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For more than a year, Adeola Fowotade has been trying to recruit people for clinical trials of COVID-19 treatments.As a clinical virologist at University College Hospital, Ibadan, Nigeria, she joined the effort in August 2020 to test the efficacy of off-the-shelf drug combinations.Her goal is to find 50 volunteers — people diagnosed with COVID-19 who have moderate to severe symptoms and who might benefit from the drug cocktail.But hiring has been going on even as Nigeria saw a surge in virus cases in January and February.After eight months, she had recruited only 44 people.
“Some patients declined to participate in the study when approached, and some agreed to stop halfway through the trial,” Fowotade said.Once the case rate began to drop in March, it was nearly impossible to find participants.That made the trial, known as NACOVID, difficult to complete.”We couldn’t meet our planned sample size,” she said.The trial ended in September and fell short of its recruitment target.
Fowotade’s troubles mirror the problems faced by other trials in Africa — a major problem for countries on the continent that don’t have access to enough COVID-19 vaccines.In Nigeria, the continent’s most populous country, only 2.7 percent of people are at least partially vaccinated.This is only slightly below the average for low-income countries.Estimates suggest that African countries will not have enough doses to fully vaccinate 70% of the continent’s population until at least September 2022.
That leaves few options for fighting the pandemic right now.Although treatments such as monoclonal antibodies or the antiviral drug remdesivir have been used in wealthy countries outside of Africa, these drugs need to be administered in hospitals and are expensive.Pharmaceutical giant Merck has agreed to license its pill-based drug molnupiravir to manufacturers where it can be widely used, but questions remain about how much it will cost if approved.As a result, Africa is finding affordable, easily accessible medicines that can reduce COVID-19 symptoms, reduce the disease burden on healthcare systems, and reduce deaths.
This search has encountered many obstacles.Of the nearly 2,000 trials currently exploring drug treatments for COVID-19, only about 150 are registered in Africa, the vast majority in Egypt and South Africa, according to clinicaltrials.gov, a database run by the United States.The lack of trials is a problem, says Adeniyi Olagunju, a clinical pharmacologist at the University of Liverpool in the UK and NACOVID lead researcher.If Africa is largely missing from COVID-19 treatment trials, its chances of getting an approved drug are very limited, he said.”Add that to the extremely low availability of vaccines,” Oragonju said.”More than any other continent, Africa needs an effective COVID-19 therapy as an option.”
Some organizations are trying to make up for this shortfall.ANTICOV, a program coordinated by the non-profit Drugs for Neglected Diseases Initiative (DNDi), is currently the largest trial in Africa.It is testing early treatment options for COVID-19 in two experimental groups.Another study called Repurposing Anti-Infectives for COVID-19 Therapy (ReACT) – coordinated by the non-profit foundation Medicines for Malaria Venture – will test the safety and efficacy of repurposing drugs in South Africa.But regulatory challenges, a lack of infrastructure, and difficulties in recruiting trial participants are major obstacles to these efforts.
“In sub-Saharan Africa, our healthcare system has collapsed,” said Samba Sow, national lead researcher at ANTICOV in Mali.That makes trials difficult, but more necessary, especially in identifying drugs that can help people in the early stages of the disease and prevent hospitalization.For him and many others studying the disease, it’s a race against death.”We can’t wait until the patient is seriously ill,” he said.
The coronavirus pandemic has boosted clinical research on the African continent.Vaccinologist Duduzile Ndwandwe tracks research on experimental treatments at Cochrane South Africa, part of an international organisation that reviews health evidence, and said the Pan-African Clinical Trials Registry registered 606 clinical trials in 2020, compared with 2019 408 (see ‘Clinical trials in Africa’). By August this year, it had registered 271 trials, including vaccine and drug trials. Ndwandwe said: “We have seen many trials expanding the scope of COVID-19.”
