Which drug therapies benefit patients with nonsevere COVID-19?

A systematic review and network meta-analysis of existing drug treatments for mild to moderate COVID-19 reveals that nirmatrelvir-ritonavir and remdesivir can possibly reduce hospital admissions, while corticosteroids and molnupiravir show potential in lowering hospitalizations.

In addition, symptom duration may be reduced with the use of azithromycin, corticosteroids, favipiravir, molmupiravir, and umifenovir.

“For most other interventions, the evidence remains uncertain regarding their impact on patient-important outcomes or indicates they are probably not beneficial,” the investigators said.

A total of 259 trials involving 166,230 patients were identified, of which 187 (72 percent) met the eligibility criteria. Compared with standard care, only nirmatrelvir-ritonavir (25 fewer per 1,000, 95 percent confidence interval [CI], 28‒20; moderate certainty) and remdesivir (21 fewer per 1,000 (28‒7 fewer; moderate certainty) probably reduced hospital admissions. [BMJ 2025;389:e081165]

Molnupiravir and systemic corticosteroids also reduced admissions of COVID-19 patients to hospitals, but the evidence had low certainty.

Azithromycin, compared with standard care, potentially reduced time to symptom resolution (mean difference 4 days fewer, 95 percent CI, 5‒3; moderate certainty). Likewise, corticosteroids, favipiravir, molnupiravir, and umifenovir possibly shortened symptom duration (moderate to high certainty).

On the other hand, the use of lopinavir-ritonavir vs standard care resulted in more adverse effects that resulted in treatment discontinuation.

Mortality

“According to our classification, no drug was convincingly different from standard care for the outcomes of mortality, mechanical ventilation, venous thromboembolism, and clinically important bleeding, [but] rating the certainty using a different target may provide important insights,” the investigators said. “For example, some interventions suggested little or no effect.”

Low-certainty evidence suggested that molnupiravir and the combination of nirmatrelvir-ritonavir provided little or no survival benefit. For mechanical ventilation, JAK inhibitors also offered little or no benefit based on moderate-certainty evidence.

In addition, moderate-certainty evidence revealed little to no benefit for venous thromboembolism with prophylactic-dose anticoagulation, which potentially resulted in little or no increase of clinically important bleeding.

“Several interventions do not seem to result in a benefit for any patient important outcomes, including ACEi/ARB, aspirin, colchicine, fluvoxamine, hydroxychloroquine, ivermectin, and lopinavir-ritonavir,” the investigators said. “Lopinavir-ritonavir increases the risk of adverse effects leading to drug discontinuation and increases length of hospital stay.”

Data sources

In this study, the investigators searched the COVID-19 Living Overview of Evidence Repository from 1 January 2023 to 19 May 2024, as well as the WHO COVID-19 database (up to 17 February 2023) and six Chinese databases (up to 20 February 2021). Studies published between 1 December 2019 and 28 June 2023 were identified.

Pairs of independent reviewers screened the articles. A Bayesian network meta-analysis was carried out following duplicate data abstraction. The investigators evaluated risk of bias using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of available evidence using the grading of recommendations assessment, development, and evaluation (GRADE).

Following GRADE guidance, drug treatments were classified from the most to the least beneficial or harmful for each outcome.