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Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatic fibrosis, and chronic infection can frequently progress to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Treatment with pegylated interferons (INFs) plus ribavirin has been shown to be more effective than pegylated INFs alone or standard INFs with or without ribavirin. The early response of HCV to treatment with peg-INF has been used to predict treatment outcomes in infected patients, emphasizing the importance of viral kinetics and genotyping in their treatment. Mathematic modelling of viral dynamics has shown the importance of optimal doses of drug, with early virologic response at week 12 predictive of sustained virologic response. Maintaining INF concentration above a therapeutically effective level is necessary to prevent viral rebound and subsequent treatment failure. Once-weekly dosing with peg-INF- α2a, which has a longer half-life than other forms of INF, plus daily dosing with ribavirin, has been shown to be effective in reducing viral load. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the clinical features, pathologic changes, and viral RNA kinetics in the course of acute and subacute experimental coxsackievirus B3 (CVB3) infection in a murine model. Methods: Five-week-old A/J inbred male mice were divided into 5 groups. Four of those groups were inoculated intraperitoneally with 5 × 104 (group 1), 1 × 105 (group 2), 5 × 105 (group 3), or 1 × 106 (group 4) PFU of CVB3. Control mice were inoculated with uninfected Vero cell lysate in DMEM. Mice from each group were sacrificed on days 7 or 14 after inoculation. Results: Bloody diarrhea, earlier weight loss, perianal swelling, and death were correlated with higher viral load. One of ten mice in group 3 and 5 of 10 mice in group 4 died spontaneously between days 4 and 12 after inoculation. All of the remaining 34 mice of infected groups demonstrated extensive pancreatic inflammation. Focal myocarditis developed in only 4 (11.8%) of those 34 subjects. Amylase and creatine kinase activities in the serum were increased in the mice of infected groups. CVB3 RNA was detected in the heart and pancreatic tissue in all subjects. The CVB3 RNA copy number in pancreatic tissue was not correlated with the severity of inflammation. Conclusions: In the murine model, viral loading dose determines the clinical features of CVB3-induced infection, and the severity of pancreatitis is not correlated with the viral loading dose or tissue level of viral RNA. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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Abstract: SARS-associated coronavirus was identified as the etiological agent of severe acute respiratory syndrome and a large virus pool was identified in wild animals. Virus generates drug resistance through fast mutagenesis and escapes antiviral treatment. siRNAs targeting different genes would be an alternative for overcoming drug resistance. Here, we report effective siRNAs targeting structural genes (i.e., spike, envelope, membrane, and nucleocapsid) and their antiviral kinetics. We also showed the synergistic effects of two siRNAs targeting different functional genes at a very low dose. Our findings may pave a way to develop cost effective siRNA agents for antiviral therapy in the future. [Copyright &y& Elsevier]

Background/Aims : Recombinant human albumin-interferon alfa (alb-IFN) is a novel 85.7-kD recombinant protein consisting of interferon alfa-2b genetically fused to human serum albumin. Methods : A phase 2, open-label, dose-ranging study was conducted in IFN-alfa-naïve patients with genotype 1 chronic hepatitis C to evaluate the antiviral activity, safety, and pharmacokinetics of alb-IFN. Fifty-six patients were enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts of 200, 450, 670, 900, and 1200μg. Results : A 2 log10 IU/mL or greater reduction in hepatitis C virus (HCV) RNA at Week 4 was observed in 69% (18/26) of patients who received the higher alb-IFN doses of 900 and 1200μg. The mean HCV RNA reduction at Week 4 in these two higher-dose cohorts was 3.2 log10 IU/mL. Modeling of viral kinetics demonstrated a biphasic response that was dose dependent. Adverse events were mostly mild to moderate in severity. The most common adverse events were headache (73%), chills (63%), fatigue (61%), and arthralgia (55%). The median terminal half-life was 141h consistent with previous alb-IFN data from IFN-alfa-experienced patients. Conclusions : Alb-IFN demonstrated significant antiviral activity and was well tolerated in patients with HCV genotype 1 infection. [Copyright &y& Elsevier]

