Viral Kinetics In Patients Research Articles

Modelling the mechanisms of antibody mixtures in viral infections: the cases of sequential homologous and heterologous dengue infections.

Antibodies play an essential role in the immune response to viral infections, vaccination or antibody therapy. Nevertheless, they can be either protective or harmful during the immune response. Moreover, competition or cooperation between mixed antibodies can enhance or reduce this protective or harmful effect. Using the laws of chemical reactions, we propose a new approach to modelling the antigen-antibody complex activity. The resulting expression covers not only purely competitive or purely independent binding but also synergistic binding which, depending on the antibodies, can promote either neutralization or enhancement of viral activity. We then integrate this expression of viral activity in a within-host model and investigate the existence of steady-states and their asymptotic stability. We complete our study with numerical simulations to illustrate different scenarios: firstly, where both antibodies are neutralizing and secondly, where one antibody is neutralizing and the other enhancing. The results indicate that efficient viral neutralization is associated with purely independent antibody binding, whereas strong viral activity enhancement is expected in the case of purely competitive antibody binding. Finally, data collected during a secondary dengue infection were used to validate the model. The dataset includes sequential measurements of virus and antibody titres during viremia in patients. Data fitting shows that the two antibodies are in strong competition, as the synergistic binding is low. This contributes to the high levels of virus titres and may explain the antibody-dependent enhancement phenomenon. Besides, the mortality of infected cells is almost twice as high as that of susceptible cells, and the heterogeneity of viral kinetics in patients is associated with variability in antibody responses between individuals. Other applications of the model may be considered, such as the efficacy of vaccines and antibody-based therapies.

Early Viral Kinetics in Patients with Chronic Hepatitis C Treated with Direct-Acting Antivirals

Early Viral Kinetics in Patients with Chronic Hepatitis C Treated with Direct-Acting Antivirals

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

PurposeAdequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course.MethodsA cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed.ResultsForty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10–1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00–16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26–46.75, vs 18 days, IQR 16–46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6–15.5) for non-IMV and 49.5 days (IQR 36.8–82.5) for IMV patients.ConclusionsOur results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19.

Ribavirin facilitates early viral kinetics in chronic hepatitis C patients receiving daclatasvir/asunaprevir.

Ribavirin (RBV) remains crucial in difficult-to-cure chronic hepatitis C patients receiving directly acting antivirals (DAAs). The current study aimed to address whether RBV enhanced early viral kinetics in patients with DAAs. Hepatitis C virus (HCV) genotype-1b patients were allocated to daclatasvir/asunaprevir +weight-based RBV (1000-1200mg/day) for 12-24weeks. HCV RNA levels were compared at day 1, week 1, week 2, and week 4 of treatment. The sustained virological response rate was 100% (67/67) and 96.7% (59/61) in the RBV and non-RBV group, respectively. The HCV RNA levels at treatment week 2 (W2) were significantly lower in the RBV group than in the non-RBV group (0.42±0.81 log IU/mL vs 0.79±1.03 log IU/mL, P=0.04). Among the intermediate responders who remained to have detectable RNA after W1 of treatment, patients with RBV had a significantly higher rate of undetectable HCV RNA (71.4% vs 36.0%, P=0.003) and lower HCV RNA level at W2 (0.55±0.89 log IU/mL vs 1.32±1.04 log IU/mL, P=0.001). A more significant magnitude of HCV RNA reduction was also noted from baseline to day 1 (3.15±0.38 log IU/mL vs 2.80±0.70 log IU/mL, P=0.009) and W1 to W2 (1.40±0.65 log IU/mL vs 0.88±0.78 log IU/mL, P=0.007) in the RBV group compared to the non-RBV group among the intermediate responders. Logistic regression analysis revealed that adding RBV independently predicted undetectable HCV RNA at W2 (odds ratio/confidence interval: 4.74/1.54-14.57, P=0.007) in the intermediate responders. Adding RBV to DAAs improved early viral kinetic, in particular, for intermediate responders.

