WHO, doctors, others split over ‘coronavirus drugs’

• ‘Patients treated with hydroxychloroquine, chloroquine may die’
• Africans are likely to react differently to drugs, experts insist
• Remdesivir, others not licensed to treat COVID-19, says NCDC

The World Health Organisation (WHO), research institutes, medical doctors and pharmacists are divided over safety concerns emanating from the use of malaria drugs, hydroxychloroquine and chloroquine that are undergoing clinical trials for COVID-19 patients.

The global health body on Monday temporarily halted the study of hydroxychloroquine as a potential COVID-19 treatment drug.

At a media briefing in Geneva, Switzerland on Monday, the Director-General, WHO, Dr. Tedros Adhanom Ghebreyesus, said that the decision was made after an observational study published on Friday in a medical journal, The Lancet described how seriously ill COVID-19 patients who were treated with hydroxychloroquine and chloroquine are more likely to die.

Ghebreyesus said that an independent executive group was reviewing the use of hydroxychloroquine in WHO’s Solidarity Trial. The executive group represents 10 of the participating countries in the trial.
“The review will consider data collected so far in the Solidarity Trial and, in particular robust randomized available data, to adequately evaluate the potential benefits and harms from this drug.

“The Executive Group has implemented a temporary pause of the hydroxychloroquine arm within the Solidarity Trial while the data is reviewed by the Data Safety Monitoring Board,” Ghebreyesus disclosed.

The trial, which involves actively recruiting patients from more than 400 hospitals in 35 countries, is a global research effort to find safe and effective therapeutics for COVID-19.

Ghebreyesus added that the other arms of the trial were continuing.

The Director-General of the Nigeria Centre for Disease Control (NCDC), Dr. Chikwe Ihekweazu, told The Guardian yesterday that chloroquine and hydroxychloroquine were not licensed to treat COVID-19 in Nigeria.

“At the moment, chloroquine, hydroxychloroquine and Remdesivir are not licensed to treat COVID-19 in Nigeria. However, ongoing research has shown promising results largely with Remdesivir.”

According to the NCDC boss, medicines have to undergo clinical trials to ensure their safety and effectiveness in the treatment of COVID-19.

“At the moment, Remdesivir has shown the most promising results in studies done. A United States government-run clinical trial showed that Remdesivir appeared to be effective in reducing recovery times for COVID-19 patients. This drug has also shown promising results in previous research for other coronaviruses such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS),” the epidemiologist said.

But, according to Ihekweazu, the same level of success had not been recorded in chloroquine studies for COVID-19.

“In fact, they have shown an opposite effect–an increase in harmful outcomes. Before any of these drugs can be licensed for use in the management of COVID-19 cases, we need confirmation of their safety and effectiveness through randomised clinical trials.

“WHO is leading a large clinical trial called the Solidarity Trial, where further evidence on the safety and effectiveness of these drugs will be generated.”

Ihekweazu said the NCDC was working very closely with its sister agencies, National Agency for Food and Drug Administration and Control (NAFDAC), Nigerian Institute for Medical Research (NIMR) and Nigerian Institute for Pharmaceutical Research and Development (NIPRD) to ensure that Nigeria was part of ongoing research, including the WHO-led Solidarity Trial, to be able to access treatments for COVID-19 when available.

But the Director-General of the Nigerian Institute for Medical Research (NIMR) Yaba, Lagos, Prof. Babatunde Salako, in an interview with The Guardian, said the drugs might be beneficial to Africans with the virus because they might behave differently when treated with them.

According to Salako, the WHO has not banned the use of hydroxychloroquine and chloroquine but has temporarily suspended clinical trials of the drugs while assessing safety issues.

He said: “There is a large study published recently in Lancet which showed that both drugs have safety issues suggesting that more casualties happened in the trial arm of both drugs. To that extent, one will need to be cautious with the use of both drugs. However, Africans have used chloroquine for many years without much ado, although not for COVID-19. Our response to the infection is so different that using chloroquine to treat COVID-19 among Africans may also behave differently. We, therefore, need to investigate further how Africans will respond. What the WHO did was temporary suspension while assessing the safety issue. It is possible that they may still use it in their trial.”

To a consultant public health physician and leader of a team of medical experts managing some COVID-19 isolation centres in Lagos, Prof. Akin Osibogun, only a randomised clinical trial can settle the debate on the safety and effectiveness of the drugs in treating COVID-19 patients.

He told The Guardian that most of the studies reported so far on hydroxychloroquine and chloroquine use in COVID-19 had been largely observational.

Osibogun, who is the immediate past Chief Medical Director (CMD) of Lagos University Teaching Hospital (LUTH), Idi-Araba, said: “To really answer the question as to whether these drugs make a difference to treatment outcomes, you need randomised clinical trials.”

“The WHO is conducting a multi-country clinical trial on the two drugs and Nigeria would join. This is the WHO Solidarity Trial. In addition to participating in the WHO Trial, a trial with an additional arm is also being planned in Lagos. Clinical Trials can answer questions like effect on length of hospitalization, need for assisted respiration and outcome such as mortality. Are outcomes of interest better in one treatment group over another treatment group?

