract

Purpose: On May 1, 2020, one of us (GM) reported an initial profound disparity in COVID mortality rates between developed western nations (DWN) and countries in malaria-endemic regions.1 We sought to confirm and understand this disparity.

Methods: We performed a comparative analysis of COVID fatality rates from March 1, 2020, until June 1, 2021. We compared six sub-Saharan African countries (SSA), selected for their high rates of malaria (Nigeria, DR Congo, Uganda, Mozambique, Côte d’Ivoire, and Niger), to four DWNs with essentially no malaria. Raw mortality data was obtained from Our World in Data.2,3 The end-of-month numbers were cross checked for accuracy. We searched the scientific literature to determine known roles of antimalarial drugs in the COVID pandemic and the individual antimalarial agents used in these SSA countries.

Results: Official data indicates that people living in the DWN died from COVID at a rate of approximately 150 times that of people in the SSA group. When corrected for age differences, the DWN fatality rates were approximately 25 times those of SSA. This profound disparity persisted over the study period. There is a strong correlation between the use of antimalarial drugs and low death rates. Two antimalarial drugs, with reported anti-SARS-CoV-2 activity, artemisinin and the atovaquone and proguanil combination (AV-PG), were in widespread use in SSA. No antimalarial was in widespread use in the DWN. HCQ is used to treat autoimmune disease, but its use was largely prohibited for COVID treatment.

Conclusion : The profoundly lower mortality rates for people living in SSA versus the DWN appears to be explained by widespread use of antimalarial drugs which have crossover efficacy against SARS-CoV-2. The two most likely drugs are artemisinin and AV-PG. Such anti-COVID crossover effects of antimalarial drugs have been largely overlooked/ignored by those with health policy authority in DWN but deserve urgent and thorough examination.

Keywords: COVID, artemisinin, Africa, malaria, atovaquone-proguanil, death

Introduction

More than 3.2 million people have died from SARS-CoV-2 worldwide. Early in the COVID pandemic, in March 2020, one of us (GM) observed the inverse relationship between malaria prevalance and COVID fatalities. On May 1, 2020, he reported superior COVID outcomes in malaria-endemic countries and predicted that this success was due to antimalarial drugs and thus would continue.1 The data indicates that COVID was far more dangerous in the group of four developed Western nations (DWN). At that time, the overwhelming majority of the world’s

experts predicted just the opposite - a catastrophic outcome for Africa - particularly sub-Saharan Africa.

This work was always about the interplay between malaria and COVID. Six SSA countries studied were selected for study because of their high rates of malaria. This study began at a time when experts argued that Africa would have catastrophic COVID outcomes. The evidence of the inverse relationship between COVID and malaria is compelling. We sought to understand why.

The hypothesis of that first paper was that there exists an inverse relationship between endemic malaria and the incidence and severity of COVID-19. It was further hypothesized that the antimalarials “attenuated,” were “effective against,” or “inhibited” SARS-CoV-2, thus producing a “protective” or “prophylactic” or “spill-over” effect. This was initially seen in the context of arriving travelers taking antimalarials; thus, it was hypothesized that “antimalarial agents may play a role in the prevention of transmission or seeding by incoming travelers to sub- Saharan Africa.”

About six weeks later (06/15/20) a second paper was written.4 In the U.S. it was strongly asserted, with little evidence, that Africans or at least African Americans in the U.S. are more susceptible to COVID infection and death. If the arguments of these U.S. experts were true as presented, then Africans in Africa, who all too often had the same poor social determinates of health as well as essentially the same genetic makeup, would experience catastrophic COVID outcomes as well. This, of course, was the prevailing opinion of virtually all experts in the Spring of 2020. The second paper also noted that the profoundly superior outcomes initially seen in SSA were persisting. The conclusion of that second paper was that, at least on a worldwide scale, differences in COVID mortality are not readily explained in racial or socially determined terms. Something else must be at play. The second hypothesis, that antimalarial drugs have crossover efficacy against SARS-CoV-2, was fully conceptualized in the second paper.

This third paper now demonstrates that, fifteen months in this pandemic, the COVID outcomes in SSA remain profoundly and persistently superior to the U.S. and the DWNs. This strongly suggests the truth of the second hypothesis, that there exists a crossover efficacy of antimalarial drugs against SARS-CoV-2. That is to say, the prolonged superior COVID outcomes seen in the SSA countries, are due to the widespread availably and usage of antimalarial drugs especially atovaquone-proguanil (“AV-PG”), marketed as Malarone® and artemisinin.

Another antimalarial, hydroxychloroquine (HCQ), has always been an issue in the current pandemic. HCQ is the prototypical antimalarial, or at least was so in the past. Evidence demonstrates that HCQ has had success against SARS-CoV-2 in this present pandemic. This paper documents that the widespread prohibition and criminalization of early, outpatient treatment with HCQ has failed. (Figure 4.) We further note that HCQ is no longer widely used to treat malaria in SSA, so HCQ is not primarily responsible for the beneficial effect seen there. All these facts suggest that there exist other antimalarial agents used in the SSA countries which explain the profound 96% decrease in COVID mortality seen there. For the reasons which follow, we argue that two other drugs, AV-PG and artemisinin primarily explain the profoundly lower COVID mortality rates reported in SSA.

Material and Methods

The authors set out to study the disparity between the COVID outcomes in malaria- endemic SSA versus DWNs. This is an observational, epidemiological study. The experimental

design was to follow this disparate fatality rate and reevaluate month after month. We followed and analyzed official governmental statistics for the six SSA countries and four DWNs for the first fifteen months of the COVID pandemic.

The six specific SSA countries to be studied were not cherry-picked for inclusion because of low incidence of COVID. It was noticed by some observers early in the pandemic that malaria may confer a protective effect against COVID. This rarely got beyond a mere observation. The six SSA countries were selected specifically to test the hypothesis that there exists an inverse relationship between a country’s prevalence of malaria and its COVID outcome as measured by fatality rate. The SSA countries are Nigeria, DR Congo, Uganda, Mozambique, Côte d’Ivoire, and Niger. The six SSA countries were selected for study because they have the world’s highest rates of endemic malaria as determined by the WHO’s World Malaria Report for 2019. That report stated that “nineteen countries in sub-Saharan Africa and India carried almost 85% of the global malaria burden.” These “six countries accounted for more than half of all malaria cases worldwide.” 5

Raw mortality data was originally obtained from the total_deaths.csv file downloaded from Our World in Data.2 This data source ceased being populated in November 2020. After that the data was migrated to a file named owid-covid-data.csv.3 The cumulative fatality rates were reviewed at the end of each month. The numbers were routinely cross checked for accuracy against the Coronavirus COVID Global Cases Dashboard from The Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) Whiting School of Engineering.6 We performed a comparative analysis of death rates from COVID from the beginning of the pandemic until June 1, 2021. The cumulative fatality rates are reproduced graphically. Figure 1.

In the original May 2020, paper, the data were analyzed by epidemiologist and biostatistician, Dr. Khuder, one of the original authors. Dr. Khuder also verified the statistical significance of the data in the second, “Two Cities” paper in June 2020.4 The more recent data was reverified using an online Z score calculator for two population proportions at www.socscistatistics.com.

To maximize the accuracy of the data, it was adjusted for age. We used a simplified age- adjustment method because age-banded fatality data was not found for the SSA countries. The study country with the largest geriatric population is Italy at about 23%. The U.S. is 15.2%. The percentage of geriatric patients in the SSA countries averages about 3%. The fatality rates are adjusted accordingly. The age-adjusted fatality rates for the six SSA countries are a statistical fiction created to adjust for the differences in age demographics because these SSA countries have a lower percentage of elderly residents.

