Antiviral Treatment of Mild-to-Moderate COVID-19

Ella Castle

  Funded through sponsorship by Pfizer Private Limited. Medscape approached Pfizer Private Limited to fund the production of this editorial article. Please see bottom of page for full disclaimer.   Background Although the emergency phase of the coronavirus disease 2019 (COVID-19) pandemic ended in May 2023, the virus is still […]


Funded through sponsorship by Pfizer Private Limited. Medscape approached Pfizer Private Limited to fund the production of this editorial article. Please see bottom of page for full disclaimer.



Although the emergency phase of the coronavirus disease 2019 (COVID-19) pandemic ended in May 2023, the virus is still circulating globally and evolving.[1,2,3] Most people now recover without treatment, but it can still be serious and life-threatening in anyone who is affected.[1] However, people aged >60 years and those with existing medical conditions, including high blood pressure, diabetes, obesity, immunosuppression, cancer, and pregnancy, have a higher risk of serious illness.[1]

Vaccinations and antiviral drugs were developed following characterisation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — the virus that causes COVID-19.[1] Vaccination has proved effective against COVID-19, reducing the severity of the disease, hospitalisations, and mortality, and minimising the likelihood of new variants emerging.[2,3] Furthermore, unvaccinated people have a higher risk of severe symptoms.[1] Vaccination therefore continues to have a critical role in the global response to COVID-19, particularly in high-risk groups.

Several outpatient treatment options are now available for patients with mild-to-moderate COVID-19 at risk of progression to severe disease (Table 1) supported by evidence from randomised controlled trials and real-world studies.[2,4–16] These include the oral antivirals molnupiravir and nirmatrelvir–ritonavir and the intravenous antiviral remdesivir.[17–19]

Organisations across the world have published guidance on the management of patients with COVID-19.[2,4–6,20] However, clinicians need clarity on which patient groups should be treated, when treatment needs to be initiated, and how to determine the most appropriate therapeutic option. An expert group was therefore convened to discuss:

  • Risks and burden associated with progression to severe COVID-19

  • Patients at risk for progression to severe COVID-19

  • Optimal timing of COVID-19 treatment

  • Considerations for selection of the most appropriate treatment, including patient- and treatment-related characteristics.

Table 1: Treatments for patients with mild-to-moderate COVID-19 at risk of progression to severe COVID-19.[17–19] A

(A) This table is based on UK marketing authorisations, please check local prescribing information.
COVID-19=coronavirus disease 2019; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

Current status of COVID-19

Tobias Welte (TW): What is the current status of COVID-19 in Southeast Asia? (group discussion took place October 2023)

Liang En Wee (LEW): Singapore is currently at the end of a wave driven by various Omicron XBB subvariants. The local Ministry of Health continues to provide genomic sequencing in order to better understand the prevailing SARS-CoV-2 subvariant in community circulation. Hospitalisation rates are generally low and intensive care units (ICUs) are typically not occupied by COVID-19 cases, so it is now a mild disease in Singapore.[21] This is probably due to our high vaccination rates: 79% of the population had received one booster dose by September 2022 and booster vaccine uptake was high, especially amongst the elderly;[22] and there is still some residual protection although uptake has reduced since vaccination campaigns wound down.[21]

Chee Tao Chang (CTC): COVID-19 is well controlled in Malaysia. We have almost no deaths currently and very few patients requiring hospitalisation, ventilation, or ICU admission.[23]

TW: Is COVID-19 still reported in the media and are people still concerned or is this no longer a topic of daily discussions?

CTC: It is no longer so much of a concern. People are generally not wearing face masks, even in hospitals, and they do not self-test if they have symptoms that could be COVID-19, such as a runny nose or fever, and treat it as normal flu or cold.

TW: How is testing implemented currently? Are all outpatients and admissions tested or only those patients with symptoms?

CTC: Testing is not common except for patients who are admitted or scheduled for operations. Outpatients are no longer tested.

LEW: The situation in Singapore is similar. Testing is mainly symptom based, although there are still national surveillance programmes in which a small proportion of patients who present with respiratory symptoms to primary healthcare clinics are tested to determine the incidence of COVID-19 and other respiratory viruses.

TW: One of the problems we face is that the symptomatology of COVID-19 has changed with the current variants. Previously, respiratory symptoms predominated, but sore throat and abdominal pain are now more common,[24] so it is more difficult to identify COVID-19 early in its course. Furthermore, the antigen test is not as sensitive for the new variants.[25] Ideally, we would have access to polymerase chain reaction (PCR) tests, but these are not universally available and so underdiagnosis can result in an underestimate of the incidence of COVID-19.

