The authors frame their analysis around the fundamental steps of the orthohantavirus infection cycle. Viral entry begins when the Gn glycoprotein docks onto host surface receptors, including β3-integrins and protocadherin-1 (PCDH1). Once internalized via endocytosis, the acidification of the endosomal compartment triggers a conformational change in the viral envelope that drives membrane fusion, releasing the viral genome into the cytoplasm. The viral RNA-dependent RNA polymerase (RdRp) then initiates both transcription and genome replication. Structural proteins and newly synthesized RNA genomes assemble at the Golgi complex or plasma membrane before budding out as mature infectious virions. Each of these stages presents a distinct molecular vulnerability that chemists and virologists can exploit with rationally designed small molecules, peptides, or biologics.

Among the most extensively characterized entry inhibitors are cyclic peptides identified through phage display libraries. Early work identified cyclic nonapeptides that bind the β3-integrin receptor used by pathogenic orthohantaviruses such as Sin Nombre virus (SNV), Hantaan virus (HTNV), Seoul virus (SEOV), and Puumala virus (PUUV) to enter human endothelial cells. Of seventy sequences screened, eleven showed inhibitory effects exceeding 80 percent against SNV in vitro, with the most potent, CPFVKTQLC, demonstrating high inhibitory potency when presented on phage particles. This peptide was subsequently refined through alanine substitution and deletion scanning to a minimal functional unit, the cyclic pentapeptide cyclo-[CPFVC]. However, because free monovalent peptides proved less effective than phage-displayed versions, researchers pivoted toward multivalent presentation on nanoparticles, targeting the viral glycoproteins directly rather than the host receptor. When the peptide CLVRNLAWC was displayed on 100-nanometer nanoparticles at a 4:1 ratio, inhibition of SNV rose from 9 percent as a free peptide to 32.5 percent. The peptide CQATTARNC achieved even greater efficacy, surpassing 50 percent inhibition when the nanoparticle-to-virus ratio was increased to 20:1.

Building on these strategies, investigators extended the approach to Andes virus (ANDV) by eluting peptide libraries from purified virions using monoclonal antibodies against the Gn and Gc glycoproteins. A key finding was that combining peptides targeting different Gn- and Gc-specific sequences produced synergistic inhibition significantly more powerful than single-peptide treatments, underscoring the value of simultaneously engaging multiple viral epitopes. To transition from biological peptides to drug-like molecules, researchers used the three-dimensional structure of the refined pentapeptide cyclo-[CPFVC] in a ligand-based virtual screening campaign evaluating over 600,000 small molecules. This effort identified compounds such as G319–0078 and 8012-0652, which were approximately 2,000 times more potent than the original cyclic peptides, achieving high-affinity inhibition in the nanomolar range with EC50 values between 1.3 and 2.5 nanomolar in vitro. These molecules represent a compelling proof of concept that computational screening can transform a modest peptide lead into a highly potent preclinical candidate warranting further in vivo evaluation.

A distinct strategy targets the membrane fusion process itself. The orthohantavirus Gc glycoprotein functions as a class II fusion protein, and completing membrane fusion requires a major structural relocation of Domain III (DIII) to achieve the post-fusion state. Exploiting this mechanical vulnerability, researchers demonstrated that viral entry can be blocked using recombinant fragments and synthetic peptides derived from the Gc DIII and stem region. These fragments allow initial Gc trimerization to proceed but ultimately prevent membrane hemifusion and fusion pore formation. The recombinant DIII fragment inhibited ANDV fusion by approximately 70 percent at 25 micromolar and demonstrated cross-reactivity by reducing PUUV-mediated fusion by 50 percent. Even greater potency was observed with the R2 peptide, derived from the C-terminal portion of the Gc stem region, which inhibited ANDV fusion by up to 95 percent in vitro. Although efficacy dropped to a 70 percent cross-reduction against PUUV-mediated fusion at 20 micromolar due to high genetic divergence between the two viruses, the results still demonstrate meaningful cross-protective potential.

