Commonalities between country protocols and discrepancies vis-à-vis the WHO recommendations
According to the crosscutting analysis conducted on 30 country protocols used to treat COVID-19 in the WHO African region, even though WHO African countries adopted and adapted protocols based on their context, the findings demonstrated some commonalities between countries. The assessed protocols present treatments by disease severity, and most of recommended specific therapeutics were candidates originally proposed to undergo clinical trial for COVID-19 treatment. Basically, for severe and critical COVID-19, in compliance with WHO recommendations, where described all countries recommend oxygen therapy to increase and maintain SpO2 > 90%, vasopressors products to treat hypotension during septic shock, anticoagulant to prevent and treat venous or arterial thromboembolism, crystalloids fluids for hydration and resuscitation and AB therapy to kill all likely pathogens.
However, significant discrepancies were noticed, when compared therapeutics recommended in country protocols against the current WHO recommendations published in the tools designed to guide clinicians’ practices and policy makers. The difference resides in whether the country protocols still recommending therapeutics already dropped from Solidarity clinical trials after proving the potential harms would outweigh the potential benefices, other therapeutics are validated to be used in the non-recommended phase of the disease or just some analyzed protocols do not validate therapeutics strongly recommended by WHO.
Considering the presented data in both figures and tables (1,2,3 and 4); HCQ/CQ has shown to be largely approved by WHO African region, because 50% of assessed country protocols recommend HCQ/CQ to treat mild COVID-19 disease, 57% to treat moderate disease, 53% to treat severe disease and 27 % to deal with critical COVID-19 disease. As established in prior conducted studies, HCQ/CQ previously described as a potent inhibitor of most coronaviruses including SARS-CoV-1 [8, 9, 10], were promoted since the beginning of the pandemic in China to demonstrate the potential broad-spectrum antiviral activity [11, 12], and immunomodulatory effects [12, 13]. They have been proposed to undergo investigation for their possible effect against SARS-CoV-2 in clinical trial , including solidarity trial [14, 15]. In some countries such as United States of America, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the use of hydroxychloroquine and chloroquine to treat COVID-19 in hospitalized patients later revoked 15 June 2020 [10, 16].
Within Africa, the ANTICOV trial, which is the largest clinical trial in Africa to treat COVID-19 cases before they become severe, brought together African scientific leaders and enrolled 13 African countries in the trial to test the same products , HCQ/CQ were considered to be the standard of care for COVID-19 disease in numerous African countries. Likewise, the Economic Community of West African States (ECOWAS) has approved the use of chloroquine to treat coronavirus patients. ECOWAS supports the supplementary anti-viral treatment of coronavirus with hydroxychloroquine should be for mild forms of the virus . The overall findings on HCQ/CQ use are consistent with the previous review study on off-label use HCQ/CQ to treat COVID-19 in Africa, which confirmed that many African countries have already approved at the national level, the use of these drugs opposing WHO warnings . WHO also reported the wide use of hydroxychloroquine with Azithromycin outside of COVID-19 clinical trials, as potential threats that could affect antimicrobial stewardship activities and drive antimicrobial resistance .
According to WHO recommendations, HCQ trial arm has been discontinued in the solidarity trial since 17 June 2020, because it has not shown results on reduction of mortality when it can be associated with cardiotoxicity risks . On 17 December 2020, an international Guideline Development Group (GDG) made a Strong recommendation against the use of HCQ/CQ in patients with COVID-19, regardless of disease severity . Based on the up-to-date evidence available and aligning with WHO recommendations; many others published large scale studies concluded on balanced benefits against risks that might occur when treating COVID-19 with HCQ/CQ, worsened by Azithromycin association . Even though HCQ/CQ may exhibit antiviral and immunomodulatory activities, there is no clinical evidence to support their use in WHO African Countries, their cardiovascular toxicity risks outweigh the targeted benefices [12, 16], they might increase the risk of lethal arrhythmias associated with QT interval prolongation [23, 24, 25]. However, a worldwide controversy about the use hydroxychloroquine and chloroquine for COVID 19 treatment was noticed, few studies reported HCQ/CQ likely to lower death rates, and advocate to encourage it use worldwide that might require further studies [17, 26].
