key: cord-0928511-w3a4ogc2
authors: Charles, Awortwe; Ingolf, Cascorbi
title: Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions
date: 2020-10-13
journal: Pharmacol Res
DOI: 10.1016/j.phrs.2020.105250
sha: 8ffe62ab98c42bbac4f277a9ee6ff4332a81b852
doc_id: 928511
cord_uid: w3a4ogc2

Drug-drug interactions (DDI) potentially occurring between medications used in the course of COVID-19 infection and medications prescribed for the management of underlying comorbidities may cause adverse drug reactions (ADRs) contributing to worsening of the clinical outcome in affected patients. First, we conducted a meta-analysis to determine comorbidities observed in the course of COVID-19 disease associated with an increased risk of worsened clinical outcome from 24 published studies. In addition, the potential risk of DDI between medications used in the course of COVID-19 treatment in these studies and those for the management of observed comorbidities was evaluated for possible worsening of the clinical outcome. Our meta-analysis revealed an implication cardiometabolic syndrome (e.g. cardiovascular disease, cerebrovascular disease, hypertension, and diabetes), chronic kidney disease and chronic obstructive pulmonary disease as main co-morbidities associated with worsen the clinical outcomes including mortality (risk difference RD 0.12, 95%-CI 0.05-0.19, p = 0.001), admission to ICU (RD 0.10, 95%-CI 0.04-0.16, p = 0.001) and severe infection (RD 0.05, 95%-CI 0.01-0.09, p = 0.01) in COVID-19 patients. Potential DDI on pharmacokinetic level were identified between the antiviral agents atazanavir and lopinavir/ritonavir and some drugs, used in the treatment of cardiovascular diseases such as antiarrhythmics and anti-coagulants possibly affecting the clinical outcome including cardiac injury or arrest because of QTc-time prolongation or bleeding. Concluding, DDI occurring in the course of anti-Covid-19 treatment and co-morbidities could lead to ADRs, increasing the risk of hospitalization, prolonged time to recovery or death on extreme cases. COVID-19 patients with cardiometabolic diseases, chronic kidney disease and chronic obstructive pulmonary disease should be subjected to particular carefully clinical monitoring of adverse events with a possibility of dose adjustment when necessary.

Other clinical complications such as acute kidney and cardiac injuries were considered. We excluded studies conducted in children, pre-clinical models, case reports, letters, editorial commentaries, reviews, and meta-analysis.

The risk difference method was used to estimate weights of individual study outcome using the Mantel-Haenszel method with random-effect model in the R statistical software (version 3.4.2). The statistical heterogeneity between study outcomes were visualized using the forest plot and the inter-study heterogeneity estimated by calculating the Ԏ 2 , I 2 and H 2 statistics, and by computing Cochran's Q test statistics [18, 19] . An I 2 values lower J o u r n a l P r e -p r o o f than 25% was considered as low heterogeneity, values of 26-50% indicated moderate heterogeneity and values greater than 50% to indicate a high heterogeneity. A Cochran's Q test statistics with p-value of < 0.05 was an indication of statistical significance heterogeneity. The trim and fill method was used to determine hypothetical missing studies as evidence of publication bias when necessary (Supplementary figure1).

The data on drugs used in the course of COVID-19 and the primary indication were collected from www.ashp.org/COVID-19 as well as metabolizing enzymes involved in their biotransformation from www.drugbank.ca. The potential of drugs used in the course of COVID-19 infection reported in the included studies to interact with other drugs used for the management of comorbidities which could precipitate ADRs likely to further worsen clinical outcome of COVID-19 based on our meta-analysis was assessed using the www.covid19-druginteractions.org database. Here, potential DDIs are classified into four groups: (i) no clinically significant interaction expected; (ii) potential interaction likely to be of weak intensity with monitoring or dosage adjustment unlikely to be required; (iii) potential clinically significant interaction that may require close monitoring, alteration of drug dosage or timing of administration; and (iv) drugs should not be co-administered.

We subsequently focused our analysis only on the latter. The clinical relevance of such DDI were risk ranked into five categories based on the quality of evidence as: (0) unlikely -no evidence of preclinical or clinically significant interaction, (1) very low -in vitro or animal studies, single case reports, parallel or crossover single dose pharmacokinetic (PK) study without area under plasma concentrations (AUCs), PK study in infected or healthy subjects, (2) low -multiple case reports, crossover or parallel steady state PK J o u r n a l P r e -p r o o f 8 without AUCs, parallel or crossover single dose PK study with AUCs, metabolism study with probe substrates, observational PK in infected patients, (3) moderate -cross-over, parallel steady state PK study with AUCs and (4) high -data based on randomized, controlled interaction trial with clinical or validated surrogate endpoints.

