What’s in the web for family physicians — navigating through the maze of COVID-19 treatment

Sio-pan Chan 陳少斌，Wilbert WB Wong 王維斌，Alfred KY Tang 鄧權恩

HK Pract 2021;43:11-12

COVID-19 has been rampaging the world for over 2 years. During this period, we have witnessed the unprecedented pace of development of different strategies to fight against this deadly virus. Different treatment modalities starting from only supportive treatments to effective vaccines and specific antiviral agents. So far all treatments are under emergency uses and may not represent the best or definitive treatment.

Back in early 2020, when COVID-19 first appeared in the US, a group of frontline critical care physicians had formed an organisation called FLCCC ALLIANCE. This alliance was largely responsible for formulating the early treatment protocols for prevention and treatment of COVID-19. However, because of its promotion of hydroxychloroquine and Ivermectin as treatments for COVID-19, the influence of this alliance is fading fast from the main stage. Some of the protocols set by the FLCCC are now considered as improper medical practice by various authorities. Most readers may remember it took a US court order for a patient to continue Ivermectin treatments initiated by the patient's family doctor.

There are so much disinformation, misinformation and controversies at the management of COVID-19, it is difficult for busy clinicians to follow the tsunami of information on a daily basis. However, since early 2022, Hong Kong has experienced an unprecedented fifth wave of COVID-19 surge by the Omicron variant, most doctors got involved in COVID-19 one way or the other. Many of us were scrambling for information on management of COVID-19. We consider this a good time to review the different available treatments. We shall provide evidence from literature for various drugs/agents claimed to have beneficial effects on COVID-19. It is up to the readers to make their own judgement.

Oral Nirmatrelvir (Paxlovid) for High-Risk, Nonhospitalised Adults with COVID-19

Nirmatrelvir is an orally administered protease (Mpro) inhibitor with potent pan–human-coronavirus invitro inhibitory activity.

Authors of this study conducted a phase 2–3 double-blind, randomised, controlled trial in which symptomatic, unvaccinated, nonhospitalised adults at high risk for progression to severe COVID-19 were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. COVID-19–related hospitalisation or death from any cause through day 28, viral load, and safety were evaluated. A total of 2246 patients underwent randomisation; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group).

Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P <0.001; relative risk reduction, 88.9%).

Paxlovid is a strong CYP3A inhibitor with many drug-drug interactions, notable examples include statins, anticoagulants and antiarrhythmics. The emergency use of Paxlovid was approved during the Delta variant wave and limited to unvaccinated patients who were symptomatic, not admitted into hospital and with high risk of developing severe illness. With the emergence of the more infectious but less virulent Omicron variant, the population at large is likely to have been infected or vaccinated, whether the more liberal use of Paxlovid at present is justifiable for its high cost remains to be validated by further clinical trials.

Molnupiravir for Oral Treatment of COVID-19 in Nonhospitalised Patients

Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. It is a mutagenic agent and works by inducing errors in mutations of RNA virus, hence reducing the chances of successful viral replication. Because of its mutagenic property, it is contraindicated in pregnancy, and during lactation.

The authors conducted a phase 3, double-blind, randomised, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in non-hospitalised, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19 and at least one risk factor for severe COVID-19 illness.

A total of 1433 participants underwent randomisation; 716 were assigned to receive molnupiravir and 717 to receive placebo.

The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalisation for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval [CI], −11.3 to −2.4; P=0.001).

Early treatment with molnupiravir reduced the risk of hospitalisation or death in at-risk, unvaccinated adults with COVID-19. The efficacy was only 30%.

Vitamin D insufficiency as a major risk factor in determining the outcome of SARS-COVID 2.

It is known that vitamin D plays a protective role in upper respiratory tract infections such as influenza. There is no consensus on the “normal” blood level - most would consider a blood level of 25(OH) vitamin D of 30ng/dl (75mmol/dl) as sufficient. A recent study from Israel provides convincing evidence that vitamin D deficiency plays a major role in predicting the outcome of COVID-19. This study concluded that 26 percent of coronavirus patients died if they were vitamin D deficient soon before hospitalisation, compared to 3% who had normal levels of vitamin D.

