Recommendations for the Outpatient Drug Treatment of Patients With COVID-19

The 22^nd version of the S2e guideline for family physicians of the German College of General Practitioners and Family Physicians (DEGAM) (1) and the updated S3 guideline on inpatient treatment (2) were published on COVID-19 in February 2022 under the auspices of

• the German Society for Medical Intensive Care and Emergency Medicine (DGIIN)
• the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI)
• the German Society for Pneumology and Respiratory Medicine (DGP) and
• the German Society for Infectious Diseases (DGI).

The aim was to formulate recommendations for the outpatient drug treatment of patients with COVID-19 based on available scientific evidence, which should be applied for unselected primary care patients as well as in specialized outpatient care facilities. The most important recommendations for outpatient drug treatment are presented and briefly explained below. The long versions of both guidelines, including the evidence reports, are published on the homepage of the Association of the Scientific Medical Societies in Germany (AWMF) (3).

Methods

The evidence analysis was based on preliminary work of the COVID-19 Evidence Ecosystem (CEOsys) project, funded by the German Federal Ministry of Education and Research until the end of 2021, and was updated in January 2022 by subgroups of the CEOsys team with regard to fluvoxamine, corticosteroids, nirmatrelvir/ritonavir, molnupiravir, remdesivir, and sotrovimab. A literature search was conducted using the Cochrane COVID-19 Study Register which includes MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), Web of Science, medRxiv, and Research Square. Only final published randomized controlled trials (RCT) were included, i.e., no preprints (except those in medRxiv) or press releases. Trial assessment was endpoint-based using the GRADE methodology (“Grading of Recommendations Assessment, Development and Evaluation” [4]) and applying the digital guideline tool MAGICapp (5).

Conflict of interest was assessed using AWMF rules and regulations (6). Recommendations were developed during structured consensus conferences after applying the GRADE Evidence to Decision Framework (7).

The recommendations were made on three levels according to AWMF regulations:

• strong recommendation = should / should not (recommendation grade A)
• recommendation = ought to / ought not to (recommendation grade B)
• recommendation open = may (be considered) /  may (be disregarded) (recommendation grade 0)

Results

The recommendations for outpatient drug treatment are summarized in the Box and in Table 1, and data on the use of sotrovimab, remdesivir, nirmatrelvir/ritonavir, molnupiravir and budesonide inhalation are shown in Table 2. Additional explanations are summarized in the text.

Box

Drug treatment options for the out-patient treatment of patients with COVID-19

Table 1

Drugs not recommended for outpatient treatment of COVID-19

Table 2

Benefit of drug treatment options in COVID-19 outpatients as demonstrated in randomized controlled trials (RCT)

Fluvoxamine, colchicine, acetylsalicylic acid, azithromycin, ivermectin, systemic steroids and vitamin D3

These substances are not recommended for the treatment of outpatients with COVID-19. Brief justifications may be found in Table 1.

SARS-CoV-2 neutralizing monoclonal antibodies/ sotrovimab

Of all the monoclonal antibodies currently available in Germany and approved for COVID-19 treatment, only sotrovimab demonstrates efficacy against the Omicron BA.1 and BA1.1 variants in in vitro neutralization activity studies (26). However, recent studies on the Omicron subvariant BA.2, which is now dominant in many regions, indicate significantly reduced in vitro activity of sotrovimab, with up to 35-fold increased effective inhibitory concentrations as compared with the wild type (27). It is difficult to assess the implications of this loss of activity in clinical efficacy. From a pharmacokinetic perspective, it seems unlikely that the currently recommended intravenous dose of 500 mg will have sufficient therapeutic efficacy in BA.2 subvariant infections. Based on this, the U.S. Food and Drug Administration (FDA) has withdrawn emergency approval for sotrovimab for areas where BA.2 is responsible for more than 50% of SARS-CoV-2 infections (28). The BA.2 subline variant already accounted for approximately 95% of infections in Germany in calendar week 14/2022 (29).

Benefit

See Table 2 for the benefit of treatment with sotrovimab.

Adverse reactions

There was no increased incidence of side effects in comparison with placebo during the 24-week observation period.