To better understand the role of antimalarials in the treatment of SARS-CoV-2, the worldwide use of the antimalarials, HCQ, AV-PG and artemisinin was reviewed. To better understand the particular contributions of the three antimalarial drugs in achieving the extraordinarily low rates of COVID fatality in SSA, a review of their specific use in SSA was undertaken.

To review this material regarding COVID outcomes in SSA and the potential roles of antimalarial drugs in early, outpatient treatment, we employed various search engines including PubMed, Research Gate, Google Scholar, medRxiv, bioRxiv, Elsevier’s SSRN and various sources of government and news data sources. Government and quasi-government health data sources included the World Health Organizations’ Annual Malaria Report (2019 and 2020) and various countries’ Presidential Malaria Initiatives for recent years.

Because this pandemic placed all of us in fast moving, uncharted waters, we also utilized less overtly scientific sources such as newspaper and other periodicals. We were particularly searching for government policy pronouncements and other relevant materials to enable us to better understand what was happening in SSA. The various data sources were reviewed for information regarding the use of antimalarials to treat COVID in the study countries.

Results

There are two classes of results. The first was statistical data collected and analyzed regarding the COVID fatality rates of the two groups of countries. The second class of results was the review of the use of particular antimalarial agents in the six SSA countries. These results addressed the two hypotheses set forth in the original May 2020 paper: 1) the number of COVID deaths are inversely related to the incidence of Malaria; and 2) the improved COVID outcomes in malaria-endemic countries are due to a crossover efficacy of antimalarial drugs. This crossover efficacy is thought to be due to the use of AV-PG and artemisinin.

COVID fatality rates in SSA remain extraordinarily low and inversely related to the incidence of malaria. The COVID fatality rates utilized were those reported by their governments and collated by JHU and other respected sources. These COVID fatality rates in these SSA countries started low. The COVID fatality rates in the SSA countries started low and stayed low over fifteen months of study. The data were reviewed and recalculated once a month on the first of the month. The data were finalized on June 1, 2021. At the time of publication, the average raw, population-adjusted fatality rate of the six SSA countries was 12.5 deaths per million (“dpm”). U.S. dpm were 1,804. The average raw dpm for the DWN was 1,886. The average raw, population-adjusted fatality rate for the entire world from Our World in Data (OWID) is 457 deaths per million. The raw, population-adjusted fatality ratio of DWNs over SSA continued to average approximately 150:1 after thirteen months of pandemic. It remained strikingly constant.

The data were adjusted for age as described. At the time of publication, the average age- adjusted fatality rate computed for the six SSA countries was 97 deaths per million. This is the statistical fiction described above. (When adjusted for age, the U.S. rate goes up as well because the U.S. has significantly fewer elderly residents than Italy.) The age-adjusted fatality ratio of US/Western nations over SSA continued to average approximately 25:1. DWN fatality rates are 25 times those of SSA.

The disparity in COVID outcomes (fatality rates) between the US/Western nations and SSA was persistent and profound. The raw, population-adjusted fatality ratio of US/Western nations over SSA remained approximately 150 (167x on June 1, 2021). On an age-adjusted basis, the U.S. and Western death rates were 26 times that of the six SSA countries. (Figure 1). The age-adjusted COVID fatality rate in SSA is about 4% that of the U.S. and the rest of the DWN. (Table 1). This disparity is still confirmed by other data sources (e.g. JHU). fn1, 7, 8

The evidence presented here is what the FDA calls Real-World Data (RWD) or Real-World Evidence (RWE). The “FDA uses RWD and RWE to monitor post market safety and adverse

1E.g., the Lagos/NYC data as it was in the previous June 2020, “Two Cities” article.4 On May 11, 2021, the total COVID fatality rate in Lagos was 439 or 29 dpm.11 The cumulative fatality rate reported in NYC was 28,000 total deaths (as of May 17, 202129) or 3,333 dpm.12 Again, this is about a one-hundred-fold difference.

events and to make regulatory decisions.” The FDA notes that “observational studies are increasingly being used to “generate innovative, new treatment approaches.” 9

It is impossible to study the COVID pandemic without some consideration of HCQ. HCQ is the prototypical “antimalarial” agent. In the media, HCQ is often described as “the antimalarial drug HCQ.” Though criticized and prohibited in the U.S., HCQ is still successfully used to treat COVID around the world. HCQ remains perhaps the greatest controversy in the COVID pandemic. HCQ was always touted as an antimalarial agent. A search on PubMed reveals the existence of 2,588 articles on HCQ and COVID in about sixteen months’ time. 10

HCQ has been widely successful in the treatment of COVID around the world. In a metanalysis of 1.8 billion patients, the c19study group reported that “the treatment group has a 69.9% lower death rate.”11 There is arguably no institution more representative of modern “science,” especially contemporary western science than the American Association for the Advancement of Science (“AAAS”). The AAAS is epitomized by its (rather audaciously named) flagship publication “Science.” Now in the COVID pandemic, even the AAAS has acknowledged the association between the use of HCQ and superior COVID outcomes worldwide. In an AAAS EurekAlert! The AAAS cited a c19 study of the use of HCQ around the world. 12,13 (Figure 2.) Figure 3 shows the corollary, the COVID outcomes of those same countries around the world.14

Despite the criticisms and prohibitions by the purported best and brightest of U.S. physicians and scientists, HCQ is successfully used in the U.S. as well. Its precursor, quinine has been used for 220 years. HCQ is said to have been used to treat malaria for 65 years. The public and many in the scientific community appear to have a continued interest in HCQ. Shortly after Dr. Raoult’s first publication in March 2020,15 Dr. Zev Zelenko, practicing near the U.S. COVID epicenter in New York, began to report his success in treating COVID with HCQ. 16 In June 2020, well-known Yale epidemiologist, Harvey Risch, MD, PhD, published his epidemiologic evidence of the efficacy of HCQ. 17 At least by October 2020, Dr. Brian Tyson was publicly reporting his success in treating COVID in southern California. 18 Dr. Tyson was one of the coauthors on Dr. McCullough’s paper (below). His associate, Dr. Fareed, was one of the treating physicians appearing along with Dr. McCullough and Dr. Risch before the Senate Homeland Security Committee. 20 In August 2020, Peter McCullough, MD, PhD, and a large group of coauthors published the seminal article, at least in the U.S., on early, outpatient treatment of COVID in the American Journal of Internal Medicine. 21 Space does not permit the cataloging of the many other physicians who have reported success in treating SARS-CoV-2 with HCQ. When a dozen physicians staged a social media press conference in Washington, D.C. on July 27, 2020, NBC reported that they were viewed 20 million times on Facebook before they were censored.22 The public has a real interest in HCQ.

In the U.S. especially, early outpatient treatment of COVID with the antimalarial HCQ was widely criticized by health agencies and experts. This includes: the FDA,23 the CDC,24 Dr. Fauci,

the director of the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH and advisor to presidents Biden and Trump,25,26 Dr. Fauci’s agency, the NIH,27 and the World Health Organization.28 Studies from North America are 3.7 times more likely to report negative results than studies from the rest of the world combined.29

HCQ was not only criticized, it was widely banned throughout the U.S., often under the full weight of law. In Ohio, for example, this included the Board of Pharmacy,30 the Ohio Attorney General and both of Ohio’s two U.S. Attorneys.31,32

America’s prohibition and even criminalization of HCQ has failed. This can be seen not just in the OWID graph (Figure 4, below), but also in the now infamous May 22, 2020, Lancet article entitled – “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID: a multinational registry analysis.” 33 Its lead author was the endowed chair of cardiology at Harvard, Prof. Mandeep R Mehra, MD. The newly released article was touted on CCN on Friday afternoon, May 22, 2020.34 On the basis of the Lancet article, the WHO immediately terminated all HCQ research worldwide.35 The data for the Lancet article was reportedly collected and held by a company called Surgisphere.36 Surgisphere turned out to be a complete fraud, and it vanished when the fraud was exposed.37 The article, later known as “Lancetgate,” was subsequently withdrawn.38 A related article was retracted from the New England Journal of Medicine. 39 In an interview with The New York Times, Dr. Richard Horton, the editor in chief of The Lancet, “called the paper retracted by his journal a ‘fabrication’ and ‘a monumental fraud.’” 40

