The Combination of Nirmatrelvir and Ivermectin Exerts Strongly Synergistic Antiviral and Anti-Inflammatory Effects Against Murine Coronavirus Infection of Macrophages
et al., International Journal of Molecular Sciences, doi:10.3390/ijms27167316, Aug 2026
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.0000000001 from 106 studies, recognized in 24 countries.
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In vitro study showing strong synergistic antiviral and anti-inflammatory effects with the combination of ivermectin and nirmatrelvir for RAW264.7 murine macrophages infected with murine hepatitis virus (MHV).
The combination achieved at least 5-6 log10 reduction in live virus titer and 3 log10 reduction in viral RNA load at concentrations lower than either monotherapy, with a Bliss synergy score of 9.95 for live virus titer.
The combination also markedly suppressed key pro-inflammatory cytokines implicated in cytokine storm, including IL-6 (reduced to undetectable levels), TNFα (7.5-fold reduction), IL-1β (9.3-fold reduction), and MCP-1 (3-fold reduction).
Authors hypothesize that the benefit comes from complementary host-targeting mechanisms, potentially including importin-mediated nuclear transport inhibition and STAT3-mediated IL-6 suppression.
Nirmatrelvir combined with azithromycin or doxycycline showed only additive or mildly additive antiviral effects (Bliss scores of 3.79 and 0.66, respectively) with limited immunomodulatory activity.
This study uses a murine coronavirus model rather than SARS-CoV-2 directly. The results are reasonably likely to generalize qualitatively to SARS-CoV-2, although the magnitude of the effect and degree of synergy may differ. MHV and SARS-CoV-2 are both betacoronaviruses with conserved replication machinery, nirmatrelvir directly targets the conserved coronavirus main protease, and prior ivermectin-remdesivir synergy has been observed in both MHV and SARS-CoV-2 models. The study uses murine RAW264.7 macrophages rather than human airway cells, so species- and cell-type-specific factors may alter the observed synergy.
Studies show synergistic antiviral effects for ivermectin in combination with favipiravir7, niclosamide6, paxlovid1, and remdesivir2-5, which may allow increased efficacy and/or similar efficacy at lower doses, potentially reducing dose-dependent side effects.
78 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N776, Dengue45,77,78 , HIV-178, Simian virus 4079, Zika45,80,81 , West Nile81, Yellow Fever82,83, Japanese encephalitis82, Chikungunya83, Semliki Forest virus83, Human papillomavirus61, Epstein-Barr61, BK Polyomavirus84, and Sindbis virus83.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins76,78,79,85 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing46, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination49,86, shows dose-dependent inhibition of wildtype and omicron variants44, exhibits dose-dependent inhibition of lung injury66,71, may inhibit SARS-CoV-2 via IMPase inhibition45, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation17, inhibits SARS-CoV-2 3CLpro59, may inhibit SARS-CoV-2 RdRp activity8,36, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages65, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation87, may interfere with SARS-CoV-2's immune evasion via ORF8 binding12, may inhibit SARS-CoV-2 by disrupting CD147 interaction88-91, may inhibit SARS-CoV-2 attachment to lipid rafts via spike NTD binding10, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1963,92, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage16, significantly mitigates bleomycin-induced pulmonary fibrosis by reducing collagen accumulation and inflammatory cell infiltration64, improves oxidative stress markers while suppressing myofibroblast proliferation64, may minimize SARS-CoV-2 induced cardiac damage48,54, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation93, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses9, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways43, increases Bifidobacteria which play a key role in the immune system94, has immunomodulatory56 and anti-inflammatory75,95 properties, and has an extensive and very positive safety profile96.
Study covers ivermectin and paxlovid.
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How et al., 16 Aug 2026, Singapore, peer-reviewed, 3 authors.