However, trials of coronavirus treatments are still lacking.In March 2020, the World Health Organization (WHO) launched its flagship Solidarity Trial, a global study of four potential COVID-19 treatments.Only two African countries participated in the first phase of the study.The challenge of delivering health care to critically ill patients has kept most countries from joining, said Quarraisha Abdool Karim, a clinical epidemiologist at Columbia University in New York City, based in Durban, South Africa.”This is an important missed opportunity,” she said, but it sets the stage for more trials of COVID-19 treatments.In August, the World Health Organization announced the next phase of the solidarity trial, which will test three other drugs.Five other African countries participated.
The NACOVID trial by Fowotade aims to test the combination therapy on 98 people in Ibadan and three other sites in Nigeria.People in the study were given the antiretroviral drugs atazanavir and ritonavir, as well as an antiparasitic drug called nitazoxanide.Although the recruitment target was not met, Olagunju said the team is preparing a manuscript for publication and hopes the data will provide some insights into the drug’s effectiveness.
The South African ReACT trial, sponsored in Seoul by South Korean pharmaceutical company Shin Poong Pharmaceutical, aims to test four repurposed drug combinations: the antimalarial therapies artesunate-amodiaquine and pyrrolidine-artesunate; Favipiravir, the flu antiviral drug used in combination with nitre; and sofosbuvir and daclatasvir, an antiviral combination commonly used to treat hepatitis C.
Using repurposed drugs is very attractive to many researchers because it may be the most feasible route to quickly finding treatments that can be easily distributed.Africa’s lack of infrastructure for drug research, development and manufacturing means countries cannot easily test new compounds and mass-produce drugs.Those efforts are critical, says Nadia Sam-Agudu, a pediatric infectious disease specialist at the University of Maryland who works at the Nigeria Institute of Human Virology in Abuja.”If effective, these treatments may prevent serious illness and hospitalization, as well as possibly [stop] continued transmission,” she added.
The continent’s largest trial, ANTICOV, was launched in September 2020 in the hope that early treatment could prevent COVID-19 from overwhelming Africa’s fragile health care systems.It is currently recruiting more than 500 participants at 14 locations in the Democratic Republic of Congo, Burkina Faso, Guinea, Mali, Ghana, Kenya and Mozambique.It aims to eventually recruit 3,000 participants in 13 countries.
A worker at a cemetery in Dakar, Senegal, in August as a third wave of COVID-19 infections hit.Image credit: John Wessels/AFP/Getty
ANTICOV is testing the efficacy of two combination treatments that have had mixed results elsewhere.The first mixes nitazoxanide with inhaled ciclesonide, a corticosteroid used to treat asthma.The second combines artesunate-amodiaquine with the antiparasitic drug ivermectin.
The use of ivermectin in veterinary medicine and the treatment of some neglected tropical diseases in humans has caused controversy in many countries.Individuals and politicians have been demanding its use to treat COVID-19 due to insufficient anecdotal and scientific evidence about its efficacy.Some of the data supporting its use is questionable.In Egypt, a large study supporting the use of ivermectin in COVID-19 patients was withdrawn by a preprint server after it was published amid allegations of data irregularity and plagiarism.(The authors of the study argue that the publishers did not give them the opportunity to defend themselves.) A recent systematic review by the Cochrane Infectious Diseases Group found no evidence to support the use of ivermectin in the treatment of COVID-19 infection (M. Popp et al al . Cochrane Database Syst. Rev. 7, CD015017; 2021).
Nathalie Strub-Wourgaft, who runs DNDi’s COVID-19 campaign, said there was a legitimate reason to test the drug in Africa.She and her colleagues hope it can act as an anti-inflammatory when taken with an antimalarial drug.If this combination is found to be lacking, DNDi is ready to test other drugs.
“The ivermectin issue has been politicized,” said Salim Abdool Karim, an epidemiologist and director of the Durban-based Centre for AIDS Research in South Africa (CAPRISA).”But if trials in Africa can help solve this problem or make an important contribution, then it’s a good idea.”
Based on the data available to date, the combination of nitazoxanide and ciclesonide looks promising, Strub-Wourgaft said.”We have encouraging preclinical and clinical data to support our choice of this combination,” she said.Following an interim analysis last September, Strub-Wourgaft said ANTICOV is preparing to test a new arm and will continue to use two existing treatment arms.
