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Jonas Söderholm,
Jesper Waldenström,
Galia Askarieh,
Massimo Pilli,
Pierre-Yves Bochud,
Francesco Negro,
Jean-Michel Pawlotsky,
Stefan Zeuzem,
Carlo Ferrari,
Gunnar Norkrans,
Rune Wejstål,
Johan Westin, Avidan U Neumann,
Bart L Haagmans,
Magnus Lindh,
Gabriele Missale,
Kristoffer Hellstrand,
Martin Lagging
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ABSTRACT: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50-80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells.
Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8(+) T cells.
Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8(+) T cells (P = 0.02).
Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8(+) T cells.
PLoS ONE 01/2013; 8(2):e56991. · 4.09 Impact Factor
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Stéphanie Pascarella,
Sophie Clément,
Michael T Dill,
Stéphanie Conzelmann,
Martin Lagging,
Gabriele Missale, Avidan U Neumann,
Jean-Michel Pawlotsky,
Stefan Zeuzem,
Laura Rubbia-Brandt,
Pierre-Yves Bochud,
Francesco Negro
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ABSTRACT: BACKGROUND & AIMS: Antiviral treatment of chronic hepatitis C is not invariably successful, costly and associated with serious side-effects, and therefore should be indicated only when the chances of benefitting patients exceed the potential risks. The suppressor of cytokine signalling (SOCS) family members have been suggested to affect the rate of virological response to therapy, but the published evidence is conflicting. METHODS: We measured the intrahepatic SOCS1, SOCS3 and SOCS7 mRNA levels in 107 chronic hepatitis C patients and assessed their clinical and histological correlates with the virological response to therapy and with some factors known for affecting treatment outcome. RESULTS: By multivariate analysis, SOCS1, SOCS3 and SOCS7 mRNA levels were not associated with rapid or sustained virological response. Similarly, no association was found between the levels of any intrahepatic SOCS mRNA and those of the homeostasis model assessment of insulin resistance. Conversely, SOCS1 (OR 2.185, 95% CI 1.223-3.906, P=0.0083) and SOCS3 (OR 40.601, 95% CI 2.357-699.25, P=0.0108) mRNA level (but not SOCS7), together with age (OR 1.156, 95% CI 1.049-1.275, P=0.0036), were independently associated with cirrhosis. CONCLUSIONS: Intrahepatic SOCS1, SOCS3 and SOCS7 mRNA levels do not predict virological response to therapy in chronic hepatitis C. The association between SOCS1, SOCS3 and cirrhosis warrants further study.
Liver international: official journal of the International Association for the Study of the Liver 10/2012; · 3.82 Impact Factor
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Geert Bezemer,
Arthur R Van Gool,
Elke Verheij-Hart,
Bettina E Hansen,
Yoav Lurie,
Juan I Esteban,
Martin Lagging,
Francesco Negro,
Stefan Zeuzem,
Carlo Ferrari,
Jean-Michel Pawlotsky, Avidan U Neumann,
Solko W Schalm,
Robert J de Knegt
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ABSTRACT: Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study).
The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128).
At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL.
Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.
BMC Gastroenterology 01/2012; 12:11. · 2.42 Impact Factor
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ABSTRACT: Mathematical modeling of hepatitis C viral (HCV) kinetics is widely used for understanding viral pathogenesis and predicting treatment outcome. The standard model is based on a system of five non-linear ordinary differential equations (ODE) that describe both viral kinetics and changes in drug concentration after treatment initiation. In such complex models parameter estimation is challenging and requires frequent sampling measurements on each individual. By borrowing information between study subjects, non-linear mixed effect models can deal with sparser sampling from each individual. However, the search for optimal designs in this context has been limited by the numerical difficulty of evaluating the Fisher information matrix (FIM). Using the software PFIM, we show that a linearization of the statistical model avoids most of the computational burden, while providing a good approximation to the FIM. We then compare the precision of the parameters that can be expected using five study designs from the literature. We illustrate the usefulness of rationalizing data sampling by showing that, for a given level of precision, optimal design could reduce the total number of measurements by up 50 per cent. Our approach can be used by a statistician or a clinician aiming at designing an HCV viral kinetics study.
