Preprint Exploratory analyses of Immunologic Features in a Randomized, Placebo-Controlled Trial of Nirmatrelvir/Ritonavir for [LC], 2026,Bhattacharjee,Iwasaki+

[SNT Gatchaman]

Exploratory analyses of Immunologic Features in a Randomized, Placebo-Controlled Trial of Nirmatrelvir/Ritonavir for Long COVID

Spoiler: Authors

Bornali Bhattacharjee; Mitsuaki Sawano; William B Hooper; Kexin Wang; Alexandra Tabachnikova; Valter Silva Monteiro; Peiwen Lu; Pavlina Baevova; Gisele C Rodrigues; Victoria L Fisher; Cesar Caraballo; Rohan Khera; Shu-Xia Li; Jeph Herrin; Dany Christian; Andreas Coppi; Frederick Warner; Julie Holub; Yashira Henriquez; Maria A Johnson; Theresa B Goddard; Erica Rocco; Amy C Hummel; Mohammad Al Mouslmani; Kevin D Carr; Lawrence Charnas; Magdia De Jesus; Dale Nepert; Paula Abreu; Frank W Ziegler; John Spertus; Leying Guan; Harlan Krumholz; Akiko Iwasaki

This exploratory analysis of PAX LC, a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial examined whether treatment with nirmatrelvir/ritonavir (NMV/r) versus placebo/ritonavir (PBO/r) in individuals with Long COVID could reveal immune features associated with symptom improvement.

Eighty-two participants (n=45 PBO/r; n=37 NMV/r) provided blood samples at baseline (Day 0) and post-treatment (Day 28). Baseline demographic and immunological phenotypes were similar in the two groups.

No significant differences were observed in major immune cell populations or organ function markers between NMV/r vs. PBO/r groups, or before vs. after the treatment. Modest hematologic changes were noted in the NMV/r arm. SARS-CoV-2-specific IgG levels remained constant, with changes in total immunoglobulin subtypes and isotypes in both arms.

Both arms showed similar shifts in cytokine levels. Notably, the levels of S1 and Spike proteins in circulation remained unchanged post-treatment. Regardless of the treatment arm, participants with self-reported symptom improvement showed reductions in the level of the inflammatory chemokine RANTES.

Taken together, the findings of this study demonstrate limited virological and immunological changes in response to nirmatrelvir, contributing insights into the reason for the lack of benefit of the 15-day NMV/r treatment in Long COVID.


Web | DOI | PDF | Preprint: MedRxiv | Open Access

 

[Hutan]

Regardless of the treatment arm, participants with self-reported symptom improvement showed reductions in the level of the inflammatory chemokine RANTES.

That's interesting.
duration of Long COVID symptoms (72–1392 days)

However, more than 30 cytokines were significantly increased or decreased in both the PBO/r (Fig 4C; extended data table 1) and NMV/r (Fig 4C; extended data table 1) arms, with substantial overlap in the specific cytokines affected by day 28 compared to baseline. Among these, a decrease in an inflammatory chemokine RANTES (CCL5), with primary binding specificity to the C-C chemokine receptor type 5 (CCR5)27, were observed upon treatment in both study arms and this decrease was further validated by ELISA in both the PBO/r (Wilcoxon rank-sum test; p = 0.0066) and the NMV/r arms (p = 0.0490) (Fig. 4E, F).

Participants who reported improvement in at least 4 out of the 5 measures were classed as Improvers.
No significant differences in likelihood of being in the Improvers group for sex, age, number of vaccines
Here's the chart for the RANTES levels.



So, quite a few of the Unimproved also had declines. It would have been good to know if duration of symptoms played any part in who improved over the 28 days. Some of the participants had only had symptoms for 3 months or so and so could be expected to recover.

If you look at the red dots on the chart, some of the improvers had high baseline values, whereas the levels at day 28 were all quite similar (and, as far as I can work out, in the normal healthy range). So, I'd like to check that it wasn't the people who had LC for a few months who improved and had reduced RANTES levels, with the initial high levels just being something to do with the acute illness. It sounds as though higher levels of RANTES is normal during acute mild Covid-19.

The results of two randomized placebo-controlled trials of Maraviroc, a bonafide CCR5 antagonist (NCT06974084, NCT06511063) will be informative in understanding whether the CCL5-CCR5 pathway plays a pathological role in Long COVID.