Colchicine as an add on to standard therapy.

Colchicine has been known to be a potent antiinflammatory agent. There are evidence that by adding colchicine to the standard treatments, it could reduce the likelihood of developing a severe inflammatory reaction and hence could result in a better outcome. Also there are studies to show more beneficial effects if given in the early phase of this disease. However, due to drug interaction, it should not be given to anyone who is going to receive the antiviral Paxlovid treatment.

Melantonin

The use of melantonin is a potential treatment option to reduce the severity of COVID-19 symptoms due to its known anti-inflammatory, immunomodulatory and protective antioxidant mechanisim. This study investigated the effect of melatonin on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Only RCTs that compared the clinical efficacy of melatonin with a placebo in the treatment of patients with COVID-19 were included. The primary outcome measure was the clinical recovery rate. The clinical recovery rates were 94.2% (81/86) and 82.4% (70/85) in the melatonin and control groups, respectively. Overall, patients receiving melatonin had a higher clinical recovery rate than did the controls (odds ratio [OR]: 3.67; 95% CI: 1.21−11.12; I2 = 0%, p = 0.02). The risk of intensive care unit admission was numerically

lower in the melatonin group than in the control group (8.3% [6/72] vs. 17.6% [12/68], OR: 0.45; 95% CI: 0.16−1.25; I2 = 0%, p = 0.13), and the risk of mortality was numerically lower in the melatonin group than in the control group (1.4% [1/72] vs. 4.4% [3/68], OR: 0.32; 95% CI: 0.03−3.18; I2 = 0%, p = 0.33). In conclusion, melatonin may help improve the clinical outcomes of patients with COVID-19.

Azithromycin

Azithromycin has known to have in-vitro antiviral properties and immunomodulatory effects, it is the most widely antibiotic used the treatment of COVID-19 in its various stages of disease. Various trials have failed to demonstrate clear effectiveness. However, most trials were not performed in ideal conditions. It remains as a good choice due to its antibacterial properties in respiratory infections.

Ivermectin

Perhaps this is the single most controversial drug use in the treatment of COVID-19. Ivermectin is an anti-parasitic drug widely used in developing countries. It has demonstrated in-vitro studies and in hamsters for its effectiveness versus the SARS-COVID 2 virus. It was claimed to be effective in early trials including RCT trials and also in real life use in few countries including India and Brazil on population-wide use for prophylaxis and treatment. However, such claims have been rebuked by many academics because of flaws found in such trials. Most interestingly, in the PRINCIPLE trial conducted by Oxford University, a large scale study designed to settle the effectiveness of many drugs including some mentioned above, the ivermectin arm was put on hold, citing shortage of supply of ivermectin. Ivermectin is not officially recommended for COVID-19 by WHO, FDA, CDC and EU authorities, although it is still widely used in developing countries for the same purpose.

A meta-analysis for Lianhua Qingwen (連花清瘟膠囊) on the treatment of Coronavirus disease 2019 (COVID-19)

As one of the drugs recommended in the Chinese guidelines, Lianhua Qingwen Granules or Capsules (LQ) are widely used. This systematic review and metaanalysis aims to evaluate the clinical efficacy of LQ on the treatment of COVID-19.

A total of 3 trials including 245 COVID-19 patients were enrolled. Compared with the control group, the LQ group showed significant difference in reducing the rate of development of severe or critical conditions, as well as significant improvement on the disappearance rate clinical symptoms: fever, fatigue and anhelation, but no significance on expectoration of sputum. Nevertheless, better quality trials with more observational indicators may yield more conclusive results.

Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection

Morbidity and mortality resulting from COVID-19 infections are associated with multisystem organ failure due to a rapid increase in cytokine production. Fluoxetine has been shown to reduce the different mechanisms that cause the cytokine storm that leads to COVID-19 fatalities. Such result was further substantiated by a large scale TOGETHER Trial.