The grading on quality of evidence of DDI was conducted for each medication prescribed for the treatment or management of comorbidities against individual COVID-19 therapies.

Subsequently, the z-score was calculated and used to construct heatmaps in www.

software.broadinstitute.org/morpheus.

A literature search was conducted to extract eligible studies for the meta-analysis. Of 467 records screened for eligibility, 24 prospective and retrospective case studies with a total of 5,586 COVID-19 affected patients were included in the meta-analysis (Figure 1 ). Data on the underlying comorbidities was drawn from the reported clinical characterization of the affected patients. Comorbidities reported include cardiovascular diseases, cerebrovascular disease, chronic kidney disease, chronic liver disease, chronic obstructive pulmonary disease (COPD), hypertension, diabetes, malignancy, human immunodeficiency virus (HIV) and others. The mean age of the affected patients ranged from 41 years to 63 years (Table 1) .

Based on the 24 identified eligible studies, a meta-analysis was conducted to determine comorbidities which may be associated with an increased risk of clinical outcome in Table 2 . Table 3 . The use of hydroxychloroquine and lopinavir/ritonavir in COVID-19 was suspended or stopped in the WHO SOLIDARITY trial. According to the International Steering Committee interim trial report, hydroxychloroquine and lopinavir/ritonavir produced little or no decline in the mortality of hospitalized COVID-19 patients when compared to standard of care (www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-andlopinavir-ritonavir-treatment-arms-for-covid-19). However, these drugs are still used for the COVID-19 infection at some hospitals in other countries. Hence, both drugs were included in our DDI analysis.

According to the analysis, co-administration of some drugs used for the treatment or management of comorbidities together with atazanavir and lopinavir/ritonavir (used as therapies for COVID-19) could increase the risk of adverse outcome of COVID-19 patients by evidence of potential pharmacokinetic interactions. E.g. an increase in plasma exposure of antiarrhythmics (e.g. amiodarone, bepridil, disopyramide, dofetilide, flecainide and quinidine), drugs prescribed for pulmonary hypertension (e.g. bosentan and sildenafil), angina pectoris (e.g. ranolazine), heart failure (e.g. eplerenone, ivabradine), erectile dysfunction (e.g. sildenafil), few anti-hypertensives (e.g. aliskiren and lercanidipine), antithrombotics and anticoagulants (e.g. ticagrelor and rivaroxaban), and statins (e.g. lovastatin and simvastatin) was detected due to a potential inhibition mainly of CYP3A4 by atazanavir or lopinavir/ritonavir ( Table 4 .

We further estimated the potential interaction of combination therapies (e.g. azithromycin/nitazoxanide, hydroxychloroquine/azithromycin, and INF-β-1a/lopinavirritonavir/ribavirin) for COVID-19 because some of the included studies reported coadministration of these medications. In general, lack of evidence of clinically significant DDI was found. Potential interaction between other COVID-19 drugs (e.g. remdesvir, darunavir/cobistat, favipiravir, nitazoxanide, ribavirin, tocilizumab, sarilumab, IFN-β-1a, oseltamivir and anakinra) and co-medications prescribed for the treatment of existing comorbidities identified based on the meta-analysis were found to be of a low certainty.

