COVID-19 Global Rheumatology Alliance discourages off-label use of hydroxychloroquine

Last updated: 04-03-2020

Read original article here

COVID-19 Global Rheumatology Alliance discourages off-label use of hydroxychloroquine

An international group of more than a dozen rheumatologists have cosigned an article published in Annals of Internal Medicine discouraging the off-label use of hydroxychloroquine for COVID-19, until said use is justified by data and the drug’s supply is replenished.

“There is enough rationale to justify the continued investigation of the efficacy and safety of HCQ in hospitalized patients with COVID-19,” Alfred H.J. Kim, MD, PhD, of the Washington University School of Medicine, in St. Louis, Missouri, and colleagues wrote. “It is critical to reiterate that although viral clearance is important, clinical outcomes are much more relevant to patients. There currently are no data to recommend the use of HCQ as prophylaxis for COVID-19, although we eagerly await data from trials under way.”

“Thus, we discourage its off-label use until justified and supply is bolstered,” they added. “The HCQ shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases who depend on HCQ for their survival.”

The authors penned the editorial on behalf of the COVID-19 Global Rheumatology Alliance, a grassroots organization established on March 12 in response to the international pandemic. The group counts among its steering committee academic and community rheumatologists, as well as patient representatives, all with the mission of providing a secure, de-identified, international case reporting registry.

An international group of more than a dozen rheumatologists have cosigned an article discouraging the off-label use of hydroxychloroquine for COVID-19, until said use is justified by data and the drug’s supply is replenished.

In the editorial, the authors detailed the brief yet frantic history of how hydroxychloroquine has come to be used and studied as a potential treatment for COVID-19. The now widely circulated trial conducted by Gautret and colleagues, a small, nonrandomized study, reported a higher frequency of SARS–CoV-2 clearance from the nasopharynx after 6 days of treatment with hydroxychloroquine, plus azithromycin if necessary, compared with the untreated control group.

“Given the urgency of the situation, some limitations of this study may be acceptable, including the small sample size, use of an unvalidated surrogate end point, and lack of randomization or blinding,” Kim and colleagues wrote. “However, other methodological flaws also noted by others may affect the validity of the findings, even in the current setting, where an efficacious treatment is desperately needed.”

According to the authors of the opinion piece, the Gautret study is limited by several potentially substantial confounders, ranging from how participants in the treatment and control groups were recruited, to the fact that participants in the treatment group demonstrated a lower viral load than those in the control group, to issues with data measurement and imputation.

In addition, just 20 of the 26 patients in the treatment group were included in the final analysis despite meeting the baseline eligibility criteria, Kim and colleagues wrote. According to the study, six participants were excluded because of missing data due to early treatment cessation, sparked by either nausea, hospital discharge, ICU transfer or death. As such, participants with the “most serious and clinically relevant outcomes” were left out of the analysis, Kim and colleagues wrote.

Then, despite all of this, came President Donald Trump’s press conference. Delivered on March 19, just days after the Gautret study was published, it saw the president imply that the FDA had approved hydroxychloroquine to treat patients with COVID-19. FDA Commissioner Stephen Hahn, MD, soon after clarified that the agency must first conduct a clinical trial to determine whether the drug is safe and effective, and at what dose, for the disease.

However, that clarification would prove ineffective at tempering the public’s interest in the drug. “Despite the study's substantial limitations, a simplification and probable overinterpretation of these findings was rapidly disseminated by the lay press and amplified on social media, ultimately endorsed by many government and institutional leaders,” Kim and colleagues wrote. “Public interest in HCQ rapidly grew. The study's findings were extrapolated to include the use of HCQ to prevent COVID-19 infection or as postexposure prophylaxis, indications for which there are currently no direct supporting data.”

This, they added, has led to widespread shortages of hydroxychloroquine, negatively impacting patients with rheumatoid arthritis and lupus who rely on the drug to reduce flares and prevent organ damage.

“Hydroxychloroquine shortages could place these patients at risk for severe and even life-threatening flares; some may require hospitalization when hospitals are already at capacity,” Kim and colleagues wrote. “Until reliable evidence is generated and adequate supply chains have been put in place, rational use of HCQ in patients with COVID-19 must be emphasized, such as use in investigational studies.”

According to the authors, although severely ill patients with COVID-19 may need to be treated off-label, in lieu of large randomized trials, physicians and researchers must still champion rigorous data interpretation.

“In critical situations, large randomized controlled trials are not always feasible or ethical, and critically ill patients may need to be treated empirically during times of uncertainty,” they wrote. “However, it is our responsibility as clinicians, researchers, and patient partners to promote proper and rigorous interpretation of results, particularly in our interactions with the nonscientific community. We must consider the societal implications of published work in these unprecedented times.” – by Jason Laday

Disclosures: Kim reports personal fees from Exagen Diagnostics and GlaxoSmithKline, as well as grants from the NIH and the Rheumatology Research Foundation. Please see the published article for all other authors’ relevant financial disclosures.

