Even as signs of risks continue to mount, chloroquine is increasingly receiving an emergency-use designation for the treatment of coronavirus in many countries, reports Associate Editor ADEKUNLE YUSUF
Without a cure yet, coronavirus continues to decimate the human race – leaving authorities in 208 countries and territories with the same challenge of how to contain the spread of a disease that has killed close to 70,000 people. As the race towards finding a cure lingers in laboratories, with global cases surging beyond 1,200,000, many are in a hurry to see the world enjoy a respite through a coronavirus vaccine or drug.
But with the situation of things, it appears the waiting game may not last forever, as chloroquine is being touted in many quarters as a potential remedy for managing coronavirus cases. Around the world, researchers, healthcare professionals and drug regulatory authorities are working hard to learn more about the efficacy of chloroquine for treating coronavirus. However, perhaps due to exigencies of the pandemic, drug regulators in many countries are giving the anti-malaria drug emergency approval for possible clinical trial treatment of the disease.
Things changed on a frenetic pace last month, when President Donald Trump of the United States threw his weight behind chloroquine, describing it as a possible “game-changer” in the fight against the coronavirus pandemic. The drug has since received an emergency-use designation from US regulators. The US Health and Human Services Department said it accepted 30 million doses of hydroxychloroquine from Novartis AG’s Sandoz unit. Normally used to treat malaria, hydroxychloroquine yielded promising yet inconclusive results in a small coronavirus trial.
Chloroquine and hydroxychloroquine are medications commonly used to treat malaria, a widespread disease that afflicts hundreds of millions of people around the world. Malaria is not caused by a virus; it is caused Plasmodium parasites that are carried by mosquitoes, which spread the parasites to humans when they bite. These drugs also inhibit the immune system, which makes them useful for treating autoimmune diseases, like rheumatoid arthritis, in which a person’s immune system registers part of the body as foreign and attacks it.
However, while Trump has said the drug is safe, health experts have warned that it does carry significant side effects. Some people have been sickened, with reported deaths in the US and France, after taking various versions to try to ward off the new illness. Trump said over 1000 patients in New York, one of the pandemic’s hot spots, were receiving treatment using hydroxychloroquine. “Let’s see how it works. It may, it may not,” Trump said in one of his daily briefings. Reports had it that some COVID-19 patients treated at French hospitals with hydroxychloroquine and chloroquine experienced fatal heart side effects. Australian health officials have restricted the use of the two drugs for the treatment of COVID-19; while the World Health Organisation Director-General, Tedros Adhanom Ghebreyesus, has also cautioned against the use of unproven treatments against coronavirus.
NAFDAC ordered emergency chloroquine production
Last month, the Prof Moji Adeyeye-led National Agency for Food and Drug Administration and Control (NAFDAC) ordered the manufacturing of chloroquine for an emergency stock for possible clinical trial treatment of coronavirus. The agency said the anti-malaria drug was reported to function as anti-viral at both the entry and post-entry stages of coronavirus infection. Chloroquine has also been reported as a potential broad-spectrum antiviral drug, it said.
She noted that Lagos would begin a clinical trial of the drug to evaluate its effectiveness while calling on the public to desist from its use without the guidance of a medical doctor or clinician for cases of clinical trial treatment of COVID-19. “Chloroquine, an old anti-malarial, is being re-purposed for the clinical trial treatment of coronavirus 2019-nCoV. The drug was first tested in vitro (in the lab) using standard assays to measure the effects on the cytotoxicity, virus yield and infection rates of 2019-nCoV.
“The drug was reported to function as antiviral at both the entry and post-entry stages of 2019-nCoV infection. Chloroquine has also recently been reported as a potential broad-spectrum antiviral drug. In a very recent publication, chloroquine was reported in a press briefing by the State Council of China, indicating that chloroquine phosphate had demonstrated marked efficacy and acceptable safety in treating COVID-19 associated pneumonia in a multi-centre clinical trial conducted in China.
“The study involved 10 hospitals in Wuhan, Jingzhou, Guangzhou, Beijing, Shanghai, Chongqing and Ningbo, and 100 patients. The investigators reported that chloroquine phosphate is superior to the control in inhibiting pneumonia associated with COVID-19, and shortening the course of the disease,” she said.
