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Background Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs. Methods Participants were nonhospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S-gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant. Results Study participants receiving single- or dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared with single-active mAb treatment, treatment with dual-active mAbs led to faster viral load decline at study days 3 (P <.001) and 7 (P <.01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than with placebo (2.6% vs 0%; P <.001) and were more frequently detected in the setting of single-active compared with dual-active mAb treatment (7.3% vs 1.1%; P <.01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death. Conclusions Compared with single-active mAb therapy, dual-active mAbs led to similar clinical outcomes but significantly faster viral load decline and a lower risk of emergent resistance. [ABSTRACT FROM AUTHOR]

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Introduction: Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes. Materials and methods: Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4. Results: Viral levels showed a drop from 108 to 105 copies/µg RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2 mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3 days after administration. Conclusion: To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate. [ABSTRACT FROM AUTHOR]

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post–peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410. [ABSTRACT FROM AUTHOR]

Detection of SARS-CoV-2 RNA in serum, viremia, has been linked to disease severity and outcome. The kinetics of viremia in patients receiving remdesivir has not been thoroughly studied and could help predict treatment response and outcome. We investigated the kinetics of SARS-CoV-2 viremia and factors associated with baseline viremia, viral clearance and 30-day mortality in patients receiving remdesivir. An observational study including 378 hospitalised patients (median age 67 years, 67% male) sampled with serum SARS-CoV-2 RT-PCR within ± 24 h of initiation of remdesivir treatment. Baseline viremia was present in 206 (54%) patients with a median Ct value of 35.3 (IQR = 33.3–37.1). In patients with baseline viremia, the estimated probability of viral clearance was 72% by day 5. Ct values decreased significantly during remdesivir treatment for viremic patients, indicating an increase in viral load. In total, 44 patients (12%) died within 30 days, and mortality was significantly associated with viremia at baseline (OR = 2.45, p = 0.01) and lack of viral clearance by day 5 (OR = 4.8, p = < 0.01). Viral clearance was not associated with any individual risk factor. Viremia appears to be a prognostic marker before and during remedesivir treatment. The resolution of viremia was similar to patients not receiving remdesivir in other studies, and the decrease in Ct values during treatment questions the antiviral capacity of remdesivir in vivo. Prospective studies are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Background Mathematical models explain how antivirals control viral infections. Hepatitis C virus (HCV) treatment results in at least 2 phases of decline in viremia. The first phase reflects clearance of rapidly produced virions. The second phase is hypothesized to derive from loss of infected cells but has been challenging to prove. Methods Using single-cell methods, we quantified the number of hepatitis C virus (HCV)-infected hepatocytes in liver biopsies taken before and within 7 days of initiating direct-acting antivirals (DAAs) in a double-blinded randomized controlled trial testing 2 (sofosbuvir-velpatasvir) versus 3 (sofosbuvir-velpatasvir-voxilaprevir) DAAs. Results We employed thousands of intrahepatic measurements in 10 persons with chronic genotype 1a HCV infection: median proportion of infected hepatocytes declined from 11.3% (range, 1.3%–59%) to 0.6% (range, <0.3%–5.8%), a loss of 75%–95% infected hepatocytes. Plasma viremia correlated with numbers of HCV-infected hepatocytes (r = 0.77; P <.0001). Second-phase plasma dynamics and changes in infected hepatocytes were indistinct (P =.16), demonstrating that second-phase viral dynamics derive from loss of infected cells. DAAs led to a decline in intracellular HCV RNA and interferon-stimulated gene expression (P <.05 for both). Conclusions We proved that second-phase viral dynamics reflect decay of intrahepatic burden of HCV, partly due to clearance of HCV RNA from hepatocytes. Clinical Trials Registration NCT02938013. [ABSTRACT FROM AUTHOR]

The introduction of direct‐acting antiviral (DAA) treatment of hepatitis C virus (HCV) infected patients has greatly increased treatment success rates. However, viral response kinetics to DAA treatment may depend on pre‐existing resistance‐associated substitutions (RASs) in HCV. The aim of this study was to describe how pre‐existing RASs affect DAA treatment‐induced reduction in HCV RNA titers in HCV genotypes 1‐ and 3‐infected individuals. Patients with HCV genotype 1 infection (N = 31) treated with either sofosbuvir/ledipasvir/ribavirin or paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin and HCV genotype 3‐infected patients (N = 16) treated with either sofosbuvir/daclatasvir/ribavirin or sofosbuvir/ribavirin were analyzed. HCV RNA levels were determined at baseline and frequently during treatment, and RAS profiles were obtained by deep sequencing at baseline. In total, 33/47 (70.2%) of the patients had baseline RASs. However, treatment‐specific RASs were detected at baseline only in 12.9% and 18.8% of HCV genotypes 1‐ and 3‐infected patients, respectively. In genotype 1‐infected individuals, reduction in HCV RNA titer during the first week of treatment was not affected by evidence of either treatment‐specific RASs or cirrhosis or treatment regimen. In genotype 3‐infected individuals receiving sofosbuvir/daclatasvir/ribavirin, the presence of daclatasvir‐specific NS5A RASs at baseline correlated with a reduced decline of HCV RNA in the first treatment week. For both genotypes 1‐ and 3‐infected individuals, cirrhosis but not treatment‐specific RAS were associated with the time of clearance of HCV RNA. It is, however, important to note that this study involves DAA regimens that were used only during the original introduction of interferon‐free DAA‐based treatments. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, leading to a variety of symptoms in the unborn child that range from asymptomatic to death in utero. Our objective was to better understand the mechanisms of placental infection by HCMV clinical strains, particularly during the first trimester of pregnancy. We thus characterized and compared the replication kinetics of various HCMV clinical strains and laboratory strains by measuring viral loads in an ex vivo model of first trimester villi and decidua, and used NGS and PCA analysis to analyze the genes involved in cell tropism and virulence factors. We observed that first trimester villi and decidua are similarly permissive to laboratory and symptomatic strains, and that asymptomatic strains poorly replicate in decidua tissue. PCA analysis allowed us to segregate our clinical strains based on their clinical characteristics, suggesting a link between gene mutations and symptoms. All these results bring forth elements that can help better understand the mechanisms that induce the appearance of symptoms or in the congenitally infected newborn. [ABSTRACT FROM AUTHOR]

The Zika virus (ZIKV) epidemic brought new discoveries regarding arboviruses, especially flaviviruses, as ZIKV was described as sexually and vertically transmitted. The latter shows severe consequences for the embryo/fetus, such as congenital microcephaly and deficiency of the neural system, currently known as Congenital ZIKV Syndrome (CZS). To better understand ZIKV dynamics in trophoblastic cells present in the first trimester of pregnancy (BeWo, HTR-8, and control cell HuH-7), an experiment of viral kinetics was performed for African MR766 low passage and Asian-Brazilian IEC ZIKV lineages. The results were described independently and demonstrated that the three placental cells lines are permissive and susceptible to ZIKV. We noticed cytopathic effects that are typical in in vitro viral infection in BeWo and HTR-8. Regarding kinetics, MR766lp showed peaks of viral loads in 24 and 48 hpi for all cell types tested, as well as marked cells death after peak production. On the other hand, the HTR-8 lineage inoculated with ZIKV-IEC exhibited increased viral production in 144 hpi, with a peak between 24 and 96 hpi. Furthermore, IEC had peak variations of viral production for BeWo in 144 hpi. Considering such in vitro results, the hypothesis that maternal fetal transmission is probably a way of virus transmission between the mother and the embryo/fetus is maintained. [ABSTRACT FROM AUTHOR]