For immunosuppressed patients, severe disease often has a typical course involving pneumonia.[26] However, in elderly patients, severe disease is typified by deterioration of other organ functions, including worsening cardiovascular disease, renal function, and diabetes control.[27,28] This more diffuse picture of the disease and its consequences can be a barrier to treating patients in general and particularly to early treatment of high-risk patients.

Treatment of COVID-19 in high-risk populations

High-risk populations

TW: At-risk patients who can become severely ill and require hospitalisation broadly fall into two groups – patients with other medical conditions and elderly patients.[2,4–6] The former group includes patients who are immunosuppressed, including transplant patients, those with autoimmune disease, particularly if they are taking B-cell-depleting treatments or anti-CD20 drugs, and patients with haematological malignancies, mainly lymphoma and leukaemia. People older than 65–70 years are more likely to be hospitalised, [29] likely due to the strong association between multi-organ disease – chronic heart disease, chronic lung disease, and chronic kidney failure – and severe COVID-19.

LEW: My hospital (Singapore General Hospital) has a large transplant programme and a large cancer centre, and our patients with a history of prior transplant, haematological malignancies and usage of previous B-cell-depleting therapies are considered at risk.[30,31]

CTC: Patients who are immunocompromised are prioritised for oral antivirals for COVID-19 to prevent them progressing to severe disease.

Available treatments

Prescribers should refer to the individual summaries of product characteristics for further information and recommendations regarding the use of pharmacological therapies. For off-licence use of medicines, the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented.

TW: Three treatments are available: remdesivir, which is given intravenously, and nirmatrelvir–ritonavir and molnupiravir, which are orally administered.[17–19] In Europe, we use nirmatrelvir–ritonavir as an oral treatment for outpatients and remdesivir for intravenous treatment of hospitalised patients.

LEW: Remdesivir and nirmatrelvir–ritonavir are typically used in Singapore; we have some stock of molnupiravir but it is not in common use. Ritonavir-boosted nirmatrelvir is the first line oral antiviral unless contraindicated by drug interactions or patient characteristics.[5] Our government pays for oral antivirals in the outpatient setting, but patients in hospital have to seek reimbursement from our national medical savings schemes or insurance.

CTC: Our first line in Malaysia is also nirmatrelvir–ritonavir, unless it is contraindicated, in which case we would start molnupiravir.[4] We start patients who cannot take these drugs on remdesivir;[4] however, that is not common.

TW: A study from the Cleveland Clinic, found that only around third of their patients that had been assessed as eligible to receive antiviral treatment were treated with nirmatrelvir-ritonavir.[32] For patients diagnosed in an outpatient setting the percentage receiving antiviral treatment will be far lower. What percentage of your patients are treated with antivirals?

LEW: In Singapore, about 7% of people aged >60 years receive nirmatrelvir–ritonavir as outpatients.[33]

TW: Autoimmune patients and transplant patients normally take multiple drugs, which raises the risk of interaction. How do you manage drug–drug interactions of nirmatrelvir–ritonavir with other medications and the side effects of this treatment?[34]

LEW: Ritonavir-boosted nirmatrelvir is not such an issue for patients with haematological malignancies, but it can be for transplant patients, especially those on tacrolimus, because of the risk of drug interactions. Alternatively, we can bring the patient into hospital for remdesivir, but it is logistically more complicated and expensive as the patient has to be admitted. We can also administer intravenous remdesivir in the outpatient setting, but this requires intravenous access and more frequent clinic visits. 

TW: Is this drug interaction a major issue or is it overestimated, because we do not see as many side-effects as expected in clinical practice.

CTC: The impact of drug interactions could be overestimated. Doctors and pharmacists follow guidelines very strictly given nirmatrelvir–ritonavir is a recently authorised oral antiviral for COVID-19 due to concerns about its safety and will avoid using it if the patient is started on any drug listed as having interactions, even if the patient is immunocompromised or at high risk of severe disease for other reasons.

TW: The USA and Europe are taking a more personalised approach to treatment for patients at risk of side effects. A paper published in Clinical Infectious Disease showed that a modified dose of nirmatrelvir–ritonavir in patients with chronic kidney disease is still effective and with a favourable safety profile.[35] Reducing the immunosuppressive medication for about 5 days can also make it possible to use nirmatrelvir–ritonavir in transplant patients.[36] Is this personalised approach also used in Singapore?

LEW: Previously, we did not use nirmatrelvir–ritonavir often in our renal transplant population, preferring remdesivir. For instance, in a cohort of renal transplant patients treated at our centre, amongst those who received antivirals (N=207), the majority (N=195) received remdesivir, and only a minority received oral antivirals.[30] However, with more familiarity with nirmatrelvir–ritonavir and because of the ease of administration, without requiring admission, we have loosened the criteria and begun to individualise treatment. There is still concern for some transplant patients whose immunosuppression is not stable and requires frequent dose adjustment, and their primary physicians may be more hesitant.