Starting a trial was a challenge, even for DNDi with extensive work experience on the African continent.Regulatory approval is a major bottleneck, Strub-Wourgaft said.Therefore, ANTICOV, in collaboration with WHO’s African Vaccine Regulatory Forum (AVAREF), established an emergency procedure to conduct a joint review of clinical studies in 13 countries.This can expedite regulatory and ethical approvals.“It allows us to bring together states, regulators and ethics review board members,” Strub-Wourgaft said.
Nick White, a tropical medicine expert who chairs the COVID-19 Clinical Research Consortium, an international collaboration to find solutions to COVID-19 in low-income countries, said that while the WHO’s initiative was good, But it still takes longer to get approval, and research in low- and middle-income countries is better than research in rich countries.Reasons include the strict regulatory regimes in these countries, as well as authorities that are not good at conducting ethical and regulatory scrutiny.That has to change, White said.”If countries want to find solutions to COVID-19, they should help their researchers do necessary research, not hinder them.”
But the challenges don’t stop there.Once the trial begins, lack of logistics and electricity could hinder progress, Fowotade said.She stored the COVID-19 samples in a -20 °C freezer during the power outage at the Ibadan hospital.She also needs to transport the samples to the Ed Center, a two-hour drive away, for analysis.”I sometimes worry about the integrity of the stored samples,” Fowotade said.
Olagunju added that when some states stopped funding COVID-19 isolation centers in their hospitals, recruiting trial participants became more difficult.Without these resources, only patients who can afford to pay are admitted.”We started our trial based on the government’s knowledge program in charge of funding isolation and treatment centers. No one expected to be interrupted,” Olagunju said.
Although it is generally well-resourced, Nigeria is clearly not a participant in ANTICOV.”Everyone is avoiding clinical trials in Nigeria because we don’t have the organization,” said Oyewale Tomori, a virologist and chair of Nigeria’s COVID-19 Ministerial Advisory Committee of Experts, which works to identify effective strategies and best practices to deal with COVID-19 .
Babatunde Salako, director of the Nigerian Institute of Medical Research in Lagos, disagrees.Salako said Nigeria has the knowledge to conduct clinical trials, as well as hospital recruitment and a vibrant ethics review committee that coordinates the approval of clinical trials in Nigeria.”In terms of infrastructure, yes, it can be weak; it can still support clinical trials,” he said.
Ndwandwe wants to encourage more African researchers to join clinical trials so that its citizens have equitable access to promising treatments.Local trials can help researchers identify practical treatments.They can address specific needs in low-resource settings and help improve health outcomes, says Hellen Mnjalla, clinical trials manager for the Wellcome Trust Research Program at the Kenya Institute of Medical Research in Kilifi.
“COVID-19 is a new infectious disease, so we need clinical trials to understand how these interventions will work in African populations,” Ndwandwe added.
Salim Abdul Karim hopes the crisis will inspire African scientists to build on some of the research infrastructure built to combat the HIV/AIDS epidemic.”Some countries like Kenya, Uganda and South Africa have very developed infrastructure. But it’s less developed in other areas,” he said.
To intensify clinical trials of COVID-19 treatments in Africa, Salim Abdool Karim proposes the creation of an agency such as the Consortium for Clinical Trials of COVID-19 Vaccines (CONCVACT; created by the African Centers for Disease Control and Prevention in July 2020) to coordinate treatment across the continent test.The African Union – the continental body representing 55 African member states – is well placed to shoulder this responsibility.”They’re already doing this for vaccines, so it can be extended to treatments as well,” said Salim Abdul Karim.
The COVID-19 pandemic can only be overcome through international cooperation and fair partnerships, Sow said.”In the global fight against infectious diseases, a country can never be alone — not even a continent,” he said.
11/10/2021 Clarification: An earlier version of this article stated that the ANTICOV program was run by DNDi.In fact, DNDi is coordinating ANTICOV, which is run by 26 partners.
Post time: Apr-07-2022