Statistics in Medicine 02/2011; 30(10):1045-56. · 1.88 Impact Factor
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ABSTRACT: We examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models. African Americans and whites had a similar distribution of IL28B genotypes (P = 0.5). The IL28B CC genotype was overrepresented (P = 0.015) in patients infected with HCV genotype-3 compared with genotype-1. In both genotype-1 and genotype-3, the first-phase viral decline and the average pegylated interferon-alpha-2a effectiveness during the first week of therapy were larger (trend P <= 0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second slower phase of viral decline (days 2-29) and infected cells loss rate, [delta], were larger (P = 0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.
JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2011; 56(2):95-9. · 4.43 Impact Factor
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ABSTRACT: We examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models. African Americans and whites had a similar distribution of IL28B genotypes (P = 0.5). The IL28B CC genotype was overrepresented (P = 0.015) in patients infected with HCV genotype-3 compared with genotype-1. In both genotype-1 and genotype-3, the first-phase viral decline and the average pegylated interferon-alpha-2a effectiveness during the first week of therapy were larger (trend P ≤ 0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second slower phase of viral decline (days 2-29) and infected cells loss rate, δ, were larger (P = 0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.
JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2011; 56(2):95-99. · 4.43 Impact Factor
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Martin Lagging,
Galia Askarieh,
Francesco Negro,
Stephanie Bibert,
Jonas Söderholm,
Johan Westin,
Magnus Lindh,
Ana Romero,
Gabriele Missale,
Carlo Ferrari, Avidan U Neumann,
Jean-Michel Pawlotsky,
Bart L Haagmans,
Stefan Zeuzem,
Pierre-Yves Bochud,
Kristoffer Hellstrand
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ABSTRACT: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients.
In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR.
Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.
PLoS ONE 01/2011; 6(2):e17232. · 4.09 Impact Factor
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ABSTRACT: In this article, we estimated the basic reproductive numbers by mathematical modeling and computer simulation using the hospitalization data of influenza type A (H3N2) from the United States as provided by the Centers for Disease Control and Prevention (CDC) from the 2001 to 2006 influenza seasons, respectively. The mean value of basic reproductive number from the 2001-2002 to 2005-2006 influenza seasons is 1.2440, with a 95% confidence interval of 1.1170-1.3710. Our model predicts that the proportion of vaccination of susceptible is 20% and 60 million doses of vaccines should be prepared for each influenza season in the United States. The chi-square test of goodness of fit indicates that our model fits the data reasonably well.
Journal of computational biology: a journal of computational molecular cell biology 12/2010; 17(12):1689-96. · 1.69 Impact Factor
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ABSTRACT: Antibodies are thought to exert antiviral activities by blocking viral entry into cells and/or accelerating viral clearance from circulation. In particular, antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) confer protection, by binding circulating virus. Here, we used mathematical modeling to gain information about viral dynamics during and after single or multiple infusions of a combination of two human monoclonal anti-HBs (HepeX-B) antibodies in patients with chronic hepatitis B. The antibody HBV-17 recognizes a conformational epitope, whereas antibody HBV-19 recognizes a linear epitope on the HBsAg. The kinetic profiles of the decline of serum HBV DNA and HBsAg revealed partial blocking of virion release from infected cells as a new antiviral mechanism, in addition to acceleration of HBV clearance from the circulation. We then replicated this approach in vitro, using cells secreting HBsAg, and compared the prediction of the mathematical modeling obtained from the in vivo kinetics. In vitro, HepeX-B treatment of HBsAg-producing cells showed cellular uptake of antibodies, resulting in intracellular accumulation of viral particles. Blocking of HBsAg secretion also continued after HepeX-B was removed from the cell culture supernatants. CONCLUSION: These results identify a novel antiviral mechanism of antibodies to HBsAg (anti-HBs) involving prolonged blocking of the HBV and HBsAg subviral particles release from infected cells. This may have implications in designing new therapies for patients with chronic HBV infection and may also be relevant in other viral infections.