Background: Yellow fever is a mosquito-borne zoonotic disease, caused by yellow fever virus (YFV). Between 2017-2019 more than 504 human cases and 176 deaths were confirmed in the outskirts of São Paulo city. Throughout this outbreak, studies suggested a potential association between YFV viremia and mortality.Methods: Viral RNA was measured using RT-qPCR in plasma samples collected at up to 5 time points, between 3-120 days after symptoms onset.Results: 84 patients with confirmed YFV infection were included. Most were males; median age was 42, and 30 (36%) died. Deceased patients were older than survivors (p = 0.003) and had a higher viremia across all time points (p = 0.0006). Mean values of viremia had a positive, statistically significant correlation with peak values of neutrophils, indirect bilirubin, AST, INR and creatinine. Finally, a Cox proportional hazards model adjusted for age and laboratory variables showed that viremia is independently associated with death, with a mean 1.84-fold increase (84%) in the hazard of death (p < 0.001) for each unit increase in mean log10 viremia.Conclusion: Our results raise the importance of monitoring YFV viremia and suggest a potential benefit of antiviral drugs or neutralizing monoclonal antibodies early in the course of this infection to improve disease outcomes. [ABSTRACT FROM AUTHOR]

Respiratory Syncytial Virus (RSV) bronchiolitis is the leading cause of hospitalization in infants. The role of RSV load in disease severity is still debated. We present the interim results of a prospective monocentric study enrolling previously healthy infants hospitalized for RSV bronchiolitis, collecting nasopharyngeal aspirates every 48 h from admission to discharge, and evaluating RSV load dynamics in relation to clinical outcome measures of bronchiolitis severity, including: need, type and duration of oxygen therapy, length of hospitalization, and the bronchiolitis clinical score calculated at admission. The results showed that the highest viral replication occurs within the first 48 hours after admission, with a significant decrease at subsequent time points (p < 0.0001). Moreover, higher RSV-RNA values were associated with the need for oxygen therapy (p = 0.03), particularly high-flow nasal cannula type (p = 0.04), and longer duration of respiratory support (p = 0.04). Finally, higher RSV load values were correlated with lower white blood cells, especially lymphocyte counts and C-reactive protein levels (p = 0.03, p = 0.04, and p = 0.01, respectively), as well as with patients of a younger age (p = 0.02). These data suggest that RSV may actively contribute to the clinical severity of bronchiolitis, together with other potential non-viral factors. [ABSTRACT FROM AUTHOR]

Simple Summary: Red sea bream iridovirus (RSIV) has been reported to be susceptible to various marine fish species in Asian countries such as South Korea, and it causes significant economic losses due to massive mortalities in rock bream (Oplegnathus fasciatus) in particular. However, studies on the impact of the virus shed from RSIV-infected rock bream on other fish species are limited. Here, we investigated the dynamics of the virus by simulating the natural conditions of RSIV infection in rock bream and examining its release into seawater and the risk of horizontal transmission through cohabitation with other fish species. Our data demonstrated that the virus shed from RSIV-infected rock bream caused high mortality rates in surrounding fish species through horizontal transmission. Our findings suggest the potential for RSIV-infected rock bream in farms to spread the disease to neighboring farms. Additionally, our results demonstrated a high correlation between RSIV load and viral shedding ratio in rock breams, as well as between RSIV load and histopathological infection grades. Red sea bream iridovirus (RSIV) causes significant economic losses in aquaculture. Here, we analyzed the pathogenicity, viral shedding, and transmission dynamics of RSIV in rock bream (Oplegnathus fasciatus) by employing immersion infection and cohabitation challenge models. Rock bream challenged by immersion exposure exhibited 100% mortality within 35 days post RSIV exposure, indicating that the viral shedding in seawater peaked after mortality. At 25 °C, a positive correlation between the viral loads within infected rock bream and virus shedding into the seawater was observed. Specific RSIV lesions were observed in the spleen and kidney of the infected rock bream, and the viral load in the spleen had the highest correlation with the histopathological grade. A cohabitation challenge mimicking the natural transmission conditions was performed to assess the virus transmission and determine the pathogenicity and viral load. The RSIV-infected rock breams (donors) were cohabited with uninfected rock bream, red sea bream (Pagrus major), and flathead grey mullet (Mugil cephalus) (recipients) at both 25 °C and 15 °C. In the cohabitation challenge group maintained at 15 °C, no mortality was observed across all experimental groups. However, RSIV was detected in both seawater and the recipient fish. Our results provide preliminary data for further epidemiological analyses and aid in the development of preventive measures and management of RSIVD in aquaculture. [ABSTRACT FROM AUTHOR]

We describe the clinical and demographic characteristics, virological follow‐up, and management of five confirmed monkeypox cases from New Delhi, India without any international travel history. The viral load kinetics and viral clearance were estimated in oropharyngeal swabs (OPS), nasopharyngeal swabs (NPS), EDTA blood, serum, urine, and various lesion specimens on every fourth day of follow‐up ranging from 5 to 24 post onset day (POD) of illness. All five cases presented with mild to moderate‐grade intermittent fever, myalgia, and lesions on the genitals, groins, lower limb, trunk, and upper limb. Four cases had non‐tender firm lymphadenopathy. No secondary complications or sexually transmitted infections were recorded in these cases except for the presence of viral hepatitis B infection marker hepatitis B virus surface antigen (HBsAg) in one case. All the cases were mild and had a good recovery. A higher viral load was detected in lesion fluid (POD 9), followed by lesion roof (POD 9), urine (POD 5), lesion base (POD 5), and OPS/NPS (POD 5). The monkeypox virus (MPXV) DNA was detected in clinical samples from 5th to 24th POD. These monkeypox cases without international travel history suggest the underdiagnosed monkeypox infection in the community. This emphasizes the need for active surveillance of MPXV in the high‐risk population such as men having sex with men and female sex workers. [ABSTRACT FROM AUTHOR]

The viral kinetics of SARS-CoV-2 has been considered clinically important. While remdesivir and corticosteroids are recommended for COVID-19 patients requiring oxygen support, there is a limited number of published reports on viral kinetics in hospitalised patients with COVID-19 treated with remdesivir or corticosteroids. We conducted a retrospective study by collecting longitudinal samples from the nasopharynx/throat of 123 hospitalised patients (median age 55 years, 74% male) with COVID-19, to evaluate the effects of remdesivir and corticosteroid treatment on viral RNA levels. The subjects were divided into four groups: those receiving remdesivir (n = 25), betamethasone (n = 41), both (n = 15), or neither (n = 42). Time to viral RNA clearance was analysed using Kaplan-Meier plots, categorical data were analysed using Fisher's exact test, and Kruskal-Wallis for continuous data. Viral RNA decline rate was analysed using a mixed effect model. We found no significant difference in SARS-CoV-2 RNA decline rate or time to SARS-CoV-2 RNA clearance between the groups. Moreover, clinical status at baseline was not correlated with time to viral clearance. Since SARS-CoV-2 RNA kinetics was not affected by treatment, repeated sampling from the upper respiratory tract cannot be used to evaluate treatment response. [ABSTRACT FROM AUTHOR]

