A new phase 2 trial raises questions about nirmatrelvir-ritonavir’s broader efficacy, as other studies highlight its effectiveness in reducing mortality among immunocompromised COVID-19 patients.
A phase 2, double-blind, randomized trial of nirmatrelvir-ritonavir for Long COVID published in The Lancet, showed no statistically significant improvements in health outcomes compared to placebo. The trial included 100 participants (66% female, 34% male) from 48 US states, all with persistent Long COVID symptoms, who were randomly assigned to either the nirmatrelvir-ritonavir (49 participants) or placebo-ritonavir (51 participants) group to assess efficacy, safety, and tolerability.
The primary efficacy endpoint was the change in the PROMIS-29 Physical Health Summary Score (PHSS), which measures physical health across domains like fatigue and physical function. At baseline, the nirmatrelvir-ritonavir group had a mean PHSS score of 39.6, while the placebo group had 36.3. After 28 days, the adjusted mean change in PHSS was 0.45 for the treatment group and 1.01 for the placebo group, resulting in an adjusted mean difference of -0.55 (p=0.54), showing no significant improvement in physical health outcomes for Long COVID patients.
In terms of safety, treatment-emergent adverse events were more common in the nirmatrelvir-ritonavir group, with 76% of participants reporting at least one adverse event compared to 55% in the placebo group. The most frequently reported adverse event was dysgeusia (taste disturbances), which affected 35% of the treatment group. No deaths or serious adverse events occurred during the study period. Early discontinuation due to adverse events was noted in two participants in the nirmatrelvir-ritonavir group and one in the placebo group.
In contrast, a recent cohort study based in Hong Kong that involved 2,217 immunocompromised patients hospitalized with COVID-19 found that nirmatrelvir-ritonavir significantly reduced the risk of post-acute inpatient death by 42%. This study also showed a reduced risk of hospitalization due to acute respiratory distress syndrome. The antiviral was slightly less effective in immunocompromised patients (with a 5% lower efficacy in reducing post-acute inpatient mortality compared to immunocompetent individuals), and its effect on reducing post-acute hospitalizations was less pronounced in the immunocompromised group.
Nirmatrelvir-ritonavir did not significantly improve the PROMIS-29 Physical Health Summary Score in Long COVID patients.
Adverse events occurred in 76% of participants in the nirmatrelvir-ritonavir group compared to 55% in the placebo group, with dysgeusia as the most common side effect.
The Hong Kong study found a 42% reduction in post-acute inpatient mortality in immunocompromised COVID-19 patients treated with nirmatrelvir-ritonavir.
The differential effectiveness of nirmatrelvir-ritonavir in Long COVID patients versus immunocompromised COVID-19 patients highlights potential mechanisms underlying the treatment’s efficacy. In Long COVID patients, the lack of improvement may suggest that viral persistence is less of a factor in symptomatology compared to immunocompromised individuals, where impaired viral clearance leads to prolonged disease and increased risk of severe outcomes. Immunocompromised patients are more susceptible to persistent viral replication, which may explain why the antiviral significantly reduced mortality and hospitalization outcomes in this group.
Both studies highlight the importance of viral persistence and immune status in antiviral treatment. Nirmatrelvir-ritonavir showed limited efficacy for Long COVID but reduced mortality in immunocompromised patients, emphasizing the need for tailored treatment strategies based on immune function and viral load.