There is now overwhelming evidence the U.S. COVID outcomes are far worse than the rest of the world. This fact can easily be computed from the most widely used data sources, the JHU COVID Dashboard. This graph can also be easily produced on the OWID website. (Figure 4.) 41, fn2 If this data is not accurate, how can we trust any data in the COVID pandemic? Even if the SSA data is disregarded, there remain some 185 other countries to compare to the U.S. It is indisputable that U.S. results are at least twice as poor as the rest of the world - probably four times worse.42

For the purposes of this paper one must consider the role of HCQ. HCQ is used to fight COVID in Africa, but the prevalence of HCQ in Africa to treat Malaria or COVID is not precisely known. The authors make no claim of possessing exhaustive knowledge of the usage rates of HCQ to treat either malaria or COVID in these SSA countries. A few things have been discovered. For approximately the past fifteen years, HCQ has been supplanted as the recommended antimalarial drug in SSA. Artemisinin is the preferred drug. However, change is slow and there are anecdotal reports of continued use of HCQ in many countries for various reasons, especially confirmed or suspected malaria.

About twenty reports of HCQ use in the treatment of COVID in SSA have been documented by the c19study group. 42 There is additional documentation of intentional use of HCQ to treat COVID in SSA. fn3 Even if there is significant HCQ use in SSA, the fact of the reported COVID outcomes in these six countries being so much better than anywhere else, argues

2The OWID graph (Figure 4) is slightly inaccurate because the U.S. data is included in the world data. This skews the world data higher. When the U.S. fatality rate is truly compared to the rest of the world minus the U.S. data, the rates are: U.S. 1748 deaths per million (dpm), rest of world = 347 dpm, fatality ratio, US/World = 5.04x. (May 1, 2021).

3Writing in the journal, Research and Reports in Tropical Medicine Ethiopian Anteneh Belayneh reported that “many African countries have already approved at the national level to use these drugs to treat COVID by opposing WHO warnings.” Belayneh specifically noted that HCQ was used to treat COVID in Nigeria, Uganda, and Mozambique. 3 Belayneh reported that “the Anadolu Agency showed that Nigeria goes into clinical trials with hydroxychloroquine.” A Nigerian medical director was quoted as saying, “The narrative might change later, but for now, we believe in hydroxychloroquine.” Belayneh reported, “Uganda recorded good results by treating COVID patients with hydroxychloroquine or chloroquine.” Dr. Diana Atwine, secretary of the Ministry of Health stated, “Uganda has scored good results from using these drugs. She also added that these drugs are not new for them, and they know well about the side effects.” 3

for another explanation besides HCQ. There is no sufficient evidence that HCQ alone could explain the very low fatality rates seen in these six SSA countries. This is especially true because, as seen below, the available evidence indicates that other antimalarial agents may be more widely used in these six countries than HCQ.

A second antimalarial agent, AV-PG, appears to be effective against SARS-CoV-2 as

well.fn4 The efficacy of other antimalarial agents was hypothesized in the author’s first paper (May 2020).3

We know that the SARS-CoV-2 virus originated in China, and there was significant exchange of travelers between China and SSA.43 In the first paper, we hypothesized that this seeding of SSA was inhibited by the use of prophylactic antimalarial agents. In the second paper, we identified AV-PG (Malarone) by name as the suspected antimalarial prophylactic drug used by arriving travelers. It is reported that most visitors (95%) to the six SAA countries are taking prophylactic antimalarial drugs.44 It is publicized that 70% of the time the antimalarial drug taken is AV-PG.45 This would have been true of travelers from China as well. fn5 AV-PG is the antimalarial agent recommended for prophylaxis in all six of the studied SSA countries. 46

AV-PG is also now being shown to be effective against SARS-CoV-2 in vitro. Since the first paper, there have been studies demonstrating in vitro efficacy of AV-PG/atovaquone against SARS-COV-2. 47,48,49 This confirms the diminished seeding of SARS-COV-2 in the SSA countries because of the use of antimalarial AV-PG in arriving travelers. AV-PG’s effectiveness is shown by epidemiologic and in vitro evidence. The authors are unaware of any current confirming human studies.50

The inhibition of seeding of SARS-CoV-2 by arriving travelers would have had the most impact early in the pandemic. Later, COVID would be spread by person-to-person transmission within the country. Experts now agree that the profoundly superior COVID outcomes have persisted, month after month. The persistence of superior outcomes seen in this SSA countries after an initial period of seeding by travelers and the success of HCQ elsewhere suggests that there is some in-country factor which is inhibiting person-to-person transmission of SARS-CoV-2 in these SSA countries. This epidemiologic evidence suggests that another mechanism, a third antimalarial drug is inhibiting person-to-person transmission in the SSA countries. That third drug is believed to be artemisinin.6 This may be the most effective treatment of COVID yet. Like AV- PG, artemisinin is an antimalarial aggressively used in the six SSA countries.

4Malarone® is the brand name for the combination of atovaquone and proguanil, effective in the treatment of and especially the prophylaxis against malaria. This paper will use the accepted generic abbreviation AV-PG.

5The Chinese know malaria.5 Malaria has been known to be present in China for hundreds of years. In 1940, China had 3 million cases of malaria with 300,000 deaths.5 Malaria has now been entirely eradicated from China. China would be highly motivated to prevent its travelers from importing malaria back to China. China has a sophisticated CDC believed to be modeled after the U.S. CDC.5 As part of their CDC, the Chinese have a National Institute of

Parasitic Diseases (NIPD) “designated as the WHO Collaborative Center for Malaria, Schistosomiasis and Filariasis since 1980.”5 The Chinese generally follow US CDC and WHO recommendations, and China has a master plan to eliminate malaria. This would include strong antimalarial prophylaxis among its many citizens traveling to Africa.5,5 Like other world travelers to SSA, Chinese travelers would have followed CDC guidelines and used AV-PG as prophylaxis. This explains the low initial COVID infection rate in the six SSA countries.

6Artemisinin is recommended for the treatment of malaria. Artemisinin is THE drug of choice to treat malaria in our six countries and in many countries around the world. It was recommended as the drug of first choice in most of these

Figure 5 is a graph published by Ezenduka, et al in the Malaria Journal.51 It is illustrative of the relative use of artemisinin usage in the treatment of malaria in Nigeria. There, the President’s Malaria Initiative for 2021 indicates that in a country of about 223 million people there is need for about 30 million ACT courses.52 Artemisinin use is reported to be widely available in Nigeria.53 Artemisinin is also widely used in DR Congo,54,55 Uganda,56 Mozambique,57 Côte d'Ivoire,58 and Niger.59 Thus, all the six SSA countries studied utilize large amounts of artemisinin

-about 200,000,000 ACT courses, about two thirds of the global artemisinin production.60 Artemisinin is also reported to be widely and readily available, at least in Nigeria.61 Artemisinin’s widespread use is epidemiologically associated with superior COVID outcomes in the six SSA countries.

Finally, this crossover efficacy of artemisinin is supported by the fact that, as with AV-PG, there is not only epidemiological evidence of artemisinin’s effectiveness against COVID, there is newly emerging in vitro evidence of efficacy as well. fn7

There is also increasing interest in the use of ivermectin in the treatment of COVID. 62 Ivermectin, used to treat river blindness (onchocerciasis), is not an antimalarial, but the geographical distribution of onchocerciasis almost exactly parallels that of malaria in SSA. “More than 99% of infected people live in 31 countries in sub-Saharan Africa” including all six of the countries studied here.63,64,65, 66 The use of Ivermectin seems to produce a 66-73% reduction in mortality rate overall, not the 96% reduction reported in SSA.67,68

Amodiaquine, like HCQ, is another congener of chloroquine that is no longer recommended for single drug chemoprophylaxis of P. falciparum malaria because of toxicity.69 Amodiaquine is used in some artemisinin-based ACT malaria therapies.71,74 This is further evidence of the efficacy of antimalarial drugs, even chloroquine congeners, in the treatment of COVID. The potential role of amodiaquine per se is only beginning to be elucidated and like ivermectin, is beyond the scope of this paper.