Simple Summary: Red sea bream iridoviral disease (RSIVD) generates serious economic losses by causing mass mortality events of rock bream during the season with high water temperature in the Republic of Korea and other Asian countries. However, very few studies have investigated RSIV kinetics in rock bream under various rearing water temperatures. In this paper, we investigated the viral load shedding of RSIV into seawater after artificially infecting rock bream (Oplegnathus fasciatus) with the virus. Overall, our data suggest that the viral load shedding of RSIV into seawater varies depending on water temperature and virus inoculation concentration. Our results reveal the potential of non-invasive virus detection approaches, such as the utilization of environmental DNA in fish farms. In addition, we showed that the quantitative analysis of seawater viruses can indirectly improve our understanding of disease progression in fish, potentially contributing to enhanced disease control. Red sea bream iridoviral disease (RSIVD) causes serious economic losses in the aquaculture industry. In this paper, we evaluated RSIV kinetics in rock bream under various rearing water temperatures and different RSIV inoculation concentrations. High viral copy numbers (approximately 103.7–106.7 RSIV genome copies/L/g) were observed during the period of active fish mortality after RSIV infection at all concentrations in the tanks (25 °C and 20 °C). In the group injected with 104 RSIV genome copies/fish, RSIV was not detected at 21–30 days post-infection (dpi) in the rearing seawater. In rock bream infected at 15 °C and subjected to increasing water temperature (1 °C/d until 25 °C) 3 days later, the virus replication rate and number of viral copies shed into the rearing seawater increased. With the decrease in temperature (1 °C/d) from 25 to 15 °C after the infection, the virus replicated rapidly and was released at high loads on the initial 3–5 dpi, whereas the number of viral copies in the fish and seawater decreased after 14 dpi. These results indicate that the number of viral copies shed into the rearing seawater varies depending on the RSIV infection level in rock bream. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) establishes a lifelong latent infection in healthy humans, kept under immune control by cytotoxic T cells (CTLs). Following paediatric haematopoetic stem cell transplantation (HSCT), a loss of immune surveillance leads to opportunistic outgrowth of EBV-infected cells, resulting in EBV reactivation, which can ultimately progress to post-transplant lymphoproliferative disorder (PTLD). The aims of this study were to identify risk factors for EBV reactivation in children in the first 100 days post-HSCT and to assess the suitability of a previously reported mathematical model to mechanistically model EBV reactivation kinetics in this cohort. Retrospective electronic data were collected from 56 children who underwent HSCT at Great Ormond Street Hospital (GOSH) between 2005 and 2016. Using EBV viral load (VL) measurements from weekly quantitative PCR (qPCR) monitoring post-HSCT, a multivariable Cox proportional hazards (Cox-PH) model was developed to assess time to first EBV reactivation event in the first 100 days post-HSCT. Sensitivity analysis of a previously reported mathematical model was performed to identify key parameters affecting EBV VL. Cox-PH modelling revealed EBV seropositivity of the HSCT recipient and administration of anti-thymocyte globulin (ATG) pre-HSCT to be significantly associated with an increased risk of EBV reactivation in the first 100 days post-HSCT (adjusted hazard ratio (AHR) = 2.32, P = 0.02; AHR = 2.55, P = 0.04). Five parameters were found to affect EBV VL in sensitivity analysis of the previously reported mathematical model. In conclusion, we have assessed the effect of multiple covariates on EBV reactivation in the first 100 days post-HSCT in children and have identified key parameters in a previously reported mechanistic mathematical model that affect EBV VL. Future work will aim to fit this model to patient EBV VLs, develop the model to account for interindividual variability and model the effect of clinically relevant covariates such as rituximab therapy and ATG on EBV VL. [ABSTRACT FROM AUTHOR]

Mathematical models, some of which incorporate both intracellular and extracellular hepatitis C viral kinetics, have been advanced in recent years for studying HCV–host dynamics, antivirals mode of action, and their efficacy. The standard ordinary differential equation (ODE) hepatitis C virus (HCV) kinetic model keeps track of uninfected cells, infected cells, and free virus. In multiscale models, a fourth partial differential equation (PDE) accounts for the intracellular viral RNA (vRNA) kinetics in an infected cell. The PDE multiscale model is substantially more difficult to solve compared to the standard ODE model, with governing differential equations that are stiff. In previous contributions, we developed and implemented stable and efficient numerical methods for the multiscale model for both the solution of the model equations and parameter estimation. In this contribution, we perform sensitivity analysis on model parameters to gain insight into important properties and to ensure our numerical methods can be safely used for HCV viral dynamic simulations. Furthermore, we generate in-silico patients using the multiscale models to perform machine learning from the data, which enables us to remove HCV measurements on certain days and still be able to estimate meaningful observations with a sufficiently small error. [ABSTRACT FROM AUTHOR]

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 withinhost parameters such as the infected cell half-life and the withinhost 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. [ABSTRACT FROM AUTHOR]

Aims: We propose the use of in silico mathematical models to provide insights that optimize therapeutic interventions designed to effectively treat respiratory infection during a pandemic. A modelling and simulation framework is provided using SARS‐CoV‐2 as an example, considering applications for both treatment and prophylaxis. Methods: A target cell‐limited model was used to quantify the viral infection dynamics of SARS‐CoV‐2 in a pooled population of 105 infected patients. Parameter estimates from the resulting model were used to simulate and compare the impact of various interventions against meaningful viral load endpoints. Results: Robust parameter estimates were obtained for the basic reproduction number, viral release rate and infected‐cell mortality from the infection model. These estimates were informed by the largest dataset currently available for SARS‐CoV‐2 viral time course. The utility of this model was demonstrated using simulations, which hypothetically introduced inhibitory or stimulatory drug mechanisms at various target sites within the viral life‐cycle. We show that early intervention is crucial to achieving therapeutic benefit when monotherapy is administered. In contrast, combination regimens of two or three drugs may provide improved outcomes if treatment is initiated late. The latter is relevant to SARS‐CoV‐2, where the period between infection and symptom onset is relatively long. Conclusions: The use of in silico models can provide viral load predictions that can rationalize therapeutic strategies against an emerging viral pathogen. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) kinetics remain understudied, including the impact of remdesivir. In hospitalized individuals, peak sputum viral load occurred in week 2 of symptoms, whereas viremia peaked within 1 week of symptom-onset, suggesting early systemic seeding of SARS-CoV-2. Remdesivir treatment was associated with faster viral decay. [ABSTRACT FROM AUTHOR]

V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated in vitro and in vivo data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response elicited by V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration. Estimates of viral infection and replication which were calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t1/2 = 4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses. [ABSTRACT FROM AUTHOR]