The Synergistic effect of interferon (IFN) and ribavirin for patients with chronic hepatitis C has been demonstrated, but ribavirin has no apparent direct antiviral effect against hepatitis C virus (HCV) when used as monotherapy. To elucidate the mechanism of ribavirin on enhanced HCV eradication when used in combination therapy, we investigated the serum HCV dynamics of free-virions (FV) and immune-complexes (IC) in genotype-1b infected patients treated with IFN- α2b alone ( n = 11) or in combination with ribavirin ( n = 15). Serum FV- and IC-HCV RNA were separated by immunoprecipitation using anti-human immunoglobulin and quantified serially using real-time detection polymerase chain reaction. At the first phase (day 0–2), the decline of FV- and IC-HCV RNA was similar between the two treatment groups. At the second phase (day 2–28), the decline of IC was significantly faster in patients treated with IFN plus ribavirin compared with IFN alone [exponential decay slope = 0.079 ± 0.036 vs 0.048 ± 0.027 log10/day, P = 0.0248; half-life = 81.1 ± 21.4 vs 135.1 ± 61.4 h, P = 0.0053], although the second phase FV-decline was not significantly different between the two treatment groups. The fast second phase decline of IC was associated with sustained virological response to therapy. These results suggest that ribavirin may modulate the humoral immune response against HCV and trigger a favourable response to IFN. In conclusion, analysis of early IC-HCV dynamics is useful for predicting the response to therapy and for understanding the mechanism of action of antiviral drugs in chronic hepatitis C patients. [ABSTRACT FROM AUTHOR]

Abstract: To evaluate the predictive value of early virologic response (EVR) of achieving a sustained virologic response (SVR), an open, prospective trial including 42 patients with chronic hepatitis C genotype 1b was performed with directly observed 24-week treatment with interferon α-2b plus ribavirin. We assessed the predictive values of EVR at days 3, 7, 14, and weeks 4, 8, and 12 of the SVR. The SVR in an intention-to-treat analysis was 19.0%. Patients who reached SVR presented a significantly faster reduction in plasma viral load. Stepwise multiple logistic regression analysis of the factors (gender, age, IFN dosage, ribavirin dosage, HCV RNA, ISDR, and loss of HCV RNA at week 4) revealed that loss of HCV RNA at week 4 was the only independent variable of treatment outcome (P =0.0039). A viral load at treatment day 3 above 100kIU/ml, at day 7 above 50kIU/ml, and at day 14 above 10kIU/ml was 100% predictive for virologic non-response in all except 1 patient. The cutoff levels for HCV RNA at days 3 and 14 of treatment were associated with an algorithm of the failure to detect HCV RNA after 12 weeks of treatment. In conclusions, a very early virologic response assessment could be useful for prediction of later outcome of combination therapy in chronic hepatitis C genotype 1b. [Copyright &y& Elsevier]

Objective: Patients with high titer (≥100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1–191 of the core region and amino acids 2209–2248 of NS5A, and early viral kinetics. Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response. Methods: Serum HCV-RNA was frequently quantified in patients with chronic hepatitis C (n=270) treated with peginterferon alfa-2a (180μg/week) and ribavirin (1000–1200mg/day). After 6 weeks patients were classified as rapid (RVR), slow (SPR), flat (FPR), or null responders (NUR) and randomized within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy (48 weeks) or shorter combination therapy (24 weeks) for RVR, triple therapy with histamine (1mg/day) (48 weeks) or prolonged combination therapy (72 weeks) for SPR, triple therapy for FPR, and high-dose peginterferon (360μg/week) plus ribavirin for NUR patients. Results: Patients were categorized as RVR (n=171), SPR (n=65), FPR (n=10), or NUR (n=22). Overall end-of-treatment and sustained virologic response rates were 77 and 60% in the individualized and 77 and 66% in the standard treatment arm, respectively. Histamine in addition to peginterferon and ribavirin and high-dose peginterferon plus ribavirin did not improve virologic response rates in patients with FPR and NUR, respectively. Conclusions: An improvement in virologic efficacy was not achieved with the available individualized treatment options. [Copyright &y& Elsevier]

Background/Aims: Currently, there are no effective therapies available for patients with chronic hepatitis C who have failed to respond to optimal interferon alfa-based regimens. The aims of this pilot study were to assess the antiviral activity and safety of interferon gamma in chronic hepatitis C. Methods: Patients with chronic hepatitis C, genotype 1, who had not responded to or who had relapsed after therapy with interferon alfa and ribavirin were enrolled in a trial of interferon gamma 1b given in doses of 100, 200 or 400μg subcutaneously three times weekly for 4 weeks. Frequent blood samples were obtained for HCV RNA levels. Results: Fourteen patients were enrolled. Geometric mean HCV RNA levels remained unchanged. Serum aminotransferase levels also did not change, while there were significant decreases in neutrophil counts (−41% from baseline) and hematocrit (−5%). Low grade fever and malaise were common with the first injection of interferon gamma, but no serious side effects were encountered. Conclusions: Although relatively well tolerated, interferon gamma in doses of 100–400μg thrice weekly had no effect on HCV RNA levels in patients with chronic hepatitis C who had failed to achieve a sustained response to interferon alfa-based therapies. [Copyright &y& Elsevier]

