Biomedical subjects
Publications and source records attributed to Avidan U Neumann.
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BACKGROUND: We investigated associations between interferon (IFN)-gamma-inducible protein (IP)-10 and liver histological results, viral kinetic response, and treatment outcome in patients infected with hepatitis C virus (HCV) genotypes 1-4. METHODS: Plasma IP-10 was monitored before, during, and after treatment with pegylated IFN- alpha 2a and ribavirin in 265 HCV-infected patients. RESULTS: In univariate analyses, a low baseline IP-10 level was significantly associated with low baseline viral load, rapid viral response (RVR), a sustained viral response (SVR), body mass index <25 kg/m2, and less-pronounced fibrosis, inflammation, and steatosis (for HCV genotypes other than 3). When the results of the univariate analyses were included in multivariate analyses, a low plasma IP-10 level, low baseline viral load, and genotype 2 or 3 infection were independent predictors of an RVR and SVR. IP-10 levels decreased 6 weeks into treatment and remained low in patients with an SVR. By contrast, plasma levels of IP-10 rebounded in patients who had detectable HCV RNA after the completion of treatment. Using cutoff IP-10 levels of 150 and 600 pg/mL for predicting an SVR in patients infected with HCV genotype 1 yielded a specificity and sensitivity of 81% and 95%, respectively. CONCLUSION: Baseline IP-10 levels are predictive of the response to HCV treatment.
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BACKGROUND/AIMS: Recombinant human albumin-interferon alfa (alb-IFN) is a novel 85.7-kD recombinant protein consisting of interferon alfa-2b genetically fused to human serum albumin. METHODS: A phase 2, open-label, dose-ranging study was conducted in IFN-alfa-naïve patients with genotype 1 chronic hepatitis C to evaluate the antiviral activity, safety, and pharmacokinetics of alb-IFN. Fifty-six patients were enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts of 200, 450, 670, 900, and 1,200 microg. RESULTS: A 2 log(10) IU/mL or greater reduction in hepatitis C virus (HCV) RNA at Week 4 was observed in 69% (18/26) of patients who received the higher alb-IFN doses of 900 and 1,200 microg. The mean HCV RNA reduction at Week 4 in these two higher-dose cohorts was 3.2 log(10) IU/mL. Modeling of viral kinetics demonstrated a biphasic response that was dose dependent. Adverse events were mostly mild to moderate in severity. The most common adverse events were headache (73%), chills (63%), fatigue (61%), and arthralgia (55%). The median terminal half-life was 141 h consistent with previous alb-IFN data from IFN-alfa-experienced patients. CONCLUSIONS: Alb-IFN demonstrated significant antiviral activity and was well tolerated in patients with HCV genotype 1 infection.
Plasma from 173 patients with HCV genotype 1 infection was analyzed for IP-10 levels prior to treatment with pegylated interferon-alpha-2a and ribavirin. Significantly lower IP-10 levels were observed in patients achieving a rapid viral response (RVR) (P < .0001), even in those with body mass index (BMI) > or = 25 kg/m2 (P = .004) and with baseline viral load > or = 2 million IU/mL (P = .001). Similarly, significantly lower IP-10 levels were observed in patients obtaining a sustained viral response (SVR) (P = .0002), including those having higher BMI (P < .05), higher viral load (P = .0005), and both higher BMI and viral load (P < .03). In multivariate logistic regression analyses, a low IP-10 value was independently predictive of both RVR and SVR. A baseline cutoff IP-10 value of 600 pg/mL yielded a negative predictive value (NPV) of 79% (19/24) for all genotype 1-infected patients, which was comparable with that observed using a reduction in HCV-RNA by at least 2 logs after 12 weeks of therapy (NPV 86%; 19/22); by combining the two, 30 of 38 patients (NPV 79%) potentially could have been spared unnecessary therapy. In patients having both higher BMI and viral load, cut-off levels of 150 and 600 pg/mL yielded a positive predictive value (PPV) of 71% and NPV of 100%, respectively. In conclusion, pretreatment IP-10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load. A substantial proportion of the latter patients may achieve SVR in spite of unfavorable baseline characteristics if their pretreatment IP-10 level is low. Thus, pretreatment IP-10 analysis may prove helpful in decision-making regarding pharmaceutical intervention.