Aim: This study investigated the stability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on 16 common environmental surface materials. Background: SARS-CoV-2 is the causative agent of severe coronavirus disease, a significant public health concern that quickly led to a pandemic. Contamination of environmental surface materials is of concern, with previous studies identifying long-term detection of infectious particles on surfaces. These contaminated surfaces create an increased risk for contact transmission. Methods: Surface materials were inoculated with 10,000 plaque forming units and samples were collected 4, 8, 12, 24, 30, 48, and 168 hours post infection (hpi). Viral titers were determined for each sample and time point using plaque assays. Nonparametric modeling utilized the Turnbull algorithm for interval-censored data. Maximum likelihood estimates for the survival curve were calculated. Parametric proportional hazards regression models for interval censored data were used to explore survival time across the surface materials. Results: There was a sharp decline in recoverable virus after 4 hpi for all tested surfaces. By 12 hpi, infectious SARS-CoV-2 was recoverable from only four surfaces; and by 30 hr, the virus was recoverable from only one surface. There were differences in survival curves based on the materials although some groups of materials are similar, both statistically and practically. Conclusions: While very low amounts of infectious SARS-CoV-2 are recoverable over time, there remains a risk of viral transmission by surface contamination in indoor environments. Individuals and institutions must follow appropriate procedures to decontaminate indoor environment and increase diligence for hand hygiene and personal protective equipment. [ABSTRACT FROM AUTHOR]

COVID‐19 has hit the world by surprise, causing substantial mortality and morbidity since 2020. This narrative review aims to provide an overview of the epidemiology, induced impact, viral kinetics and clinical spectrum of COVID‐19 in the Asia‐Pacific Region, focusing on regions previously exposed to outbreaks of coronavirus. COVID‐19 progressed differently by regions, with some (such as China and Taiwan) featured by one to two epidemic waves and some (such as Hong Kong and South Korea) featured by multiple waves. There has been no consensus on the estimates of important epidemiological time intervals or proportions, such that using them for making inferences should be done with caution. Viral loads of patients with COVID‐19 peak in the first week of illness around days 2 to 4 and hence there is very high transmission potential causing community outbreaks. Various strategies such as government‐guided and suppress‐and‐lift strategies, trigger‐based/suppression approaches and alert systems have been employed to guide the adoption and easing of control measures. Asymptomatic and pre‐symptomatic transmission is a hallmark of COVID‐19. Identification and isolation of symptomatic patients alone is not effective in controlling the ongoing outbreaks. However, early, prompt and coordinated enactment predisposed regions to successful disease containment. Mass COVID‐19 vaccinations are likely to be the light at the end of the tunnel. There is a need to review what we have learnt in this pandemic and examine how to transfer and improve existing knowledge for ongoing and future epidemics. See relatedEditorial [ABSTRACT FROM AUTHOR]

Purpose: Data on the efficacy, dosing and safety of letermovir for the compassionate therapeutic use of CMV infections are limited. Methods: Clinical and virological efficacy of letermovir was assessed in a retrospective single-centre study of patients who received letermovir for the compassionate therapeutic use of CMV infections. Results: Letermovir initiation yielded prompt treatment response in 7 out of 9 patients (77.7%). Conclusion: Letermovir may be an effective and well tolerated option in the compassionate treatment of CMV infections, although recurrence of CMV and emergence of resistance may be issues. [ABSTRACT FROM AUTHOR]

HBV‐DNA levels are low or even undetectable in the majority HDV‐infected patients. The impact of PEG‐IFNα on HBV‐DNA kinetics in HDV‐infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV‐RNA–positive patients were randomized to receive PEG‐IFNα‐2a plus tenofovir‐disoproxil‐fumarate (PEG‐IFNα/TDF, n = 59) or placebo (PEG‐IFNα/PBO; n = 61) for 96 weeks. At week 96, HBV‐DNA was still quantifiable in 71% of PEG‐IFNα/PBO‐treated patients but also in 76% of PEG‐IFNα/TDF‐treated patients, despite low HBV‐DNA baseline values. Surprisingly, a transient HBV‐DNA increase between weeks 12 and 36 was observed in 12 in PEG‐IFNα/TDF‐treated and 12 PEG‐IFNα/PBO‐treated patients. This increase was positively associated with HBsAg loss [(P = 0.049, odds ratio (OR) 5.1] and HDV‐RNA suppression (P = 0.007, OR 4.1) at week 96. Biochemical markers of cell death (M30 and ALT) were higher during the HBV‐DNA peak but no distinct systemic immune pattern could be observed by screening 91 soluble inflammatory markers. In conclusion, an early increase in HBV‐DNA during PEG‐IFNα‐2a therapy occurred in more than 20% of patients, even in TDF‐treated patients. This transient HBV‐DNA rise may indicate PEG‐IFNα–induced cell death and lead to long‐term HDV‐RNA suppression and HBsAg loss. [ABSTRACT FROM AUTHOR]

Hepatitis B virus RNA (HBV RNA)–containing particles are encapsidated pre‐genomic RNA (pgRNA) detectable in chronically infected patients in addition to virions (HBV DNA) that have been suggested as a marker of the treatment efficacy. This makes promising the use of core protein allosteric modulators, such as RG7907, which disrupt the nucleocapsid assembly and profoundly reduce HBV RNA. Here, we developed a multiscale model of HBV extending the standard viral dynamic models to analyse the kinetics of HBV DNA and HBV RNA in 35 patients treated with RG7907 for 28 days. We compare the predictions with those obtained in patients treated with the nucleotide analog tenofovir. RG7907 blocked 99.3% of pgRNA encapsidation (range: 92.1%–99.9%) which led to a decline of both HBV DNA and HBV RNA. As a consequence of its mode of action, the first phase of decline of HBV RNA was rapid, uncovering the clearance of viral particles with half‐life of 45 min. In contrast, HBV DNA decline was predicted to be less rapid, due to the continuous secretion of already formed viral capsids (t1/2 = 17 ± 6 h). After few days, both markers declined at the same rate, which was attributed to the loss of infected cells (t1/2 ≅ 6 ± 0.8 days). By blocking efficiently RNA reverse transcription but not its encapsidation, nucleotide analog in contrast was predicted to lead to a transient accumulation of HBV RNA both intracellularly and extracellularly. The model brings a conceptual framework for understanding the differences between HBV DNA and HBV RNA dynamics. Integration of HBV RNA in viral dynamic models may be helpful to better quantify the treatment effect, especially in viral‐suppressed patients where HBV DNA is no longer detectable. [ABSTRACT FROM AUTHOR]

Background: Abnormal liver function has been reported in patients with COVID-19 infection. The aim of our study was to report on the prevalence of liver injury in our cohort, to evaluate the association of mild versus severe liver injury with mortality in COVID-19 patients and to scrutinize the temporal pattern of viral detection and liver injury. Methods: We present data from a German cohort of 147 SARS-CoV-2 infected patients. The patients were divided into 3 groups according to their liver status during treatment. The first group included patients without elevated alanine aminotransferase or bilirubin, the third group patients meeting the biochemical criteria of acute liver failure (ALF), and the second group all other patients. Results: Liver injury was detected in 75 (50.7%) and 93 (63%) patients by admission and during treatment, respectively. ALF was associated with the male sex, younger age, and higher BMI. Mortality was associated with the presence of ALF (OR = 9.423, 95% CI: 2.410–36.858) in contrast to milder liver injury (OR 1.101, 95% CI: 0.435–2.791). In 30% of patients with mild liver injury and in 50% of ALF patients, peak liver injury was observed at a time point when the virus was no longer detectable in the respiratory tract. Conclusion: Mild liver injury was not associated with worse outcome in our cohort, and the pattern of liver injury did not fit well to the theory of SARS-CoV-2 directly causing liver impairment. Instead, severe liver injury in our cohort was associated multiple-organ failure and acute vascular events. [ABSTRACT FROM AUTHOR]