This study aimed to find how ribavirin increases viral disappearance in patients with hepatitis C virus (HCV) of genotype 1 and high baseline viral loads (>5.0 ×105 copies/mL) when given with interferon (IFN). Using the real-time quantitative polymerase chain reaction, we measured serum HCV in 20 patients during the first 12 weeks of therapy with IFN-α2b and ribavirin. Controls were 10 similar patients given IFN-α2b alone. IFN-α2b was given at 6 MU daily for 2 weeks, and then three times weekly. Ribavirin was given at 600 or 800 mg daily. Serum HCV RNA decreased rapidly in the first phase, during the first 24 h of therapy (day 0), and more slowly in the early second phase (days 1–14). The median decrease was by 1.41 and 0.078 log 10/day in these two phases in the combination therapy group, and 0.90 and 0.081 log 10/day in the monotherapy group. The difference between groups in the first phase was not significant (P = 0.24), nor was that in the next phase (P = 0.68). Later in the second phase, between days 14 and 84, the median decrease was larger in the combination therapy group (0.030 log 10/day) than in the monotherapy group (0.015 log 10/day,P = 0.035). In patients with HCV genotype 1 and high viral loads, the effects of ribavirin with IFN-α appeared slowly, after the earliest days of treatment. A long-term favourable outcome of combination therapy may be associated with a rapid viral decline in this later phase of therapy. [ABSTRACT FROM AUTHOR]

Oral therapy for chronic hepatitis B remains suboptimal. Mathematical modelling of viral decay kinetics to rapidly assess potential antiviral regimens has proved valuable for human immunodeficiency virus and cytomegalovirus. We defined the kinetics of viral replication in 10 chronic hepatitis B patients randomized to lamivudine 100 mgvs600 mg for 48 weeks. Viral decay kinetics conformed to a biphasic pattern in nine of 10 subjects. Persons receiving 600 mg daily of lamivudine exhibited a 1.6-fold faster decay rate in the infected cell compartment (0.028/dayvs0.017/day,P = 0.06) and a greater overall change in serum viral load when compared with those receiving 100 mg (4.06vs1.52 log10 copies/mL,P = 0.08). More potent therapy appeared to result in more rapid decrease in the infected cell population. Studies using mathematical modelling of viral decay may be a useful method to evaluate single or combination therapy for HBV infectionin vivo. [ABSTRACT FROM AUTHOR]

Background/Aims: To elucidate the mechanisms of action of interferon (IFN) against hepatitis C virus (HCV), we studied the serum HCV dynamics of free-virions (FV) and immune-complexes (IC) in patients treated with IFN.Methods: FV and IC were separated by immunoprecipitation using anti-human immunoglobulin and quantified serially using real-time detection-polymerase chain reaction.Results: Initially [1st phase (0–24 h)], the FV decreased more rapidly compared to IC [exponential decay slope (EDS)=1.78±0.42 vs. 0.99±0.31 log10/day, P<0.001; half-life=5.65±2.02 vs. 12.5±2.83 h, P<0.0001], but at the 2nd phase (1–14 days), half-life of FV was significantly longer than that of IC (101±117 vs. 14.2±1.08 h, P<0.005). Regarding response to IFN, the decline slope was not significantly different at the 1st phase, but at the 2nd phase, the FV-HCV RNA decreased more slowly in non-responders than in sustained responders to IFN (EDS=0.05±0.02 vs. 0.34±0.19 log10/day, P<0.005; half-life=186±112 vs. 15.3±1.85 h, P<0.005).Conclusions: The presence of escape mutants from the neutralizing antibodies may be involved in resistance to IFN. Analyzes of FV- and IC-HCV dynamics are useful for predicting the IFN efficacy and understanding the mechanism of IFN action in chronic hepatitis patients. [Copyright &y& Elsevier]

Background/Aims: To address the molecular mechanism for enhanced antiviral efficacy associated with a frequent dosing of interferon (IFN)-beta.Methods: Serum hepatitis C viral (HCV) dynamics, double-stranded RNA-activated protein kinase (PKR) mRNA and MxA mRNA levels in peripheral blood mononuclear cells (PBMC) were analyzed serially in 140 patients who were randomly assigned to a twice daily (3 MU bid) or once daily (6 MU qd) administration group.Results: In twice daily group, the rate of HCV decline during the second phase was 2-fold greater than in the once daily group (P=0.04). Peak PKR and MxA gene expression levels in the first phase (observed 4 h after a single administration) were 2-fold higher in the once daily group. However, the expression in the second phase was maintained at a significantly higher level in the twice daily group. Initial and peak expression levels were related to initial viral load. Basal expressions in PBMC were significantly correlated with those in the liver tissue (PKR, r=0.81; MxA, r=0.75, respectively, P<0.0001).Conclusions: Our data suggest that elimination of HCV-infected cells is enhanced by twice daily dosing of IFN-beta, and that this enhanced effect is associated with a higher intracellular expression of PKR and MxA during the second phase. [Copyright &y& Elsevier]