The DG of NAFDAC noted that chloroquine was discontinued in Nigeria many years ago for use as anti-malarial because of the resistance that the parasite developed against it. “Therefore, sourcing the raw material – active pharmaceutical ingredient- chloroquine phosphate could be difficult. About four weeks ago, I approached a local manufacturing company (May and Baker), a member of Pharmaceutical Manufacturing Group of Manufacturing Association of Nigeria, whose flagship product in the past was chloroquine, to make a batch of the drug for emergency stock. The company had NAFDAC approval for the production of the drug as anti-malarial many years ago before the discontinuation.”
Despite initial difficulty expressed by the managing director of the company (May and Baker), the hurdle was later removed, leading to the production of the drug with more to be manufactured, NAFDAC said. “He called shortly after that he was able to get the API and was asked to manufacture a batch for emergency stock just in case more people become exposed and infected with the virus. The batch has been manufactured and the company plans to make more batches if needed. NAFDAC is giving expedited provisional approvals for the manufacture of any commodities for preventing contracting the disease (sanitizers), and drug or medical device that could be used for the clinical trial testing and treatment of COVID-19 pandemic.
“The agency had reduced the 120 working days for approval to 10 days due to the crisis. Lagos State will be starting a clinical trial on chloroquine to evaluate the effectiveness. Chloroquine works by increasing endosomal pH from the acidic environment required for virus/cell fusion, resulting in the inhibition of infection of SARS-CoV. NAFDAC advises the public to desist from its use without the guidance of a medical doctor or clinician for cases of clinical trial treatment of COVID-19. It has side effects such as gastrointestinal upset, blurred vision, headache and pruritis (itching). The itching can be relieved by using an antihistamine. Prolonged use can also cause retinopathy or vision impairment,” NAFDAC boss said.
Following this, Lagos State Government announced two weeks ago that it would commence the clinical trial of chloroquine for treating COVID-19. Lagos, Nigeria’s commercial nerve centre, has remained the epicentre of the disease in the country. According to Prof Adeyeye, other researchers in France and the US have used the drug for the clinical trial treatment of COVID-19 and they reported the effectiveness of the drug. “Lagos State will be starting a clinical trial on chloroquine to evaluate the effectiveness,” she said.
NAFDAC said chloroquine works by increasing endosomal pH from the acidic environment required for virus/cell fusion, resulting in the inhibition of infection of SARS-CoV. It also interferes with the glycosylation of cellular receptor, angiotensin-converting enzyme 2. This may inhibit the virus-receptor binding and terminate the infection. The antiviral and anti-inflammatory effects of chloroquine contribute to the efficacy in treating COVID-19 patients, she said, explaining how the drug works in combating the disease. NAFDAC, however, emphasised the need for the public to “desist from its use without the guidance of a medical doctor or clinician for cases of clinical trial treatment of COVID-19”. The drug has side effects such as gastrointestinal upset, blurred vision, headache, and pruritis (itching). Prolonged use can also cause retinopathy or vision impairment, the agency stressed.
Fate of chloroquine in Europe
In Europe, chloroquine and hydroxychloroquine are also allowed to be used but only in clinical trials or emergency use programmes. The European Medicines Agency (EMA) admitted last week that chloroquine and hydroxychloroquine, two medicines currently authorised for malaria and certain auto-immune diseases, are being investigated worldwide for their potential to treat coronavirus infection. However, efficacy in treating COVID-19 is yet to be shown in studies, the agency added.
Experts have warned that it is very important that patients and healthcare professionals only use chloroquine and hydroxychloroquine for their authorised uses or as part of clinical trials or national emergency use programmes for the treatment of COVID-19. However, both chloroquine and hydroxychloroquine can have serious side effects, especially at high doses or when combined with other medicines, EMA warned. To avoid complications, drug authorities warned that the two drugs must not be used without a prescription and supervision by a doctor; prescriptions should not be given outside their authorised uses except in the setting of a clinical trial or nationally agreed protocols.