Applicability of the study results

The results of the clinical study on sotrovimab are applicable to the current situation to only a limited degree, since at the time the study was conducted there was a dominance of virus variants that are no longer prevalent today and that were associated at the time with a comparatively high level of pathogenicity. Twenty-two percent of the study participants were ≥65 years of age and had the following pre-existing conditions: body mass index >30 in 63%; drug-controlled diabetes in 23%; moderate to severe asthma in 16%, and chronic obstructive lung disease (COLD) in 4%; immunosuppressed patients were not included in the study. Unvaccinated patients, pregnant and breastfeeding women were also excluded; women had to use reliable contraception until 24 weeks after therapy. Sotrovimab is approved for children aged 12 years and older and weighing 40 kg and more—but only adults were included in the study.

Treatment feasibility

See below under remdesivir, as there are similar points to consider here.

Remdesivir (in the out-patient care setting)

Benefit

See Table 2 for the benefits of remdesivir.

Adverse reactions

There was no difference with respect to acute adverse reactions in comparison with placebo. Laboratory result changes were probably slightly more frequent under remdesivir. Serious adverse events (SAE) were less frequent in the remdesivir group than in the placebo group (49 fewer patients/1000; 95% confidence interval: [20; 60]). This result is due to the fact that respiratory and COVID-19 events were predominantly counted as SAE and were more frequent in the placebo group. There were too few events to make any statement about SAE that were not COVID-19-related. Patients must be monitored during the 30- to 120-minute infusions and afterward because of potential hypersensitivity reactions.

Applicability of the study results

Study participants presented with risk factors for severe COVID-19 slightly more often than in the sotrovimab and molnupiravir studies. For instance, 30% of study participants were ≥60 years of age, 62% had diabetes mellitus, 55% were overweight (BMI ≥30), 48% had hypertension, 24% had chronic lung disease, 8% had cardio- or cerebrovascular disease, 5% had cancer, 4% were immunosuppressed, and 3% had mild to moderate renal impairment. All participants were unvaccinated. The recruitment period was prior to the period of Omicron predominance. Three children and adolescents below 18 years of age were in the remdesivir group, nevertheless remdesivir is approved for over 12-year-olds.

Treatment feasibility with sotrovimab and remdesivir

The amount of time and effort involved for patients and those treating them is high. Sotrovimab requires a single infusion lasting at least 30 minutes followed by one hour monitoring. Remdesivir is administered on three consecutive days, in each case with a minimum half-hour infusion and a one-hour observation period. For this reason, treatment is logistically difficult to provide in primary care practices. It is most likely possible in hospital outpatient clinics, practices specializing in treating corona when appropriate, or during short-term hospital admissions (30). Both drugs are available only through special pharmacies (31). The inclusion criteria for the sotrovimab and remdesivir trials are so broad that they would overwhelm limited capacity if administered in the same way in usual care settings.

Nirmatrelvir/Ritonavir

The study leading to approval had not yet been published at the time of the consensus conference of both guideline groups. The recommendation is therefore derived from the S3 guideline on inpatient therapy, which was published a while later and so was able to incorporate this study.

Benefit

See Table 2 for the benefits of nirmatrelvir/ritonavir.

Adverse reactions

There was no difference with respect to acute adverse events (AE) in comparison with placebo. With regard to SAE, an effect in favor of nirmatrelvir/ritonavir was suggested by the lower rate of COVID-19-related hospitalizations. Drug-specific side effects reflected a disadvantage of nirmatrelvir/ritonavir, mainly due to disorders of taste and diarrhea. Long-term side effects have not (yet) been evaluated.

Applicability of the study results

Applicability to the current pandemic situation is limited because, for example, study participants had to be unvaccinated and had to have had no prior SARS-CoV-2 infection. Participants were not allowed to receive co-medications that are predominantly metabolized by CYP3A4. The recruitment period was prior to the Omicron wave. Overweight was present in 81% of the study population, 61% had at least two risk factors for severe disease, and seronegativity was present in only 52% (despite inclusion criteria to the contrary).

Treatment feasibility

It may be assumed that physicians and patients prefer an oral therapy option. However, nirmatrelvir/ritonavir would not be a suitable treatment option for many patients due to interactions with existing long-term medications. A recently published paper on interaction management (32) and an interaction check app from Liverpool (33) may be helpful for assessing what, if any, action is needed when using nirmatrelvir/ritonavir. Procurement of the drug is well regulated (34).