A mouse-adapted strain of Ebola Zaire virus produces a fatal infection when BALB/cj mice are infected intraperitoneally (ip) but subcutaneous (sc) infection with the same virus fails to produce illness and confers long-term protection from lethal ip rechallenge. To identify immune correlates of protection in this model, we compared viral replication and cytokine/chemokine responses to Ebola virus in mice infected ip (10 PFU/mouse), or sc (100 PFU/mouse) and sc “immune” mice rechallenged ip (106 PFU/mouse) at several time points postinfection (pi). Ebola viral antigens were detected in the serum, liver, spleen, and kidneys of ip-infected mice by day 2 pi, increasing up to day 6. Sc-infected mice and immune mice rechallenged ip had no detectable viral antigens until day 6 pi, when low levels of viral antigens were detected in the livers of sc-infected mice only. TNF-α and MCP-1 were detected earlier and at significantly higher levels in the serum and tissues of ip-infected mice than in sc-infected or immune mice challenged ip. In contrast, high levels of IFN-α and IFN-γ were found in tissues within 2 days after challenge in sc-infected and immune mice but not in ip-infected mice. Mice became resistant to ip challenge within 48 h of sc infection, coinciding with the rise in tissue IFN-α levels. In this model of Ebola virus infection, the nonlethal sc route of infection is associated with an attenuated inflammatory response and early production of antiviral cytokines, particularly IFN-α, as compared with lethal ip infection. [Copyright &y& Elsevier]

Hepatitis C virus (HCV) RNA is thought to be less stable than HCV core antigen (HCV-Ag), however there have been few studies on comparing the stability of HCV-Ag with that of HCV-RNA in vitro. The aim of this study is to evaluate serial levels of HCV-Ag and HCV-RNA in serum before and after incubation at 4 or 25 °C for 7 days to estimate an assay suitable for general laboratory use. In this study, we demonstrate that HCV-Ag levels are highly reproducible (coefficients of variation (CVs); 0.89–6.92%) and stable (84.8% of the initial level) with incubation of even 25 °C for 7 days, whereas HCV-RNA levels are much less reproducible (CVs; 9.13–29.66%) and decrease dramatically (15.1% of the initial level) after incubation, particularly at 25 °C. The measurement of the HCV-Ag level was found to be suitable for HCV quantification with serum samples stored either at 4 °C or under unknown conditions. Additionally, it successfully eliminated inhibitors such as heparin from plasma and could be applied to a variety of clinical specimens. Our data suggest the significance of measuring the HCV-Ag level during clinical management independently of the HCV-RNA level, particularly because of its high stability. [Copyright &y& Elsevier]

The treatment of chronic hepatitis C is currently based on a combination of pegylated interferon (IFN)-α and ribavirin. When successful, this treatment leads to sustained HCV clearance which, in virtually all cases, signifies viral eradication. However, approximately 20% of patients with hepatitis C virus (HCV) genotype 2 or 3 infection, and 50% of patients with genotype 1 infection, fail to eradicate the virus. The risk of treatment failure is related to multiple factors, including the treatment schedule, adherence of therapy, host factors, and the severity of HCV-associated disease. Viral factors can also lead to true “HCV resistance”. The mechanisms underlying this resistance are unknown, but indirect evidence suggests that chronic infection is associated with phenomena that protect HCV from the antiviral action of IFN-α and hinder the clearance of infected cells. This article discusses current knowledge of the mechanisms of action of IFN-α and ribavirin, the virological characteristics of chronic hepatitis C treatment success and failure, and possible underlying mechanisms. [Copyright &y& Elsevier]

summary. Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG-IFN-α -2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN-α -2a (days 0 and 1), and before and during weekly 180 μ g PEG-IFN-α -2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty-eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV-RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN-α -2a was greater in virological responders (1.05 log [0.25–1.67]) than in nonresponders (NR) (0.34 [0.14–0.65]; P =0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG-IFN-α -2a. All patients with an initial decline > 1.4 log became sustained responders. Five of 12 patients with a log change < 0.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG-IFN-α -2a is different to that on standard IFN. In spite of a lower initial response PEG-IFN-α -2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness. [ABSTRACT FROM AUTHOR]