Comorbidities associated with poor clinical outcome of COVID-19 in affected patients are widely reported in other studies [20] [21] [22] . The results of our meta-analysis confirmed hypertension, cardiovascular disease, and diabetes being strongly associated with increased mortality and severe courses of COVID-19. Patients with cerebrovascular disease were more likely to be admitted to ICU or even die. Interestingly, in the set of studies included into the meta-analysis, chronic kidney disease and malignancies were associated with increasing the risk of mortality whilst COPD increases the severity of COVID-19 in affected patients. In general, patients with these underlying comorbidities have greater risk of upper respiratory tract infections and pneumonia because of dysfunctional innate and adaptive immune system [20, 22] . reported in studies included in the meta-analysis. Based on our findings, of a greater safety concern was prolonged cardiac repolarization and QT interval by pharmacokinetic interaction of atazanavir and lopinavir/ritonavir with some drugs, used in the treatment of cardiovascular diseases such as ivabradine in heart failure, ranolazine in symptomatic treatment of angina pectoris, the antiarrhythmics amiodarone disopyramide and quinidine or the formerly used calcium channel blocker bepridil (a drug with putative anti-viral properties) via inhibition of CYP3A4 which may further increase the risk of torsade de pointes (TdP) [23] [24] [25] . Consequences of such interaction may increase risk of hospitalization, prolonged time to recovery and finally sudden cardiac death in extreme cases. Other risk factors of QTc-time prolongation and TdP include hypokalemia and chronic heart failure. Furthermore, atazanavir and lopinavir/ritonavir could interact with antithrombotics and anticoagulants (e.g. ticagrelor, dabigatran and rivaroxaban) through CYP3A4 and P-glycoprotein to induce bleeding complication [10] . Interestingly, a recent retrospective study found the use of statins in hospitalized COVID-19 patients to be associated with a lower risk of all-cause mortality and a favorable recovery profile compared to the non-statin group [26] . However, with regards to DDI, statins (e.g. [27] [28] [29] . Hence, the use of less DDI-proned statins should be preferred. In Asthma, plasma concentration of salmeterol could increase due to inhibition of CYP3A4 by lopinavir/ritonavir. Such combination may result in salmeterol related side-effects including QTc-time prolongation, palpitations, and tachycardia [28, 30] .

Adverse events detected in these patients while co-treatment with drugs used in the course of COVID-19 e.g. azithromycin, chloroquine, and hydroxychloroquine and antihypertensives are not based on pharmacokinetic interactions but on known risks of TdP by prolonged cardiac polarization and QT interval of such combinations [31] [32] [33] .

Nonetheless, hydroxychloroquine and chloroquine are also known to be inhibitors of cytochrome P450 2D6 (CYP2D6) hence contributing to an increased risk of TdP of the older antiarrhythmics flecainide and mexiletine [32] [33] [34] [35] . Here, adjusting the recommended dose of hydroxychloroquine from 800 mg on day 1, followed by 400 mg daily for 4 -7 days to a lower dose may be necessary to avoid potential adverse events (https://www.fda.gov/media /13653 7/download).

We additionally considered the potential interaction of combination therapies for COVID-19 azithromycin/nitazoxanide, hydroxychloroquine/azithromycin, tocilizumab/remdesivir, and triple combination (IFN-β-1a, lopinavir/ritonavir and ribavirin) used to tackle the pandemic. Studies have shown synergistic effects of these combinations therapies on inhibition of SARS-CoV-2 replication [36] [37] [38] [39] . Generally, DDI of such combinations are J o u r n a l P r e -p r o o f uncertain due to lack of evidence. The azithromycin/hydroxychloroquine combination related TdP may occur as side effect of single or both drugs [31] [32] [33] 37] . The antimalaria agent hydroxychloroquine is an inhibitor of P-glycoprotein [40] . However, pharmacokinetic interaction of azithromycin with hydroxychloroquine is unexpected because the former is not a sensitive substrate of P-glycoprotein [40, 41] . Besides, hydroxychloroquine has long terminal elimination half-life (40-60 days) which may cause the risk of cardiac polarization and QT prolongation to persist even after discontinuation [34, 42] .

Prediction of DDI however could be hampered, since COVID-19 patients may experience phenoconversion whereby some genotypic extensive metabolizers transiently exhibit a decline in drug metabolizing enzyme activities comparable to that of poor metabolizers because of cytokine storm [43, 44] . The problem of phenoconversion due to hyperactive immune system may increase the cardiac related side effects of drugs used in the course of COVID-19 (e.g. hydroxychloroquine) as consequence of prolonged plasma exposure [31, 33, 42] . Additionally, genetic polymorphism in drug metabolizing enzymes and transporters might worsen the side effects of drugs used for COVID-19 or in combination with other medications in individuals with defective genes.

On the other side, drugs used in the main regimens of hypertension, heart failure or diabetes did not show evidence of DDIs. In particular inhibitors of the renin angiotensin aldosterone system (RAAS) seem to be safe and concerns that the treatment with ACEinhibitors could increase the risk of SARS-CoV-2 infections through elevation of the ACE-2 expression were not confirmed so far [45, 46] .