On the other hand, the data pointed out the extensive validation of AB products at the earliest stage of the disease, around 53% and 80% of analyzed protocols recommend the regimen with AB products including Azithromycin at mild and moderate level respectively, for suspected co-infections. Similar findings on the increased rates of antimicrobial prescription for COVID-19 patients were established throughout different published studies, that could further worsen the global burden of antimicrobial resistance (AMR), especially in Africa where health systems are weak [27, 28]. The situation could be exacerbated by Azithromycin widely combined with HCQ/QC to treat COVID-19 [19, 29]. Tackling identified antibiotic resistance in all part of the world remains a high priority for WHO, the world urgently needs to change the way it prescribes and uses antibiotics . Few countries in the WHO African region have implemented the WHO Policy Package to combat antimicrobial resistance (AMR) and have national AMR plans in place [31, 32]. The situation requires strong measures to fight against AMR in the pandemic era, strengthen and enforce existing antibiotic use regulations and revise existing protocols [32, 33]. Antibiotics should mostly be reserved for those suffering from severe and critical COVID-19 [27, 34].
The current WHO clinical guidance does not recommend AB therapy for mild or moderate COVID-19 unless bacterial infections exist [4, 5]. From a recent review, only few patients with COVID-19 experience a secondary bacterial or fungal infection [4, 28, 35], there is no strong evidences to support the association with respiratory bacterial or fungal co-infection . Ideally, blood culture would be recommended prior to the initiation of antimicrobial therapy even in severe cases, to avoid short-term side effects of AB products in patients and negative long-term consequences of increased antimicrobial resistance, associated with morbidity and mortality increase, health care costs as well as the economic burden on families and societies [4, 27].
Centered to the results analysis, the antiviral Remdesivir was also counted among the commonly recommended therapeutics in the WHO African region. Twenty-seven percent (27%) of assessed country protocols recommend Remdesivir to treat severe and critical COVID-19. Remdesivir, was proposed early among antivirals to be repurposed in the clinical trial including solidarity trial for COVID 19 treatment [15, 37, 38]. Many conducted clinical trial have not shown interesting results for its proper recommendation and approval in the treatment of COVID-19 [15, 38, 39]. Although until today evidence is not enough to support Remdesivir as an effective therapeutic for COVID-19 patients, this antiviral is one of the reported therapeutics under use in different countries and has been granted an EUA in some countries such as United States of America (USA) [40, 41, 63], and endorsed in the National Health Institute (NHI) treatment guidelines . Further studies are needed to fully assess Remdesivir’s role in COVID-19 treatment.
As per WHO clinical Guidance, Remdesivir is not recommended to be administered as a treatment or prophylaxis for COVID-19 outside the context of clinical trials. Moreover, on 20 November 2020, a conditional recommendation against the use of Remdesivir in hospitalized patients regardless the disease severity, was expressed in the WHO living guide by the international Guideline Development Group (GDG) .
The antiviral Lopinavir /Ritonavir (LPV/r) is also validated within the WHO African region to treat COVID-19. Thirteen percent (13%) of analyzed protocols validate LPV/r to treat Mild disease, 23% for Moderate and Severe disease and 17% to treat critical COVID-19. LPV/r was among the potential antivirals registered in the Chinese COVID-19 Diagnosis and Treatment Plan, to be repurposed for COVID-19 treatment. It has been recommended as a first-line or second-line in many countries [15, 44]. However, based on the preliminary results made public on 29 June 2020, LPV/r did not improve clinical outcomes for hospitalized patients, whether in monotherapy or combined with interferon , while the overall benefit-risk profile may not be positive [42, 46, 47]. LPV/r has been dropped from solidarity clinical trial since 4 July 2020 . On 17 December 2020, an international Guideline Development Group (GDG) made a Strong recommendation against the use of LPV/r in patients with COVID-19, regardless of disease severity . In addition to gastrointestinal side effects reported , both Lopinavir and Ritonavir might be associated with hepatotoxicity, lower bone mineral density, severe bleeding in patients with hemophilia, the decrease in High Density Lipoprotein (HDL) and the Increase in Low Density Lipoprotein (LDL) .