An international group of more than a dozen rheumatologists have cosigned an article published in Annals of Internal Medicine discouraging the off-label use of hydroxychloroquine for COVID-19, until said use is justified by data and the drug’s supply is replenished.

“There is enough rationale to justify the continued investigation of the efficacy and safety of HCQ in hospitalized patients with COVID-19,” Alfred H.J. Kim, MD, PhD, of the Washington University School of Medicine, in St. Louis, Missouri, and colleagues wrote. “It is critical to reiterate that although viral clearance is important, clinical outcomes are much more relevant to patients. There currently are no data to recommend the use of HCQ as prophylaxis for COVID-19, although we eagerly await data from trials under way.”

“Thus, we discourage its off-label use until justified and supply is bolstered,” they added. “The HCQ shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases who depend on HCQ for their survival.”

The authors penned the editorial on behalf of the COVID-19 Global Rheumatology Alliance, a grassroots organization established on March 12 in response to the international pandemic. The group counts among its steering committee academic and community rheumatologists, as well as patient representatives, all with the mission of providing a secure, de-identified, international case reporting registry.

In the editorial, the authors detailed the brief yet frantic history of how hydroxychloroquine has come to be used and studied as a potential treatment for COVID-19. The now widely circulated trial conducted by Gautret and colleagues, a small, nonrandomized study, reported a higher frequency of SARS–CoV-2 clearance from the nasopharynx after 6 days of treatment with hydroxychloroquine, plus azithromycin if necessary, compared with the untreated control group.

“Given the urgency of the situation, some limitations of this study may be acceptable, including the small sample size, use of an unvalidated surrogate end point, and lack of randomization or blinding,” Kim and colleagues wrote. “However, other methodological flaws also noted by others may affect the validity of the findings, even in the current setting, where an efficacious treatment is desperately needed.”

According to the authors of the opinion piece, the Gautret study is limited by several potentially substantial confounders, ranging from how participants in the treatment and control groups were recruited, to the fact that participants in the treatment group demonstrated a lower viral load than those in the control group, to issues with data measurement and imputation.

In addition, just 20 of the 26 patients in the treatment group were included in the final analysis despite meeting the baseline eligibility criteria, Kim and colleagues wrote. According to the study, six participants were excluded because of missing data due to early treatment cessation, sparked by either nausea, hospital discharge, ICU transfer or death. As such, participants with the “most serious and clinically relevant outcomes” were left out of the analysis, Kim and colleagues wrote.

Then, despite all of this, came President Donald Trump’s press conference. Delivered on March 19, just days after the Gautret study was published, it saw the president imply that the FDA had approved hydroxychloroquine to treat patients with COVID-19. FDA Commissioner Stephen Hahn, MD, soon after clarified that the agency must first conduct a clinical trial to determine whether the drug is safe and effective, and at what dose, for the disease.

However, that clarification would prove ineffective at tempering the public’s interest in the drug. “Despite the study's substantial limitations, a simplification and probable overinterpretation of these findings was rapidly disseminated by the lay press and amplified on social media, ultimately endorsed by many government and institutional leaders,” Kim and colleagues wrote. “Public interest in HCQ rapidly grew. The study's findings were extrapolated to include the use of HCQ to prevent COVID-19 infection or as postexposure prophylaxis, indications for which there are currently no direct supporting data.”

This, they added, has led to widespread shortages of hydroxychloroquine, negatively impacting patients with rheumatoid arthritis and lupus who rely on the drug to reduce flares and prevent organ damage.

“Hydroxychloroquine shortages could place these patients at risk for severe and even life-threatening flares; some may require hospitalization when hospitals are already at capacity,” Kim and colleagues wrote. “Until reliable evidence is generated and adequate supply chains have been put in place, rational use of HCQ in patients with COVID-19 must be emphasized, such as use in investigational studies.”

According to the authors, although severely ill patients with COVID-19 may need to be treated off-label, in lieu of large randomized trials, physicians and researchers must still champion rigorous data interpretation.

“In critical situations, large randomized controlled trials are not always feasible or ethical, and critically ill patients may need to be treated empirically during times of uncertainty,” they wrote. “However, it is our responsibility as clinicians, researchers, and patient partners to promote proper and rigorous interpretation of results, particularly in our interactions with the nonscientific community. We must consider the societal implications of published work in these unprecedented times.” – by Jason Laday

Disclosures: Kim reports personal fees from Exagen Diagnostics and GlaxoSmithKline, as well as grants from the NIH and the Rheumatology Research Foundation. Please see the published article for all other authors’ relevant financial disclosures.


Read the rest of this article here