Our review of antimalarials used in SSA through various search engines found some expected but limited consideration of the repurposing of AV-PG and artemisinin as treatments for COVID. These SSA antimalarials have attracted little attention for the treatment of COVID.

malaria-endemic countries beginning in about 2005. Artemisinin is usually given as combination therapy (ACT) as the first-line therapy for treatment of malaria.

Artemisinin is produced commercially for the treatment of falciparum malaria and marketed internationally as Alaxin, Armiqin, Artequik, Dimisinex, and in the U.S., Coartem. About twenty different brands of artesunate-containing antimalarial drugs and ten brands of artemether-lumefantrine were sourced in the southwestern part of Nigeria alone. Approximately 221 metric tons of artemisinin are produced each year, most of it by a hybrid process.6 Approximately 60 tons is produced in one plant in China alone.6

7Nair, et. al. found that “artemisinin alone showed an estimated IC50 of about 70 μM.” “In contrast, the antimalarial drug amodiaquine had an IC50 = 5.8 μM.” 7 Chuanxiong Nie, et. al. reported that artemisinin inhibited a variety of viruses including SARS-CoV-2. The authors found that the artemisinin derivative Artesunate was most effective and that the commercial drink, Covid-Organics may be effective as well.7 Ruiyuan et. al. found the artemisinin derivative Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28±1.12μM.7 Thus, there is developing in vitro evidence of efficacy of artemisinin against SARS-Cov-2. This is corroborative of the epidemiologic evidence presented above. In short, the antimalarial agent, artemisinin, is widely used to treat malaria in SSA countries. Artemisinin’s broad usage is associated with the world’s best COVID outcomes and supported by in vitro as well as epidemiological evidence.

Across multiple databases, there are about 80 studies of HCQ for every study of artemisinin. There are a few in vitro studies, even fewer still human studies.

Discussion

The raw, population-adjusted fatality ratio of US/Western nations over SSA remained at 150:1. This is the “two orders of magnitude reported more than a year ago.1 It remained strikingly constant. fn8

To obtain the most reliable data, we adjusted for age. It is critical to note that the percentage of elderly residents in the SSA countries is not zero. It is about 20% of the number found in the U.S. Thus, the expected COVID death rate in SSA is not zero. The death rate expected in SSA would be about 20% of the U.S. COVID death rate. Thus, based upon 20% of the U.S. rate of 1,804 dpm, the expected fatality rates in the six SSA countries would be about 360 dpm per million. It is not. It is reported to be 12.5 dpm. The statistically created age-adjusted average fatality rate for the SSA countries is 97 dpm. The age-adjusted fatality ratio of the DWNs over SSA remained approximately 25:1. The age-adjusted COVID fatality rates in SSA are about 4% that of the U.S. and the other DWN. The disparity in COVID outcomes (fatality rates) between the US/Western nations and SSA is profound and persistent. This disparity contradicts the commonly perceived social determinates of disease. Another paper discussing that subject (Two Cities) was produced last year.4 The data disparity was and remains highly statistically significant with a p value

<0.0001. 70 The evidence presented here is what the FDA calls Real World Data (RWD) or Real- World Evidence (RWE). It is useful and reliable.

Some have criticized or rejected the reported African COVID outcomes as inaccurate – for a variety of reasons. They seem too good to be true. The SSA data reported here runs contrary to virtually all American scientists who assert that African Americans are more prone to SARS-CoV-2 infection. fn9 The disparity in the COVID outcomes between SSA and the DWN remained profound and persistent and a great surprise to the experts as seen below.

In our review of antimalarial used in SSA through various search engines, we did not find similar epidemiological studies linking the superior clinical outcomes of SSA with the widespread use of these specific antimalarials. Nor did we find similar papers linking poor COVID outcomes with the prohibition and criminalization of early, outpatient antimalarial treatment. Nor did we

8The SSA data remained strikingly constant with the slight exception of Mozambique. Its rate began to pull away from the crowd a bit about three months ago. Mozambique’s rate has been about three times that of the other five SSA countries. Those other five SSA countries have remain tightly consistent.

9American scientists typically attribute increased COVID incidence to social determinates of disease such as poverty, poor access to health care, etc. Thus, the crossover hypothesis, that antimalarial drugs are effective against COVID, and even the inverse relationship to malaria itself, both run uphill or against the tide or the conventional wisdom. Some say the African death rates are falsely low because of a lack of testing. If so, where are the bodies of those who died of the misattributed cause? Some say deaths are being concealed. Either way, it seems implausible that six countries are conspiring to hide tens of thousands of corpses. It is arrogant, insulting, or worse to assert that Africans hide, ignore, or cannot count COVID deaths. There is evidence that Africans and others are monitoring for unreported COVID deaths. 9,9 We must accept that the fatality rates reported by multiple government agencies and reflected on the JHU Dashboard are real. Other explanations have been offered: climate, genetics, BCG, or the malarial infection itself. These alternative explanations have generally fallen to the wayside and are beyond the scope of this paper. No other alternative explanation discredits the crossover hypothesis suggested here by the data. The second, Lagos paper (“Two Cities,” 06/15/20) provides a more comprehensive analysis of the assertion that persons of African descent are more susceptible to SARS-Cov-2 infection and death.4

find similar papers contrasting the prohibition of early, outpatient COVID treatment in the West with the superb clinical outcomes associated with the widespread use of AV-PG and artemisinin as we see in SSA. We did find the consideration of HCQ to be inescapable with 2,588 citations in Pub Med.10 There are three aspects of HCQ which impact this study of SSA.

HCQ is widely and successfully used around the world to treat COVID. The c19study group documents 1.8 billion patients studied with those treated with HCQ having a 70% decrease in mortality.11

America’s prohibition and criminalization of early, outpatient treatment, notably with the antimalarial drug HCQ (and ivermectin) has failed with the U.S. having a fatality rate four times the rest of the world. (Figure 4.)

HCQ has some use in SSA as noted above, but that use is thought insufficient to explain SSA’s remarkably superior COVID outcomes. 43,fn4 HCQ’s success elsewhere opens the door for consideration of other drugs, possibly antimalarials. AV-PG is a likely candidate. AV-PG is most recommended for malaria prophylaxis in all arriving foreign travelers. AV-PG is the drug most widely used as malarial prophylaxis by travelers arriving to the six SSA countries. AV-PG explains some of the surprise.

Initial SARs-CoV-2 transmission in a country is due to seeding by arriving travelers. Here, SARs-CoV-2 transmission to SSA early in the pandemic was essentially nonexistent. People traveled to SSA from Europe and especially from China before and at least initially during the pandemic. AV-PG is efficacious for prophylaxis and treatment of malaria and like HCQ, appears to have a shared, crossover efficacy in prophylaxis and treatment of SAR-Cov-2. The low rates of COVID fatality seen here in SSA are thus associated with the world’s highest per capita use rates of antimalarial drug AV-PG in arriving travelers. There is no reason to believe that traveling Chinese do anything differently. The evidence indicates that virtually all travelers arriving in SSA were taking AV-PG. About 95% of travelers to SSA take antimalarial prophylaxis and about 70% of those are taking AV-PG. High usage rates of the antimalarial AV-PG are associated with superior COVID outcomes. The countries with the world’s highest per capita use of the antimalarial AV-PG have the world’s best COVID outcomes. However, AV-PG probably does not play nearly as big a role in persistence of the disparity of outcomes as it did in producing the low fatalities seen in SSA in the early days of the pandemic. A third antimalarial drug is thought to explain the persistence of the disparity; a third antimalarial drug is thought to be even more effective and impactful. It is artemisinin.