Albumin-interferon-alpha (IFN-alpha) is a novel 85.7-kDa recombinant protein consisting of IFN-alpha that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-alpha in IFN-alpha-experienced patients with chronic hepatitis C. Albumin-IFN-alpha was administered in 22 escalating doses (7-900 microg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-alpha had a favourable safety profile at doses up to 900 microg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159 h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for > or = 28 days following a single injection of albumin-IFN-alpha at doses of > or = 40 microg. Dose-dependent antiviral activity was observed in this IFN-alpha-experienced study population. Antiviral activity of > or = 1.0-log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-microg cohorts and in 59% (16/27) in the 400- to 900-microg double-injection cohorts. These results support further clinical studies of albumin-IFN-alpha for the treatment of patients with chronic hepatitis C.
BACKGROUND/AIMS: The existence of an extrahepatic hepatitis C virus replication compartment is an important question for optimizing therapy and preventing the infection of liver grafts. An extraheptic replication compartment could be indicated if viral decline during the anhepatic phase is not a single exponential. However, the duration of the anhepatic phase is too short (0.5-2h) to allow such analysis. Here we mathematically analyze viral decline during liver transplantation beyond the period of the anhepatic phase and examine the possibility of viral compartmentalization. METHODS: Viral load of 30 patients undergoing liver transplantation was frequently measured. Simulation and non-linear fitting of differential equation models were used to test different compartmentalization hypotheses. RESULTS: In 16 of the patients (56%), a bi-phasic viral decline was observed which is explained by the existence of a second replication compartment. This extrahepatic compartment is responsible for about 3.1% of virus in circulation and the mean half-life of its infected cells is 2.6 days. The remaining patients, with a single exponential decline, have either a second compartment with relatively low contribution or no second compartment. CONCLUSIONS: These results provide a first quantitative picture of the extrahepatic hepatitis C viral contribution and may suggest new approaches for viral clearance.
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BACKGROUND/AIMS: The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response. METHODS: Serum HCV-RNA was frequently quantified in patients with chronic hepatitis C (n=270) treated with peginterferon alfa-2a (180 microg/week) and ribavirin (1000-1200 mg/day). After 6 weeks patients were classified as rapid (RVR), slow (SPR), flat (FPR), or null responders (NUR) and randomized within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy (48 weeks) or shorter combination therapy (24 weeks) for RVR, triple therapy with histamine (1 mg/day) (48 weeks) or prolonged combination therapy (72 weeks) for SPR, triple therapy for FPR, and high-dose peginterferon (360 microg/week) plus ribavirin for NUR patients. RESULTS: Patients were categorized as RVR (n=171), SPR (n=65), FPR (n=10), or NUR (n=22). Overall end-of-treatment and sustained virologic response rates were 77 and 60% in the individualized and 77 and 66% in the standard treatment arm, respectively. Histamine in addition to peginterferon and ribavirin and high-dose peginterferon plus ribavirin did not improve virologic response rates in patients with FPR and NUR, respectively. CONCLUSIONS: An improvement in virologic efficacy was not achieved with the available individualized treatment options.
BACKGROUND & AIMS: Although hepatitis C virus kinetics and immune determinants during primary infection have been described, the virus-host interplay is not fully understood. We used mathematical modeling to elucidate and quantify virus-host dynamics. METHODS: Ten chimpanzees were infected intrahepatically with H77-RNA (n = 3) or intravenously with infected serum. Blood samples were taken 1-3 times per week for 6 months. A new model was fitted to the observed HCV RNA and alanine aminotransferase (ALT) kinetics. RESULTS: After infection, viral levels increased in a biphasic manner with a transient decline in between. This can be explained by a partial block (mean, 91%) of virion production, possibly due to an endogenous type I interferon response. After reaching maximum levels, a long viral plateau (mean, 6.1 log cp/mL) can be explained by blind homeostasis and lack of susceptible cells. Modest elevations in ALT levels (21-93 IU/L) were concurrently observed, indicating a shorter half-life of infected versus noninfected hepatocytes (mean ratio, 2.6). Following the ALT flare, viral titers rapidly declined to a lower (mean, 4.5 log cp/mL; n = 6) or undetectable level (n = 4). This decline is compatible with increased cell death (mean minimal estimate half-life, 28.7 days) and noncytolytic clearance (mean maximal estimate half-life, 24.1 days) of infected cells. CONCLUSIONS: Our results quantify virus-host dynamics during primary HCV infection and suggest that endogenous type I interferon slows virus production in the early acute phase. Partial or effective virus control correlates with the half-life of infected cells regulated by both cytolytic and noncytolytic mechanisms.