Molnupiravir

Benefit

See Table 2 for the benefits of molnupiravir.

Adverse reactions

There was no difference with respect to AE and SAE in comparison with placebo. The studies have not (yet) evaluated long-term side effects. Molnupiravir is potentially mutagenic. Its use in pregnant women is not allowed due to its teratogenic potential as demonstrated in animal studies. Effective contraception (in the case of hormonal contraception, an additional barrier method, for example, condom) is necessary for women of childbearing age for the five-day therapy and an additional four days if sexual abstinence is not maintained. Treated men must not father children for at least three months after the last dose. The effect of molnupiravir on male germ cells beyond three months is uncertain. In animal studies, molnupiravir was shown to interfere with the conversion of cartilage into bone; it must therefore not be used in children and adolescents. The mode of action of molnupiravir is based on its induction of mutations in the viral genome. It is unknown whether this may promote the development of new SARS-CoV-2 variants. Combination therapies with other antiviral agents and with monoclonal antibodies have not been studied.

Applicability of the study results

The applicability of the phase 3 trial data to the treatment-naive population is limited. Recruitment was prior to the Omicron wave. The study population was as follows: age above 60 years in 17%, obesity in 74%, diabetes in 16%, severe heart disease 12%, renal impairment 6%, COPD 4%, active cancer 2%. All participants were unvaccinated; a previous infection was probable in 20% due to the presence of positive nucleocapsid antibodies.

Treatment feasibility

Patient reluctance is expected due to teratogenicity and potential mutagenicity. One advantage of this substance is its oral mode of administration. Pharmacies can order molnupiravir from wholesalers using a doctor’s prescription and have the drug delivered to patients. This could theoretically lead to delays in starting therapy (however, according to individual reports, treatment implementation appears to be going well).

Budesonide inhalation as a form of therapy

Benefit

See Table 2 for the benefits of budesonide inhalation.

Adverse reactions

AE and SAE showed no difference between the treatment groups and placebo. Known side effects of inhaled steroids include hoarseness, dysphonia, and oropharyngeal candidiasis.

DEGAM and the other professional societies have weighted these study results in different ways in terms of their importance, which has led to somewhat varying recommendations (Box).

Applicability of the study results

Applicability has been established through previous experience with normal care of bronchial asthma and chronic obstructive pulmonary disease.

Thromboembolism prophylaxis (prophylactic dose)

Benefit

Two RCT involving COVID-19 patients with mild disease status are available (35, 36). Standard thromboembolic prophylaxis showed no advantages as compared with placebo treatment in terms of mortality, hospitalization rate plus death, hospitalization rate due to cardio-pulmonary events plus death, or occurrence of any thrombotic events. Standard thromboembolic prophylaxis did not result in a statistically significant improvement in clinical status at 28 days.

Adverse reactions

Standard thromboembolic prophylaxis resulted in few to no adverse events (any AE) as compared with placebo. There was also no difference in terms of SAE and major bleeding.

Expert consensus

An expert consensus was formulated because critically ill patients, some of whom are immobile, are also cared for in an outpatient setting and are comparable with inpatients receiving thromboembolism prophylaxis as part of standard care. The GTH (German Society for Thrombosis and Haemostasis Research) also recommends that the indication for drug-based thromboembolism prophylaxis with a low-molecular-weight heparin should be continuously assessed and “generously” applied, regardless of the need for hospitalization (37).

Discussion

Strength of the recommendations

The trials for the 13 drug treatment options were conducted before the predominance of the Omicron variants; therefore, applicability to the current situation is uncertain. In vitro studies of monoclonal antibodies show varying efficacies for the viral variants. There is no evidence that the other medications are not effective against Omicron. In principle, current data on efficacy against the locally dominant variant must be taken into account prior to therapy with monoclonal antibodies. The COVRIIN expert group at the Robert Koch Institute can provide assistance in this respect (27). Sequencing at an individual patient level and therapy decisions based on this are impossible to achieve due to time. It is likely that drug efficacy is overestimated due to the lower pathogenicity of the Omicron variant.