Background: We report on predictors of adenovirus (ADV) viremia and correlation of ADV viral kinetics with mortality in ex vivo T-cell depleted (TCD) hematopoietic cell transplant (HCT).Methods: T cell-depleted HCT recipients from January 1, 2012 through September 30, 2018 were prospectively monitored for ADV in the plasma through Day (D) +100 posttransplant or for 16 weeks after the onset of ADV viremia. Adenovirus viremia was defined as ≥2 consecutive viral loads (VLs) ≥1000 copies/mL through D +100. Time-averaged area under the curve (AAUC) or peak ADV VL through 16 weeks after onset of ADV viremia were explored as predictors of mortality in Cox models.Results: Of 586 patients (adult 81.7%), 51 (8.7%) developed ADV viremia by D +100. Age <18 years, recipient cytomegalovirus seropositivity, absolute lymphocyte count <300 cells/µL at D +30, and acute graft-versus-host disease were predictors of ADV viremia in multivariate models. Fifteen (29%) patients with ADV viremia died by D +180; 8 of 15 (53%) died from ADV. Peak ADV VL (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.52-3.33) and increasing AAUC (HR, 2.95; 95% CI, 1.83-4.75) correlated with mortality at D +180.Conclusions: In TCD HCT, peak ADV VL and ADV AAUC correlated with mortality at D +180. Our data support the potential utility of ADV viral kinetics as endpoints in clinical trials of ADV therapies. [ABSTRACT FROM AUTHOR]

Background and Aim: 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. Methods: Hepatitis C virus (HCV) genotype‐1b patients were allocated to daclatasvir/asunaprevir +weight‐based RBV (1000–1200 mg/day) for 12–24 weeks. HCV RNA levels were compared at day 1, week 1, week 2, and week 4 of treatment. Results: 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. Conclusions: Adding RBV to DAAs improved early viral kinetic, in particular, for intermediate responders. [ABSTRACT FROM AUTHOR]

Summary: The advent of powerful direct‐acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA‐based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment‐naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA‐based treatments. [ABSTRACT FROM AUTHOR]

Viral infectious diseases are a global health concern, as is evident by recent outbreaks of the middle east respiratory syndrome, Ebola virus disease, and re-emerging zika, dengue, and chikungunya fevers. Viral epidemics are a socio-economic burden that causes short- and long-term costs for disease diagnosis and treatment as well as a loss in productivity by absenteeism. These outbreaks and their socio-economic costs underline the necessity for a precise analysis of virus-host interactions, which would help to understand disease mechanisms and to develop therapeutic interventions. The combination of quantitative measurements and dynamic mathematical modeling has increased our understanding of the within-host infection dynamics and has led to important insights into viral pathogenesis, transmission, and disease progression. Furthermore, virus-host models helped to identify drug targets, to predict the treatment duration to achieve cure, and to reduce treatment costs. In this article, we review important achievements made by mathematical modeling of viral kinetics on the extracellular, intracellular, and multi-scale level for Human Immunodeficiency Virus, Hepatitis C Virus, Influenza A Virus, Ebola Virus, Dengue Virus, and Zika Virus. Herein, we focus on basic mathematical models on the population scale (so-called target cell-limited models), detailed models regarding the most important steps in the viral life cycle, and the combination of both. For this purpose, we review how mathematical modeling of viral dynamics helped to understand the virus-host interactions and disease progression or clearance. Additionally, we review different types and effects of therapeutic strategies and how mathematical modeling has been used to predict new treatment regimens. [ABSTRACT FROM AUTHOR]

Mathematical models that describe infection kinetics help elucidate the time scales, effectiveness, and mechanisms underlying viral growth and infection resolution. For influenza A virus (IAV) infections, the standard viral kinetic model has been used to investigate the effect of different IAV proteins, immune mechanisms, antiviral actions, and bacterial coinfection, among others. We sought to further define the kinetics of IAV infections by infecting mice with influenza A/PR8 and measuring viral loads with high frequency and precision over the course of infection. The data highlighted dynamics that were not previously noted, including viral titers that remain elevated for several days during mid-infection and a sharp 4–5 log10 decline in virus within 1 day as the infection resolves. The standard viral kinetic model, which has been widely used within the field, could not capture these dynamics. Thus, we developed a new model that could simultaneously quantify the different phases of viral growth and decay with high accuracy. The model suggests that the slow and fast phases of virus decay are due to the infected cell clearance rate changing as the density of infected cells changes. To characterize this model, we fit the model to the viral load data, examined the parameter behavior, and connected the results and parameters to linear regression estimates. The resulting parameters and model dynamics revealed that the rate of viral clearance during resolution occurs 25 times faster than the clearance during mid-infection and that small decreases to this rate can significantly prolong the infection. This likely reflects the high efficiency of the adaptive immune response. The new model provides a well-characterized representation of IAV infection dynamics, is useful for analyzing and interpreting viral load dynamics in the absence of immunological data, and gives further insight into the regulation of viral control. [ABSTRACT FROM AUTHOR]

Background: It is unknown whether ribavirin (RBV) coadministration modifies the early rate of decline of hepatitis C virus (HCV) RNA in the liver versus plasma compartments, specifically.Methods: This partially randomized, open-label, phase 2 study enrolled treatment-naive, noncirrhotic patients with HCV genotype 1a. Patients were randomized 1:1 into Arms A and B, and then enrolled in Arm C. Patients received ombitasvir/paritaprevir/ritonavir plus dasabuvir for 12 weeks with either: no RBV for the first 2 weeks followed by weight-based dosing thereafter (Arm A), weight-based RBV for all 12 weeks (Arm B), or low-dose RBV (600 mg) once daily for all 12 weeks. Fine needle aspiration (FNA) was used to determine HCV RNA decline within liver.Results: Baseline HCV RNA was higher and declined more rapidly in plasma than liver; however, RBV dosing did not impact either median plasma or liver HCV RNA decline during the first 2 weeks of treatment. Liver-to-plasma drug concentrations were variable over time. The most common adverse event was pain associated with FNA.Conclusions: Coadministration of RBV had minimal visible impact on the plasma or liver kinetics of HCV RNA decline during the first 2 weeks of treatment, regardless of RBV dosing. [ABSTRACT FROM AUTHOR]