summary. A large proportion of patients fails to respond to treatment for hepatitis C. Initiation of interferon therapy is associated with a rapid first phase decline in viremia, reflecting inhibition of viral production or release from infected cells. We characterized first phase viral kinetics in previous nonresponder patients and compared the antiviral efficacy of interferon in nonresponders to that observed in naive patients. Twenty nonresponders with genotype 1 infection were evaluated. Ten received a single 15 mcg dose of interferon alfacon-1 and ten were given a 30 mcg dose. Viral kinetic data from previously untreated historical control patients with genotype 1 infection who received 9 mcg (n = 12) or 15 mcg (n = 13) of interferon alfacon-1 provided a basis for comparison. Antiviral efficacy was evaluated by calculating the reduction in HCV RNA levels during the first 24 h after interferon administration (log effectiveness). Hepatitis C virus levels decreased exponentially in previous nonresponder patients. Non-responders treated with 30 mcg of interferon alfacon-1 exhibited a greater log drop than non-responders receiving 15 mcg (P = 0.01). The log effectiveness of 15 mcg of interferon alfacon-1 in nonresponders was similar to 9 mcg in naives and was significantly < 15 mcg (P = 0.04) in naïve patients. The 30 mcg dose provided similar log effectiveness in nonresponders compared with 15 mcg in naive patients and exceeded the log effectiveness of 9 mcg in previously untreated patients (P = 0.035). Nonresponders who had greater than a 50% decrease in HCV RNA level from baseline at the end of previous treatment had a larger reduction in viral load at 24 h compared with those who had not achieved that level of response with prior therapy (P = 0.04). In conclusion, the log effectiveness of interferon was lower in nonresponders compared with treatment naive patients. The difference in antiviral effectiveness in previous nonresponders was overcome by... [ABSTRACT FROM AUTHOR]

Background/Aims: The mechanism of variable response to interferon (IFN) monotherapy in patients infected with HCV genotype 2a is still unclear. Here we investigated the response in a large group of patients infected with genotype 2a.Methods: We evaluated 394 consecutive non-cirrhotic naive patients infected with genotype 2a who received IFN monotherapy for 24 weeks, including initial aggressive induction therapy. Of these, 97 were also evaluated for early viral kinetics in serum and treatment efficacy.Results: The overall sustained response (SR) rate was 68.3% (viral load <1.0 Meq/ml (82.4%); ≥1.0 (52.4%)). Multivariate analysis identified five independent factors associated with SR; viral load <1.0 Meq/ml, total IFN dose ≥700 million units, hepatocyte steatosis none or mild, albumin ≥3.9 g/dl, and alanine aminotransferase ≥75 IU/l. The kinetic study showed that serum viral clearance at ≤1 week was the best predictor of SR, and persistence at ≥ 4 weeks was a predictor of non-SR.Conclusions: Our study suggests that viral, host and IFN treatment-related factors determine the response to IFN monotherapy in patients infected with HCV genotype 2a. Further, we report that IFN monotherapy is very effective for patients with genotype 2a, especially for those with low viral load; and that early viral kinetics is useful as a predictor of the response. [Copyright &y& Elsevier]

Background/Aims: Baseline factors and early decline in serum hepatitis C virus RNA are predictive of sustained virological response to interferon therapy in patients with chronic hepatitis C. We evaluated the prognostic value of baseline factors and early viral RNA among patients treated with peginterferon alfa-2a (40KD).Methods: Data were pooled from three randomized trials involving 814 patients treated with peginterferon alfa-2a (40KD) (90, 135, or 180 μg). Stepwise and multiple logistic regression identified independent baseline factors associated with response. Receiver operating characteristic curves for both absolute values and log10 decline in viral RNA at 4, 8, 12 and 24 weeks of therapy were created.Results: Independent prognostic factors for sustained virological response included viral genotype non-1, low pretreatment viral load, age (<40 years), no cirrhosis and body weight (<85 kg). In addition, alanine aminotransferase quotient (>3) and histological activity index score (>10) were also independently prognostic. Receiver operating characteristic curves showed that detectable or less than 2-log10 decline in viral RNA at week 12 predicted sustained virological non-response (negative predictive value is 98%).Conclusions: In patients with chronic hepatitis C treated with peginterferon alfa-2a (40KD), the decision to continue or stop treatment can be made as early as week 12. [Copyright &y& Elsevier]

summary. In patients infected with hepatitis C virus (HCV) genotype 1, sustained viral response (SVR) averages 10–40% depending on treatment regime. It has been proposed that high dose daily interferon (IFN) therapy early in therapy (induction dosing) may enhance SVR. In the present study we examined this issue and also assessed whether one could predict SVR and non-SVR, based on viral kinetics during the first month of induction therapy. End of treatment response and SVR was determined in 173 HCV infected patients who were treated with different induction doses of consensus interferon (CIFN) for one month followed by 11 months of standard 9 µg of CIFN thrice weekly (TIW). The second phase decline slope was calculated by log-linear regression on weekly measurements of serum HCV RNA during the first 7–28 days of treatment; rapid viral response (RVR) during the first month of induction dosing was defined as a decline of > 0.3 log copies/mL/week. Overall, SVR occurred in 11% of genotype 1 infected patients and 41% of patients with nongenotype 1. High dose induction therapy did not increase the rate of SVR, in either genotype 1 or genotype 2/3 infected patients. No patient without a RVR during the first month had SVR, while SVR occurred in 55% of the patients with RVR. RVR was the best predictor of SVR using multivariate analysis. These results indicate that induction dosing with CIFN does not improve SVR rates. They also suggest that early viral kinetics during the first month of therapy can predict non-SVR and thus save a patient a year long treatment which is fraught with side-effects and significant cost. [ABSTRACT FROM AUTHOR]