Applicability of the study results to the actual population of patients for whom drug therapy is being considered is also made more difficult because the study participants tended to be healthier, for example, with the majority under 60 years of age and with obesity as the most common risk factor. The broad study inclusion criteria would lead to an overload of therapy resources if implemented without due consideration. The listing of groups at risk for severe disease (38) as well as the listing of treatments and diseases that are associated with a relevant limitation of the vaccination response (39) can help in making a differentiated therapy decision.

Furthermore, almost all study participants were unvaccinated. It can be assumed that treatment response is less pronounced in vaccinated individuals.

Antiviral treatment should begin as soon as possible after diagnosis. Therefore, when PCR testing capacity is exhausted, treatment decisions must be based on clinical symptoms and a rapid lateral flow test.

In many studies, symptoms of COVID-19 disease were counted as adverse events and presented only in a summarized manner. This meant that if a substance was effective, it could appear more tolerable than placebo. Side effects should therefore be presented in a differentiated manner to provide better information.

Logistics were the source of another line of discussion. Intravenous therapy with sotrovimab and remdesivir must be monitored and followed up. This is logistically difficult to achieve in primary care practices because there are usually neither staff nor isolation rooms available for this purpose. Logistical problems also arise from the availability of these substances exclusively through specific (hospital) pharmacies (31). The list of hospital contact persons is easy to find (32) but also reveals some regional disparities. As a general rule, the focus of drug development for outpatient settings should be on inhaled, oral, SC, or IM applications, and the availability of drugs should be regulated nationwide.

The present recommendations for outpatient drug treatment of patients with COVID-19 in Germany are basically similar to international recommendations (40, e1). Differences are due to slightly varying interpretations of the study results, the (non-)availability of individual active ingredients, and the time of publication. It is therefore necessary, and intended, to continue to update the recommendations presented here on a regular basis.

Lessons regarding the future development of guidelines

It is very encouraging that nine professional societies with a wide variety of clinical experience backgrounds were able to agree on joint recommendations for eleven of twelve drug treatment options. With regard to budesonide inhalation, the difference between the recommendations is only a gradual one. The moderation by the AWMF and the meticulous, critical, and transparent evidence preparation by the (former) CEOsys team were crucial for this success. During the consensus conferences, CEOsys presented the evidence and answered subsequent questions as a neutral authority. On this basis, participants were able to contribute their assessments in line with their specific expertise. This model – evidence preparation by methodologists, discussion with physicians and patients—appears to be future-oriented for the development of methodologically high-quality, evidence-based guidelines, especially if time is of the essence and many people wish to be involved. This does, however, require funding.

The consensus-building process also highlighted some limitations. The exclusive inclusion of only previously published RCT created uncertainty when preprints were available. The last minute implementation of updates also suffers as a result of the large group size and the coordination procedures until the texts are published. An example of this is the most recent publication on the use of convalescent plasma, which is not covered further here because it has not yet been discussed (e2). A simpler option would be the purely digital creation of guidelines, for example via MAGICapp or GRADEpro. This would eliminate the time-consuming transfer of texts stored in the database to other documents. On the other hand, updating the digital content also requires significant manpower resources.

eBox

SARS-CoV-2/COVID-19 – Information & practice aids for GPs in private practice, DEGAM S2e-Guideline (AWMF-Register No. 053–054)

Conflict of interest statement
Prof. Kluge has received research funding from Daiichi Sankyo. He has received lecture fees and reimbursement of travel expenses from Daiichi Sankyo, Gilead, MSD and Pfizer. He has received consulting fees from Gilead, MSD and Pfizer.

Dr. Malin has received consulting fees from MAPLE Health Group, Atriva Therapeutics and Gilead Sciences, reimbursement of conference fees and/or travel expenses from Gilead Sciences and ViiV Healthcare.

The other authors confirm that there are no conflicts of interest.

Manuscript received: 06 April 2022, revised version accepted on: 13 April 2022

Translated from the original German by Dr. Grahame Larkin, MD

As with many other professional journals, clinical guidelines in the German Medical Journal are not subject to the peer review process, as S3 guidelines are already texts that have been assessed and discussed by experts (peers) and have a broad consensus.