The 25-fold disparity in COVID fatality between the DWN and SSA is not only profound but also persistent over 13 months. This persistently superior COVID outcomes of SSA was a great surprise to the experts. The degree of their surprise cannot be overstated. Their surprise and the persistently superior outcomes in in SSA argue for the beneficial effectiveness of a third antimalarial drug, Artemisinin.

Early in the pandemic, most experts opined that COVID’s effects on Africa would be catastrophic.71,72,73,74,75,76 At the time of the first paper suggesting better COVID outcomes in SSA, the news and the media were replete with articles anticipating and lamenting a catastrophic result for Africa and SSA in the COVID pandemic. 77,78,79,80,81,82 No doubt African economies and countries are at risk on several levels but the feared and predicted catastrophic COVID outcomes simple did not materialize (at least thus far in the fifteen months of observation in this study). The U.S. CDC was perhaps the loudest in a chorus of voices who authoritatively asserted that,

in the U.S., African Americans are more prone to infection and death from COVID than whites. 83,84,85,86,87 Against this backdrop, it was nearly impossible to consider that Black Africans could possibly have better COVID outcomes than white Westerners, but this is what the data was beginning to show.

Instead, the experts were uniformly surprised at the superior COVID outcomes produced in SSA and now reported here to be continuing fifteen months into the pandemic. For example, by October 2020, Professor Salim Abdool Karim, South Africa’s COVID ministerial advisory committee chair stated, “Most African countries do not have a peak. I do not understand why. I’m completely at sea.” 88 Perhaps most dramatic were the admissions of Steven Phillips, M.D., MPH, a medical epidemiologist, and pandemic preparedness expert formerly with the Centers for Disease Control and Prevention. He would go on to make the same observations that other authors have begrudgingly admitted over the past year, describing the “stunning observation,” that African death rates are “exponentially lower." He described the “amazing performance” and "spectacular success" of Africa and reported that Africa’s superior COVID outcomes are "no longer hypothetical." 89 Thus, about six months after the author’s original “Markedly Lower Rates of Coronavirus” paper, fn10 Dr. Phillips affirmed the author’s original hypothesis, the one hundred- fold superior outcomes in SSA. The inverse relationship between malaria endemicity and COVID fatalities is affirmed by former CDC expert Dr. Phillips and further borne out now by another six months of epidemiologic data.

Artemisinin is the drug most widely used to treat malaria throughout the six SSA countries. Artemisinin, like HCQ’s precursor quinine, is another natural products story. fn11 Artemisinin has been used for hundreds of years to treat malaria. Artemisinin is the active ingredient in a traditional Chinese herb called Artemisia annua, or sweet wormwood. Artemisinin has been considered a COVID treatment but is often described condescendingly as an herbal remedy.90 Artemisinin is not to be trivialized. Artemisinin is utilized for the treatment of malaria and is the drug most widely recommended for malaria treatment in the six SSA countries studied. Tons of artemisinin are produced worldwide, and most is used to treat malaria in SSA. The crossover efficacy of artemisinin is supported by the fact that, as with AV-PG, there is not only epidemiological evidence of artemisinin’s effectiveness against COVID, but also newly emerging in vitro evidence of efficacy as well. Artemisinin, of course, is not used in the West. High usage rates of the antimalarial artemisinin are associated with superior COVID outcomes. Thus, the countries with the world’s highest per capita use of the antimalarial artemisinin have the world’s best COVID outcomes. A year’s worth of epidemiological data, presented here, strongly suggests that it is artemisinin whose crossover efficacy caused the 96% reduction in COVID deaths in SSA.

Three other facts pertaining to the potential use of artemisinin should be borne in mind. One, artemisinin is available in a parenteral formulation. It might be an antimalarial which has potential for use in patients with more advanced disease. Two, increased use of artemisinin to treat COVID might lead to increased malarial resistance to the drug. This will have to be monitored carefully. Three, malaria is still a catastrophic disease. Any use of artemisinin to treat COVID must not detract from the drug’s availability to treat malaria. The repurposing of other

10Originally submitted April 27, 2020. 3

11Artemisinin is the active agent derived from the Artemisia annua plant. It is commonly used in combination regimens known as ACTs, e.g. artemether-lumefantrine, artesunate-amodiaquine, etc. Because of these multiple combinations and compound names, for the purpose of this paper, these drugs will be lumped together under the name artemisinin.

antimalarial agents such as artemisinin and AV-PG should be thoroughly investigated by the world’s medical and scientific experts.

Ivermectin and Amodiaquine both show promise in the treatment of COVID but consideration of these agents is generally beyond the scope of this paper. 91 It is pertinent to note that Ivermectin seems to produce a 66-73% reduction in mortality rate overall, not the 96% reduction reported in SSA.81,82 For this reason, the crossover efficacy of the antimalarials is thought to be the more important causal factor and the more efficacious COVID treatment. The success of Ivermectin is, at minimum, a further example of how other various drugs like antimalarials may be repurposed to treat COVID. If Ivermectin is the causal factor in the superior outcomes of SSA, this is more reason to study Ivermectin and SSA as vigorously as possible. 92 Amodiaquine is important as another congener of chloroquine; it was shown in at least one study to have the greatest in vitro efficacy against SARS-CoV-2 - greater than artemisinin alone.74

Some have attempted to ignore the SSA experience completely. Perhaps the greatest surprise has been the utter failure of western medicine and science in the COVID pandemic. As noted above in the results, the U.S. and the West produced COVID outcomes which are approximately four times (300%) worse than the rest of the world. No one saw this coming. Western criticism, prohibition, and criminalization of HCQ has failed. (Figure 4.) The SSA experience is greatly corroborated by the failure of HCQ prohibitions in the West. Even if the SSA experience is ignored, Western prohibitions of HCQ treatment have still failed. The SSA experience is real and cannot be ignored. HCQ has been successfully used in many parts of the world. It appears to be used to some degree in SSA and may contribute to SSA’s success, but there exists no convincing evidence that HCQ is the primary cause of the superior COVID outcomes seen there. For this reason, the authors submit that two other antimalarial drugs produce better COVID outcomes than HCQ. They are AV-PG and artemisinin.

There is no doubt that SSA is fragile, both in terms of health care and economically. This is what so many experts saw and feared early in the pandemic. Nothing in this paper should be construed to trivialize these concerns. Whatever value artemisinin and other antimalarials may bring to the early, outpatient treatment of COVID must be balanced against their necessity and requisite availability of these drugs for the treatment of malaria. Any use of artemisinin or other currently used antimalarial in the treatment of COVID must be managed with great care.

Conclusion

A country’s COVID fatality rate is inversely related to its prevalence of malaria. The countries with the world’s highest per capita use of the antimalarial AV-PG have the world’s best COVID outcomes. The countries with the world’s highest per capita use of the antimalarial artemisinin have the world’s best COVID outcomes. This data strongly suggests that antimalarial agents have a crossover efficacy in the treatment of COVID. The data indicates that countries with the highest usage rates of these two newer antimalarial agents, artemisinin and AV-PG, experience 96% fewer COVID deaths than the West.

Recommendations for Further Study

Despite Africa’s health vulnerability and economical fragility, this may be a window of opportunity for SSA to be of great benefit to the rest of the world. This paper is a plea for further investigation. While protecting the supplies needed to treat malaria, medical researchers should proceed, with haste and vigor, to further investigate the repurposing of antimalarial agents, especially artemisinin and AV-PG, for the treatment of COVID.

Funding: There was no funding for this paper.