summary. It has recently been shown that upon initiation of interferon (IFN) treatment there is a biphasic decline in hepatitis C virus (HCV) RNA levels. In preliminary results, the rate of second phase viral decline has been shown to be an excellent predictor of treatment response. In this analysis, we determined whether the first phase viral kinetic parameters affected the rate of second phase viral decline. We also assessed whether first phase viral kinetic parameters could be used to predict treatment response within 24 h of initiating treatment. This study is a retrospective analysis of two completed studies from which detailed kinetic data were obtained in patients infected with genotype 1 HCV. In both studies, viral levels were measured frequently over the first 24 h, allowing the determination of IFNs effectiveness in blocking viral production and the viral load at the end of the first phase (v1 ). The second phase decline slope was calculated by log-linear regression on measurements of serum HCV RNA during days 2, 7 and 14. In study one, sustained viral response (SVR) rates were obtained, allowing the determination of the first phase's predictive power for SVR. Logistic regression and fisher exact tests were used to analyse data. In study one, no patient achieved SVR without an IFN effectiveness greater than 98% and a V1 less than 250 000 copies/mL. When V1 and IFN effectiveness werecombined to predict SVR, a negative predictive value= 100%, positive predictive value=71% and accuracy of 95% was obtained after only 24 h of IFN treatment. Both studies illustrated strong correlations for both IFN effectiveness and V1 with the rate of 2nd phase slope (P < 0.001). V1 also correlated significantly with a calculation of infected cell loss (delta), which is a major determinant of the second phase viral decline. These results suggest that early viral kinetics may predict lack of response after only 24 h of... [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the effect on HCV RNA levels of using induction dosing with 5 MU interferon-alpha2b (IFN) given daily for four weeks followed by 5 MU IFN given three times a week (TIW) for 44 weeks vs standard noninduction TIW dosing of 5 MU IFN for 48 weeks. We randomly assigned 135 patients with chronic hepatitis C to induction therapy or noninduction therapy. After four weeks of therapy 17/65 (26.1%) patients had undetectable HCV viral levels in the induction group compared with 16/64 (25.0%) patients in the noninduction group. The mean HCV viral levels were similar at four weeks in patients who received induction and noninduction therapy. Mean HCV viral titers in the induction group increased from 4 to 16 weeks, whereas the mean viral titers in the noninduction group decreased during this time (P < 0.0001). HCV RNA was undetectable at the end of therapy in 17/66 (25.8%) in the induction group and 21/68 (30.9%) in the noninduction group. The sustained virologic response rate 24 weeks after the end of therapy was 14/67 (20.9%) in the induction group compared with 13/68 (19.1%) in the noninduction group. These results indicate that an initial four week period of daily interferon confers no benefit in the treatment of patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Treatment for hepatitis C virus infection is limited in patients not responding to traditional therapy. Amantadine is effective for influenza infections and has been studied in patients with hepatitis C. Our aim was to determine the efficacy and safety of amantadine and to study the viral kinetics following amantadine therapy. Twelve patients with detectable HCV antibodies received amantadine 100 mg, orally twice daily. Serial HCV RNA and ALT blood samples were drawn and adverse effects were evaluated. Mean HCV RNA levels did not decrease in the first 24 hr of amantadine therapy but did decline significantly by day 3, only to rebound by day 7. All HCV RNA levels remained detectable throughout therapy and were not different from baseline values. Thirty-three percent of the patients obtained normal ALT levels after the first 24 hr of treatment and levels remained within normal range throughout the study period. More than a third of the patients discontinued therapy due to severe adverse effects occurring within one to three months after initiating treatment. In conclusion, although amantadine therapy alone was not effective, it should be considered as an adjunctive form of therapy along with interferon and ribavirin. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze of HCV kinetics during interferon treatment administered daily or three times weekly. Seventy-seven naive patients were randomized to two treatment courses starting with four weeks of high-dose interferon administered daily or three times weekly. Twenty-two patients (28.6%) achieved end-of-treatment response and nine (11.7%, four of whom received daily induction) sustained response. The initial decline of viral load was sharper in patients receiving daily induction, but the rates of early RNA clearance were independent of treatment schedule, being higher in patients with genotype non-1. Detectable HCV RNA during treatment predicted nonresponse more significantly than high pretreatment viral load or genotype 1. HCV RNA at week 2 was the best predictor (100% sensitivity in patients receiving daily induction). In conclusion, daily induction increased the HCV decline slope, but not the rate of virological response. HCV RNA at week 2 reliably identified nonresponders. [ABSTRACT FROM AUTHOR]