Corresponding author
Prof. Dr. med. Hanna Kaduszkiewicz

Christian-Albrechts-Universität zu Kiel

Medizinische Fakultät, Institut für Allgemeinmedizin

Michaelisstr. 5, Gebäude U30, 24105 Kiel

Cite this as:
Kaduszkiewicz H, Kochen MM, Kluge S, Malin JJ, Weibel S, Skoetz N, on behalf of the guideline group: Clinical practice guideline: Recommendations for the outpatient drug treatment of patients with COVID-19. Dtsch Arztebl Int 2022; 119: 342–9. DOI: 10.3238/arztebl.m2022.0203

►Supplementary material

eReferences, eBox:
www.aerzteblatt-international.de/m2022.0203

References

1. Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin: S2e Leitlinie – SARS-CoV-2/Covid-19 – Informationen & Praxishilfen für niedergelassene Hausärztinnen und Hausärzte – Living Guideline (Stand 02/2022). www.awmf.org/leitlinien/detail/ll/053-054.html (last accessed on 3 April 2022).

2. AWMF S3 Leitlinie – Empfehlungen zur stationären Therapie von Patienten mit COVID-19 – Living Guideline (Stand 02/2022). Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF); 2022. www.awmf.org/leitlinien/detail/ll/113-001LG.html (last accessed on 3 April 2022).

3. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften: COVID-19 Leitlinien/Handlungsempfehlungen. www.awmf.org/die-awmf/awmf-aktuell/aktuelle-leitlinien-und-informationen-zu-covid-19/covid-19-leitlinien.html (last accessed on 3 April 2022).

4. Balshem H, Helfand M, Schünemann HJ, et al.: GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64: 401–6

5. MAGIC Evidence Ecosystem Foundation: MAGICapp. www.magicapp.org (last accessed on 3 April 2022).

6. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften: AWMF-Regelwerk Leitlinien: www.awmf.org/leitlinien/awmf-regelwerk.html (last accessed on 3 April 2022).

7. Alonso-Coello P, Schünemann HJ, Moberg J, et al.: GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ 2016; 353: i2016

8. Lenze EJ, Mattar C, Zorumski C, et al.: Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19—a randomized clinical trial. JAMA 2020; 324: 2292–300

9. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al.: Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health 2022; 10: e42–51

10. Mikolajewska A, Fischer AL, Piechotta V, et al.: Colchicine for the treatment of COVID-19. Cochrane Database Syst Rev 2021; 10: CD015045

11. Connors JM, Brooks MM, Sciurba FC, et al.: Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA 2021; 326: 1703–12

12. Popp M, Stegemann M, Riemer M, et al.: Antibiotics for the treatment of COVID-19. Cochrane Database Syst Rev 2021; 10: CD015025

13. Popp M, Stegemann M, Metzendorf MI, et al.: Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev 2021; 7: CD015017

14. Wagner C, Griesel M, Mikolajewska A, et al.: Systemic corticosteroids for the treatment of COVID-19. Cochrane Database Syst Rev 2021; 8: CD014963

15. Stroehlein JK, Wallqvist J, Iannizzi C, et al.: Vitamin D supplementation for the treatment of COVID-19: a living systematic review. Cochrane Database Syst Rev 2021; 5: CD015043

16. Gupta A, Gonzalez-Rojas Y, Juarez E, et al.: Early treatment for covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med 2021; 385: 1941–50

17. Gottlieb RL, Vaca CE, Paredes R, et al.: Early remdesivir to prevent progression to severe COVID-19 in outpatients. N Engl J Med 2022; 386: 305–15

18. Hammond J, Leister-Tebbe H, Gardner A, et al.: Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 2022; 386: 1397–408

19. Khoo SH, Fitzgerald R, Fletcher T, et al.: Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicrob Chemother 2021; 76: 3286–95

20. Fischer II WA, Eron Jr JJ, Holman W, et al.: A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med 2022; 14: eabl7430 MEDLINE

21. Caraco Y, Crofoot GE, Moncada PA, et al.: Phase 2/3 trial of molnupiravir for treatment of covid-19 in nonhospitalized adults. NEJM Evid 2021; 1: 2.