TW: Relapse can occur after treatment with nirmatrelvir–ritonavir,[37] patients who have completed the 5-day course and then test negative subsequently experience viral or symptom rebound. Have you also seen this and, if this is the case, what do you do?

LEW: This rebound phenomenon has been described, but in most of the cases it is virological rebound, with the virus detectable by PCR but patients symptomatically and clinically much better compared with the initial phase, especially if they were pretreated. In most of these cases, we only undertake close monitoring, as most resolve on their own. A subset of patients, especially those with heavy B-cell depletion prior to COVID-19, have difficulty clearing the virus, and we may use alternative antivirals. I am not sure whether the delay in clearance is related to the drug or a particular patient profile.

TW: If the immunoglobulin level is very low — for example, in patients with B-cell lymphoma — we give immunoglobulin supplementation.

LEW: In my personal experience, a patient with Good syndrome, which has very low immunoglobulin levels, improved after regular immunoglobulin, but he was also treated heavily with antivirals for COVID.[38]

One of the major issues now is that we no longer have a reliable monoclonal antibody for this group of patients, as they have lost much of their effectiveness with some of the variants.[39–42] Monoclonal antibodies are expensive, and the predominant strains in Singapore are XBB related, so we know that monoclonal antibodies may not be so effective. We also have overlapping transmission from different strains, and it is difficult to know which strains patients have and therefore whether monoclonal antibodies will be fully effective. Most of our recent cases have also been fairly mild.

TW: The new variants change receptors quickly and are so different from each other that it can be hard to determine which monoclonal antibodies could be used. By comparison, there is no resistance for antivirals and they remain effective for all variants.

CTC: I agree. In some but not all severe cases, monoclonal antibodies are effective, but the cost of monoclonal antibodies is a consideration, so their use is decided on a case-by-case basis. Monoclonal antibodies were used in a few cases during an outbreak last year but are rarely used now because the prevalence of severe COVID-19 has reduced.

The importance of early intervention

TW: Early intervention is the key to antiviral treatment for COVID-19. My personal experience is that it is effective if started in the first 5, at most 7, days after infection, but the impact is reduced if it is started later than this.

CTC: Early treatment is important. According to our Ministry of Health guidelines,[4] oral antivirals have to be started within 5 days of diagnosis of COVID-19. If this time limit is exceeded, doctors will not start antivirals because they are expected to be ineffective. However, because these drugs are always started within 5 days, we are uncertain whether they will be effective after 5 days.

TW: In Europe, we have problems getting the diagnostic result from the laboratory to the responsible physician and then to the patient, so we lose time before treatment starts.

LEW: Early diagnosis is also difficult in Singapore. Transplant patients usually inform the transplant coordinator to which they have been assigned that they have COVID-19 after self-testing using antigen kits. Based on that, we have a mechanism to bring them into our outpatient clinic for assessment, confirmation of diagnosis, and prescribing of oral antivirals. For patients who may not be so proactive and those from different hospitals, late presentation can be an issue. For immunocompromised patients, we sometimes start oral antivirals beyond 5 days, but, anecdotally, the effects are not as good and patients usually do not respond as well.

TW: It has been difficult to educate general practitioners (GPs) in Europe about which patients should start early treatment. Do you have educational programmes?

LEW: It is important to engage primary care to ensure they refer transplant patients and those with haematological malignancies or cancer to tertiary care, because treatment uptake is still very low due to a combination of prescriber attitude and patient resistance to these drugs. We developed guidance for GPs to describe at-risk populations and a treatment algorithm to guide drug selection. The guidance was developed with input from infectious disease physicians and pharmacists and disseminated to GPs by the primary care division of the Ministry of Health in Singapore. A network of private primary care clinics is also activated during pandemics to provide subsidised treatment and testing.

CTC: Educational materials are disseminated through professional bodies, such as the Malaysian Medical Association, General Practitioner Society, and Malaysian Pharmacy Society. The Ministry of Health also uses social media platforms to increase public awareness and uptake of antivirals.

TW: The pandemic showed that this kind of education is not easy and we do not have structures in place to bring information from experts to general practice. This will be important to resolve for the next pandemic that will undoubtedly come.

The future of COVID-19 therapy

TW: What do we need in the future in terms of studies and data?

LEW: Data on real-world use of oral antivirals in population-based studies from around the world, including Southeast Asia, Singapore, and Malaysia, show the continued effectiveness of oral antivirals in reducing COVID-19-related hospitalisations and severe disease, even in the era of XBB variants.[13–16] The issue is their cost-effectiveness, which varies depending on the target population—for example, in the local setting in Singapore, nirmatrelvir–ritonavir must be given to 170 patients to prevent one hospitalisation, but this decreases to 42 immunocompromised patients.[33] Looking to the future, monoclonal antibodies with broad effectiveness against many of the new variants will be extremely helpful.