TRIM5α polymorphism in rhesus macaques (RM) limits the genetic pool of animals in which we can perform simian immunodeficiency virus (SIV) studies without first screening animals for permissive TRIM5α genotypes. We have previously shown that polymorphisms in the TRIM5α B30.2/SPRY domain impact the level of SIVsmm viremia in RM and that amino acid substitutions (P37S/R98S) in the capsid N-terminal domain (CA-NTD) enables the virus to overcome restriction in RMs with the restrictive homozygous TRIM5α TFP/TFP genotype. Since this genotype also negatively impacted the development of central nervous system (CNS) lesions in animals infected with the parental source of CL757, we sought to generate a TRIM5α TFP/TFP -resistant clone, SIV-804E-CL757-P37S/R98S (CL757-SS), using a similar strategy. Unexpectedly, viral replication of CL757-SS was impaired in RMs with either the permissive TRIM5α TFP/Q or the restrictive TRIM5α TFP/TFP genotype. Analysis of the virus which emerged in the latter animals led to the discovery of a preexisting mutation relative to other SIVs. This P146T substitution in a conserved disordered linker region in the C-terminal domain of capsid (CA-CTD) has been shown to inhibit proper formation of HIV-1 capsid particles. Restoration of this residue to proline in the context of the TRIM5α-SS escape mutations not only restored viral replication, but also enhanced the infectivity of our previously reported neurotropic clone, even in RMs with permissive TRIM5α genotypes. IMPORTANCE SIV infection of rhesus macaques has become a valuable model for the development of AIDS vaccines and antiretroviral therapies. Polymorphisms in the rhesus macaque TRIM5α gene can affect SIV replication, making it necessary to genetically screen macaques for TRIM5α alleles that are permissive for SIV replication. This limits the pool of animals that can be used in a study, thereby making the acquisition of animals needed to fulfill study parameters difficult. We have constructed a viral clone that induces neuroAIDS in rhesus macaques regardless of their TRIM5α genotype, while also highlighting the important role the disordered linker domain plays in viral infectivity.

The nasal epithelium lining the human upper airway is the primary portal of entry for several respiratory pathogens, including the recently emerged SARS-CoV-2 virus responsible for the ongoing COVID-19 pandemic. Here, we describe in detail methods for in vitro ALI differentiation of primary cells collected from human donors, to obtain differentiated hNECs. This can serve as a physiologically relevant model to investigate various aspects of host-pathogen responses to SARS-CoV-2 and other emerging respiratory viruses., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The within-host viral kinetics of SARS-CoV-2 infection and how they relate to a person's infectiousness are not well understood. This limits our ability to quantify the impact of interventions on viral transmission. Here, we develop viral dynamic models of SARS-CoV-2 infection and fit them to data to estimate key within-host parameters such as the infected cell half-life and the within-host reproductive number. We then develop a model linking viral load (VL) to infectiousness and show a person's infectiousness increases sublinearly with VL and that the logarithm of the VL in the upper respiratory tract is a better surrogate of infectiousness than the VL itself. Using data on VL and the predicted infectiousness, we further incorporated data on antigen and RT-PCR tests and compared their usefulness in detecting infection and preventing transmission. We found that RT-PCR tests perform better than antigen tests assuming equal testing frequency; however, more frequent antigen testing may perform equally well with RT-PCR tests at a lower cost but with many more false-negative tests. Overall, our models provide a quantitative framework for inferring the impact of therapeutics and vaccines that lower VL on the infectiousness of individuals and for evaluating rapid testing strategies., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Objectives: We aim to study the viral kinetics and host inflammatory response of RSV infection in older adults, and their correlation with disease severity., Methods: We performed a prospective observational study in adults with RSV infection. We serially collected nasal-throat swabs for quantification of RSV-A and RSV-B viral load, and peripheral blood samples for measurement of cytokine/chemokine concentrations. The study endpoints were (i) requiring supplemental oxygen therapy, and (ii) non-invasive ventilation, intensive care, or died within 30 days of admission. We performed multivariable logistic regression models to identify independent variables for severe disease., Results: We enrolled 71 hospitalized patients and 10 outpatients treated for RSV infection (median age 75 years, 51% male, and 74% with comorbidities). Among hospitalized patients, 61% required supplemental oxygen therapy, and 18% had severe disease requiring non-invasive ventilation or intensive care, or died within 30 days. Inflammatory cytokine/chemokines IL-6, CXCL8/IL-8, CXCL9/MIG and CXCL10/IP-10 increased significantly during the acute phase of illness. IL-6 concentration was independently associated with severe disease after adjusting for confounding factors. RSV viral load was not associated with disease severity throughout the course of illness., Conclusion: Host inflammatory response is a major marker of severe disease in older adults with RSV infection., Competing Interests: Declaration of Competing Interest No conflict of interest declared., (Copyright © 2021 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is correlated with covalently closed circular DNA. We aimed to investigate the utility of serum HBV pgRNA in chronic hepatitis B patients receiving nucleos(t)ide analogue treatment and those achieving HBsAg loss. One hundred and eighty-five patients were enrolled for studying long-term HBV pgRNA kinetics during treatment. Twenty patients achieving HBsAg loss after treatment were enrolled for examining HBV pgRNA kinetics around HBsAg loss. HBV pgRNA significantly decreased in the high baseline HBV pgRNA (≥6 log copies/mL) group but significantly increased in the low baseline HBV pgRNA (<4 log copies/mL) group after 3-month entecavir treatment. Among the 20 patients achieving HBsAg loss, 13 (65%) patients had serum HBV pgRNA higher than the limit of detection (LOD, 1466 copies/mL) when they achieved HBsAg loss. Finally, all 20 patients had HBV pgRNA going below the LOD within 3 years after achieving HBsAg loss. In conclusion, baseline serum HBV pgRNA alone is insufficient for predicting the trajectory of HBV pgRNA. Most patients still had HBV pgRNA higher than the LOD when they achieved HBsAg loss. Further studies on HBV pgRNA kinetics around HBsAg loss would provide an enhanced basis for further applications of HBV pgRNA. [ABSTRACT FROM AUTHOR]