Pursuant to the survey findings, corticosteroids are also generally used in Africa to treat severe and critical disease. About 47% of countries recommend corticosteroids for severe disease, while 60% of assessed protocols indicate the same products to respond to critical disease. They act by mitigating the immune response reaction and reduce cytokine formation. Most guidelines produced early in the covid-19 pandemic strongly discouraged the use of steroids for covid-19. However, the detail with which this recommendation was made varied widely. The use of steroids in acute respiratory infections such as covid-19 was originally contested, but the debate was complex and relies on the interpretation of observational studies and surrogate outcomes .
Nevertheless, WHO strongly recommends systemic corticosteroid therapy for the treatment of all patients with severe and critical COVID-19 [4, 50]. On the 2nd September 2020, WHO published a guidance for clinicians and health care decision-makers with a strong recommendation on the systemic use of corticosteroids, for the treatment of all patients with severe and critical COVID-19, and a conditional recommendation against systemic corticosteroids in patients with non-severe COVID-19 . Many other studies established the efficacy of corticosteroids in hospitalized patients who require supplemental oxygen, with the greatest effect observed in patients who require ventilation [42, 52, 53]. The product is not recommended out of hospital treatment and for patients who do not require oxygen .
The use of Tocilizumab and Interferon rarely endorsed in the analyzed protocols were also among potential therapeutics proposed to undergo clinical trial for COVID 19 treatment. However, they are not recommended by WHO for the treatment or prophylaxis of COVID-19, outside the context of clinical trials. As per available evidence, Interferon has no effect on the overall mortality, initiation of ventilation and the duration of hospital stay in hospitalized patients. Nevertheless, important side-effects have been described while their use [4, 55]. In the other hand, some studies concluded Tocilizumab not effective for preventing intubation or death in hospitalized patients , while in others studies Tociluzimab was reputed to calm the inflammatory storm and reduce mortality in severe patients with COVID-19. Some countries endorsed the same products in their protocols [42, 57]. Tociluzumab was among potential therapeutics formally included in the diagnosis and treatment program of COVID-19 of the national health commission of China since 3 March 2020 .
Even though a controversy may be noticed for some therapeutics, until there is sufficient evidence, WHO cautions against physicians and medical associations recommending or administering unproven treatments to patients with COVID-19 . During times of crisis, transparent guidelines from the World Health Organization may be the only source of direction available to clinicians globally. They may be adopted internationally with only minor local adaptations [58, 59].
Impact on the quality of care, the procurement and the supply chain, for the continuity of essential health services
The need to redirect supplies to treat patients with COVID-19, compounded by general supply chain disruptions because of the outbreak on other sectors, is likely to lead to stock-outs of resources needed for essential services. Supply is dynamic during a pandemic and there are elevated risks of shortages .
Country treatment protocols and guidelines are important tools for effective use of therapeutics to provide optimal therapy and contribute efficiently to the country’s economy. The use of non-recommended therapeutics is an unnecessary treatment likely to cause the resources wastages, the products shortage and stock out, increase of the products prices, or sometime induce substandard and falsified products as well as unnecessary stockpiling, that can lead to the supply chain and supplies management disruption, without counting probable harms on people’s health. Studies reported HCQ /CQ stock piling and shortages in some African countries such as South Africa, while falsified and substandard CQ emerged in Cameroon and the Democratic Republic of Congo [18, 61], poisoning and toxic effects reported in Nigeria , with increased market prices.
Drug supply usually base on standards treatment protocols and guidelines especially in countries with limited resources; the use of inappropriate therapeutics may misguide the procurement and forecasting process where unnecessary products may be largely procured on the detriment of essential products to respond to the disease, without counting probable harms on people’s health that misused medicines might cause.
Throughout the conducted survey, the identified prescription of medicines for off-label use may be subject to national laws and regulations. All health care workers in member states should be aware of and comply with the laws and regulations governing their practice in COVID-19 response . International partners as well as key players involved in COVID-19 response would play a strategic role, by procuring and availing only relevant products in the COVID-19 context.
Even though updating protocols timely may be difficult especially during the pandemic outbreak, where information are changing and updated time to time when new scientific knowledge emerges; it is the utmost way to ensure appropriate therapy and overcome the pandemic burden, especially in WHO African region with limited resources.