P-C13 Impact of HIV status, HCV genotype, and number of DAAs on HCV viral kinetics in patients with HCV genotype 1 receiving DAA therapy

P-C13 Impact of HIV status, HCV genotype, and number of DAAs on HCV viral kinetics in patients with HCV genotype 1 receiving DAA therapy

Predicting Therapeutic Results of Interferon Based Treatment by Modeling the First Week Viral Kinetics in Patients with Chronic Hepatitis C

Background: The present study aimed to develop an optimal model predictive of the treatment response one week after initiating antiviral therapy. Patients and Methods: In all, 166 patients completed the treatment and were followed up for six months. Results: A viral response was achieved in 14 (8.4%) genotype 1 (G1) and 32 (19.3%) non-genotype 1 (G0) patients at week one after initiation of therapy and 45 (27.1%) G1 and 90 (54.2%) G0 patients at week four. A sustained viral response (SVR) was achieved in 50 (30.1%) G1 and 83 (50.0%) G0 patients, in 13 (29.5%) G1 and 31 (70.5%) G0 patients whose antiviral response was achieved at one week, and in 37 G1 (32.2%) and 78 G0 (67.8%) patients whose antiviral response was achieved at four weeks. The HCV viral kinetic parameter π (i.e., 1: α, α was defined as the area under the line y [viral load]=– a[x{time}] between week 0 and week 1) was found to be the best performing test for predicting SVR (p<0.0001). Regression analysis identified π as the only independent predictor of SVR (p=0.043). Conclusions: The use of bio-mathematical models of HCV kinetics can reliably predict SVR one week after starting therapy.

Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP‐C and PROPEL studies

The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C). We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin. Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1). Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.

Cholestasis correlates with higher DPPIV activity and higher IP-10 serum levels in patients with chronic hepatitis C

A significant proportion of end stage liver disease is caused by chronic hepatitis C (HCV) infection. Studies have shown that high baseline interferon-gamma-inducible protein-10 (IP-10) concentration correlates with nonresponse to peginterferon/ribavirin therapy and with first and second phase viral kinetics in patients with chronic hepatitis C infection. IP-10 serum concentrations are good surragete parameters for intrahepatic induction of interferon stimulated gene (ISG) activation. Recently higher IP-10 serum concentrations were described as antagonist forms of IP-10 cleaved by DPPIV (Casrouge et al., JCI 2011).

Implications of PNPLA3 polymorphism in chronic hepatitis C patients receiving peginterferon plus ribavirin

Homozygosity for the PNPLA3 p.I148M polymorphism influences steatosis and fibrogenesis in chronic hepatitis C (CHC). To evaluate the effect of p.148M/M on sustained virological response (SVR) and viral kinetics in patients who underwent antiviral therapy with peg-interferon and ribavirin, stratified according to viral genotype and fibrosis severity, and secondarily, the interaction with interleukin-28B ( IL28B ) genotype on liver damage. In this observational study, we considered 602 treatment-naïve consecutive patients from tertiary referral centres in Milan and Vienna [61% genotype 1 (G1), 30% advanced fibrosis, 33% IL28B rs12979860 CC]. The p.148M/M genotype, detected in 8% of patients, did not influence SVR in the overall series (P = 0.29), but it was associated with SVR (3/17, 17% vs. 56/121, 46%; P = 0.034) and complete early viral response (4/17, 23% vs. 68/121, 56%; P = 0.018) in G1/4 patients with advanced fibrosis. After adjustment for age, viral load, IL28B CC genotype, treatment dose, and steatosis, p.148M/M remained a predictor of SVR in G1/4 patients with advanced fibrosis (OR 0.23, 95% CI 0.04-0.87). The p.148M/M genotype was associated with more advanced fibrosis in the overall series (P = 0.049), whereas the rs12979860 IL28B CC genotype only in patients negative for p.148M/M (P = 0.017), independently of age, BMI and alanine transaminase levels (OR 1.51, 95% CI 1.01-2.27). PNPLA3 p.148M/M genotype was negatively associated with SVR and early viral kinetics independently of steatosis, albeit only in difficult-to-cure G1/4 patients with advanced fibrosis, whereas stratification for the p.148M/M PNPLA3 genotype unmasked an association between IL28B CC genotype and more severe liver fibrosis.

Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1

Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1

Peripheral Blood Lymphocyte Dynamics and Viral Kinetics in Patients with Chronic Active Hepatitis B Virus Infection Treated By Tenofovir

We investigated serum viral kinetics and peripheral blood lymphocyte dynamics in chronic hepatitis B patients during the first year of tenofovir therapy. Fifteen patients, naive to any kind of previous antiviral therapy, were included in this study. The patients received tenofovir daily 245mg for 48 weeks. Fifteen age and gender compatible healthy subjects were enrolled as the control group. Clinical, biochemical, immunological and virological parameters were assessed at baseline, then at the first, third, sixth and twelfth months. CD4+CD25+FOXP3+ nTregs percentages were significantly higher in the study group than that of healthy controls, CD4+CD28+ and CD4+CD38+ T cell percentages were significantly lower in the study group than those of control group (p<0.001). Twelve cases had undetectable HBV DNA levels after the one year therapy. We determined that there was an increase of the CD28+co-stimulator molecule on both the CD4+ and CD8+ T cells while a decrease of the CD8+CD38+ T cells, CD4+CD38+ T cells and CD4+CD25+FOXP3+ nTregs, in patients with tenofovir treatment, but only CD4+CD25+FOXP3+ nTregs were statistically significant. We found that both viral load and CD4+CD25+FOXP3+ nTreg percentages decreased significantly in patients with chronic hepatitis B virus infection during 1 year course of tenofovir treatment.

Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1

We studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0-28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 Caucasian Americans (CA) with HCV genotype 1. We studied the relationship between IL28B 16 gene-related SNP rs12979860 and early viral kinetics (day 0-28) 17 during peginterferon and ribavirin treatment, in 171 African 18 Americans (AA) and 188 Caucasian Americans (CA) with HCV 19 genotype 1. Compared to non-C/C genotypes, C/C was associated with greater declines in serum HCV RNA during phase 1 (day 0-2), phase 2 (day 7-28), and day 0-28 and higher response (undetected HCV RNA) rates at weeks 4 and 12 in AA and CA. A static phase and increases in HCV RNA from day 2 to 7 were more common in patients with non-C/C genotypes. C/C was also associated with higher week 24, 48, and 72 response rates in CA (p<0.01) but not in AA. At baseline, SNP genotype was the only independent predictor of phase 1; SNP genotype and phase 1 were independent predictors of phase 2 (p<0.001). There were no racial differences in HCV RNA declines during phase 1, day 2-7, phase 2, and day 0-28 with the same SNP genotype. AA with C/C and C/T genotypes had lower week 24, 48, and 72 (SVR) rates than did CA (p=0.03). SNP C/C predicted higher SVR rates in AA and CA with high baseline HCV RNA (≥ 600,000 IU/ml), and in CA with ≥ 1 log(10)IU/ml decrease in HCV RNA from day 0 to 28. SNP rs12979860 is strongly associated with both phase 1 and phase 2 HCV RNA kinetics in AA and CA with HCV genotype 1.