Aim 25-Hydroxy vitamin D (Vit D) plays a role in treatment outcomes in chronic hepatitis C virus (HCV) infection. We aimed to clarify whether HCV replication is inhibited by Vit D in HCV replicon cells. Clinical implication was assessed for rapid virological response (RVR) and sustained virological response (SVR) among those patients receiving antiviral therapy. Methods Cell survival and viral loads were observed in Con1 (genotype 1b) and J6/JFH (genotype 2a) cells treated with different doses of Vit D. Three groups of patients with different treatment responses were recruited to assess their Vit D levels: group A, RVR−/SVR−; group B, RVR+/SVR−; and group C, RVR+/SVR+. Results The viral load of Con1 cells decreased by 69%, 80%, and 86% following treatment with 1 μM, 5 μM, and 10 μM Vit D, respectively ( P < 0.0001). In J6/JFH cells, it decreased by 12%, 55%, and 80.5% following treatment with 1 μM, 5 μM, and 10 μM Vit D, respectively ( P < 0.0001). There was a significant increase of Vit D between chronic hepatitis C groups, ranging from 4.4 ± 5.6 ng/mL in group A ( n = 44), to 17.2 ± 11.6 ng/mL in group B ( n = 44), and 32.5 ± 37.5 ng/mL of group C ( n = 44) ( P < 0.001). Advanced fibrosis (odds ratio = 0.13, 95% confidence interval = 0.04-0.41, P < 0.001) and Vit D deficiency (<10 ng/mL) (odds ratio = 0.11, 95% confidence interval = 0.03-0.43, P = 0.001) were predictive of SVR in the multivariate regression analysis. Conclusion Vitamin D decreases HCV replication and also contributes to early treatment viral kinetics. [ABSTRACT FROM AUTHOR]

Background: Nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens may potentially minimize antiretroviral (ART) toxicities, but demonstrate mixed efficacy and toxicity results. The impact of an integrase strand transfer inhibitor (INSTI) and protease inhibitor (PI) regimen on HIV viral dynamics and T cell kinetics remains underdescribed. Objective: To compare the effect of raltegravir + ritonavir boosted lopinavir (RAL + LPV/r) to efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) on HIV kinetics and T cell dynamics. Methods: Fifty participants naïve to ART underwent HIV viral kinetic sampling evaluated using biexponential mixed effects modeling. A subset of 28 subjects (with complete viral suppression) underwent flow cytometry and evaluation of soluble markers of inflammation at weeks 0, 4, and 48 of ART. Results: RAL + LPV/r compared to EFV/TDF/FTC resulted in a prolonged first phase viral decay rate (18 vs. 13 daysp < 0.01). From weeks 0 to 4, RAL + LPV/r was associated with a trend toward greater decreases in activated CD4+T cells (−3.81 vs. −1.18p = 0.09) and less decreases in activated effector memory CD4+T cells (−0.63 vs. −2.69p-0.07). These trends did not persist to week 48. No differences were noted at any time point for soluble markers of immune activation. Conclusions: The prolonged first phase viral decay observed with RAL + LPV/r in persons starting ART did not result in differences in viral suppression at week 48. We also observed trends in declines in certain cellular markers of immune activation but it remains unclear if this could translate to long-term immunologic benefits in persons on an INSTI + PI. [ABSTRACT FROM AUTHOR]

Background: Amino acid (aa) 70 substitution (R70Q/H) in the core protein of hepatitis C virus (HCV) genotype 1b has been shown to be one of the key factors in determining resistance for pegylated interferon-α plus ribavirin combination therapy (PEG-IFNα/RBV). But the exact mechanisms remain unclear. The aim of this study was to investigate the dynamic response of wild and mutant core codon 70 strains to PEG-IFNα/RBV treatment. Methods: One hundred twelve Chinese patients with chronic HCV 1b infection were enrolled and received a standard protocol of 48 weeks of PEG-IFNα/RBV therapy and 24 consecutive weeks of follow-up. Serial blood samples were obtained at pretreatment baseline, and again at weeks 2, 4, 8, 12, and 24 during therapy for the quantification of 70R and 70Q/H strains. Dynamic characteristics and association with early virological response (EVR), sustained virological response (SVR) and IL28B genotypes were analyzed. Results: Of the 112 patients enrolled in this study, 93.8 % (105/112) were infected with mixture of 70R and 70Q/H strains before treatment. The 70Q/H strain was dominant in 20.5 % of patients. 42.9 % of patients with dominant 70Q/H exhibited EVR versus 88.6 % of patients with dominant 70R (P < 0.001). Furthermore, 35.0 % of patients with dominant 70Q/H exhibited SVR versus 77.4 % with dominant 70R (P < 0.001). However, regardless of the dominant strain, virological response types or the IL28B SNP genotypes, 70Q/H strains always exhibited the same response to treatment as the 70R strains and the percentage of HCV harboring the 70Q/H substitution did not change significantly during treatment. Conclusions: Although the ratio of 70Q/H to 70R is related to the virological response, 70Q/H strains always exhibited the same response as the 70R strains during PEG-IFNα/RBV treatment. Substitution of R70Q/H alone is not enough to lead to resistance to therapy. Positive selection for 70Q/H induced by IFNα was not observed. [ABSTRACT FROM AUTHOR]

Background & Aims Intravenous silibinin ( SIL) is a potent antiviral agent against hepatitis C virus ( HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa ( IFN)-free treatment with SIL plus ribavirin ( RBV) can achieve sustained virological response ( SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. Methods A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of peg IFN+ RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. Results Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+ RBV was feasible, safe and achieved SVR (week-33). Conclusions We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated. [ABSTRACT FROM AUTHOR]

Ribavirin remains essential to chronic hepatitis C treatment. This paper investigates the influence of ribavirin priming to steady state before combined pegylated-interferon/ribavirin treatment on viral kinetics, ribavirin trough concentrations, genetic variability within HCVcore, -NS5B and -NS5A, and response to antiviral therapy. A prospective cohort study was made of 27 chronic hepatitis C genotype 1 naıï ve patients who received four weeks of ribavirin followed by pegIFN-α-2a/ribavirin for 48 weeks (Group A). The results obtained were compared with those for a control/historical group (Group B). In addition, direct sequencing and pyrosequencing were applied to determine ribavirin monotherapy-induced sequence changes. The rapid, early, and sustained virological response values obtained were 48%, 89%, and 52%, respectively, in Group A, and 52%, 90%, and 52% in Group B (P>0.05). In the four-week combined treatment, the Group A patients showed a greater decrease in HCV-RNA (2.3 log10 IU/ml vs. 1.2 log10 IU/ml; P=0.04), lower alanine aminotransferase levels (23.5±1.33 U/L vs. 60.11±18U/L; P<0.001) and higher mean ribavirin trough concentrations (3.28±1.26 mg/L vs. 1.74±0.7 mg/L; P=0.001). No general increase in rates of nucleotide substitutions in the ribavirin monotherapy- treated patients was observed in NS5B, ISDR, or PKRbd, but there was a decrease in silent mutations in the HCV core (P=0.04). This result was confirmed by pyrosequencing in the NS5A region. It is concluded that the ribavirin priming combined treatment with pegIFN-a-2a does not improve sustained virological response rates in HCV genotype 1 naıÏve infected patients. However, the greater reductions in viral load and alanine aminotransferase levels, together with the higher ribavirin trough concentration values obtained, could reflect the greater effectiveness of the treatment. Ribavirin does not have a mutagenic effect on the virus in patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Viral kinetic (VK) modeling has led to increased understanding of the within host dynamics of viral infections and the effects of therapy. Here we review recent developments in the modeling of viral infection kinetics with emphasis on two infectious diseases: hepatitis C and influenza. We review how VK modeling has evolved from simple models of viral infections treated with a drug or drug cocktail with an assumed constant effectiveness to models that incorporate drug pharmacokinetics and pharmacodynamics, as well as phenomenological models that simply assume drugs have time varying-effectiveness. We also discuss multiscale models that include intracellular events in viral replication, models of drug-resistance, models that include innate and adaptive immune responses and models that incorporate cell-to-cell spread of infection. Overall, VK modeling has provided new insights into the understanding of the disease progression and the modes of action of several drugs. We expect that VK modeling will be increasingly used in the coming years to optimize drug regimens in order to improve therapeutic outcomes and treatment tolerability for infectious diseases. [ABSTRACT FROM AUTHOR]