CTC: I believe we need more data in transplant and immunocompromised patients, because most trials are conducted in outpatient populations who are at low risk. We also need to look at the subpopulation of pregnant and nursing women, because they currently cannot receive antivirals due to safety concerns.

TW: What is important in terms of development of antivirals? I believe that an oral form of remdesivir may be very helpful, because intravenous treatment is difficult and not feasible in most patients. As ritonavir is the component responsible for drug–drug interactions,[34] a medication such as nirmatrelvir that is effective without ritonavir would also be a step forward.

CTC: I look forward to a compound with fewer drug interactions that would allow more patients to be eligible, a compound that is more specific to target the virus or any bacteria, which should improve the efficacy of the antiviral, and a drug with fewer side-effects, because nirmatrelvir–ritonavir, for example, produces gastrointestinal problems that reduce adherence.[18] I agree that administration route is important, and combining drugs into one tablet and reducing duration of treatment could increase convenience and so adherence.

LEW: I agree that we need to optimise existing drugs to overcome current barriers if we are to reach a larger population of patients.

CTC: We also need to increase accessibility of these drugs, so that more lower and middle income countries can have access to oral antivirals.

The continued importance of vaccination

TW: Even with the availability of treatments for COVID-19, vaccination is still essential to prevent the disease and reduce its severity. Although there was enthusiasm for vaccination during the pandemic, people are tired of talking about COVID-19 and its prevention. We need to continue to promote the positive benefits of vaccination to clinicians and patients.

CTC: In the initial stages, vaccination rates were high and over 80% of the population have received 2 doses, but this decreased to 50% for the first booster dose, and then only 2.5% for the second booster.[43] Our population is no longer talking about vaccination and are particularly reluctant to have the COVID-19 vaccine.

LEW: The situation is similar in Singapore, with enthusiasm for COVID-19 vaccinations somewhat diminished in the current climate compared with during the height of the pandemic.

TW: In Germany, COVID-19 vaccination is typically given by GPs, without any involvement from vaccination specialists, hospitals, or pharmacists.

LEW: The vaccination is also given by government or GP primary care clinics in Singapore. There has been some scaling down in terms of resources for the vaccination programme, but it is still freely available at a large number of centres. Low uptake is related more to COVID-19 fatigue than resource availability.

CTC: In Malaysia, we have government and private healthcare provision. Vaccination was available in hospitals and private clinics during the pandemic, but we have seen a decrease in vaccination in both settings. In the private sector, GPs are still administering vaccinations, but the public is less keen on private vaccination as they have to pay for it.

TW: With new vaccinations on the horizon, such as respiratory syncytial virus and those that reduce the burden of short- and long-term cardiovascular disease, we will need more engagement from a broader group of healthcare providers. I personally believe that pharmacies could have an important role in vaccination programmes.

CTC: I agree, and most pharmacists are interested in taking on vaccination, although they recognise they will need more training on their administration, and the Ministry of Health will also need to support a role for pharmacists in vaccination.

TW: One of the barriers to vaccination is the size of the vials, as each vial contains six doses, which can be problematic, as GPs need at least six people to be vaccinated at a given time otherwise some doses have to be destroyed. One-shot vials are urgently needed. We should also capitalise on the fact that COVID-19 vaccines can be administered at the same time as the flu vaccine, with no loss of immunity and no increase in side-effects.

Key points
  • Early treatment is key in overcoming the progress of COVID-19 disease, and healthcare systems need to be organised to ensure that oral antivirals can be started as early as possible following infection

  • Public health organisations, supported by experts, need to develop and disseminate education programmes to raise awareness of the importance of early diagnosis and treatment in patients at high risk of severe COVID-19 disease

  • More personalised treatment is needed for at-risk groups who are taking other treatments that may interact with antiviral agents, such as transplant patients, patients taking immunosuppressive drugs, and elderly patients

  • An effective vaccination programme covering all at-risk patient groups is still required and patients need to be encouraged to continue to have booster doses

  • Investment in healthcare systems is needed to ensure they are more effective as we continue to recover from COVID-19 and prepare for the next pandemic.

Jemma Lough, independent medical writer, helped draft this article.

Funded through sponsorship by Pfizer Private Limited. Medscape approached Pfizer Private Limited to fund the production of this editorial article. Pfizer Private Limited has had no influence over the selection of the authors or the content of the article and has reviewed it for technical accuracy only. The sponsorship fee included an honorarium for the authors, who were contracted and paid by Medscape Editorial. The views and opinions of the authors are not necessarily those of Pfizer Private Limited, or of Medscape, its publisher, advisers, or advertisers, all of which disclaim all and every liability and/or claims in this regard. No part of this publication may be reproduced in any form without the permission of the publisher.

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