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Modeling complex decay profiles of hepatitis B virus during antiviral therapy.

ABSTRACT: Typically, hepatitis B virus (HBV) decays in patients under therapy in a biphasic manner. However, more complex decay profiles of HBV DNA (e.g., flat partial response, triphasic, and stepwise), for which we have no clear understanding, have also been observed in some treated patients. We recently introduced the notion of a critical drug efficacy, epsilon(c), such that if overall drug efficacy, epsilon(tot), is higher than the critical drug efficacy (i.e., epsilon(tot) > epsilon(c)) then viral levels will continually decline on therapy, while if epsilon(tot) < epsilon(c), then viral loads will initially decline but will ultimately stabilize at a new set point, as seen in flat partial responders. Using the idea of critical efficacy and including hepatocyte proliferation in a viral kinetic model, we can account for these complex HBV DNA decay profiles. The model predicts that complex profiles such as those exhibiting a plateau or shoulder phase, as well as a class of stepwise declines, occur only in patients in whom the majority of hepatocytes are infected before therapy.We show via kinetic modeling how a variety of HBV DNA decay profiles can arise in treated patients.

SUBMITTER: Dahari H

PROVIDER: S-EPMC3712859 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Modeling complex decay profiles of hepatitis B virus during antiviral therapy.

Dahari Harel H Shudo Emi E Ribeiro Ruy M RM Perelson Alan S AS

Hepatology (Baltimore, Md.) 20090101 1

<h4>Unlabelled</h4>Typically, hepatitis B virus (HBV) decays in patients under therapy in a biphasic manner. However, more complex decay profiles of HBV DNA (e.g., flat partial response, triphasic, and stepwise), for which we have no clear understanding, have also been observed in some treated patients. We recently introduced the notion of a critical drug efficacy, epsilon(c), such that if overall drug efficacy, epsilon(tot), is higher than the critical drug efficacy (i.e., epsilon(tot) > epsilo ...[more]

PMID: 19065674

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Project description:Pegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. Treatment failure occurs either by nonresponse (minimal declines in viral titer) or relapse (robust initial responses followed by rebounds of viral titers during or after therapy). HCV is highly variable genetically. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences.Pre- and post-therapy sequences were analyzed for 10 nonresponders and 10 relapsers from the Virahep-C clinical study. Pre-therapy interpatient diversity among the relapsers was higher than in the nonresponders in the viral NS2 and NS3 genes, and post-therapy diversity was higher in the relapsers for most of HCV's ten genes. Pre-therapy diversity among the relapsers was intermediate between that of the non-responders and responders to therapy. The average mutation rate was just 0.9% at the amino acid level and similar numbers of mutations occurred in the nonresponder and relapser sequences, but the mutations in NS2 of relapsers were less conservative than in nonresponders. Finally, the number and distribution of regions under positive selection was similar between the two groups, although the nonresponders had more foci of positive selection in E2.The HCV sequences were unexpectedly stable during failed antiviral therapy, both nonresponder and relapser sequences were under selective pressure during therapy, and variation in NS2 may have contributed to the difference in response between the nonresponder and relapser groups. These data support a role for viral genetic variability in determining the outcome of anti-HCV therapy, with those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy.ClinicalTrials.gov NCT00038974.

Project description:The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy in clinical studies. In this study, the relationship between NS5A mutations and selection pressures before and during antiviral therapy and virologic response to therapy were investigated. Full-length NS5A clones were sequenced from 20 HCV genotype 1-infected patients in a prospective, randomized clinical trial of IFN induction (daily) therapy and IFN plus ribavirin combination therapy. Pretreatment NS5A nucleotide and amino acid phylogenies did not correlate with clinical IFN responses and domains involved in NS5A functions in vitro were all well conserved before and during treatment. A consensus IFN sensitivity-determining region (ISDR(237-276)) sequence associated with IFN resistance was not found, although the presence of Ala(245) within the ISDR was associated with nonresponse to treatment in genotype 1a-infected patients (P<0.01). There were more mutations in the 26 amino acids downstream of the ISDR required for PKR binding in pretreatment isolates from responders versus nonresponders in both HCV-1a- and HCV-1b-infected patients (P<0.05). In HCV-1a patients, more amino acid changes were observed in isolates from IFN-sensitive patients (P<0.001), and the mutations appeared to be concentrated in two variable regions in the C terminus of NS5A, that corresponded to the previously described V3 region and a new variable region, 310 to 330. Selection of pretreatment minor V3 quasispecies was observed within the first 2 to 6 weeks of therapy in responders but not nonresponders, whereas the ISDR and PKR binding domains did not change in either patient response group. These data suggest that host-mediated selective pressures act primarily on the C terminus of NS5A and that NS5A can perturb or evade the IFN-induced antiviral response using sequences outside of the putative ISDR. Mechanistic studies are needed to address the role of the C terminus of NS5A in HCV replication and antiviral resistance.

Project description:Background. Hepatitis B virus (HBV) infections are perinatally transmitted from chronically infected mothers. Supplemental antiviral therapy during late pregnancy with lamivudine (LAM), telbivudine (LdT), or tenofovir (TDF) can substantially reduce perinatal HBV transmission compared to postnatal immunoprophylaxis (IP) alone. However, the cost-effectiveness of these measures is not clear. Aim. This study evaluated the cost-effectiveness from a societal perspective of supplemental antiviral agents for preventing perinatal HBV transmission in mothers with high viral load (>6 log10 copies/mL). Methods. A systematic review and network meta-analysis were performed for the risk of perinatal HBV transmission with antiviral therapies. A decision analysis was conducted to evaluate the clinical and economic outcomes in China of four competing strategies: postnatal IP alone (strategy IP), or in combination with perinatal LAM (strategy LAM + IP), LdT (strategy LdT + IP), or TDF (strategy TDF + IP). Antiviral treatments were administered from week 28 of gestation to 4 weeks after birth. Outcomes included treatment-related costs, number of infections, and quality-adjusted life years (QALYs). One- and two-way sensitivity analyses were performed to identify influential clinical and cost-related variables. Probabilistic sensitivity analyses were used to estimate the probabilities of being cost-effective for each strategy. Results. LdT + IP and TDF + IP averted the most infections and HBV-related deaths, and gained the most QALYs. IP and TDF + IP were dominated as they resulted in less or equal QALYs with higher associated costs. LdT + IP had an incremental $2,891 per QALY gained (95% CI [$932-$20,372]) compared to LAM + IP (GDP per capita for China in 2013 was $6,800). One-way sensitivity analyses showed that the cost-effectiveness of LdT + IP was only sensitive to the relative risk of HBV transmission comparing LdT + IP with LAM + IP. Probabilistic sensitivity analyses demonstrated that LdT + IP was cost-effective in most cases across willingness-to-pay range of $6,800 ? $20,400 per QALY gained. Conclusions. For pregnant HBV-infected women with high levels of viremia, supplemental use of LdT during late pregnancy combined with postnatal IP for infants is cost-effective in China.

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Modeling complex decay profiles of hepatitis B virus during antiviral therapy.

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Modeling complex decay profiles of hepatitis B virus during antiviral therapy.

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