Background & Aims PROPHESYS is a large, multinational, non-interventional prospective cohort study of chronic hepatitis C patients treated with peginterferon alfa/ribavirin. This subanalysis assesses rates of premature treatment discontinuation stratified by on-treatment virological response ( VR). Methods This PROPHESYS subanalysis is restricted to treatment-naive, hepatitis C virus (HCV) genotype (G)1/2/3 mono-infected patients who received peginterferon alfa-2a (40KD)/ribavirin with intended treatment duration of 48 (G1) or 24 weeks (G2/3). Early virological responses were classified into four mutually exclusive categories [rapid VR (RVR), complete early VR ( cEVR), partial EVR ( pEVR), no RVR/EVR], using standard criteria. Results The likelihood for shortening treatment owing to good efficacy was highest among patients with an RVR and HCV RNA ≤400 000 IU/ ml (G1 10.0%; G2/3 5.8%) whereas for poor efficacy, it was highest in G1 non-RVR/EVR patients with HCV RNA >400 000 IU/ ml (56.6%). Factors significantly associated with early treatment discontinuation as a result of good efficacy in G1 patients included RVR vs. no RVR/EVR and, at baseline, lower HCV RNA, lower FIB-4 score, HCV infection via injection drug use. For G2/3 patients, factors included lower baseline HCV RNA and G2 vs. G3 infection. Most patients started with the recommended peginterferon alfa-2a dose, but a high proportion received a higher-than-recommended ribavirin dose. Conclusions Despite international guidelines, few physicians used early viral kinetics to abbreviate treatment. Therefore, relatively few patients with an RVR and low baseline HCV RNA abbreviated treatment. In addition, there were deviations in ribavirin starting doses, suggesting that physicians tailor treatment according to local guidelines or previous experience. [ABSTRACT FROM AUTHOR]

Hepatitis C virus ( HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV-specific immune response during retreatment for experienced patients in a phase Ib study with E1E2 MF59 vaccine. Seventy-eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon-( IFN)/ribavirin-( RBV)] were randomly assigned to vaccine ( V:23), Peg- IFNα2a-180-ug/qw and ribavirin 1000-1200-mg/qd for 48 weeks ( P/R:25), or their combination ( P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0-4-8-12-24-28-32-36. Neutralizing of binding ( NOB) antibodies and lymphocyte proliferation assay ( LPA) for E1E2-specific- CD4 + T cells were performed at week 0-12-16-48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response ( SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients ( P = 0.023 and 0.025, P = 0.019 and <0.001, respectively). Among the 22 patients with the strongest direct antiviral effects of IFN (ε ≥ 0.800), those treated with P/R + V (10) reached lower HCV- RNA levels ( P = 0.026) at week 16. HCV E1E2 MF59 vaccine in combination with Peg- IFNα2a + RBV was safe and elicited E1E2 neutralizing antibodies and specific CD4 + T cell proliferation. Upon early response to IFN, vaccinations were associated with an enhanced second phase viral load decline. These results prompt phase II trials in combination with new antiviral therapies. [ABSTRACT FROM AUTHOR]

Purpose: Clevudine 30 mg showed potent antiviral activity with a marked post-treatment antiviral effect. However, long-term treatment with clevudine monotherapy induced resistance and myopathy in some cases. The objective of this study is to evaluate the preliminary efficacy and safety of the combination of clevudine 20 mg and adefovir compared to clevudine monotherapy. Methods: Seventy-four patients were randomized to either a combination of clevudine 20 mg and adefovir or clevudine 20 or 30 mg and were treated for 2 years. The viral kinetics for 24 weeks, virological response [VR; hepatitis B virus (HBV) DNA less than 300 copies/ml], and the biochemical response [BR; normal alanine aminotransferase (ALT)] were assessed. Results: There was no difference in baseline characteristics among the three groups. Viral kinetics study showed no statistically significant difference among them during 24 weeks. The combination group showed 95 % virological response with a statistically significant difference compared to the clevudine 30 mg (67 %) and 20 mg (71 %) groups ( p = 0.0376). Biochemical response rates were similar in all groups (78-94 %). No resistance was reported in the combination group, while 20 % of patients treated with clevudine 30 mg or 20 mg reported resistance during 2 years. Muscle-related symptoms such as myalgia (1 in clevudine 30 mg, 1 in the combination group) and muscle weakness (1 in clevudine 30 mg, 2 in clevudine 20 mg) were reported in five patients (7 %); of these, three patients discontinued the study. Conclusion: We concluded that the combination of clevudine 20 mg and adefovir produced a potent antiviral response together with a good resistance profile compared to clevudine monotherapy at 96 weeks in this pilot study. [ABSTRACT FROM AUTHOR]

Background Study C210 was a Phase IIa, exploratory trial to assess the activity of telaprevir on hepatitis C virus (HCV) early viral kinetics in treatment-naïve patients infected with genotype 4 (G4) HCV. Methods Patients were randomized to receive peginterferon and ribavirin alone, telaprevir monotherapy (T arm), or telaprevir in combination with peginterferon/ribavirin (TPR arm) for 15 days, followed by a 46- or 48-week standard treatment phase. The current analysis aimed to characterize the genotype and phenotype of HCV G4 variants emerging during telaprevir treatment Results Five of the 8 (62.5%) patients in the telaprevir (T) arm had viral breakthrough (vBT) during the investigational treatment phase (between baseline and Day 15), compared to no patients in the TPR arm. HCV G4 viral variants with a T54A/T mutation were detected in two of these patients, as well as two other patients with detectable HCV RNA at the end of telaprevir treatment. Emergence of the T54A/T mutation was associated with a 2- to 4-fold decreased susceptibility to telaprevir. All patients with vBT during the investigational treatment phase or with a T54A/T mutation achieved undetectable HCV RNA 12 or 24 weeks after end of treatment with subsequent peginterferon/ribavirin treatment. Conclusions In this analysis in G4 HCV-infected patients, more patients in the telaprevir monotherapy arm experienced vBT with resistant variants compared to none with telaprevir combination therapy. The most commonly selected mutation T54A in telaprevir-treated G4 HCV patients was previously described in the context of G1 infection. [ABSTRACT FROM AUTHOR]

Response to pegylated interferon-alpha and ribavirin (IFN-α/RBV) treatment for chronic hepatitis C virus (HCV) infection is influenced by host genetic factors, but their role for IFN-α–free, direct-acting antiviral (DAA) regimens is unclear. An exonic deletion allele (IFNL4-ΔG) bolsters the established association with IFN-α/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir along with RBV, IFNL4-ΔG is associated with slower early viral decay, due to slower loss of free virus (P = .039) and decreased drug efficacy (P = .048), suggesting functional relevance of IFN-λ4 in IFN-α–free DAA therapies. [ABSTRACT FROM AUTHOR]