Hopefully, the world may not have to wait for too long as large clinical trials are underway to generate the robust data needed to establish the efficacy and safety of chloroquine and hydroxychloroquine in the treatment of COVID-19. Such trials will enable authorities to give reliable advice based on solid evidence to healthcare professionals and patients. Considering the urgency and the pressure healthcare systems face to save lives during the COVID-19 pandemic, some countries, including the US and France, have put strict protocols in place to allow the experimental use of these two medicines in patients with severe forms of COVID-19.
Chloroquine and hydroxychloroquine are vital medicines for patients with auto-immune conditions such as lupus. It is important that such patients are still able to obtain them and do not face shortages caused by stockpiling or use outside the authorised indications. In some countries, prescribing of the medicines has been restricted to reduce the risk of shortages. Patients have been to use chloroquine or hydroxychloroquine only if they have been prescribed by a doctor or a doctor is supervising the treatment. As for healthcare professionals, EMA said chloroquine and hydroxychloroquine should preferably be used in the context of clinical trials for coronavirus. Outside clinical trials, the two drugs can be used following nationally established protocols. “Chloroquine and hydroxychloroquine should continue to be used in chronic conditions. To prevent unnecessary strain on supply chains, patients should only receive their usual supply of medicines. Healthcare professionals should not write prescriptions that cover more than the usual duration,” EMA said.
Chloroquine was also among the first group of therapies Chinese scientists identified as being effective in curbing the new coronavirus. Clinical trials on about 130 patients demonstrated the drug’s ability to reduce the severity of the illness and speed up virus clearance, according to China’s Ministry of Sciences and Technology. Chloroquine phosphate was officially recommended on Feb. 19 in the COVID-19 treatment guidelines published by China’s National Health Commission, along with a few other drugs as antiviral treatments for patients.
The commission recommended no more than a 10-day course of chloroquine for adult patients. China’s recommendation to use chloroquine in treatment was quickly followed by a warning. Days after the treatment guideline update, health authorities in Hubei province, China’s worst-hit region where the outbreak started and which accounted for the majority of its cases, asked hospitals to closely watch for, and immediately report, any adverse side effects of chloroquine phosphate. The drug is known to have short-term side effects such as nausea, diarrhoea and tinnitus while long-term use can irreversibly impair eyesight. It’s forbidden for pregnant women as it can cause congenital defects in babies.
Will a COVID-19 vaccine be ready soon?
By merely according to coronavirus a pandemic designation, public health professionals are of the view that the WHO has helped to accelerate the prospect of a vaccine, since only a vaccine can prevent people from getting sick. Afterall, containment strategies have only been effective in slowing down the spread of respiratory disease in many countries.
Already, about 35 companies and academic institutions are racing to create such a vaccine, at least four of which already have candidates they have been testing in animals. The first of these – produced by Boston-based biotech firm Moderna – will enter human trials imminently. But as human trials begin, even if they go well and a cure is found, experts say there are many barriers before global immunisation is feasible. This unprecedented speed is thanks in large part to early Chinese efforts to sequence the genetic material of Sars-CoV-2, the virus that causes COVID-19. China shared that sequence in early January, allowing research groups around the world to grow the live virus and study how it invades human cells and makes people sick.
And the stage where any approach is most likely to stumble is clinical or human trials, which, for some of the candidates, are about to get underway. Clinical trials, an essential precursor to regulatory approval, usually take place in three phases. The first, involving a few dozen healthy volunteers, test the vaccine for safety, monitoring for adverse effects. The second, involving several hundred people, usually in a part of the world affected by the disease, look at how effective the vaccine is, and the third does the same in several thousand people. But there’s a high level of attrition as experimental vaccines pass through these phases.
It’s for these reasons that taking a vaccine candidate to regulatory approval typically takes a decade or more, and why President Trump sowed confusion when, at a meeting at the White House on 2 March, he pressed for a vaccine to be ready by the US elections in November. In the meantime, there is another potential problem. As soon as a vaccine is approved, it’s going to be needed in vast quantities – and many of the organisations in the COVID-19 vaccine race simply don’t have the necessary production capacity. Once a COVID-19 vaccine has been approved, professionals believe a further set of challenges or barriers to immunisation will surface: politics and economics. Reason: countries will be forced to compete with one another for medicines during a pandemic. But until then, medical experts say humanity’s best hope is to contain the disease as much as possible through the washing of hands and social distancing measures.