10-07-2025
Most COVID-19 Drugs Fall Short, Meta-Analysis Confirms
Treatment options for mild-to-moderate COVID-19 are becoming increasingly well established. A systematic review and network meta-analysis published in The BMJ evaluated 40 treatments across 187 randomized trials involving more than 166,000 participants. Only two antivirals, nirmatrelvir-ritonavir (Paxlovid) and remdesivir, were found to moderately reduce the risk for hospitalization.
No treatment reduced mortality, although some treatments were associated with a shorter duration of symptoms. These findings are expected to guide future World Health Organization (WHO) treatment recommendations.
SARS-CoV-2, the virus responsible for COVID-19, emerged in late 2019 and continues to circulate worldwide. In 2024, Italy recorded 3154 COVID-19-related deaths, according to the Istituto Superiore di Sanità, despite a sharp decline in surveillance. Since the start of the pandemic, more than 8000 clinical trials have been conducted to identify effective treatment options.
Disease Phases
COVID-19 progresses through two distinct phases: An early viral replication phase (mild disease) and a later inflammatory phase (severe disease), which may lead to a cytokine storm, respiratory failure, and multiorgan dysfunction. As each phase involves different biological mechanisms, the treatment effectiveness must be assessed accordingly. This meta-analysis specifically focused on patients with mild-to-moderate COVID-19, a population for which therapeutic evidence remains limited.
Study Design
Researchers conducted a systematic review and network meta-analysis using the COVID-19 Living Overview of Evidence database, which compiles all randomized clinical trials related to COVID-19. The final analysis included 187 trials with data from 166,230 participants, which compiled all randomized clinical trials related to COVID-19.
Mild-to-moderate COVID-19 was defined according to the WHO criteria as follows: oxygen saturation ≥ 90% on room air; respiratory rate ≤ 30 breaths per minute; and no signs of respiratory distress, acute respiratory distress syndrome, sepsis, or septic shock. The primary outcomes included mortality, hospitalization, mechanical ventilation, adverse events leading to treatment discontinuation, and time-to-symptom resolution. The certainty of evidence was assessed using the GRADE approach.
Hospitalization and Duration
Paxlovid reduced hospitalizations by 25 per 1000 patients treated, with an estimated range of 20-28 fewer cases and moderate-certainty evidence. Remdesivir had a slightly smaller effect, preventing 21 hospitalizations per 1000 patients (range, 7-28 fewer), also with moderate certainty. Molnupiravir and corticosteroids may help reduce hospitalizations, but the evidence is of low certainty. Doxycycline shortened hospital stay by 1.33 days, with an estimated range of 0.03-2.63 days shorter, supported by moderate-certainty evidence.
Lopinavir-ritonavir (Kaletra) increased hospital stay by 1.77 days (range, 0.34-2.19 days longer) and was the only treatment clearly linked to adverse events that led to stopping treatment, both with high-certainty evidence.
Symptom Duration
Azithromycin showed the greatest benefit in shortening symptom duration, reducing it by an average of 4 days (typically from 5 days to 1 day), with moderate certainty. Other agents that shortened symptom duration by 2-3.5 days included molnupiravir, systemic corticosteroids, favipiravir, and umifenovir. All these findings were supported by moderate- to high-certainty evidence.
Limitations
The main limitation of this review was the small number of events for many drugs and outcomes, which resulted in serious imprecision. This limitation may be due to the study's focus on patients with mild or moderate COVID-19, who were less likely to be hospitalized or die. Consequently, many estimates remain uncertain. Symptom resolution data were also limited because of inconsistencies in how the studies measured and reported outcomes.
Conclusions
No drug demonstrated a significant benefit for most of the outcomes. Conversely, high-certainty evidence indicates that few treatments are ineffective.
'According to our classification, no drug was convincingly different from standard care for the outcomes of mortality, mechanical ventilation, venous thromboembolism, or clinically important bleeding. However, rating certainty using a different target may provide important insights. For example, some interventions suggested little or no effects. For mortality, low-certainty evidence suggested that nirmatrelvir-ritonavir and molnupiravir provided little or no benefit. For mechanical ventilation, moderate-certainty evidence indicated that JAK inhibitors provide little or no benefit to patients. Moderate-certainty evidence suggests that prophylactic-dose anticoagulation provides little or no benefit for venous thromboembolism and results in little or no increase in clinically important bleeding. Several interventions do not appear to offer any benefit for patient-important outcomes, including angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, aspirin, colchicine, fluvoxamine, hydroxychloroquine, ivermectin, and lopinavir-ritonavir. Lopinavir-ritonavir also increases the risk of adverse effects leading to treatment discontinuation and prolongs hospital stay,' the authors said.
The authors added that drug efficacy is not the only factor that clinicians should consider.
'Some of the included drugs have downsides that were not captured in this review; however, further details are available in the guidelines. For example, molnupiravir may be carcinogenic, nirmatrelvir-ritonavir has numerous critical drug-drug interactions, and remdesivir is administered intravenously. Thus, while this review provides an overview of the evidence, individual considerations — such as patient values and preferences, contraindications, drug-drug interactions, and drug-specific adverse events not included in this review — must be considered when deciding whether to use any medication' the authors concluded.