Hepatology 09/2010; 52(3):875-85. · 11.66 Impact Factor
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ABSTRACT: The pharmacokinetics and pharmacodynamics of pegylated-interferon-alpha-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome.
Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 microg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed.
Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p=0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (delta), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p=0.013], 0.27 vs. 0.11 day(-1) [p=0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p=0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p=0.114). Genotype 1 had a significantly lower delta compared to genotype 3 (median 0.14 vs. 0.23 day(-1) [p=0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC(50)) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p=0.034]).
Both the HCV-infected cell loss rate (delta) and the maximum effectiveness of the first dose of PEG-IFN-alpha-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV.
Journal of Hepatology 09/2010; 53(3):460-7. · 9.26 Impact Factor
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ABSTRACT: A longitudinal discriminant analysis is applied to build predictive models based on repeated measurements of serum hepatitis C virus RNA. These models are evaluated through the partial area under the receiver operating curve index (PA index) and, the final selection of the best model is based on cross-validated estimates of the PA index. Models are compared by building 95% bootstrap confidence interval for the difference in PA index between two models. Data from a randomised trial, in which chronic HCV patients were enrolled, are used to illustrate the application of the proposed method to predict treatment outcome.
Statistical Methods in Medical Research 03/2010; 20(3):275-89. · 2.44 Impact Factor
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Galia Askarieh,
Asa Alsiö,
Paolo Pugnale,
Francesco Negro,
Carlo Ferrari, Avidan U Neumann,
Jean-Michel Pawlotsky,
Solko W Schalm,
Stefan Zeuzem,
Gunnar Norkrans,
Johan Westin,
Jonas Söderholm,
Kristoffer Hellstrand,
Martin Lagging
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ABSTRACT: High systemic levels of interferon-gamma-inducible protein 10 kDa (IP-10) at onset of combination therapy for chronic hepatitis C virus (HCV) infection predict poor outcome, but details regarding the impact of IP-10 on the reduction of HCV RNA during therapy remain unclear. In the present study, we correlated pretreatment levels of IP-10 in liver biopsies (n = 73) and plasma (n = 265) with HCV RNA throughout therapy within a phase III treatment trial (DITTO-HCV). Low levels of plasma or intrahepatic IP-10 were strongly associated with a pronounced reduction of HCV RNA during the first 24 hours of treatment in all patients (P < 0.0001 and P = 0.002, respectively) as well as when patients were grouped as genotype 1 or 4 (P = 0.0008 and P = 0.01) and 2 or 3 (P = 0.002, and P = 0.02). Low plasma levels of IP-10 also were predictive of the absolute reduction of HCV RNA (P < 0.0001) and the maximum reduction of HCV RNA in the first 4 days of treatment (P < 0.0001) as well as sustained virological response (genotype 1/4; P < 0.0001). To corroborate the relationship between early viral decline and IP-10, pretreatment plasma samples from an independent phase IV trial for HCV genotypes 2/3 (NORDynamIC trial; n = 382) were analyzed. The results confirmed an association between IP-10 and the immediate reduction of HCV RNA in response to therapy (P = 0.006). In contrast, pretreatment levels of IP-10 in liver or in plasma did not affect the decline of HCV RNA between days 8 and 29, i.e., the second-phase decline, or later time points in any of these cohorts. CONCLUSION: In patients with chronic hepatitis C, low levels of intrahepatic and systemic IP-10 predict a favorable first-phase decline of HCV RNA during therapy with pegylated interferon and ribavirin for genotypes of HCV.