Reply to Guedj et al.: Early transient increase of hepatitis C virus viral load in genotype 1 and 2 infections, and the use of mathematical modeling

We appreciate the comments of Guedj et al. (1) on our paper addressing the association of IL28B gene variations with mathematical modeling of viral kinetics in patients with chronic hepatitis C treated with pegylated IFN plus ribavirin therapy (2). Regarding the distribution of the blips among hepatitis C virus (HCV) genotypes, we not only found a lower virion production rate but earlier blips among patients with HCV genotype 2 infection than those with genotype 1 infection. The time for the observed maximal viral load and the estimated time for maximal viral load were significantly different between these two genotypes (genotype 1 vs. 2: 0.33 ± 0.35 vs. 0.19 ± 0.12; P = 0.0048 and P = 0.0106 for the t test and Wilcoxon test), and the time for the maximal value also showed that patients with HCV genotype 1 infection had a poorer virological response than those with genotype 2 infection (Table 1). However, as reported in our paper, although HCV genotype has long been known as a predictor of achieving sustained virological response (SVR) in patients treated with combination therapy, it also serves as a latent factor of viral kinetics, especially for virion production rate. Thus, the impact of HCV genotype on SVR was not significant in our regression models, and viral kinetic parameters were still better than HCV genotype in the prediction of SVR.

Characterization of viral kinetics in patients with hepatitis B e antigen‐positive chronic hepatitis B

A study was conducted during a 1 year follow-up to characterize the viral kinetics in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and to develop a model of predicting the probability of spontaneous HBeAg seroconversion. Fifty-seven patients with HBeAg-positive chronic hepatitis B were enrolled with monthly follow-ups from three Phase III clinical trial placebo groups. According to serial viral loads, 30 patients (52.6%) with the stationary pattern maintained stable HBV DNA levels with fluctuations of less than 1.5 log copies/ml. Twenty patients (35.1%) with the declining pattern exhibited a spontaneous decline of more than 1.5 log copies/ml without a following rebound of at least 1.5 log copies/ml. The remaining seven patients (12.3%) had the wavering pattern. Both declining and wavering patterns, when compared with the stationary pattern, had significantly higher hepatic necroinflammation in terms of ALT and Knodell scores at the baseline and peak ALT levels during the follow-up period. The declining pattern had a significantly better clinical outcome in terms of the lowest final HBV DNA and a reduction in the necroinflammatory score after 1 year. Furthermore, the declining pattern had a favorable HBeAg seroconversion rate (40%) compared with the wavering (14.3%) and stationary patterns (0%). A regression equation, incorporating simultaneous serum bilirubin, ALT, and HBV DNA levels, predicted the probability of HBeAg seroconversion with a sensitivity of 76.8% and a specificity of 74.7%. In conclusion, different viral kinetic patterns in patients with chronic hepatitis B implicate distinct clinical significance and immunologic perspective.

Viral kinetics in patients with hepatitis C genotype 1, treated with high-dose daily interferon, high-dose pegylated interferon and pegylated interferon combined with daily interferon

Depts. Gastroenterology & Hepatology1 Virology2, Erasmus Medical Center, Rotterdam, The Netherlands Abstracts of the Netherlands Societies of Gastroenterology and the Netherlands Society of Hepatology

Peginterferon-α-2a (40KD) and Ribavirin for 16 or 24 Weeks in Patients With Genotype 2 or 3 Chronic Hepatitis C

Peginterferon-α-2a (40KD) and Ribavirin for 16 or 24 Weeks in Patients With Genotype 2 or 3 Chronic Hepatitis C

Viral kinetics in patients with lamivudine-resistant hepatitis B during adefovir–lamivudine combination therapy

Mathematical analysis of viral kinetics during lamivudine-adefovir combination therapy has not yet been performed in patients with lamivudine-resistant hepatitis B. In 8 patients with lamivudine-resistant hepatitis B, adefovir dipivoxil (10 mg/day) was added to ongoing lamivudine. Viral decay during the first 8 weeks of combination therapy was described by a biphasic model to determine the efficacy: epsilon, of blocking viral production, the clearance: c, of free virus, and the loss of infected cells: delta. Median epsilon was 98%, median c was 0.7/day, and median delta was 0.07/day. No significant association was found between viral kinetic and baseline parameters and virologic and biochemical treatment response. When compared with viral kinetic constants reported for higher dose adefovir dipivoxil monotherapy, epsilon was lower (P=0.026) and delta was higher (P=0.008) in this study whereas c did not differ between both studies. Although a recent study did not show any differences in the reduction of HBV DNA comparing monotherapy with adefovir dipivoxil to adefovir-lamivudine combination therapy in patients with lamivudine-resistant chronic hepatitis B, mathematical analysis of early viral kinetics suggests an additional effect of lamivudine on the infected cell loss during adefovir-lamivudine combination therapy.