Contact: micctk@nus.edu.sg (corresponding author), wilsonhzy@gmail.com, lexin.teh02@gmail.com.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract:
Article
The Combination of Nirmatrelvir and Ivermectin Exerts Strongly Synergistic Antiviral and Anti-Inflammatory Effects Against Murine Coronavirus Infection of Macrophages
Wilson Z. Y. How 1 , Le Xin Teh 1 and Vincent T. K. Chow 1,2, *
- 1 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117545, Singapore; wilsonhzy@gmail.com (W.Z.Y.H.); lexin.teh02@gmail.com (L.X.T.)
- 2 Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 117545, Singapore
* Correspondence: micctk@nus.edu.sg
Abstract
The emergence of SARS-CoV-2 variants and antiviral resistance highlights the need for improved therapeutic strategies against COVID-19 and other coronavirus infections. By pairing direct-acting antivirals with repurposed host-modulating drugs, combination therapy approaches may enhance antiviral efficacy while mitigating inflammation. In this study, we evaluated the effects of combining Nirmatrelvir (a SARS-CoV-2 main protease inhibitor) with Ivermectin, Azithromycin or Doxycycline-using a murine hepatitis virus (MHV) infection model of RAW264.7 macrophages. Checkerboard assays demonstrated that the Nirmatrelvir-Ivermectin combination exhibited strongly synergistic antiviral activity. This combination achieved potent inhibition of live virus titer of at least 5 to 6 log10 and reduction in viral RNA load of 3 log10, at drug concentrations much lower than the respective monotherapies. The Nirmatrelvir-Ivermectin combination treatment affected the coronavirus replication cycle at the same time-point of 8 h as Nirmatrelvir monotherapy. Moreover, multiplex cytokine protein profiling revealed that Nirmatrelvir-Ivermectin markedly suppressed key pro-inflammatory cytokines and chemokines associated with the cytokine storm, including IL-6, TNFα , IL-1 β , and MCP-1. Conversely, the combinations of Nirmatrelvir with Azithromycin or Doxycycline exhibited only additive or mildly additive effects, with alterations in certain cytokine levels. These findings support the potential of Nirmatrelvir-Ivermectin as a promising novel combination therapy with both antiviral and anti-inflammatory benefits, warranting further in vivo validation and clinical investigation.
Keywords: Nirmatrelvir; Ivermectin; Azithromycin; Doxycycline; antiviral; anti-inflammatory; combination therapy; repurposed drugs; murine hepatitis virus; coronavirus
DOI record:
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"DOI": "10.3390/ijms27167316",
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"URL": "http://dx.doi.org/10.3390/ijms27167316",
"abstract": "<jats:p>The emergence of SARS-CoV-2 variants and antiviral resistance highlights the need for improved therapeutic strategies against COVID-19 and other coronavirus infections. By pairing direct-acting antivirals with repurposed host-modulating drugs, combination therapy approaches may enhance antiviral efficacy while mitigating inflammation. In this study, we evaluated the effects of combining Nirmatrelvir (a SARS-CoV-2 main protease inhibitor) with Ivermectin, Azithromycin or Doxycycline—using a murine hepatitis virus (MHV) infection model of RAW264.7 macrophages. Checkerboard assays demonstrated that the Nirmatrelvir–Ivermectin combination exhibited strongly synergistic antiviral activity. This combination achieved potent inhibition of live virus titer of at least 5 to 6 log10 and reduction in viral RNA load of 3 log10, at drug concentrations much lower than the respective monotherapies. The Nirmatrelvir–Ivermectin combination treatment affected the coronavirus replication cycle at the same time-point of 8 h as Nirmatrelvir monotherapy. Moreover, multiplex cytokine protein profiling revealed that Nirmatrelvir–Ivermectin markedly suppressed key pro-inflammatory cytokines and chemokines associated with the cytokine storm, including IL-6, TNF-α, IL-1β, and MCP-1. Conversely, the combinations of Nirmatrelvir with Azithromycin or Doxycycline exhibited only additive or mildly additive effects, with alterations in certain cytokine levels. These findings support the potential of Nirmatrelvir–Ivermectin as a promising novel combination therapy with both antiviral and anti-inflammatory benefits, warranting further in vivo validation and clinical investigation.</jats:p>",
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