“Randomised clinical trial is best suited to answer that question. It is after such studies that health authorities, including the WHO, can speak authoritatively either way,” Osibogun said.

The President, Nigerian Association of Resident Doctors (NARD), Dr. Aliyu Sokombo, said: “I think the controversy exists because the drug has not undergone the various stages of preclinical and clinical trials to ascertain the efficacy and safety as a drug of choice in treating COVID-19 perhaps because of the desperation to have a drug for the disease.

“Let’s all wait and allow the drug to go through the complete clinical trial and get certified as efficacious by the relevant authorities before jumping at it.”

The President of the Pharmaceutical Society of Nigeria (PSN), Mazi Sam Ohuabunwa, disagrees with Ihekweazu. The pharmacist said: “Hydroxychloroquine/ Chloroquine has shown some usefulness in managing this illness. Anecdotal and published reports from Nigeria and elsewhere suggest its usefulness, though some reports seem to suggest otherwise.

“Having said that, my firm recommendation is that no one should take the product without the recommendation of his healthcare provider. It is the responsibility of the healthcare provider to determine the risk-benefit ratio, before deciding whether to place him on the product or not. It should not be used without being recommended or usage being monitored through pharmacovigilance.”

A virologist/vaccinologist and Chief Executive Officer (CEO) of Innovative Biotech Limited, Keffi, Dr. Simon Agwale, said: “Let science-speak. There is an ongoing WHO-led multi-country clinical trial. Lagos State has also started its own clinical trials. So let the science speak. The new studies tested hydroxylchloroquine and chloroquine on very sick patients with COVID-19. The WHO-led clinical trials are going to use different parameters. Medical experts are divided. The situation has been politicized. So let us wait and allow science to provide the verdict.”

Indeed, the Lagos State government and the NAFDAC are conducting independent clinical trials on the use of hydroxychloroquine and chloroquine in the treatment of coronavirus patients. The results of the trials were not out as at press time.

Meanwhile, US and French authorities have authorised the use of chloroquine and hydroxychloroquine, but the European Union (EU) regulator and WHO say science does not support the decision.

According to reports, with no “adequate, approved and available” alternative, the US Food and Drug Administration (FDA) is allowing the use of the antimalarial drugs hydroxychloroquine and chloroquine to treat COVID-19.

The FDA’s emergency use authorisation (EUA) issued last week gives physicians the option to prescribe the drugs, which President Donald Trump has recommended. The decision bypassed the usual drug approval process, including double-blind and placebo-controlled clinical trials, stoking a worldwide debate about whether the drugs are appropriate for treating the disease.

Under the EUA, hydroxychloroquine and chloroquine can be used only in a hospital setting to treat COVID-19 in adults and adolescents who weigh at least 50 kg and are not able to participate in a clinical trial. The drugs must also be obtained from the national stockpile to protect the supply for other patients who have relied on them for years to control autoimmune diseases, including lupus and rheumatoid arthritis. But three days after the EUA, a surge in demand forced the agency to declare a shortage of both drugs.

So far, France is one of a few countries that also permit the drugs to be used for patients with COVID-19. Opposition has come from the European Medicines Agency, the EU’s pharmaceutical regulator, which reiterated earlier this week that studies had not yet documented that the drugs could effectively treat COVID-19.

Meanwhile, a large observational study, published last Friday in the journal The Lancet, suggests that treatment with the antimalarial drug chloroquine or its analogue hydroxychloroquine (taken with or without the antibiotics azithromycin or clarithromycin) offers no benefit for patients with COVID-19. The study analysed data from nearly 15,000 patients with COVID-19 receiving a combination of any of the four-drug regimens and 81,000 controls.

Treatment with these medications among patients with COVID-19, either alone or in combination with macrolide antibiotics, was linked to an increased risk of serious heart rhythm complications in these patients.

Researchers suggest these treatment regimens should not be used to treat COVID-19 outside of clinical trials until results from randomised clinical trials are available to confirm the safety and efficacy of these medications for COVID-19 patients.

Chloroquine is an antimalarial drug and its analogue, hydroxychloroquine, is used to treat autoimmune diseases including lupus and arthritis. Both drugs have a good safety profile, as treatments for those specific conditions, and the findings do not imply patients should stop taking these drugs if they are prescribed for approved conditions. They have also been shown to have antiviral effects in laboratory tests and are therefore of interest as potential treatments for COVID-19.

Lead author of the study and Executive Director of the Brigham and Women’s Hospital Center for Advanced Heart Disease in Boston, USA, Prof. Mandeep R. Mehra, said: “This is the first large scale study to find statistically robust evidence that treatment with chloroquine or hydroxychloroquine does not benefit patients with COVID-19. Instead, our findings suggest it may be associated with an increased risk of serious heart problems and increased risk of death. Randomised clinical trials are essential to confirm any harms or benefits associated with these agents. In the meantime, we suggest these drugs should not be used as treatments for COVID-19 outside of clinical trials.”