P0843 : On-treatment viral kinetics do not predict SVR in patients with advanced liver disease receiving sofosbuvir in combination with daclatasvir or simeprevir for 12 weeks

Hézode, Christophe; Chevaliez, Stéphane; Scoazec, Giovanna; Bouvier‐Alias, Magali; Ruiz, Isaac; François, Murielle; Mallat, Ariane; Feray, C.; Pawlotsky, J.-M.

doi:10.1016/s0168-8278(15)31045-x

Cited by 13 publications

(12 citation statements)

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“…This may partly explain why in our small cohort, 98% of patients achieved SVR12 compared to 95% SVR4 (n=189/200) in the larger French cohort. In agreement with other studies of DAA regimens, viral kinetics (at weeks 4, 8 and 12) performed in the study by Hezode et al did not predict SVR4 in patients receiving SOF in combination with DAC or SIM for 12 weeks [11, 12, 33, 34] . However in the era of DAA high SVR rates, it is far less important to predict treatment outcome.…”

Section: Discussionsupporting

confidence: 90%

“…The percentage of patients with HCV<15 IU/ml by week 4 of SOF+SIM or SOF+DAC treatment in the current study (88%) was higher compared to a larger French cohort (n=200) in which 53% were HCV <12 IU/ml[33]. This may partly explain why in our small cohort, 98% of patients achieved SVR12 compared to 95% SVR4 (n=189/200) in the larger French cohort.…”

Section: Discussioncontrasting

confidence: 65%

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HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir

Dahari

Canini

Graw

et al. 2016

Journal of Hepatology

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Background&Aims Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained-virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. Methods 58 chronic-HCV patients were treated with 12-week sofosbuvir+simeprevir(n=19), sofosbuvir+daclatasvir(n=19), or sofosbuvir+ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12 weeks post EOT. Mathematical modeling was used to predict the time to cure,i.e,<1 virus copy in the entire extracellular-body fluid. Results All but one patient who relapsed achieved SVR. Mean age was 60±11 years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV<15 IU/ml, with 27%, 74% and 91% of observations having target-not-detected, respectively. Modeling results predicted that 32(43%), 16(23%), 7(13%), 5(9%) and 3(5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13 weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir+ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43%-45% and 17%-30% in subjects who had HCV<15 IU/ml at weeks 2 and 4, respectively. Conclusions The use of early viral-kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost-saving of 16%-20% per 100-treated persons.

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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 65%

HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir

Dahari

Canini

Graw

et al. 2016

Journal of Hepatology

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“…4 A promising avenue for such reduction arises from the observation, made by several recent studies, that some patients treated with DAAs had detectable viremia at the end of treatment (EOT) but eventually attained a sustained virological response (SVR), or cure, without additional therapy. 3,[5][6][7][8][9][10][11][12] (Typically, SVR refers to undetectable viremia 12 weeks after the EOT.) For instance, in one study where 240 patients were treated with DAAs for 12 weeks, of the 86 patients available for follow-up, 22 had detectable viremia at the EOT and 20 of the latter patients eventually achieved SVR.…”

Section: Introductionmentioning

confidence: 99%

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

2018

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A fraction of chronic hepatitis C patients treated with direct‐acting antivirals (DAAs) achieved sustained virological responses (SVR), or cure, despite having detectable viremia at the end of treatment (EOT). This observation, termed EOT +/SVR, remains puzzling and precludes rational optimization of treatment durations. One hypothesis to explain EOT +/SVR, the immunologic hypothesis, argues that the viral decline induced by DAAs during treatment reverses the exhaustion of cytotoxic T lymphocytes (CTLs), which then clear the infection after treatment. Whether the hypothesis is consistent with data of viral load changes in patients who experienced EOT +/SVR is unknown. Here, we constructed a mathematical model of viral kinetics incorporating the immunologic hypothesis and compared its predictions with patient data. We found the predictions to be in quantitative agreement with patient data. Using the model, we unraveled an underlying bistability that gives rise to EOT +/SVR and presents a new avenue to optimize treatment durations. Infected cells trigger both activation and exhaustion of CTLs. CTLs in turn kill infected cells. Due to these competing interactions, two stable steady states, chronic infection and viral clearance, emerge, separated by an unstable steady state with intermediate viremia. When treatment during chronic infection drives viremia sufficiently below the unstable state, spontaneous viral clearance results post‐treatment, marking EOT +/SVR. The duration to achieve this desired reduction in viremia defines the minimum treatment duration required for ensuring SVR, which our model can quantify. Estimating parameters defining the CTL response of individuals to HCV infection would enable the application of our model to personalize treatment durations.

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“…In the initial clinical trials with SOF, HCV RNA suppression by week 4 was nearly universal and was not associated with cure, including patients infected with HCV genotype-3 who are currently considered the most difficult to treat [7, 8]. Subsequent studies did not find an association between early viral kinetics and treatment outcomes [9, 10]. As a result, on treatment HCV RNA measurements (weeks 2 and/or 4) are currently recommended by both EASL (www.easl.eu) and the AASLD/IDSA (www.hcvguidelines.org) only as a means to monitor adherence and a fixed duration of DAA therapy has eclipsed the RGT approach.…”

mentioning

confidence: 99%

Resurrection of response-guided therapy for sofosbuvir combination therapies

Dahari

Halfon

Cotler

2016

Journal of Hepatology

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P0843 : On-treatment viral kinetics do not predict SVR in patients with advanced liver disease receiving sofosbuvir in combination with daclatasvir or simeprevir for 12 weeks

Cited by 13 publications

References 0 publications

HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir

HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

Resurrection of response-guided therapy for sofosbuvir combination therapies

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