Hepatology 12/2009; 51(5):1523-30. · 11.66 Impact Factor
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Lynn Rozenberg,
Bart L Haagmans, Avidan U Neumann,
Grace Chen,
Mary McLaughlin,
Rachel S Levy-Drummer,
H Masur,
Robin L Dewar,
Peter Ferenci,
Marcelo Silva,
Maria S Viola,
Michael A Polis,
Shyam Kottilil
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ABSTRACT: In this study we sought to characterize the relationship between several pharmacokinetic and pharmacodynamic parameters and virologic responses among HIV/hepatitis C virus genotype-1 co-infected patients receiving pegylated interferon-alpha-2b (peg-IFN2b) and ribavirin. We also tried to establish the underlying mechanisms that lead to poor sustained virologic responder rates observed with African-Americans against Caucasians and compared their results with those observed in a cohort of hepatitis C virus mono-infected patients.
Among our studied population, a viral decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 predicted sustained virologic responders with negative predictive value 100% and positive predictive value 100%. African-Americans had significantly (P < 0.01) slower hepatitis C virus viral kinetics as compared to Caucasians. However, peg-IFN2b concentrations and pharmacokinetic parameters, peg-IFN2b(max) and peg-IFN2b half-life, were similar in both groups and did not predict sustained virologic responders. Nevertheless, the pharmacodynamic parameter EC(50), estimated from nonlinear fitting of the viral kinetics together with peg-IFN2b concentration data, showed that HIV/ hepatitis C virus co-infected African-Americans have lower sensitivity to interferon-alpha thus giving rise to slower viral decline. The combined pharmacokinetic/pharmacodynamic parameter IFN(max)/EC(90) was an excellent predictor of sustained virologic responders, thus showing the importance of maintaining peg-IFN2b levels above EC(90) to achieve successful treatment.
Further studies are needed to evaluate whether these pharmacodynamic predictions are a result of differential host response to peg-IFN2b or other viral factors conferring relative resistance to peg-IFN2b.
AIDS (London, England) 11/2009; 23(18):2439-50. · 4.91 Impact Factor
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Mamta K Jain,
He-Jun Yuan,
Beverley Adams-Huet,
Amanda Reeck,
Janel Shelton,
Nahid Attar,
Song Zhang, Avidan U Neumann,
David S Carney,
Michael Gale,
William M Lee
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ABSTRACT: Hepatitis C virus (HCV) quasispecies diversity is more likely to affect early viral decline during treatment of hepatitis C than is having human immunodeficiency virus (HIV) infection. We evaluated the influence of HCV therapy on changes in the nonstructural 5A (NS5A) protein.
Fifteen patients with HCV genotype 1 infection with or without HIV infection were recruited for the present study, and the decrease in the HCV RNA level was measured at early time points. The evolution of HCV NS5A quasispecies within the first week was analyzed by comparing the clones observed at later times in the study with the baseline consensus sequence of individual patients. The response to therapy was defined as an early response (ER; ie, an HCV RNA level <615 IU/mL at week 4) or a slow response (SR; ie, a detectable HCV RNA level at week 4).
HIV infection did not affect early viral kinetics. At baseline, lower diversity was seen in NS5A and in the amino and carboxyl termini of patients with an ER, compared with those with an SR. Rapid evolution of the NS5A genetic region occurred in patients with an ER (P = .01) but not in those with an SR (P = .73). The evolution was the result of an increase in the number of amino acid substitutions in the carboxyl region (P = .02) in patients with an ER.
Selective pressure appears to result in more-marked changes in individuals with an ER than in those with an SR. The carboxyl terminus was subject to the most change and may be an important determinant of phenotypic resistance to interferon-based therapy.
The Journal of Infectious Diseases 09/2009; 200(6):866-76. · 6.41 Impact Factor
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ABSTRACT: Primary human immunodeficiency virus (HIV) infection is characterized by an initial exponential increase of viral load in peripheral blood reaching a peak, followed by a rapid decline to the viral setpoint. Although the target-cell-limited model can account for part of the viral kinetics observed early in infection [Phillips, 1996. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271 (5248), 497-499], it frequently predicts highly oscillatory kinetics after peak viremia, which is not typically observed in clinical data. Furthermore, the target-cell-limited model is unable to predict long-term viral kinetics, unless a delayed immune effect is assumed [Stafford et al., 2000. Modeling plasma virus concentration during primary HIV infection. J. Theor. Biol. 203 (3), 285-301]. We show here that extending the target-cell-limited model, by implementing a saturation term for HIV-infected cell loss dependent upon infected cell levels, is able to reproduce the diverse observed viral kinetic patterns without the assumption of a delayed immune response. Our results suggest that the immune response may have significant effect on the control of the virus during primary infection and may support experimental observations that an anti-HIV immune response is already functional during peak viremia.
