2. Various antiviral agents

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At least two studies suggested that lopinavir/r pharmacokinetics in COVID-19 patients may differ from those seen in HIV-infected patients. In both studies, very high concentrations were observed, exceeding those in HIV-infected patients by 2-3 fold (Schoergenhofer 2020, Gregoire 2020). However, concentrations of protein-unbound lopinavir achieved by current HIV dosing is probably still too low for inhibiting SARS-CoV-2 replication. The EC50 for HIV is much lower than for SARS-CoV-2. It remains to be seen whether these levels will be sufficient for (earlier) treatment of mild cases or as post-exposure prophylaxis.

Other PIs

For another HIV PI, darunavir, there is no evidence from either cell experiments or clinical observations that the drug has any prophylactic effect (De Meyer 2020). It is hoped that the recently published pharmacokinetic characterization of the crystal structure of the main protease SARS-CoV-2 may lead to the design of optimized protease inhibitors. Virtual drug screening to identify new drug leads that target protease which plays a pivotal role in mediating viral replication and transcription, have already identified several compounds. Six compounds inhibited M(pro) with IC50 values ranging from 0.67 to 21.4 muM, among them two approved drugs, disulfiram and carmofur (a pyrimidine analog used as an antineoplastic agent) drugs (Jin 2020). Others are in development but still pre-clinical (Dai 2020).

Most coronaviruses attach to cellular receptors via their spike (S) protein. Within a few weeks after the discovery of SARS-CoV-2, several groups elucidated the entry of the virus into the target cell (Hoffmann 2020, Zhou 2020). Similar to SARS-CoV, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a key receptor, a surface protein that is found in various organs and on lung AT2 alveolar epithelial cells. The affinity for this ACE2 receptor appears to be higher with SARS-CoV-2 than with other coronaviruses. The hypothesis that ACE inhibitors promote severe COVID-19 courses through increased expression of the ACE2 receptor remains unproven (see chapter Clinical Presentation, page 333).

Human recombinant soluble ACE2 (APN01)

HrsACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. It may act by binding the viral spike protein (thereby neutralizing

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SARS-CoV-2) and by interfering with the renin–angiotensin system. APN01 has been shown to be safe and well-tolerated in a total of 89 healthy volunteers and patients with pulmonary arterial hypertension (PAH) and ARDS in previously completed Phase I and Phase II clinical trials. It is developed by APEIRON, a privately-held European biotech company based in Vienna, Austria. There is a report of an Austrian case of a 45-year-old woman with severe COVID-19 who was treated with hrsACE2. The virus disappeared rapidly from the serum and the patient became afebrile within hours (Zoufaly 2020). Several Phase II/III studies of hrsACE2 are ongoing.

Camostat (Foipan®)

In addition to binding to ACE2, priming or cleavage of the spike protein is also necessary for viral entry, enabling the fusion of viral and cellular membranes. SARS-CoV-2 uses the cellular protease transmembrane protease serine 2 (TMPRSS2). Compounds inhibiting this protease may therefore inhibit viral entry (Kawase 2012). The TMPRSS2 inhibitor camostat, approved in Japan for the treatment of chronic pancreatitis (trade name Foipan®), may block the cellular entry of SARS-CoV-2 (Hoffmann 2020). Clinical data are pending. Some trials are ongoing, mostly in mild-to-moderate disease.

Umifenovir

Umifenovir (Arbidol®) is a broad-spectrum antiviral drug approved as a membrane fusion inhibitor in Russia and China for the prophylaxis and treatment of influenza. Chinese guidelines recommend it for COVID-19 - according to a Chinese press release it is able to inhibit the replication of SARSCoV-2 in low concentrations of 10-30 μM (PR 2020). In a small retrospective and uncontrolled study in mild to moderate COVID-19 cases, 16 patients who were treated with oral umifenovir 200 mg TID and lopinavir/r were compared with 17 patients who had received lopinavir/r as monotherapy for 5–21 days (Deng 2020). At day 7 in the combination group, SARS-CoV-2 nasopharyngeal specimens became negative in 75%, compared to 35% with lopinavir/r monotherapy. Chest CT scans were improving for 69% versus 29%, respectively. Similar results were seen in another retrospective analysis (Zhu 2020). However, a clear explanation for this remarkable benefit was not provided. Another retrospective study on 45 patients from a non-intensive care unit in Jinyintan, China failed to show any clinical benefit (Lian 2020). There is a preliminary report of a randomized study indicating a weaker effect of umifenovir compared to favipiravir (Chen 2020).

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Oseltamivir

Oseltamivir (Tamiflu®) is a neuraminidase inhibitor that is approved for the treatment and prophylaxis of influenza in many countries. Like lopinavir, oseltamivir has been widely used for the current outbreak in China (Guan 2020). Initiation immediately after the onset of symptoms may be crucial. Oseltamivir is best indicated for accompanying influenza co-infection, which has been seen as quite common in MERS patients at around 30% (Bleibtreu 2018). There is no valid data for COVID-19. It is more than questionable whether there is a direct effect in influenza-negative patients with COVID-19 pneumonia. SARS-CoV-2 does not require neuramidases to enter target cells.

Hydroxychloroquine (HCQ) and chloroquine (CQ)

HCQ is an anti-inflammatory agent approved for certain autoimmune diseases and for malaria. The story of HCQ in the current pandemic is a warning example of how medicine shouldn’t work. Some lab experiments, a mad French doctor, bad uncontrolled studies, many rumors and hopes, reports without any evidence and an enthusiastic tweet that this had “a real chance to be one of the biggest game changers in the history of medicine” - hundreds of thousands people received an ineffective (and potential dangerous) drug. Moreover, many turned away from clinical trials of other therapies that would have required them to give up HCQ treatments. In some countries, the HCQ frenzy prompted serious delays in trial enrolment, muddled efforts to interpret data and endangered clinical research (Ledford 2020). Some countries stockpiled CQ and HCQ, resulting in a shortage of these medications for those that need them for approved clinical indications. Only a few months later, we are now facing an overwhelming amount of data strongly arguing against any use of both HCQ and CQ. So please, let’s forget it. Completely. But let us learn from the bad HQC story which should never happen again (Kim 2020, Ledford 2020).

No clinical benefit from Hydroxychloroquine (HCQ)

• In an observational study from New York City (Geleris 2020) of 1376 hospitalized patients, 811 received HCQ (60% received also azithromycin, A). After adjusting for several confounders, there was no significant association between HCQ use and intubation or death. • Another retrospective cohort of 1438 patients from 25 hospitals in the New York metropolitan region (Rosenberg 2020), there were no significant differences in mortality for patients receiving HCQ + Azithromycin (A), HCQ alone, or A alone.

Cardiac arrest was significantly more likely seen with HCQ + A (adjusted OR 2.13). • A randomized, Phase IIb trial in Brazil on severe COVID-19 patients was terminated early (Borba 2020). By day 13, 6/40 patients (15%) in the low-dose CQ group had