Hydroxychloroquine: More Rigorous Trials Are Needed

The recent controversy around hydroxychloroquine (HCQ) initially involved small, uncontrolled trials that seemed to show promise followed by countries acquiring large stockpiles of HCQ and government and media spokespersons and others advocating HCQ for therapy and prophylaxis against Covid-19.  A retrospective data analysis of patients at all US Veterans Administration Hospitals did not find a lower need for mechanical ventilation among patients with SARS-CoV-2 infection undergoing HCQ treatment with or without azithromycin (Magagnoli et al., 2020). Mortality was greater in patients treated with HCQ alone.  Similarly, a retrospective multicenter cohort study of 1438 randomly sampled patients admitted with COVID-19 in metropolitan New York City did not show decreased mortality with HCQ treatment with or without azithromycin (Rosenberg et al., 2020). Data from a randomized trial of short-term (5 days) of HCQ post-Covid-19 exposure in younger individuals (median age 40 years, with no co-morbidities) did not support use for prophylaxis for symptoms of SARS-CoV-2 infection or mitigation of disease progression (Boulwareet al., 2020).

The lack of evidence of efficacy and the observed increased mortality and incidence of abnormal heart rhythms in patients have been noted as reasons for the medical and public health consensus that HCQ should not be prescribed for Covid-19.  On June 12, 2020, the FDA revoked authorization for HCQ for preventionor treatment of Covid-19 outside of clinical trials. Currently, there are 230 ongoing clinical trials with HCQ listed on ClinicalTrials.gov; 65 of which are evaluating using HCQ as prophylaxis (ClinicalTrials.gov, June 29, 2020). After a pause (in part due to two now discredited and retracted  published studies), the World Health Organization halted the HCQ arm of its Solidarity Trial comparing four treatment arms (against standard of care) for patients diagnosed with SARS-CoV-2 infection (WHO, June 17, 2020). An NIH funded trial was also halted when its data and safety monitoring board determined that HCQ, while showing no harm, was unlikely to provide additional benefit compared to placebo control for the treatment of hospitalized patients (NIH, June 20, 2020).

In spite of this growing body of evidence, proponents continue to argue that HCQ may be prophylactic, if not therapeutic. Many providers are still prescribing HCQ (now off-label) as prophylaxis and therapy for Covid-19 and HCQ is readily available online for people who wish to use it to self-medicate.

HCQ is FDA approved for suppressive treatment and treatment of acute attacks of malaria, and  for the treatment of discoid and systemic lupus erythematosus and rheumatoid arthritis. It is a drug with well-known variable effectiveness (for the FDA approved uses) and toxicity (e.g., prolongation of the QTc interval with ventricular arrhythmia). Outcomes from HCQ therapy are influenced by the patient’s hepatic cytochrome 2D6 (CYP 2D6) genetic phenotype and concurrent Rx and OTC medications. (Juurlink, 2020) . Whether HCQ is prescribed for  approved use, or is being used off-label, there is significant potential for drug–drug interaction that could lead to an adverse drug event.

Hepatic CYP2D6 is one of 60 enzymes that can metabolize drugs and xenobiotics and, in some cases, activate prodrugs to therapeutic metabolites. HCQ is one of more than 40% of all prescription Rx (and many OTC agents) that are metabolized by CYP2D6 (Horn, 2008). Importantly, HCQ is also one of many drugs that also inhibit CYP2D6 enzyme activity. Concurrent use of HCQ with other CYP2D6 inhibitors (e.g. SSRI antidepressants such as fluoxetine, antiarrhythmics such as amiodarone, or the OTC antihistamine and common “sleep” medication diphenhydramine) may result in the patient developing toxic levels of HCQ. Importantly, HCQ also is a CYP2D6 enzyme inhibitor, thus, the patient taking HCQ will have less CYP2D6 activity to metabolize other drugs that rely on the enzyme for metabolism (e.g. the beta blocker metoprolol, or the pain reliever tramadol). Some drugs that are high risk for QTc prolongation and resulting dysrhythmia are also metabolized by CYP2D6 and interact with HCQ (e.g. the antiarrhythmic amiodarone, the antipsychotic risperidone, the SSRI antidepressant fluoxetine). Finally, a patient taking a prodrug for which an active metabolite produced by CYP2D6 is the desired therapy may be subtherapeutic for that drug (e.g., clopidogrel, tramadol).

Population estimates of CYP2D6 genetic polymorphisms indicate approximately 7% of Caucasians, 5% of African Americans and 2% of Asians have CYP2D6 phenotypes that cause them to have very low CYP2D6 enzyme levels. These individuals are said to be CYP2D6 poor metabolizers (Neafsey et al., 2009). Poor metabolizers have insufficient enzyme to break down HCQ (or other drugs that rely on CYP2D6 metabolism); toxic effects may result. Phenotyping patients for CYP2D6 is not yet in common use – and was not described in any of the aforementioned HCQ studies or ongoing clinical trials.