ABSTRACT- Aims/Background: Response rates to alpha-interferon therapy for chronic hepatitis C are poor. An early indication of efficacy would reduce the need for prolonged therapy, leading to significant cost savings. It was established that a change in quantitative hepatitis C virus RNA (HCV-RNA) titre at 4 weeks could predict the outcome of alpha-interferon therapy in chronic hepatitis C. Methods: Serum HCV-RNA titres were quantified using branched chain DNA (bDNA) assay in 26 patients who responded to alpha-interferon (serum HCV-RNA negative after 12 weeks therapy) and 11 age and sex matched non-responders. Quantitative bDNA and qualitative RT-PCR assays for HCV-RNA were measured pre-treatment and at 4 weeks. The change in quantitative HCV-RNA titre between pre-therapy and after 4 weeks was compared in the two groups. Results: Seventeen of the 37 patients had become RT-PCR negative at 4 weeks (early responders) and had an undetectable HCV-RNA titre on bDNA assay. Nine patients were RT-PCR positive at 4 weeks but negative by 12 weeks (delayed responders), and of these, 8 had an undetectable viral titre at 4 weeks on bDNA assay. The patient with a detectable HCV titre did become RT-PCR negative after 12 weeks, but subsequently became RT-PCR positive again at 24 weeks. All the non-responders had a detectable bDNA titre (>0.2 Meq/ml) at 4 weeks. Conclusions: Change in quantitative HCV-RNA titre measured by bDNA assay at 4 weeks predicts response to alpha interferon. If HCV-RNA remains detectable on bDNA assay at 4 weeks, no sustained response to treatment is found and alpha-interferon can be discontinued. [ABSTRACT FROM AUTHOR]

While the liver, specifically hepatocytes, are widely accepted as the main source of hepatitis C virus (HCV) production, the role of the liver/hepatocytes in clearance of circulating HCV remains unknown. Frequent HCV kinetic data were recorded and mathematically modeled from five liver transplant patients throughout the anhepatic (absence of liver) phase and for 4 hr post-reperfusion. During the anhepatic phase, HCV remained at pre-anhepatic levels ( n = 3) or declined ( n = 2) with t 1/2 ~1 hr. Immediately post-reperfusion, virus declined in a biphasic manner in four patients consisting of a rapid decline ( t 1/2 = 5 min) followed by a slower decline ( t 1/2 = 67 min). Consistent with the majority of patients in the anhepatic phase, when we monitored HCV clearance at 37°C from culture medium in the absence/presence of chronically infected hepatoma cells that were inhibited from secreting HCV, the HCV t 1/2 in cell culture was longer in the absence of chronically HCV-infected cells. The results suggest that the liver plays a major role in the clearance of circulating HCV and that hepatocytes may be involved., Competing Interests: LS, MN, NS, GC, GS, TC, EC, SP, AP, SC, SU, HD No competing interests declared, XF XF acted as advisor for Gilead and AbbVie