Competing interests: The authors declare that they have no competing interests.

Author details: Geoff Mitchell, MD, JD, FACEP Assistant Professor

Department of Emergency Medicine

The University of Toledo, College of Medicine gmitch@columbus.rr.com

Sonya Naryshkin, MD, FIAC, FCAP

Naryshkin Consulting

Whitewater Wisconsin

1Mitchell, Geoff and Khuder, Sadik, Markedly Lower Rates of Coronavirus Infection and Fatality in Malaria- Endemic Regions A Clue to Treatment? (April 27, 2020). Available at SSRN: https://ssrn.com/abstract=3586954 or http://dx.doi.org/10.2139/ssrn.3586954.

2Our World in Data, original source, https://covid.ourworldindata.org/data/ecdc/total_deaths.csv, Accessed November 2020.

3After November, 2020, Our World in Data, current COVID data source, owid-covid-data.csv, downloaded from https://github.com/owid/COVID-data/tree/master/public/data/, Accessed June 1, 2021.

4Mitchell, Geoff, A Tale of Two Cities Lagos, Nigeria’s Apparent Success in the War Against COVID (Crossover Prophylaxis Against Coronavirus by Antimalarial Agents) (June 16, 2020). Available at

SSRN: https://ssrn.com/abstract=3628644 or http://dx.doi.org/10.2139/ssrn.3628644 .

5World malaria report 2019. World Health Organization 2019; published Dec 4: https://www.who.int/

news-room/feature-stories/detail/world-malaria-report-2019. Accessed Apr 26, 2020.

6COVID Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU), https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6, Accessed May 28, 2021.

7Lagos Government webpage. https://covid19.lagosstate.gov.ng/, last visited May 15, 2020 @ 9:00 a.m.

8Coronavirus deaths in NYC, https://www1.nyc.gov/site/doh/covid/COVID-data.page, last visited June 4, 2020.

9Real-world data (RWD) and real-world evidence (RWE) are playing an increasing role in health care decisions, the U.S. Food and Drug Administration, https://www.fda.gov/science-research/science-and-research-special- topics/real-world-evidence, Accessed 06/07/21.

10PubMed Search Results for “covid” and “hydroxychloroquine,” April 26, 2021, https://pubmed.ncbi.nlm. nih.gov/?term=covid+and+hydroxychloroquine, April 26, 2021.

11Early treatment with hydroxychloroquine: a country-based analysis, c19study group – Covid Analysis, https://hcqtrial.com/, Accessed May 29, 2021.

12Figure 2 - Global HCQ/CQ Use, @CovidAnalysis, https://c19hcq.com/countries.html, Accessed May 29, 2021.

13Also cited by AAAS Eurekalert! Global HCQ/CQ Use, Credit c19study.com, Copyrights Dr. Alberto Boretti, Dr. Bimal Banik, Dr. Stefania Castelletto, Bentham Science Publishers, https://sciencesources.eurekalert.org/ multimedia/pub/250198.php?from=485555. , (Last visited May 4, 2021).

14Figure 3 - Cumulative confirmed deaths from COVID 19, OWID https://ourworldindata.org/grapher/cumulative- deaths-and-cases-COVID?tab=map&country=~OWID_WRL. Also published by AAAS as a “EurekAlert!”

Cumulative Confirmed Deaths, https://sciencesources.eurekalert.org/multimedia/pub/

250197.php, Credit c19study.com, Copyrights belong to Dr. Alberto Boretti, Dr. Bimal Banik, Dr. Stefania Castelletto, Bentham Science Publishers, (Last visited May 4, 2021).

15Lagier JC, Raoult D et al, Outcomes of 3,737 COVID patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. IHU COVID Task force. Travel Med Infect Dis. 2020 Jul-Aug;36:101791. doi: 10.1016/j.tmaid.2020.101791. Epub 2020 Jun 25. PMID: 32593867; PMCID:

PMC7315163, Accessed May 29, 2021.

16Dr. Vladimir Zelenko’s website, https://vladimirzelenkomd.com/, Accessed May 29, 2021.

17Risch HA. Early Outpatient Treatment of Symptomatic, High-Risk COVID Patients That Should Be Ramped Up Immediately as Key to the Pandemic Crisis. Am J Epidemiol. 2020 Nov 2;189(11):1218-1226. doi: 10.1093/aje/kwaa093. PMID: 32458969; PMCID: PMC7546206.

18Real World COVID Experience: in the Community (video presentation), Brian Tyson, M.D., https://www.americasfrontlinedoctors.org/videos/COVID-in-the-community, Accessed May 29, 2021.

19NYC Coronavirus Health Data, by borough, https://github.com/nychealth/coronavirus-data/blob/master/totals/by- boro.csv, Accessed May 29, 2021.

20Early Outpatient Treatment: An Essential Part of a COVID Solution, U.S. Senate Homeland Security, Full

Committee Hearing, November 19, 2020, https://www.hsgac.senate.gov/hearings/early-outpatient-treatment-an- essential-part-of-a-COVID-solution, Accessed May 29, 2021.

21McCullough PA, et. al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID). Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. doi: 10.31083/ j.rcm.2020.04.264. PMID: 33387997.

22Twenty-million social media views on Facebook reported by NBC News reporter Brandy Zadrozny.” https://www.cnbc.com/2020/07/28/facebook-twitter-youtube-pull-false-coronavirus-video-after-it-goes-viral.html .

23FDA Health Care Provider Fact Sheet – HCQ revoked, version date 4/27/2020, https://www.fda.gov/media/ 136537/download, Last Accessed May 28, 2021.

24CDC: Outpatient Management of Acute COVID, https://www.covid19treatmentguidelines.nih.gov/outpatient- management/, Accessed May 28, 2021.

25Dr. Fauci Interview on CNBC, Dr. Fauci says all the ‘valid’ scientific data shows hydroxychloroquine isn’t effective in treating coronavirus, https://www.cnbc.com/2020/07/29/dr-fauci-says-all-the-valid-scientific-data- shows-hydroxychloroquine-isnt-effective-in-treating-coronavirus.html, Accessed May 28, 2021.

26Caldera C. Fauci did not [and does not] approve hydroxychloroquine as a cure for coronaviruses in 2005, USA Today, August 19, 2020, https://www.usatoday.com/story/news/factcheck/2020/08/19/fact-check-fauci-did-not- approve-hydroxychloroquine-cure-2005/5559347002/, Accessed May 29, 2021.

27NIH COVID Treatment Guidelines, Chloroquine or Hydroxychloroquine With or Without Azithromycin, Last update October 9, 2020, https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/chloroquine-or- hydroxychloroquine-with-or-without-azithromycin/, Accessed May 28, 2021.

28Coronavirus disease (COVID) advice for the public: Mythbusters, https://www.who.int/emergencies/diseases/ novel-coronavirus-2019/advice-for-public/mythbusters?gclid=EAIaIQobChMIz7Os28Ww8AIVRGxvBB2rlg AtEAMYASAAEgJEiPD_BwE#chloroquine, Last visited May 4, 2021.

29HCQ for COVID: real-time meta-analysis of 238 studies, https://hcqmeta.com/, Accessed May 28, 2021.

30OAC 4729-5-30.2, Emergency Rule for Dispensing Chloroquine and Hydroxychloroquine – Effective 3/22/2020, https://www.pharmacy.ohio.gov/Documents/Pubs/Newsletter/2020/Emergency%20Rule%20for%20Dispensing%20 Chloroquine%20and%20Hydroxychloroquine%20Effective%203.22.2020.pdf, Accessed May 29, 2021.

31AG Yost, U.S. Attorneys and Pharmacy Board Issue Joint Statement Regarding Ohio Board of Pharmacy Rule, Office of the Ohio Attorney General, March 24, 2020, https://www.ohioattorneygeneral.gov/Media/News- Releases/March-2020/AG-Yost-U-S-Attorneys-and-Pharmacy-Board-Issue-Joi, Accessed May 29, 2021.