In conclusion, comorbidities including cardio-cerebrovascular diseases, hypertension, diabetes, and chronic kidney disease were associated with increased severity and mortality of COVID-19 in affected patients. DDI may be evident in these patients due to the use of polypharmacy as found in studies included in this meta-analysis. We have shown potential DDI particularly between antiretroviral drugs (atazanavir and lopinavir/ritonavir), and other drugs for treating comorbidity leading to TdP which might contribute to poorer clinical outcome (e.g. increased risk of hospitalization, prolonged time to recovery and death on extreme cases) in COVID-19 patients. This study cannot confirm whether the consequences of the DDI described change the expected course of COVID-

The authors declare no competing interests for this work.

Concerning our manuscript "Potential interactions between medications used in the course of COVID-19 and drugs related to outcome-worsening comorbidities" by C. Awortwe and I. Cascorbi, I declare on behalf of all authors no conflict of interest.

World Health Organisation, Coronavirus disease (COVID-19) situation reports.

www.who.int/emergencies/ diseases/novel-coronavirus-2019/situation-reports/ Date last accessed: 6 September 2020, (2020).

[2] C. Huang Low certainty High certainty

Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics

QT interval prolongation under hydroxychloroquine/ azithromycin association for inpatients with SARS-CoV-2 lower respiratory tract infection

Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: The Cremona experience

Pharmacologic treatment of transplant recipients infected with SARS-CoV-2

Threatening drug-drug interaction in a kidney transplant patient with Coronavirus Disease

COVID-19 treatment in patients with comorbidities: Awareness of drug-drug interactions

<scp>COVID-SAFER</scp> : Deprescribing guidance for hydroxychloroquine drug interactions in older adults

A new drug-drug interaction between hydroxychloroquine and metformin? A signal detection study

Off-label therapies for COVID-19-Are we all in this together?

Hydroxychloroquine for COVID-19? Self-medicating with malaria drugs could be lethal

Quantifying heterogeneity in a meta-analysis

Interaction of herbal products with prescribed medications: A systematic review and meta-analysis

Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis

Hypertension and COVID-19

COVID-19 and diabetes

Drugs that cause torsades de pointes and increase the risk of sudden cardiac death

Bee) Peeraphatdit, Cardiac safety of off-label COVID-19 drug therapy: a review and proposed monitoring protocol

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19

Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047

HIV protease inhibitors, saquinavir, indinavir and ritonavir: inhibition of CYP3A4-mediated metabolism of testosterone and benzoxazinorifamycin, KRM-1648, in human liver microsomes

Avoiding statin myopathy: understanding key drug interactions

Adverse Effects of β-Agonists

QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review

COVID-19 and (hydroxy)chloroquine-azithromycin combination: Should we take the risk for our patients?

QTc evaluation in COVID-19 patients treated with chloroquine/hydroxychloroquine

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Influence of hydroxychloroquine on the bioavailability of oral metoprolol

In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Intracellular ABCB1 as a possible mechanism to explain the synergistic effect of hydroxychloroquine-azithromycin combination in COVID-19 therapy

Attenuation of intestinal absorption by major efflux transporters: quantitative tools and strategies using a Caco-2 model

Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics

SARS-CoV-2: a storm is raging

Factors involved in phenoconversion of CYP3A using 4β-hydroxycholesterol in stable kidney transplant recipients

Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19

Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality

Clinical features and shortterm outcomes of 102 patients with corona virus disease 2019 in Wuhan , China 1 . Department of Cardiology , Zhongnan Hospital

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study

Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study

COVID-19 with Different Severities: A Multicenter study of clinical features

Clinical characteristics of coronavirus disease 2019 in China

Clinical findings of patients with coronavirus disease 2019 in Jiangsu province, China: A retrospective, multi-center study

Clinical characterization of 162 COVID-19 patients in Israel: Preliminary Report from a Large Tertiary Center

Clinical and laboratory findings from patients with COVID-19 pneumonia in Babol North of Iran: a retrospective cohort study

Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease

Clinical Features of Patients with Coronavirus Disease 2019 (COVID-19) from a Designated Hospital in Beijing

Clinical features and treatment of COVID-19 patients in northeast Chongqing

Clinical course and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2

Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID-19)

Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: A retrospective study

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: Retrospective case series

Risk factors for adverse clinical outcomes with COVID-19 in China: a multicenter, retrospective, observational study

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China, Allergy Eur

Clinical characteristics of 161 cases of corona virus disease 2019 (COVID-19) in Changsha

Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: A retrospective study

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Origin Design Age (years)