Journal of Theoretical Biology 05/2009; 259(4):751-9. · 2.21 Impact Factor
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ABSTRACT: Albinterferon alfa-2b is a novel, long-acting, fusion polypeptide that is dosed q2wk or q4wk. The predictive value of early virologic response during albinterferon alfa-2b or peginterferon alfa-2a treatment was investigated in interferon-naïve patients with genotype 1, chronic hepatitis C.
Four hundred and fifty-eight patients were randomized to: albinterferon 900 or 1200 microg q2wk, or 1200 microg q4wk, or peginterferon 180 microg qwk. HCV RNA was measured by real-time PCR. A linear exhaustive search algorithm was used to determine the best SVR prediction algorithm in the per-protocol population (n=368), with inclusion of key ITT analyses to assess impact.
SVR rate: 54-67% (P=NS between arms). Rapid initial virologic response rate at week 2 (RIVR; viral decline >2 log(10)IU/mL) was 32-50% and gave rise to positive predictive value of 88-97% for SVR. No initial virologic response at week 4 (NIVR; viral decline <2 log(10)IU/mL; viral load >5.5 log(10)IU/mL) demonstrated a 100% negative predictive value for SVR. A sequential prediction algorithm based on viral kinetics at weeks 2 and 4 identified four prediction groups that reliably predicted SVR, positively or negatively, in 65-72% of patients.
Improved SVR prediction was obtained by integrating absolute levels and reduction of HCV RNA at treatment week 2 and 4. Patients with RIVR had a high likelihood of achieving SVR.
Journal of Hepatology 04/2009; 51(1):21-8. · 9.26 Impact Factor
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ABSTRACT: Albinterferon-alpha-2b (albIFN) is a long-acting fusion polypeptide composed of albumin and IFN-alpha-2b. In a phase 2 study of albIFN 1500 mug q2wk or q4wk in patients with genotype 2/3 chronic hepatitis C, albIFN demonstrated sustained virological response (SVR) rates of 62-77% (intent-to-treat population).
To assess the association of initial viral kinetics during albIFN therapy with baseline factors and SVR prediction.
In all, 43 patients were treated with albIFN 1500 mug (q2wk/q4wk) plus ribavirin (RBV) 800 mg/day for 24 weeks. Hepatitis C virus (HCV)-RNA levels were measured by real-time polymerase chain reaction, insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) and serum albIFN levels by enyzme-linked immunosorbent assay. Prediction analysis was performed in a per protocol 28-patient subset who were > or =80% adherent to albIFN/RBV and had HCV-RNA levels measured at treatment day 3.
Day-3 HCV-RNA level and first-phase viral decline as well as second-phase slope of viral decline were significantly associated with SVR. In adherent patients, 82.1% had a day-3 viral load <4.2 log(10) IU/ml or first-phase decline >1.25 log(10) IU/ml, which was predictive of SVR, both positively (95.7%; sensitivity: 100%) and negatively (100%; specificity: 83.3%). As low first-phase decline was associated with a high pretreatment HOMA-IR index (P=0.004) and a low day-3 serum albIFN level (P=0.01).
First-phase viral decline with albIFN/RBV was predictive of SVR in this study and may be modulated in part by IR.
Liver international: official journal of the International Association for the Study of the Liver 03/2009; 29(9):1350-5. · 3.82 Impact Factor
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ABSTRACT: Telaprevir (TVR) is a hepatitis C virus (HCV) NS3.4A protease inhibitor that has exhibited antiviral activity in patients with HCV genotype 1 infection. The viral dynamics in patients dosed with TVR were compared with those reported for patients treated with interferon (IFN).