32U.S. Attorneys David DeVillers and Justin Herdman, Ohio Attorney General and Pharmacy Board Director issue joint statement regarding state pharmacy rule, U.S. Department of Justice, March 24, 2020, https://www.justice.gov/ usao-sdoh/pr/us-attorneys-david-devillers-and-justin-herdman-ohio-attorney-general-and-pharmacy, Accessed May 29, 2021.

33Mehra MR, et. al., Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID: a multinational registry analysis. Published: May 22, 2020 DOI: https://doi.org/10.1016/S0140-6736(20)31180-6.

34Large Study Finds Trump-Touted Drug Linked to Greater Risk of Death And Heart Arrhythmia In COVID

Treatment, CUOMO PRIME TIME, CNN Transcripts, Aired May 22, 2020 - 21:00 ET, http://transcripts.cnn.com/ TRANSCRIPTS/2005/22/CPT.01.html, Accessed May 29, 2021.

35WHO halts hydroxychloroquine trial for coronavirus amid safety fears, The Guardian, May 25, 2020, https://www.theguardian.com/world/2020/may/25/who-world-health-organization-hydroxychloroquine-trial-trump- coronavirus-safety-fears, Accessed May 29, 2021.

36Pillar, C. Who’s to blame? These three scientists are at the heart of the Surgisphere COVID scandal, Science Magazine, Jun. 8, 2020, https://www.sciencemag.org/news/2020/06/whos-blame-these-three-scientists-are-heart- surgisphere-COVID-scandal, Accessed May 29, 2021.

37The Big-Data Mystery Behind Retracted COVID Studies of Hydroxychloroquine, Other Drugs, The Wall Street Journal, June 11, 2020, https://www.wsj.com/articles/the-big-data-mystery-behind-retracted-COVID-studies-of- hydroxychloroquine-other-drugs-11591867981, Accessed May 29, 2021.

38Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID: a multinational registry analysis, The Lancet, June 4, 2020, https://www.thelancet.com/pdfs/journals/lancet/PIIS0140- 6736(20)31324-6.pdf.

39Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in COVID, The New England Journal of Medicine, June 25, 2020, N Engl J Med. DOI: 10.1056/NEJMoa2007621, https://www.nejm.org/doi/full/10.1056/ nejmc2021225.

40The Pandemic Claims New Victims: Prestigious Medical Journals, The New York Times, June 16, 2020, https://www.nytimes.com/2020/06/14/health/virus-journals.html, Accessed May 29, 2021.

41OWID graph, U.S. v. World, https://ourworldindata.org/coronavirus-data-explorer?zoomToSelection=true &country=USA~OWID_WRL®ion=World&deathsMetric=true&interval=total&perCapita=true&smoothing=0& pickerMetric=location&pickerSort=asc, Accessed May 29, 2021.

42Global adoption of COVID early treatments, https://c19adoption.com/. Accessed May 22, 2021.

43Marks S and Dahir AL, Africa, Intertwined With China, Fears Coronavirus Outbreak, The New York Times, Feb. 6, 2020, https://www.nytimes.com/2020/02/06/world/africa/africa-coronavirus-china.html, Accessed May 28, 2921.

44Lobel HO, Baker MA, Gras FA, et al. Use of malaria prevention measures by North American and European travelers to East Africa., J Travel Med. 2001 Jul-Aug;8(4):167-72, Accessed May 29, 2021.

45Nixon GL, Moss DM, Shone AE, et al. Antimalarial pharmacology and therapeutics of atovaquone. J Antimicrob Chemother. 2013;68(5):977-985. doi:10.1093/jac/dks504.

46Malaria Information and Prophylaxis, by Country, The U.S. Centers for Disease Control and Prevention, https://www.cdc.gov/malaria/travelers/country_table/n.html, Accessed May 29, 2021.

47Rakedzon S, Neuberger A, Domb AJ, Petersiel N, Schwartz E. J Travel Med., 2021 Jan 22 :taab005.

doi: 10.1093/jtm/taab005. Online ahead of print. PMID: 33480414.

48Ayman Farag, Hesham Sadek. et. al. Submitted date: 13/05/2020 Posted date: 14/05/2020 Licence: CC BY-NC- ND 4.0 (2020): Identification of Atovaquone, Ouabain and Mebendazole as FDA Approved DrugsTargeting SARS- CoV-2 (Version 4). ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12003930.v4, Accessed May 29, 2021.

49Yang CW, Peng TT, Hsu HY, Lee YZ, Wu SH, Lin WH, Ke YY, Hsu TA, Yeh TK, Huang WZ, Lin JH, Sytwu HK, Chen CT, Lee SJ. Biomed J. 2020 Aug;43(4):368-374. doi: 10.1016/j.bj.2020.05.003. Epub 2020 May 23. PMID: 32563698.

50Cochrane Database of Systematic Reviews, Issue 2 of 12, February 2021, https://www.cochranelibrary.com/ search.

51Ezenduka, C.C., Ogbonna, B.O., Ekwunife, O.I. et al. Drugs use pattern for uncomplicated malaria in medicine retail outlets in Enugu urban, southeast Nigeria: implications for malaria treatment policy. Malar J 13, 243 (2014). https://doi.org/10.1186/1475-2875-13-243.

52PMI - US Presidents Malaria Initiative for Nigeria, USAID & CDC, https://www.pmi.gov/docs/default- source/default-document-library/malaria-operational-plans/fy21/fy-2021-nigeria.pdf?sfvrsn=8, Accessed May 31, 2021.

53Personal communication, Mr. Ikwan Onkha, Lagos, Nigeria.

54Nkoli et. al., Access to artemisinin-based combination therapies and other antimalarial drugs in Kinshasa. Med Mal Infect. 2018 Jun;48(4):269-277. doi: 10.1016/j.medmal.2018.02.003. Epub 2018 Mar 9. PMID: 29530387.

55Efficacy and Safety of artemisinin-based Combination Treatments in the Democratic Republic of the Congo

(TETRDC2016),	ClinicalTrials.gov,	NIH,	https://clinicaltrials.gov/ct2/show/NCT02940756.	Accessed
May 31, 2021.

56Rasmussen SA, Ceja FG, Conrad MD, et al. Changing Antimalarial Drug Sensitivities in Uganda. Antimicrob Agents Chemother. 2017;61(12):e01516-17. Published 2017 Nov 22. doi:10.1128/AAC.01516-17.

57Nhama, et al. In vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine for the treatment of

uncomplicated falciparum malaria in children: a multisite, open-label, two-cohort, clinical trial in Mozambique. Malar J 13, 309 (2014). https://doi.org/10.1186/1475-2875-13-309.

58PMI - US Presidents Malaria Initiative for Cote de Ivoire, USAID & CDC, https://www.pmi.gov/docs/default- source/default-document-library/malaria-operational-plans/fy20/fy-2020-cote-d-39-ivoire-malaria-operational- plan.pdf?sfvrsn=6, Accessed May 31, 2021.

59PMI - US Presidents Malaria Initiative for Niger 2021, https://www.pmi.gov/docs/default-source/default- document-library/malaria-operational-plans/fy21/fy-2021-niger.pdf?sfvrsn=8, Accessed May 31, 2021.

602020 World Malaria Report, https://www.who.int/docs/default-source/malaria/world-malaria- reports/9789240015791-double-page-view.pdf?sfvrsn=2c24349d_5, pg. xix, last visited April 24, 2021.

61Mr. Ikwan Onkha, Lagos, Nigeria (personal communication, 04/17/21, 05/19/21).

62Noma, M., Zouré, H.G., Tekle, A.H. et al. The geographic distribution of onchocerciasis in the 20 participating countries of the African Programme for Onchocerciasis Control: (1) priority areas for ivermectin treatment. Parasites Vectors 7, 325 (2014). https://doi.org/10.1186/1756-3305-7-325.