Mathematical modeling of the biological effect of interferon on virus decay permits the quantification of the efficacy (epsilon) of blocking virion production in different patient populations. The viral dynamic and immunologic responses of hepatitis C virus (HCV) infection to daily interferon therapy were characterized in twelve patients co-infected with human immunodeficiency virus (HIV). Three out of the twelve patients (25%) achieved an early viral response, a two-log reduction in HCV RNA by week 12. The mean epsilon of IFN-alpha in blocking HCV and HIV production were 72% and 74%, respectively. For HCV epsilon was highest (97%) in the one patient who had a sustained viral response, while it was reduced in the other two patients (68% and 77%). Baseline HCV RNA and the number of CD3+CD56+16+ cells were inversely related (r = -0.89, p = 0.03), and baseline HCV-specific immune responses were significantly higher in the three patients with 2-log viral load reductions. These data suggest that: 1) interferon efficacy at blocking virion production is correlated with treatment outcome in HIV/HCV co-infected patients, 2) that immunodeficient patients can respond to standard IFN-alpha, 3) that both innate and adaptive immune responses may be important determinants of HCV RNA decline in response to interferon.
To study determinants of clinical outcome following HCV infection, viral kinetics, immune events, and intrahepatic cytokine markers were compared in 10 naive chimpanzees. Four of the animals cleared HCV; 6 developed persistent infections. All animals developed similar acute infections with increasing viremia from 1 to 2 weeks, followed by alanine aminotransferase (ALT) elevations and seroconversion. This viremia pattern consisted of a biphasic increase, a rapid slope (mean doubling time [t(2)] = 0.5 days) followed by a slower slope after the second week (t(2) = 7.5 days). This slowing of virus replication correlated in all animals with increased intrahepatic 2'5' oligoadenylate synthetase 1 (2OAS-1) messenger RNA (mRNA) levels and was independent of disease outcome. An effective control of virus replication was observed following increases in intrahepatic interferon gamma (IFN-gamma) mRNA and ALT levels. Although this control was associated in all animals with a 2-log decrease in virus titer, the timing occurred approximately 2 weeks later in the chronic group (P <.05). Additionally, while cleared infections were characterized by a continual decrease in virus titer, the titers in the persistent infections reached a steady state level of 10(4) to 10(5) RNA copies/mL. This inability of the immune response to sustain viral clearance in the persistent infections was associated with a reduced intrahepatic CD3e and monocyte-induced protein 1alpha (MIP-1alpha) mRNA induction. In conclusion, these data indicate that, regardless of outcome, chimpanzees generate responses that control HCV replication during the early and late acute phase. However, the pathogenesis of HCV may be determined by a more rapid onset of the induced response and the cell population that migrates to the liver.
BACKGROUND & AIMS: In the patients with chronic hepatitis C, the addition of ribavirin to interferon (IFN)-alpha significantly increases the virologic responses. Our aim was to assess the antiviral action of ribavirin on hepatitis C virus (HCV) as a function of ribavirin pharmacokinetics and to evaluate the influence of this antiviral effect on IFN-alpha efficacy. METHODS: Forty-five patients with chronic hepatitis C (genotype 1b) received various schedules of IFN-alpha and/or ribavirin administration. Frequent blood sampling was performed for HCV RNA kinetics and ribavirin pharmacokinetics assessment. RESULTS: Ribavirin monotherapy induced a significant, moderate, early, and transient viral load decrease in approximately half of the patients. The occurrence of this effect was associated with longer ribavirin clearance half-lives and higher serum ribavirin concentrations. Ribavirin antiviral effect partly reduced the rebound preceding the second IFN-alpha injection in patients receiving standard IFN-alpha 3 times per week plus ribavirin. The magnitude of the rebound was inversely related to ribavirin concentrations. These patients subsequently experienced a slow, but significant, second slope of viral decrease and cleared HCV RNA. The addition of ribavirin to daily IFN-alpha monotherapy did not have any impact on the second phase of viral decline. CONCLUSIONS: Ribavirin exerts a significant, moderate, and transient antiviral effect in a significant proportion of patients with chronic hepatitis C. The antiviral effect of ribavirin correlates with ribavirin pharmacokinetics and is partly responsible for the improved efficacy of the combination of standard IFN-alpha and ribavirin compared with IFN-alpha monotherapy by increasing the incidence of the initial response.