Natural products have also yielded promising entry inhibitors. Griffithsin (GRFT), an algae-derived lectin with demonstrated efficacy against coronaviruses, retroviruses, lentiviruses, flaviviruses, hepaciviruses, paramyxoviruses, and herpesviruses, potently inhibits ANDV entry in vitro. A synthetic trimeric variant possessing nine oligosaccharide-binding sites showed even greater potency against ANDV and SNV. In vivo, GRFT inhibited HTNV and provided partial protection in suckling mice. Its scalability and ease of purification highlight its translational potential. Separately, bovine lactoferrin (LF) prevents initial viral adsorption and adhesion of SEOV, likely by interacting with cellular glycosaminoglycans such as heparin or by sterically hindering virus binding to host β-integrin and lectin receptors. Prophylactic administration of LF one day before orthohantavirus inoculation improved survival rates in mice up to 70 percent at 160 milligrams per kilogram, with a double-administration regimen enhancing survival to over 94 percent. When combined with subsequent ribavirin treatment, the two agents functioned synergistically, profoundly reducing viral shedding and completely inhibiting viral protein expression.

Discovered through high-throughput screening of over 2,300 approved drugs and traditional Chinese medicines, cepharanthine (CEP), a compound isolated from Stephania cephalantha Hayata, has emerged as a potent viral entry and membrane fusion inhibitor. In vitro, CEP inhibited HTNV pseudovirus with an EC50 of 0.9 micromolar and reduced viral nucleic acid copies by 73 percent at 20 micromolar. In vivo, administration to BALB/c mice five hours post-infection significantly reduced infection by 93 percent at 90 milligrams per kilogram per day and 94 percent at 180 milligrams per kilogram per day. Given its established safety profile, CEP represents a high-priority candidate for repurposing and advancement into human clinical trials against orthohantaviruses.

On the replication front, ribavirin remains the historical benchmark for anti-hantaviral therapy. Once transported into host cells, ribavirin is phosphorylated into metabolites including ribavirin-5′-monophosphate, which inhibits inosine monophosphate dehydrogenase and depletes intracellular GTP, and ribavirin-5′-triphosphate, which selectively interacts with the viral RdRp as its primary mechanism of action. Incorporation of ribavirin leads to accumulation of genomic errors and dramatic loss of virus viability through error catastrophe. Preclinical evaluation confirmed that early ribavirin administration reduces viral loads and prevents severe disease in suckling mouse models infected with HTNV and hamster models infected with ANDV. Clinically, intravenous ribavirin demonstrated efficacy in a double-blind, placebo-controlled trial of 242 patients with HTNV-induced HFRS, significantly reducing hemorrhagic and overall mortality. However, efficacy varies significantly across strains and clinical syndromes. In the context of HCPS caused by ANDV, ribavirin intervention eliminated mortality compared to a 35 percent historical case-fatality rate and reduced the incidence of the severe cardiopulmonary phase from 84 to 57 percent. Conversely, in a larger placebo-controlled, double-blinded trial evaluating intravenous ribavirin for HCPS, the drug failed to demonstrate overall therapeutic efficacy, revealing no significant difference in survival between groups. Trials in HFRS caused by PUUV also showed insufficient efficacy and safety, likely due to delayed drug administration and a weaker correlation between viral load and disease severity compared to HTNV infection. Furthermore, the clinical utility of ribavirin is constrained by dose-limiting toxicities, most notably reversible hemolytic anemia reported in 71 percent of recipients.

Favipiravir (T-705), originally discovered during a screening for anti-influenza compounds, has emerged as a potent viral replication inhibitor. Upon cellular entry, host enzymes convert favipiravir into its active form, favipiravir-RTP, a purine nucleotide analogue incorporated into nascent viral RNA that induces lethal mutagenesis. Favipiravir potently inhibited ANDV and SNV in vitro and provided 100 percent survival in lethal ANDV hamster models when treatment was initiated before viremia, making it an important candidate for post-exposure prophylaxis. Combination with ribavirin produced highly synergistic effects, with peak antiviral activity observed at a ratio of 12 micromolar favipiravir to 18.75 micromolar ribavirin, achieving greater than 99 percent overall inhibition of HTNV. Additionally, ETAR (1-β-D-ribofuranosyl-3-ethynyl-[1,2,4]triazole) demonstrated high potency in vitro against HTNV and ANDV, and in vivo studies using HTNV-challenged suckling mice showed approximately 25 percent protection at doses of just 12.5 and 25 milligrams per kilogram, mirroring ribavirin’s therapeutic outcomes at a fraction of the concentration. Beyond nucleoside analogues, the viral nucleoprotein has emerged as a promising alternative target. Terpene-isoindole conjugates such as compound 18 demonstrated potent anti-HTNV activity with exceptionally low toxicity, and molecular docking suggests they bind to the highly conserved RNA-binding site of the nucleoprotein, competing with viral RNA and effectively arresting intracellular replication. Similarly, morin, a natural flavonoid found in plants like mulberry and perilla, binds directly to the core assembly region of the viral nucleoprotein, sterically hindering RNA encapsidation and disrupting the formation of functional replication complexes.

In the absence of licensed antiviral treatments, clinical management remains primarily supportive, focusing on intensive monitoring and treatment of respiratory, cardiac, and renal complications. Achieving early diagnosis remains a primary clinical challenge, as the efficacy of supportive care is substantially reduced if initiated after the onset of severe disease. Host-targeted and anti-inflammatory strategies have recently been explored to mitigate the characteristic vascular leak and cytokine storm, most notably during the 2026 cruise ship outbreak, where the JAK inhibitor baricitinib and the bradykinin B2 receptor antagonist icatibant were administered in a combined therapeutic regimen alongside ribavirin and favipiravir. Passive immunotherapy continues to be a major investigative focus, with convalescent plasma showing potential to reduce mortality and newer candidates such as the quadrivalent human polyclonal antibody SAB-163 and highly potent monoclonal antibodies demonstrating up to 100 percent protection in lethal animal models. Regarding prevention, Hantavax has been used to prevent HFRS in South Korea, and China routinely administers inactivated bivalent vaccines targeting HTNV and SEOV in endemic regions. However, a globally licensed orthohantavirus vaccine does not currently exist, leaving New World strains and HCPS without an approved preventative countermeasure. The review’s authors argue that expanding preclinical testing to include globally neglected variants, combined with modern in silico screening of extensive chemical and natural product libraries, will be essential to develop broad-spectrum hantaviral therapeutics capable of mitigating future epidemic threats.

Subject of Research: Antiviral drug discovery targeting the orthohantavirus life cycle

Article Title: Hantaviral therapeutics: life cycle targets and chemotherapeutic interventions

Article References: Kocabiyik, D. Z., de Araujo, J., Durigon, E. L., & Wrenger, C. (2026). Hantaviral therapeutics: life cycle targets and chemotherapeutic interventions. Frontiers in Cellular and Infection Microbiology, 16, Article 1972830. https://doi.org/10.3389/fcimb.2026.1972830

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1972830

Keywords: orthohantavirus, antiviral discovery, viral entry inhibitors, RNA-dependent RNA polymerase, ribavirin, favipiravir, griffithsin, cepharanthine, nucleoprotein inhibitors, HFRS, HCPS, virtual screening

The answer, according to the study, is a resounding yes. Among fifty treatment-naïve patients, forty-eight—96 percent—achieved a sustained virologic response at twelve weeks after the end of therapy, the standard benchmark for a cure. Among fifty patients previously treated with pegylated interferon plus ribavirin, the punishing regimen that dominated hepatitis C care for decades, forty-seven—94 percent—achieved the same outcome. The difference between the two groups was not statistically significant, with a p-value of 0.6, meaning that prior treatment history essentially did not matter for success with the newer regimen. In practical terms, nearly every patient in the cohort, regardless of their therapeutic past, left the study virologically cured.

To understand why this finding matters, it helps to appreciate how radically hepatitis C treatment has changed. Before the arrival of direct-acting antivirals in the mid-2010s, the standard of care combined weekly injections of pegylated interferon with oral ribavirin for up to forty-eight weeks. Interferon works indirectly, amplifying the immune system’s antiviral state, and it produces flu-like symptoms, depression, cytopenias, and a host of other toxicities. Cure rates hovered around 50 to 70 percent for the most common viral genotypes, and many patients either could not tolerate the regimen or relapsed after completing it. Direct-acting antivirals changed the equation by targeting viral proteins directly. Ledipasvir inhibits the hepatitis C virus NS5A protein, which is essential for viral replication and assembly, while sofosbuvir targets the NS5B RNA-dependent RNA polymerase, the enzyme the virus needs to copy its genome. Adding ribavirin, a nucleoside analog that enhances viral clearance through incompletely understood mechanisms, further guards against relapse in certain patient populations.

The Sana’a study enrolled one hundred adults with chronic hepatitis C between April 2019 and March 2021, dividing them evenly between the naïve and previously treated cohorts. All participants received ledipasvir/sofosbuvir plus ribavirin for twelve weeks. The researchers measured hepatitis C viral load using the COBAS TaqMan real-time polymerase chain reaction platform, a highly sensitive assay capable of detecting even trace amounts of viral RNA. Viral load was assessed at baseline and again twelve weeks after the completion of therapy to determine sustained virologic response, or SVR12. Alongside virologic endpoints, the team tracked a battery of clinical and laboratory parameters, including the liver enzymes alanine aminotransferase and aspartate aminotransferase, alpha-fetoprotein as a marker of hepatocellular carcinoma risk, and a full panel of hematological indices. Adverse events and medication adherence were recorded throughout.

The safety profile of the regimen proved reassuring. Anemia was the most frequent laboratory abnormality observed, and the researchers attributed it to ribavirin, which is well known to cause hemolytic anemia by depleting red blood cells of ATP and other nucleotides. Ribavirin-induced anemia is typically dose-dependent and reversible, and in this cohort it did not force anyone off treatment. Other adverse events were mild to moderate in severity and included fatigue, headache, nausea, and pruritus. Critically, no treatment discontinuations occurred in either group, a finding that speaks both to the tolerability of the regimen and to the adherence of the patients, who completed the full twelve weeks despite the challenges of accessing care in a resource-limited health system.

Perhaps equally notable was what did not predict treatment failure. The researchers found that age, sex, and diabetes mellitus were not associated with SVR12 outcomes, suggesting that the regimen’s efficacy was robust across the demographic and metabolic spectrum represented in the cohort. This is consistent with the broader literature on direct-acting antivirals, which have repeatedly demonstrated that host factors matter far less than they did in the interferon era. When cure rates approach the mid-nineties, there is simply little room for baseline characteristics to exert a measurable effect. The near-identical results in previously treated patients are particularly significant, because prior interferon failure has historically been one of the strongest predictors of poor response to subsequent therapy.

The Yemeni context gives these findings an urgency that extends beyond the clinic. Yemen’s health infrastructure has been severely strained by conflict, and access to specialized diagnostics and medications remains limited for much of the population. Chronic hepatitis C, if left untreated, progresses over years to cirrhosis and, in a subset of patients, to hepatocellular carcinoma, the most common primary liver cancer. Every patient cured is a patient removed from that trajectory, and every cured patient also reduces ongoing transmission in the community. The World Health Organization has set ambitious global targets for hepatitis C elimination, and achieving them will depend heavily on demonstrating that direct-acting antiviral regimens work as well in real-world, resource-constrained settings as they do in the controlled environments of pharmaceutical company trials. This study provides exactly that kind of evidence for Yemen.

The retrospective design of the study does impose limitations that the authors and readers must keep in mind. Retrospective cohorts rely on existing medical records rather than prospective randomization, which can introduce selection bias and incomplete data capture. The sample size of one hundred, while adequate for detecting the headline result, is modest, and the absence of genotype-specific subgroup analyses in the reported findings leaves open questions about whether certain viral strains circulating in Yemen respond differently to ledipasvir. The twelve-week follow-up window, while the accepted standard for SVR12, cannot capture very late relapses, although these are rare with direct-acting antiviral therapy. Nonetheless, the consistency of the results with international trial data strengthens confidence that the findings are generalizable.

The study also carries practical implications for treatment policy in Yemen and comparable settings. Because prior treatment status did not affect outcomes, clinicians in resource-limited environments may not need to reserve direct-acting antivirals exclusively for treatment-naïve patients or to construct complex algorithms based on prior interferon exposure. A single, uniform twelve-week regimen of ledipasvir/sofosbuvir plus ribavirin appears capable of curing the vast majority of chronic hepatitis C patients regardless of history. Simplification of this kind is a genuine asset where specialist expertise is scarce and where every additional diagnostic test or treatment modification adds cost and delay. The authors conclude that the regimen is safe, well tolerated, and highly effective, and that these findings support the adoption of direct-acting antivirals as the standard of care in resource-limited settings.

As the global campaign against hepatitis C moves from trial evidence to elimination targets, studies like this one fill a crucial gap. They demonstrate that the scientific advances of the past decade are not confined to wealthy health systems but can deliver near-universal cure rates in one of the world’s most challenging environments. For the ninety-five of one hundred Yemeni patients in this cohort who cleared their infection, the result is concrete: a virus that once promised cirrhosis or cancer has been eradicated from their blood with twelve weeks of oral therapy. For the clinicians and public health officials working toward hepatitis C elimination in the Eastern Mediterranean, the message is equally clear—modern antiviral therapy works, and it works for everyone.

Subject of Research: Sustained virologic response to ledipasvir/sofosbuvir plus ribavirin therapy in treatment-naïve and previously treated chronic hepatitis C patients in Yemen

Article Title: Comparison of sustained virologic responses to ledipasvir/sofosbuvir plus ribavirin therapy between previously treated and naïve patients with chronic hepatitis c in yemen: a retrospective comparative cohort study

Article References: Al-Faqih, M. H., Bahaj, S. S., Othman, A. M., Al-Amrani, M. A., & Assayaghi, R. M. (2026). Comparison of sustained virologic responses to ledipasvir/sofosbuvir plus ribavirin therapy between previously treated and naïve patients with chronic hepatitis c in yemen: a retrospective comparative cohort study. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14550-6

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14550-6

Keywords: hepatitis C, hepatitis C virus, direct-acting antivirals, ledipasvir, sofosbuvir, ribavirin, sustained virologic response, Yemen, pegylated interferon, anemia, BMC Infectious Diseases, resource-limited settings

The drug in question is favipiravir, a broad-spectrum nucleoside analogue that inhibits viral RNA-dependent RNA polymerases and is already approved for influenza treatment in several countries. The research team began by characterizing its activity against Oropouche virus in cultured Vero E6 cells, comparing it directly with ribavirin, another broad-spectrum antiviral. Favipiravir proved substantially more potent, with a mean half-maximal effective concentration of 28.4 micromolar compared with 115.7 micromolar for ribavirin. Untreated infected cells developed marked cytopathic effects, and ribavirin offered only limited protection, whereas favipiravir preserved cellular morphology in a dose-dependent fashion and robustly reduced infectious virus production. Time-of-addition experiments pinpointed the drug’s stage of action: treatment significantly reduced viral titers when administered at the time of infection or during early replication, but not at the maturation stage, consistent with favipiravir’s established mechanism of interfering with viral RNA synthesis during the post-entry replication phase.

The decisive test came in vivo. The researchers used a lethal Syrian hamster model, infecting animals intraperitoneally with 5.4 × 10⁵ plaque-forming units of the OROV TRVL 9760 strain. All vehicle-treated animals succumbed to infection by three days post-infection, without preceding overt clinical symptoms or weight loss—a fulminant course that underscores how aggressive lethal Oropouche disease can be in this model. In stark contrast, animals receiving high-dose favipiravir at 600 milligrams per kilogram per day, given orally twice daily beginning one hour before infection and continuing for six days, survived the entire 26-day observation period without any clinical signs and steadily gained weight. Lower doses of favipiravir and both tested doses of ribavirin conferred only partial protection, and notably, some animals in the ribavirin groups developed neurological symptoms, including ataxia, hindlimb weakness, and paralysis, after treatment ceased.

Virological measurements explained these divergent outcomes. Using plaque assays and reverse transcription quantitative PCR, the team tracked viral loads in serum, brain, liver, and spleen at multiple time points. Vehicle-treated animals carried high viral burdens in all tissues at two days post-infection. High-dose favipiravir, by contrast, suppressed viral replication so completely that no viral RNA or infectious virus was detectable in any tissue at any time point examined. The suboptimal regimens told a more cautionary story: although low-dose favipiravir and ribavirin reduced infectious virus in serum, liver, and spleen, infectious virus persisted in the brains of these animals at six and eight days post-infection, indicating incomplete clearance from the central nervous system that correlated with the delayed neurological disease observed after treatment withdrawal. The message is clear—insufficient antiviral pressure allows viral neuroinvasion, and neuroinvasion drives fatal disease.

Perhaps the most clinically encouraging finding concerns timing. In outbreak settings, patients rarely present before infection is already established, so a drug that works only as prophylaxis would be of limited value. The researchers therefore tested delayed treatment, initiating favipiravir at one hour before infection, at the time of infection, or at 6, 24, or 48 hours after infection. Strikingly, animals that began treatment as late as 24 hours post-infection were fully protected, with 100 percent survival and complete suppression of viral replication in systemic organs and the central nervous system. Even at 48 hours post-infection, when the therapeutic window was narrowing, favipiravir still conferred partial protection, with 50 percent survival and consistent weight gain among survivors. This therapeutic window, demonstrated in a model where untreated infection is uniformly lethal within days, substantially strengthens the case for favipiravir as a practical candidate for human Oropouche disease.

Beyond efficacy, the study’s second major contribution is mechanistic. To define the host responses associated with Oropouche virus pathogenesis and their modulation by antiviral therapy, the team performed tissue-resolved transcriptomic profiling—RNA sequencing of liver and brain collected at two days post-infection. Because the Syrian hamster genome remains less comprehensively annotated than the mouse genome, hamster genes were functionally annotated through their mouse orthologs. Principal component analysis revealed a clear transcriptional separation between infected and uninfected animals in both tissues, while favipiravir-treated animals clustered near uninfected controls, indicating that the infection-driven transcriptional upheaval was largely suppressed by the drug. This is, to the authors’ knowledge, the first in vivo, tissue-resolved transcriptomic framework of Oropouche virus infection.

The transcriptomic signatures in infected animals were distinctive and, in places, ominous. In the liver, where the virus replicated robustly, infection induced upregulation of genes involved in chemotaxis, cytokine signaling, myeloid cell differentiation, and interferon responses, alongside downregulation of metabolic pathways governing energy production and fatty acid metabolism. In the brain, antiviral and inflammatory programs were induced even more strongly, accompanied by pathways promoting immune cell recruitment. Quantitative PCR validation of selected interferon-stimulated genes—Cxcl10, Rsad2, and Isg15—confirmed strong induction at two days post-infection in both tissues of untreated animals, which was suppressed by both favipiravir and ribavirin at that early stage. At later time points, however, Rsad2 and Isg15 expression tended to remain elevated in ribavirin-treated animals, correlating with their persistent brain viral loads, whereas expression stayed low in favipiravir-treated animals. Interestingly, the canonical inflammatory cytokines Il6, Il10, and Tnf-alpha showed no significant changes at two days post-infection and did not track with viral replication, suggesting they are unlikely to be major drivers of Oropouche disease in this model.

The metabolic findings deserve particular attention. Although liver involvement is not a prominent feature of typical Oropouche fever, recent fatal human infections have been associated with markedly elevated aminotransferase levels and liver injury biomarkers, and independent studies have demonstrated hepatic infection and inflammatory responses in human liver organoids and an experimental mouse model. The simultaneous enrichment of pathways associated with positive regulation of innate immune responses and negative regulation of defense responses in high-burden animals suggests a complex, potentially dysregulated host response, in which sustained antiviral and inflammatory signaling coexists with regulatory mechanisms that constrain excessive immune activation. When viral replication remains high, such regulation appears insufficient. The concurrent downregulation of energetic, lipid metabolic, and mitochondrial pathways in the liver implies that cellular stress during high-burden infection may contribute to tissue dysfunction and injury, meaning that Oropouche pathogenesis likely reflects not only direct viral replication but also the interplay between persistent viral burden, dysregulated immunity, and disrupted metabolic homeostasis.

The authors are candid about the study’s limitations. The reliance on mouse orthologs for gene annotation means hamster-specific transcriptional features and genes lacking confident mouse orthologs may have been underrepresented. Additionally, because all vehicle-treated animals reached the humane endpoint before six days post-infection, direct comparisons of gene expression between untreated and treated animals at later time points were impossible, leaving some uncertainty about whether the later profiles reflect favipiravir’s effects or the absence of ongoing infection. These caveats notwithstanding, the study extends earlier work by Rodrigues and colleagues, who established the Syrian hamster as a relevant model of Oropouche pathogenesis, by integrating tissue-resolved transcriptomics with therapeutic intervention in a single experimental framework.

Translational considerations will shape what happens next. Favipiravir offers genuine advantages over other polymerase-targeting candidates such as 4′-fluorouridine, including oral bioavailability and prior clinical use against multiple viral diseases, and its demonstrated efficacy with delayed initiation enhances its relevance for outbreak settings where early diagnosis is difficult. Yet the drug carries known safety liabilities: teratogenic and embryotoxic effects, and an association with elevated serum uric acid and hyperuricemia. These concerns are especially pertinent for Oropouche virus, given the growing recognition of congenital and pregnancy-associated disease. The authors emphasize that further studies addressing pharmacokinetics, optimal dosing, treatment duration, and safety in relevant populations will be required before clinical application. Even so, the findings provide strong preclinical evidence that timely, potent antiviral intervention can prevent central nervous system invasion, suppress pathogenic inflammatory and metabolic programs, and avert lethal Oropouche disease—transforming the outlook for a pathogen that, until now, medicine could only watch.

Subject of Research: Favipiravir efficacy and host transcriptomic responses in lethal Oropouche virus infection

Article Title: Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy

Article References: Sousa Moraes, C., Gonzalez, G., Sato, A., Miki, S., Inoue, A., Tabata, K., Kranrod, J. W., Kabamba, C. F., Ohnuma, A., Matsuno, K., Harada, R., Saito, S., Akimoto, N., Sasaki, M., Orba, Y., Hall, W. W., Sawa, H., & Itakura, Y. (2026). Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy. PLOS Pathogens, 22(10), e1014647. https://doi.org/10.1371/journal.ppat.1014647

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014647

Keywords: Oropouche virus, favipiravir, antiviral therapy, arbovirus, neuroinvasion, Syrian hamster model, transcriptomics, interferon response, ribavirin, PLOS Pathogens, emerging infectious disease, RNA virus

Quantitative reverse transcription polymerase chain reaction testing returned cycle threshold values of 35 and 36, numbers that indicate a very low systemic viral burden. In the arithmetic of viral haemorrhagic fevers, high viraemia generally tracks with severe disease and poor outcomes, while low viral loads are usually reassuring. Yet this patient, with barely detectable virus circulating in her blood, was experiencing some of the most severe neuropsychiatric distress her care team had encountered in Lassa fever. The dissociation between her laboratory values and her clinical state is the central puzzle of the report, authored by Amos Egbedion Unuane of the Federal Medical Centre in Owo and Ambrose Alli University in Ekpoma, together with colleagues from microbiology, community medicine, chemical pathology and psychiatry departments in Nigeria.

The epidemiological backdrop matters. Nigeria remains the global epicentre of Lassa fever, an arenavirus infection transmitted to humans primarily through contact with food or household items contaminated by the urine and faeces of Mastomys rodents, particularly the multimammate mouse Mastomys natalensis. The disease has traditionally been classified as a viral haemorrhagic illness, characterised by systemic symptoms and the potential for catastrophic bleeding. But the authors note that evolving clinical patterns suggest neuropsychiatric manifestations are becoming increasingly prominent, particularly in Ondo, Edo and Bauchi States. Crucially, these neurological and psychiatric features often appear in patients who lack classic haemorrhagic signs, creating a real risk that they will be misdiagnosed as primary psychiatric disorders or as complicated malaria.

That diagnostic trap played out in this very case. The patient’s initial presentation was misread as complicated malaria, a mistake the authors describe as emblematic of the challenges facing clinicians in endemic hotspots, where atypical presentations of Lassa fever are increasingly documented. Malaria is far more common and its symptoms overlap broadly with early Lassa fever, so the default assumption in a febrile patient is understandable. But the presence of a focal seizure, followed by escalating psychiatric symptoms, should have served as a red flag. The report argues that acute psychiatric changes, refractory insomnia and seizures should be treated as critical clinical clues that warrant prompt evaluation for Lassa fever, even when haemorrhage is absent and viral loads are low.

The timeline of the infection adds another instructive detail. Seven days before her hospital admission, the patient had identified and disposed of a Mastomys species rodent at her residence. This history of rodent contact, obtained through careful clinical interviewing, provided the epidemiological link that ultimately pointed the diagnostic workup toward Lassa fever. In endemic regions, the authors suggest, such environmental histories should be actively sought in any patient presenting with fever and unexplained neurological or psychiatric features, because the window for effective treatment narrows rapidly as the infection progresses.

Treatment followed established protocols. The patient received a full course of intravenous ribavirin, the only widely available specific antiviral therapy for Lassa fever, alongside targeted supportive and symptomatic management. The response was gratifying: she achieved complete clinical recovery, with resolution of all neurological and psychiatric deficits. The outcome demonstrates that even severe neuropsychiatric complications of Lassa fever can be reversible when the diagnosis is made and appropriate therapy is delivered, reinforcing the argument that early recognition of atypical presentations is not merely an academic exercise but a determinant of survival and long-term neurological health.

The mechanistic implications of the case are perhaps its most scientifically provocative element. The authors propose two non-exclusive explanations for the marked clinico-biological dissociation they observed. The first is direct viral neurotropism: the possibility that Lassa virus, an Old World arenavirus, can invade and replicate within cells of the central nervous system, causing injury that is invisible to measurements of viral RNA in peripheral blood. The second is a sequestered neuro-inflammatory response, in which immune activity within the brain and spinal cord proceeds independently of the systemic viral burden measured in the bloodstream. Either scenario would explain how a patient with cycle threshold values of 35 and 36, indicating minimal circulating virus, could manifest seizures, tremors, emotional instability and insomnia so severe that sedation failed.

Central nervous system involvement in Lassa fever is not entirely without precedent, but the timing described in this report is notable. The authors emphasise that central nervous system morbidity may present early in the clinical course of the disease, even in the absence of an overt systemic crisis. This challenges the conventional staging of the illness, in which neurological complications are typically regarded as late phenomena of severe, high-viraemia disease. If early neuropsychiatric involvement is more common than previously appreciated, the true burden of Lassa fever-related neurological injury in endemic regions may be substantially underestimated, both because such cases go undiagnosed and because survivors with psychiatric sequelae may never be linked back to their antecedent infection.

The practical consequences of this case report extend into public health policy. The authors call for the integration of neuro-phenotyping, the systematic characterisation of neurological and psychiatric features, into revised clinical management strategies for Lassa fever. They also stress the urgency of stringent environmental rodent control, since prevention of infection at its source remains the most reliable safeguard in communities where Mastomys rodents live in close proximity to human dwellings and food stores. For frontline hospitals in Ondo, Edo, Bauchi and beyond, the message is that a febrile patient with new seizures, agitation or intractable insomnia deserves consideration of Lassa fever regardless of whether bleeding is present or viral load assays suggest a mild infection.

The report, published open access on 12 September 2026 after acceptance by BMC Infectious Diseases, was conducted in accordance with the Declaration of Helsinki, with an ethical exemption from the Health Research Ethics Committee of the Federal Medical Centre, Owo, and written informed consent from the patient for publication. It received no specific external funding. Its authors, drawn from the Federal Medical Centre’s departments of medical microbiology, community medicine, chemical pathology and psychiatry, along with Ambrose Alli University and Achievers University, argue that their single case carries a broad warning: neuropsychiatric symptoms may be significant in Lassa fever even without haemorrhage or high viral loads. In a disease that infects thousands of Nigerians each year and remains dramatically under-reported, recognising the brain as an early and independent target of the virus could reshape triage, testing and treatment across the endemic belt.

Subject of Research: Neuropsychiatric complications of clinically mild, low-viraemia Lassa fever in Nigeria

Article Title: Neuropsychiatric complications of clinically mild lassa fever with low viraemia: a case report from a global hotspot in Owo, Ondo State, Nigeria

Article References: Unuane, A. E., Oko-Uromi, D. O., Adedosu, N. A., Ayodeji, O. O., Raji, S. O., Osagbaekhoe, A. A., & Azegbeobor, J. O. (2026). Neuropsychiatric complications of clinically mild lassa fever with low viraemia: a case report from a global hotspot in Owo, Ondo State, Nigeria. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14434-9

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14434-9

Keywords: Lassa fever, neuropsychiatric, Mastomys natalensis, low viraemia, seizure, insomnia, ribavirin, Nigeria, Owo, viral neurotropism, malaria misdiagnosis, rodent control