63WHO Onchocerciasis Fact Sheet, WHO, June 14, 2019, https://www.who.int/en/news-room/fact- sheets/detail/onchocerciasis, 05/11/21, Accessed May 31, 2021.

64Noma M, Zouré HG, Tekle AH, Enyong PA, Nwoke BE, Remme JH. The geographic distribution of onchocerciasis in the 20 participating countries of the African Programme for Onchocerciasis Control: (1) priority areas for ivermectin treatment. Parasit Vectors. 2014;7:325. Published 2014 Jul 22. doi:10.1186/1756-3305-7-325.

65C.G. Meyer, P.G. Kremsner, Malaria and onchocerciasis: On HLA and related matters, Parasitology Today, Volume 12, Issue 5, 1996, Pages 179-186, ISSN 0169-4758, https://doi.org/10.1016/0169-4758(96)10011-9.

66Front Line COVID Critical Care Alliance, https://covid19criticalcare.com/, Accessed May 31, 2021.

67Ivermectin for COVID, @CovidAnalysis, May 26, 2021 https://c19ivermectin.com/, Accessed May 11&

May 31, 2021.

68Ivermectin for COVID: real-time meta analysis of 53 studies, Covid Analysis, Nov 26, 2020, https://ivmmeta.com/ (Version 69, May 5, 2021), Accessed May 31, 2021.

69Vinetz JM. Chemotherapy of Malaria. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e. McGraw-Hill; Accessed April 28, 2021. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189§ionid=172484142.

70Z Score Calculator for 2 Population Proportions, https://www.socscistatistics.com/tests/ztest/default2.aspx, Accessed May 31, 2021.

71The Economist, “Experts predict that COVID will spread more widely. The world is getting ready. Poor countries are especially vulnerable.” Feb 22, 2020, https://www.economist.com/international/2020/02/22/experts- predict-that-COVID-will-spread-more-widely, Accessed May 31, 2021.

72The Next Calamity - Coronavirus could devastate poor countries, The Economist, May 28, 2020, https://www.economist.com/leaders/2020/03/26/the-coronavirus-could-devastate-poor-countries, Accessed May 31, 2021.

73Africa is woefully ill-equipped to cope with COVID, The Economist, Mar 28, 2020, https://www.economist. com/middle-east-and-africa/2020/03/26/africa-is-woefully-ill-equipped-to-cope-with-COVID, Accessed

May 31, 2021.

74Gerson M, Coronavirus presents a crisis for Africa, The Washington Post, April 6, 2020, https://www. washingtonpost.com/opinions/2020/04/06/coronavirus-presents-crisis-africa-we-will-be-responsible-if-we-fail-help/, Accessed May 31, 2021.

75Tih F, Pandemic crisis may kill up to 3.3M Africans: UN body, Anadolu Agency, Apr 17, 2020, https://www. aa.com.tr/en/africa/pandemic-crisis-may-kill-up-to-33m-africans-un-body/1808222, Accessed May 31, 2021.

76ECA Report: COVID in Africa: Protecting Lives and Economies, African Renewal, The U.N., https://www. un.org/africarenewal/news/coronavirus/eca-report-COVID-africa-protecting-lives-and-economies, Accessed May 31, 2021.

77Nordling L, A ticking time bomb’: Scientists worry about coronavirus spread in Africa, Science Magazine,

AAAS, March 15, 2020, https://www.sciencemag.org/news/2020/03/ticking-time-bomb-scientists-worry-about- coronavirus-spread-africa, Accessed May 24, 2021.

78Watkins K, Africa faces a catastrophe to dwarf all others, The Financial Times, March 20, 2020, https://www.ft.com/content/d8891a18-6fbf-4462-9b9c-4aefe20733e9, Accessed May 24, 2021.

79MUHUMUZA R, ‘Complete collapse of economies’ ahead as Africa faces virus, The Associated Press, April 5,

2020, https://apnews.com/article/united-nations-financial-markets-ap-top-news-international-news-virus-outbreak- c79a173993d39ffe5773449ebaf9b9f8, Accessed May 24, 2021.

80McVeigh K & Boseley S, African countries braced for ‘inevitable’ arrival of coronavirus, Feb 12, 2020, https://www.theguardian.com/global-development/2020/feb/12/african-countries-braced-for-inevitable-arrival-of- coronavirus, Accessed May 24, 2021.

81Allyson Bear, A Nightmare Scenario: Coronavirus Could Devastate Africa, Feb. 26, 2020, https://www.usnews. com/news/best-countries/articles/2020-02-26/commentary-coronavirus-has-potential-to-devastate-africa, Accessed May 24, 2021.

82More than 15 countries in Africa report COVID cases, WHO Africa, March 13, 2020, https://www.afro.who. int/news/more-15-countries-africa-report-COVID-cases, Accessed May 24, 2021.

83Risk for COVID Infection, Hospitalization, and Death By Age Group, The U.S. Center for Disease Control, https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-race- ethnicity.html, Accessed May 28, 2021.

84This information was obtained from various state and territorial jurisdictions, COVID-NET (https://www.cdc.gov/

coronavirus/2019-ncov/covid-data/covid-net/purpose-methods.html, March 1, 2020 through May 1, 2021), and the National Center for Health Statistics (NCHS) provisional death counts (https://data.cdc.gov/NCHS/Provisional- Death-Counts-for-Coronavirus-Disease-C/pj7m-y5uh, data through May 8, 2021).

85Social Determinants of Health: Know What Affects Health, The CDC, https://www.cdc.gov/socialdeterminants/ index.htm, Accessed May 28, 2021.

86COVID Racial and Ethnic Disparities, The U.S. Center for Disease Control, Updated Dec. 10, 2020, https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/racial-ethnic-disparities/disparities- illness.html, Accessed May 28, 2021.

87Health Equity Considerations and Racial and Ethnic Minority Groups, Updated Apr. 19, 2021 https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/race-ethnicity.html#fn3, Accessed May 28, 2021.

88Harding A, Coronavirus in South Africa: Scientists explore surprise theory for low death rate, Sep 3, 2020, https://www.bbc.com/news/world-africa-53998374, Accessed May 31, 2021. on September 2, 2020.

89Phillips S, Why Africa leads the world in COVID performance, The Hill, October 14, 2020, https://thehill. com/opinion/healthcare/520901-why-africa-leads-the-world-in-COVID-performance, Accessed May 31, 2020.

90See e.g., Steinhauser, G. Another Malaria Cure Draws Notice in Coronavirus Outbreak, This Time in Africa, The Wall Street Journal, 2020, May 12:World. https://www.wsj.com/articles/another-malaria-cure-draws-notice-in- coronavirus-outbreak-this-time-in-africa-11589285981, Accessed May 21, 2021.

91Meyer CG, Kremsner PG, Malaria and onchocerciasis: On HLA and related matters, Parasitology Today, Volume 12, Issue 5, May 1996, Pages 179-186, https://reader.elsevier.com/reader/sd/pii/0169475896100119? token=449ED6E37890EC2D1DC20527E4282B129B56D3604A28F39492B075E8176AE00497C6918F1139C5C80 146D71D94FE1978&originRegion=us-east-1&originCreation=20210505192629, Accessed May 31, 2021.

92Meyer CG, Kremsner PG, Malaria and onchocerciasis: On HLA and related matters, Parasitology Today, Volume 12, Issue 5, May 1996, Pages 179-186, https://reader.elsevier.com/reader/sd/pii/0169475896100119? token=449ED6E37890EC2D1DC20527E4282B129B56D3604A28F39492B075E8176AE00497C6918F1139C5C80 146D71D94FE1978&originRegion=us-east-1&originCreation=20210505192629, Accessed May 31, 2021.