The population of patients with chronic hepatitis C viral infection is ageing; however, elderly, hepatitis C-infected patients are understudied and less frequently treated. This subanalysis of data from the multinational PROPHESYS study examined associations between age (≤65 vs >65 years), on-treatment virological response and sustained virological response ( SVR) in patients treated with peginterferon alfa-2a (40 KD)/ribavirin in accordance with local licences. PROPHESYS comprised three cohorts studied in 19 countries according to country-specific legal and regulatory requirements. This subanalysis includes treatment-naive HCV mono-infected patients assigned to receive peginterferon alfa-2a (40 KD)/ribavirin, with 6276 individuals aged ≤65 years and 349 aged >65 years. Rapid virological response ( RVR) rates by Week 4 were consistently lower in older genotype (G) 1 (21.6% vs 27.2% in younger patients), G2 (80.7% vs 85.1%) and G3 (60.0% vs 74.2%) patients. SVR rates were significantly lower (29.8% vs 43.0%) and relapse rates significantly higher (43.1% vs 26.7%) in older G1 patients ( P = 0.0002 vs ≤65 years). In contrast, SVR and relapse rates were similar in G2 and G3 patients regardless of age. The positive predictive value of RVR for SVR was comparable in older and younger G1 patients (66.7% vs 68.6%, respectively) and higher in older G2 (80.7% vs 75.6%) and G3 (77.8% vs 66.8%) patients. Virological response rates are generally lower in elderly CHC patients, and RVR is a reliable positive predictor of SVR in patients >65 years. [ABSTRACT FROM AUTHOR]

Ribavirin amplifies the interferon-alpha (IFN) signalling cascade. As ribavirin needs 4 weeks to reach steady state, ribavirin priming may optimize hepatic IFN sensitivity before starting a pegylated (PEG)-IFN/ribavirin combination therapy. This study investigated potential benefits of ribavirin priming prior to PEG-IFN2a/ribavirin combination therapy on viral kinetics, on-treatment and sustained virological response (SVR) in chronic hepatitis C virus (HCV) genotype 1 infection. Sixty-eight treatment naive patients were randomized 2:2:1 to ribavirin (ribavirin arm) or placebo (placebo arm) or PEG-IFN2a (PEG-IFN2a arm) for 6 weeks prior to 12 weeks of PEG-IFN2a/ribavirin combination therapy within a double-blind, placebo-controlled trial. Then, standard PEG-IFN2a/ribavirin combination therapy according to the German guidelines was continued under the responsibility of the investigators. Ribavirin was given according to body weight and PEG-IFN2a at a dose of 180 μg subcutaneously once/week. During ribavirin priming, HCV RNA showed a decline of −0.58 log10 IU/mL ( P < 0.001) that was unrelated to the IL28B rs12979860 genotype (CC vs CT/TT, P = 0.244). Ribavirin priming did neither increase the PEG-IFN2a-induced first- or second-phase viral decline ( P values >0.100) nor on-treatment response or SVR (HCV RNA undetectable at week 12 of combination therapy: ribavirin arm 56%, placebo arm 38%, PEG-IFN2a arm 50%; SVR: ribavirin arm 41%, placebo arm 54%, PEG-IFN2a arm 50%; P values >0.300). In conclusion, ribavirin monotherapy showed a significant antiviral activity that was not influenced by the IL28B genotype. Ribavirin priming prior to PEG-IFN2a/ribavirin combination therapy did neither increase the first- or second-phase viral decline nor on-treatment response or SVR. [ABSTRACT FROM AUTHOR]

Background. This partially blinded, randomized, phase 2a C210 study evaluated the antiviral activity of telaprevir-based regimens in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 4 infection.Methods. Twenty-four patients received telaprevir 750 mg every 8 hours for 15 days (T; n = 8), telaprevir in combination with pegylated interferon alfa-2a and ribavirin (Peg-IFN/RBV) for 15 days (TPR; n = 8), or Peg-IFN/RBV plus placebo for 15 days (PR; n = 8), followed by Peg-IFN/RBV for 46 or 48 weeks. The primary objective was to assess the effect of telaprevir on HCV RNA levels.Results. HCV RNA levels decreased slightly with T and PR; TPR produced substantial, rapid declines. On day 15, median reductions in the HCV RNA load from baseline were −0.77, −4.32, and −1.58 log10 IU/mL for T, TPR, and PR, respectively, and 0 patients in the T group, 1 in the TPR group, and 0 in the PR group had undetectable HCV RNA. Five of 8 patients who received telaprevir monotherapy had viral breakthrough within 15 days of treatment. Adverse event incidence was similar across treatments and comparable with the incidences from previous clinical trials. One patient (in T group) had a serious adverse event (considered unrelated to telaprevir) that led to treatment discontinuation.Conclusions. Telaprevir with Peg-IFN/RBV had greater activity than Peg-IFN/RBV treatment or telaprevir monotherapy against HCV genotype 4. Telaprevir was generally safe and well tolerated. Further investigation of telaprevir combination therapy in patients with HCV genotype 4 infection is warranted.Clinical Trials Registration. NCT00580801. [ABSTRACT FROM PUBLISHER]

Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. Methods: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. Results: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. Conclusion: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV. [ABSTRACT FROM AUTHOR]

Purpose: IL28B genotypes have a strong impact on treatment outcomes of chronic hepatitis C (CHC) and on-treatment viral kinetics. Since metabolic regulation and interferon response are highly integrated, metabolic profiles may play an important role in the link between IL28B genotypes and hepatitis C virus (HCV) infection. Thus, the association of IL28B rs8099917 genotypes with metabolic profiles and the impact of metabolic profiles on hepatitis C viral kinetic parameters were examined. Methods: A case-control analysis including 278 CHC patients and 280 subjects without chronic HCV infection was performed. The associations of IL28B rs8099917 genotype with pretreatment metabolic profiles and early viral kinetic parameters were evaluated. Results: Compared to HCV genotype 1 patients, the differences in metabolic profiles were more significant in genotype 2 patients. HCV genotype 2 patients with TT genotype had higher serum total cholesterol and high density lipoprotein (HDL) levels than those with GT genotype, and the differences remained significant when adjusted for age, sex, and body mass index ( p = 0.005 for total cholesterol; p = 0.006 for HDL). In addition, patients with higher serum TG, higher fasting blood glucose, and lower HDL had a lower viral clearance rate. Conclusions: IL28B genotypes may affect lipid profiles of CHC patients, especially in HCV-genotype 2 patients. Patients with higher serum fasting blood glucose, triglyceride, and lower HDL have a lower viral clearance rate during pegylated interferon plus ribavirin therapy. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) RNA level monitoring is currently used to guide the duration of interferon-containing treatment regimens. Nowadays, HCV RNA level quantification is based on real-time polymerase chain reaction assays that are both sensitive and accurate. Assessing the virological response to therapy is used to shorten treatment duration in early responders, in order to reduce the cost and burden of adverse events of therapy without impacting the chance of success. Whether response-guided therapy will still be useful in the era of all-oral, interferon-free regimens remains uncertain. [ABSTRACT FROM AUTHOR]