Despite the recent approval of lamivudine for the treatment of children with chronic hepatitis B virus (HBV) infection, there is insufficient information on the kinetics of HBV clearance and the factors that predict a favorable treatment response to lamivudine in this population. In a small retrospective study of 16 HBV-infected children treated with lamivudine, we examined changes in virus load and other factors associated with hepatitis B e antigen (HBeAg) clearance. High pretherapy alanine aminotransferase level, low serum HBV DNA load, and age at the start of treatment were independently associated with HBeAg clearance. HBeAg clearance was also associated with the achievement of specific levels of virus suppression, and failure to achieve those levels was associated with the development of lamivudine resistance. Additional studies are necessary to provide better indications and guidelines for the treatment of children with chronic HBV infection.
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OBJECTIVE: The recovery of CD4 target cells following antiretroviral therapy may facilitate virus production and escape from antiretroviral suppression. To address this hypothesis, we directly examined whether the CD4 target cell number increases viral production in the presence of suboptimal therapy. DESIGN: The effect of the CD4 T cell number on HIV-1 replication with a suboptimal dose of zidovudine was studied in vitro. METHODS: Varying numbers of CD4 T cells were infected with HIV-1 and treated with 1 nM zidovudine. Virus production was measured by p24 antigen capture enzyme-linked immunosorbent assay. Partial sequencing of HIV-1 pol was performed to assess zidovudine-resistant mutations. RESULTS: Wild type virus production was found to increase eightfold in cultures with 100 x 10(4) cells compared with cultures with 10 x 10(4) cells. The IC90 of zidovudine was 4 logs higher in cultures with 16 x 10(4) cells compared with cultures with 1 x 10(4) cells. No zidovudine-resistant mutations were found. CONCLUSION: Target cell availability may play a direct role in wild type HIV-1 resurgence following therapy.
BACKGROUND/AIMS: Viral decline during lamivudine therapy in chronic hepatitis B patients is bi-phasic. We studied the influence of lamivudine dose and baseline characteristics on parameters obtained from a mathematical model. METHODS: Chronic hepatitis B patients were randomized to receive 150 mg (group 1; n=11) or 600 mg (group 2; n=10) lamivudine daily for 4 weeks. Hepatitis B virus DNA was measured frequently with the Digene Hybrid Capture II test and the Roche PCR assay. RESULTS: The description of viral decline in our closely monitored patients by means of the mixed-effects approach with both the bi-phasic model and a piecewise linear regression model resulted in a good fit. Baseline alanine aminotransferase (ALT) was significantly related to the slope of the second phase of viral decline. Previous lamivudine-treated patients showed a significant slower first phase than patients naive to lamivudine treatment. CONCLUSIONS: The initial observed difference in viral decline between 150 and 600 mg of lamivudine disappeared when baseline ALT was taken into account. This strengthens the hypothesis that the level of intrinsic activity is related to the turnover of infected hepatocytes. Moreover, reintroduction of lamivudine in previously lamivudine-treated patients should be considered carefully.
In patients infected with hepatitis C virus (HCV) genotype 1, sustained viral response (SVR) averages 10-40% depending on treatment regime. It has been proposed that high dose daily interferon (IFN) therapy early in therapy (induction dosing) may enhance SVR. In the present study we examined this issue and also assessed whether one could predict SVR and non-SVR, based on viral kinetics during the first month of induction therapy. End of treatment response and SVR was determined in 173 HCV infected patients who were treated with different induction doses of consensus interferon (CIFN) for one month followed by 11 months of standard 9 microg of CIFN thrice weekly (TIW). The second phase decline slope was calculated by log-linear regression on weekly measurements of serum HCV RNA during the first 7-28 days of treatment; rapid viral response (RVR) during the first month of induction dosing was defined as a decline of > 0.3 log copies/mL/week. Overall, SVR occurred in 11% of genotype 1 infected patients and 41% of patients with nongenotype 1. High dose induction therapy did not increase the rate of SVR, in either genotype 1 or genotype 2/3 infected patients. No patient without a RVR during the first month had SVR, while SVR occurred in 55% of the patients with RVR. RVR was the best predictor of SVR using multivariate analysis. These results indicate that induction dosing with CIFN does not improve SVR rates. They also suggest that early viral kinetics during the first month of therapy can predict non-SVR and thus save a patient a year long treatment which is fraught with side-effects and significant cost.