Future results from carefully controlled clinical trials may suggest a role for HCQ for certain patients: those without increased risk of QTc prolongation; those under 65; those not taking any medications (Rx or OTC) that are metabolized by CYP2D6 or inhibit it; those who are not poor metabolizers of CYP2D6. Retrospective CYP2D6 phenotyping with stored blood samples from prior trials would provide useful information and should be conducted. As current trials are not phenotyping participants for CYP2D6, it is unlikely any of them will offer convincing support for widely prescribing HCQ either for prophylaxis or therapy of SARS-CoV-2 infection. In the haste to set up HCQ trials, failing to plan for phenotyping participant CYP2D6 and consider CYP2D6 DDIs may have led to a waste of trials – and lives.

A Simulated HCQ User Evaluated with ActualMeds

Knowing whether an individual has been prescribed HCQ in the past or is currently taking it is critical as is rapid access to all actionable medication-taking information. When an individual presents to their PCP (in person or virtually ), or to an ED, urgent care, incarceration facility or any program involved in transition in care, merely asking the patient “what medications do you take?” may not be enough to prevent an adverse drug event (ADE) or drug-drug interaction (DDI).

Consider a hypothetical case of JT, male, age 65. He is a daily runner who says he is fit with no cardiovascular risk factors or history. Five years ago, he developed paroxysmal atrial fibrillation (afib) andhis cardiologist prescribed daily amiodarone and metoprolol. (Typically, metoprolol is co-prescribed as it adds efficacy while allowing lower doses of both amiodarone and metoprolol because each inhibits the metabolism of the other.) Two weeks ago, after a virtual visit with a second provider, he was prescribed fluoxetine for depression following JT’s recent job loss. Ten days ago, JT tested positive for COVID-19. Two days ago, JT was feeling weak and got a prescription for HCQ treatment from a third provider via a virtual visit. This morning, JT feels faint and presents to the ED but has no fever, cough or other COVID-19 symptoms and his ECG is normal.

This afternoon he is transferred to a field hospital where ActualMeds is in use by pharmacists . An ECG there reveals that JT now has bradycardia (35 bpm) and a prolonged QTc interval. The pharmacist gets real-time prescribing and fill information from the ActualMeds system. The ActualMeds dashboard indicates that amiodarone and fluoxetine are both on the Beers list of medications that are potentially inappropriate for adults 65 and older due to toxicity and DDIs related to inhibition of CYP2D6 (Beers, 2019). Further, the dashboard reveals that both amiodarone, fluoxetine and HCQ prolong the QTc and inhibit the metabolism of metoprolol. Clicking on “more information” reveals that HQC can increase peak serum levels of metoprolol by as much as 65%. The pharmacist recomends that the HCQ will be discontinued, the metoprolol and fluoxetine held, and the cardiologist contacted to change the amiodarone to flecainide (not on the Beers list and now the first-line therapy for rhythm control in paroxysmal and persistent afib without structural heart disease). When interviewed, the patient revealed he was also taking OTC acetaminophen-PM (contains diphenhydramine) every night for pain relief and sleep. This was entered on the ActualMeds system and the pharmacist learns that diphenhydramine is on the Beers list and also inhibits CYP2D6 metabolism of amiodarone, metoprolol and fluoxetine! The medication reconciliation is rapidly sent to the hospital provider who uses it to  more effectively triage this patient at admission  and to integrate it with  a care plan for JT.

PJ Neafsey, PhD, Chief Scientific Officer

American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J. Am. Geriatric. Soc. 2019, Online 00:1-21,20019. DOI: 10.1111/jgs.15767 

Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. June 3, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2016638

ClinicalTrials.gov, June 5, 2020

Horn JR. Get to know an enzyme: CYP2D6. Pharmacy Times. July 1, 2008. https://www.pharmacytimes.com/publications/issue/2008/2008-07/2008-07-8624

Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. Canadian Med Assoc J 2020;April 27;192:E450-3. doi: 10.1503/cmaj.200528; early-released April 8, 2020. https://www.cmaj.ca/content/cmaj/192/17/E450.full.pdf

Magagnoli J, Narendran S, Pereira F et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. April 23, 2020. medRxiv preprint doi:https://doi.org/10.1101/2020.04.16.20065920

Manjili RH, Zarei M, Habibi M, Manijili M. COVID-19 as an Acute Inflammatory Disease. J Immunol 2020; published online 18 May; 205. doi:10.4049/jimmunol.2000413 https://www.jimmunol.org/content/jimmunol/early/2020/05/15/jimmunol.2000413.full.pdf

Neafsey P, Ginsberg G, Hattis D, et al. Genetic polymorphism in cytochrome P450 2D6 (CYP2D6): population distribution of CYP2D6 activity. J Toxicol Environ Health B Crit Rev 2009;12:334-61.

NIH Media Advisory. NIH halts clinical trial of hydroxychloroquine. National Institutes of Health. June 20, 2020. https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine

Rosenberg ES, Dufort EM, Udo T et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA.Published online May 11, 2020. doi:10.1001/jama.2020.8630

World Health Organization, 17 June, 2020 https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments