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Background. Antiretroviral therapy (ART)-mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication. Methods. A total of 23 HIV type 1 (HIV-1)-infected, virologically suppressed subjects receiving ART (CD4⁺ T-cell count, >450 cells/μL) were randomly assigned to have 180 μg/week (for arm A) or 90 μg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg-interferon alfa-2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologie failure (viral load, ≥400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed. Results. At week 12 of Peg-interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P =. 0088; arm B, P =. 0010; combined arms, P< .0001). Over 24 weeks, both arms had lower proportions of subjects who had viral load, compared with the proportion of subjects in a historical control group (arm A, P =. 0046; arm B, P =.0011). Subjects who had a sustained viral load of <400 copies/mL had decreased levels of integrated HIV DNA (P =.0313) but increased residual viral loads (P =.0078), compared with subjects who experienced end-point failure. Conclusions. Peg-interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication.

Background Interferons (IFNs) are proteins that combat viruses and regulate the immune system. Studies have demonstrated that aerosol inhalation of IFNα is both effective and safe for treating respiratory infections. However, IFNα has a short half-life and is rapidly cleared by lung defenses. Polyethylene glycol (PEG) ylation is a common strategy to extend the duration of drug action. PegIFNα-2b is a long-acting interferon formed by the covalent binding of 40 kDa Y-shaped branched PEG with recombinant human IFNα-2b. This study aimed to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics of nebulized PegIFNα-2b in healthy adult subjects, providing guidance for further clinical investigations. Methods This study employed a randomized, controlled clinical trial design with a total of 18 healthy adult subjects enrolled. Participants were randomly assigned in a 1:1:1 ratio to three groups. Treatment group 1 and group 2 received 90 µg and 180 µg of nebulized PegIFNα-2b, respectively, while the control group was administered a combination of 180 µg PegIFNα-2b and 15 mg inhalable Ambroxol Hydrochloride solution, all in a single dose. Safety, tolerability, and blood drug concentration were assessed, along with blood neopterin levels for pharmacokinetic and pharmacodynamic evaluation. Results The incidence of adverse events (AEs) was 38.9% (7/18) with no significant difference among the groups ( P  > 0.05). AEs included anemia ( N  = 5) and leukopenia ( N  = 2), predominantly of grade 1 severity (6/7), with no severe events. Blood PegIFNα-2b concentrations were below detection limits in most subjects, except one in treatment group 2. Neopterin levels were generally low in treatment group 1 and the control group, with slightly higher observed in most subjects of treatment group 2, but differences were not significant ( P  > 0.05). Conclusions Nebulized PegIFNα-2b at doses of 90 µg and 180 µg showed acceptable safety and tolerability. Minimal systemic absorption was observed following inhalation. Further studies are needed to explore its potential, especially in patients with lower respiratory tract infections. Clinical trial registration ChiCTR2300074909, retrospectively registered in https://www.chictr.org.cn/ at 20 August 2023.

Patients with low hepatitis B surface antigen (HBsAg) levels and hepatitis B virus (HBV) DNA suppression by nucleos(t)ide analogues (NAs) achieve high rate of HBsAg loss through switching to PegIFNα in pre-registration study. The aim of this study was to achieve higher rate of HBsAg loss through extended PegIFN treatment. 98 patients with HBsAg < 2,000 IU/ml and HBV DNA < 20 IU/ml were randomized to receive PegIFNα-2b or continuing NA therapy for 60 weeks. At the end of treatment (EOT) and end of follow-up (EOF), only patients who switched to PegIFNα-2b achieved HBsAg loss (32.6%) and HBsAg seroconversion (27.9% and 25.6%). Patients who switched to PegIFNα-2b also achieved higher HBeAg seroconversion rates (65.1%) and HBeAg loss (81.4% and 90.7%) than those who continued NAs treatment. On-treatment HBsAg declines predicted the responses at EOT, and HBsAg declines at post-baseline times predicted the responses at EOF. The rates of responses were not increased through extended PegIFNα treatment. For patients with low HBsAg and HBV suppression with NAs, switching to PegIFNα-2b significantly increased the rates of HBsAg loss and HBsAg seroconversion. HBsAg decline can predict the response of switching to PegIFNα-2b following from NAs.

Objective Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Design 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000–1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusions Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.

Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 μg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group. ClinicalTrials.gov NCT00803309.

Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown. Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells. Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load. PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.

Single-nucleotide polymorphisms upstream of the interleukin 28B (interferon λ3) gene (IL28B) strongly influence treatment efficacy in patients carrying hepatitis C virus (HCV) of genotype 1. In patients receiving 12 or 24 weeks of interferon-ribavirin therapy for infection with genotype 2 or 3 (n = 341), we found that rs12979860 strikingly determined the first phase of viral elimination (P <.001). In patients treated for 24 weeks, rsl2979860 also predicted the rate of sustained virologie response (P = .02), especially among those with high baseline HCV RNA levels (P = .002) or older than 45 years (P = .01). Patients carrying CC rs12979860 had higher baseline HCV RNA levels (P <.001) and did not, when treated for 12 weeks, achieve sustained virologie response more often than those carrying CTrs or Tl rs12979S6 . The results indicate that IL28B gene testing may identify patients carrying genotype 2 or 3 who could benefit from extended treatment.

Antiviral therapy (AVT) may improve liver histology in patients with advanced viral hepatitis but its effect on portal pressure remains unknown. This study was aimed to evaluate the influence of antiviral therapy (AVT) on hepatic venous pressure gradient (HVPG) in hepatitis C virus infected patients with portal hypertension. Twenty compensated patients with chronic hepatitis C, fibrosis stage 3 or 4 and HVPG > 5 mmHg received PEG-IFN alpha2b plus ribavirin. Every patient underwent liver biopsy and portal pressure measurements before and immediately after AT. Biopsies were evaluated according to METAVIR score. HVPG significantly dropped in all but one treated patient, with a mean (SD) reduction of 28.2 (12)%[13.8 (5.6) Vs. 10.2 (3.8) mmHg, p = 0.005]. The percentage of HVPG decrease was significantly greater in patients who achieved a virological end of treatment response [26.2 (12.5)% Vs. 12.7 (8.5)%, p = 0.05] and in those with a decrease of at least 2 points in the grade of inflammation [35.7 (4.5)% Vs. 22.1 (9.5)%, p = 0.015]. Nine out of 11 patients with baseline HVPG > or = 12 mmHg showed a decrease greater than 20% (3/11) or under the 12 mmHg threshold (6/11). AVT reduces HVPG in compensated patients with advanced hepatitis C (fibrosis stage 3 or 4) and portal hypertension.

Therapeutic options in response to the 2019-nCoV outbreak are urgently needed. Here, we discuss the potential for repurposing existing antiviral agents to treat 2019-nCoV infection (now known as COVID-19), some of which are already moving into clinical trials.Therapeutic options in response to the 2019-nCoV outbreak are urgently needed. Here, we discuss the potential for repurposing existing antiviral agents to treat 2019-nCoV infection (now known as COVID-19), some of which are already moving into clinical trials.

Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic 1 . Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures 2 , 3 . SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2) 4 . Here we used reverse genetics 5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4 - ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1 ) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro—both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-19 6 . A model in mouse using a species-adapted virus recapitulates features of SARS-CoV-2 infection and age-related disease pathogenesis in humans, and provides a model system for rapid evaluation of medical countermeasures against coronavirus disease 2019 (COVID-19).