Viral Kinetics in Patients with Chronic Hepatitis C Treated with the Serine Protease Inhibitor Biln 2061

We analysed viral kinetics from a 2-day treatment with BILN 2061, a serine protease inhibitor of hepatitis C virus, in patients chronically infected with genotype 1 hepatitis C virus. The efficiency (E), describing inhibition of viral production, was above 99.45% in all patients with minor or moderate fibrosis receiving doses of 200mg and 500 mg twice daily and larger than in previous studies for interferon-based treatments. However, epsilon was slightly smaller in patients with cirrhosis given 200mg and markedly smaller in patients given 25 mg. Estimates of viral clearance and infected-cell loss support conclusions on these rates and on treatment mechanisms from previous studies on interferon-alpha-based treatments.

Viral kinetics during antiviral therapy in patients with chronic hepatitis C and persistently normal ALT levels†

To the Editor: We read with great interest the article of Kronenberger et al.1 evaluating viral kinetics in patients with chronic hepatitis C and normal or elevated alanine aminotransferase (ALT) levels. The main conclusions of this study were that viral kinetics did not differ between the two groups of patients, although those with elevated GGT levels showed reduced efficacy of blocking virus production and lower infected cell loss. Although this study did accurately compare virological, demographic, and histological features between patients with normal and elevated ALT levels, fewer data are given about the differences among those with normal ALT. Indeed, patients with normal ALT might be stratified into three different groups: patients with persistently “low-normal” (updated healthy) ALT levels; patients with “high-normal” ALT levels, and subjects with normal ALT but occasional ALT flares.2, 3 Two recent prospective studies4, 5 have shown that many subjects referred to as hepatitis C virus (HCV) carriers with persistently normal ALT (PNALT) could have ALT flare-ups during the follow-up, thus proving that even prolonged observation periods might not be adequate to distinguish patients with persistent or transient ALT normality. It has been suggested that at least two different subsets of HCV carriers exist: patients with wide temporal ALT fluctuations, who could be within the normal range for several months, and true “biochemically silent” carriers, who show persistently normal ALT values.6 Although it is not clear whether these subgroups have different natural history and disease progression, liver histological activity was found to be significantly more marked among subjects with ALT flare-ups during the follow-up than in those with PNALT, and progression of fibrosis seems to accelerate after ALT flare-ups.3 Thus, we wonder if significant differences in viral kinetic were found between the 6 patients with “healthy” updated ALT levels and the 14 patients with “high-normal” ALT, and between the 5 patients with ALT flares and the 15 with PNALT. Indeed, it would be very interesting to understand whether ALT flare-ups among HCV carriers with PNALT might be due to viral factors (e.g., lower efficacy of blocking virus production/lower infected cell loss) or to nonviral factors (steatosis, drugs, alcohol). Finally, as to the patients with elevated GGT levels, we ask whether liver steatosis has been ruled out as a possible cause of GGT elevation. In particular, we wonder if significant differences were found in terms of presence and severity of steatosis between the 5 patients with PNALT and elevated GGT, and the 15 subjects with both normal ALT and GGT levels. Claudio Puoti*, Lia Bellis*, Roberto Castellacci*, Fabrizio Montagnese*, * Department of Gastroenterology and Internal Medicine, Genzano Hospital, Rome, Italy.

Interferon-$alpha; for hepatitis C: antiviral or immunotherapy?

Interferon-$alpha; for hepatitis C: antiviral or immunotherapy?