22. Bernal AJ, Gomes da Silva MM, Musungaie DB, et al.: Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med 2022; 386: 509–20 PubMed Central

23. Ramakrishnan S, Nicolau DJ, Langford B, et al.: Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med 2021; 9: 763–72

24. Yu LM, Bafadhel M, Dorward J, et al.: Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet 2021; 398: 843–55

25. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al.: Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults with symptomatic COVID-19: a randomized clinical trial. JAMA Intern Med 2022; 182: 42–9

26. Hoffmann M, Krüger N, Schulz S, et al.: The Omicron variant is highly resistant against antibody-mediated neutralization: implications for control of the COVID-19 pandemic. Cell 2022; 185: 447–56

27. Robert Koch-Institut, Fachgruppe COVRIIN: Möglicher Einsatz der neutralisierenden monoklonalen Antikörper in Abhängigkeit von der diagnostizierten SARS-CoV-2-Virusvariante. www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/COVRIIN_Dok/Monoklonale_AK.pdf?__blob=publicationFile (last accessed on 3 April 2022).

28. U.S. Food & Drug Administration: FDA updates Sotrovimab emergency use authorization. www.fda.gov/drugs/drug-safety-and-availability/fda-updates-sotrovimab-emergency-use-authorization (last accessed on 3 April 2022).

29. Robert Koch-Institut: Wöchentlicher Lagebericht zur Coronavirus-Krankheit-2019 (COVID-19). www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Situationsberichte/Wochenbericht/Wochenbericht_2022-04-21.pdf?__blob=publicationFile (last accessed on 25 April 2022).

30. Robert Koch-Institut: Liste der Krankenhäuser, die an der Versorgung mit monoklonalen Antikörpern teilnehmen. www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Therapie/Liste_KH.pdf?__blob=publi?cationFile (last accessed on 3 April 2022).

31. Robert Koch-Institut: Stern- und Satellitenapotheken (beauftragte Stellen nach § 2 Absatz 1 MedBVSV). www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Therapie/Stern-Satellitenapotheken.pdf?__blob=publicationFile (last accessed on 3 April 2022).

32. Mikus G, Foerster KI, Terstegen T, et al.: Oral drugs against COVID-19—management of drug interactions with the use of nirmatrelvir/ritonavir. Dtsch Arztebl Int 2022; 119: 263–9

33. University of Liverpool: COVID-19 Drug Interactions. www.covid19-druginteractions.org/ (last accessed on 3 April 2022).

34. Bundesinstitut für Arzneimittel und Medizinprodukte: Informationen zu Lagevrio® und Paxlovid®. www.bfarm.de/DE/Arzneimittel/Arzneimittelinformationen/covid-19-arzneimittel.html (last accessed on 3 April 2022)

35. Ananworanich J, Mogg R, Dunne MW et al.: Randomized study of rivaroxaban vs. placebo on disease progression and symptoms resolution in high-risk adults with mild COVID-19. Clin Infect Dis 2021: ciab813

36. Connors JM, Brooks MM, Sciurba FC et al.: Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial. JAMA 2021; 326: 1703–12

37. Gesellschaft für Thrombose- und Hämostaseforschung e. V.: Aktualisierte Empfehlungen zur Thromboseprophylaxe bei SARS-CoV-2 (COVID-19), Stand 21.04.2020. http://gth-online.org/wp-content/uploads/2020/04/Aktualisierte-GTH-Empfehlungen-COVID-19-1.pdf (last accessed on 3 April 2022).

38. Robert Koch-Institut: Epidemiologischer Steckbrief zu SARS-CoV-2 und COVID-19, Kapitel 15. Risikogruppen für schwere Verläufe. www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Steckbrief.html#doc13776792bodyText15 (last accessed on 3 April 2022).

39. Robert Koch-Institut. Epid Bull 2022; 2: 11. www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2022/Ausgaben/02_22.pdf?__blob=publicationFile (last accessed on 3 April 2022).

40. CDC and Infectious Diseases Society of America: COVID-19 outpatient treatment guidelines roadmap. www.idsociety.org/globalassets/covid-19-real-time-learning-network/outpatientroadmap-v10.pdf (last accessed on 11 April 2022).

e1. National Institutes of Health: Therapeutic management of nonhospitalized adults with COVID-19. www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/ (last accessed on 11 April 2022).

e2. Sullivan DJ, Gebo KA, Shoham S, et al.: Early outpatient treatment for COVID-19 with convalescent plasma. N Engl J Med. 2022; Epub ahead of print.