The dynamics of wild-type HCV genotype 1 in patients dosed with TVR monotherapy (n=36) and TVR plus pegylated interferon (PEG-IFN)-alpha2a (n=8) were quantified using a biphasic viral dynamic model.
Patients dosed with either TVR monotherapy or TVR plus PEG-IFN-alpha2a had median first and second phase decreases of 12 per day and 1.1 per day, respectively. The second phase decrease was approximately 10-fold higher than reported values for IFN-based treatments (P<0.0001). Patients dosed with TVR plus PEG-IFN-alpha2a had a median remaining viral production after blockage (1-epsilon) of -2.37 log(10). In patients dosed with TVR monotherapy, increased TVR dosage of the same schedule was related to better blockage.
These results suggested that TVR-based regimens for chronic HCV infection will lead to an early and more rapid viral decrease that could potentially result in higher sustained viral response rates as well as offer the potential for a reduced duration of treatment.
Antiviral therapy 02/2009; 14(4):591-5. · 3.16 Impact Factor
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ABSTRACT: Regulatory T cells (Tregs) were shown to be central in maintaining immunological homeostasis and preventing the development of autoimmune diseases. Several subsets of Tregs have been identified to date; however, the dynamics of the interactions between these subsets, and their implications on their regulatory functions are yet to be elucidated.
We employed a combination of mathematical modeling and frequent in vivo measurements of several T cell subsets. Healthy BALB/c mice received a single injection of either hCDR1--a tolerogenic peptide previously shown to induce Tregs, a control peptide or vehicle alone, and were monitored for 16 days. During this period, splenocytes from the treated mice were analyzed for the levels of CD4, CD25, CD8, CD28 and Foxp3. The collected data were then fitted to mathematical models, in order to test competing hypotheses regarding the interactions between the followed T cell subsets. In all 3 treatment groups, a significant, lasting, non-random perturbation of the immune system could be observed. Our analysis predicted the emergence of functional CD4 Tregs based on inverse oscillations of the latter and CD4(+)CD25(-) cells. Furthermore, CD4 Tregs seemed to require a sufficiently high level of CD8 Tregs in order to become functional, while conversion was unlikely to be their major source. Our results indicated in addition that Foxp3 is not a sufficient marker for regulatory activity.
In this work, we unraveled the dynamics of the interplay between CD4, CD8 Tregs and effector T cells, using, for the first time, a mathematical-mechanistic perspective in the analysis of Treg kinetics. Furthermore, the results obtained from this interdisciplinary approach supported the notion that CD4 Tregs need to interact with CD8 Tregs in order to become functional. Finally, we generated predictions regarding the time-dependent function of Tregs, which can be further tested empirically in future work.
PLoS ONE 01/2009; 4(12):e8447. · 4.09 Impact Factor
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ABSTRACT: Analysis of hepatitis C virus (HCV) RNA kinetics in compartments other than plasma may help in understanding HCV replication and identifying clinically significant patterns of treatment response.
After 6 weeks of pegylated interferon-alpha2a/ribavirin therapy, 74 chronic hepatitis C patients were randomized to individualized or standard treatments for another 42 weeks. HCV RNA was quantified in peripheral blood mononuclear cells (PBMCs) by TaqMan-based real-time PCR and compared to plasma HCV RNA.
HCV RNA declines in PBMCs and plasma were comparable during the initial 12 weeks of therapy (Spearman's rank correlation range over different time points, 0.73-0.97). However, a delay of HCV RNA decay in PBMCs, expected if kinetics in PBMCs only reflected kinetics in plasma, was rarely observed. For many patients, HCV RNA decline in PBMCs started as early as in plasma and for some of them the kinetics strongly differed in the two compartments, hinting at a compartment-specific HCV replication and treatment effect. Fast viral decay in PBMCs was associated with sustained virological response, but viral kinetics in PBMCs added only minor predictive information compared with kinetics in plasma.
Future kinetics studies of HCV RNA during therapy with new antivirals should take into account their compartment-specific effect.
Journal of Hepatology 07/2008; 48(6):932-8. · 9.26 Impact Factor
