Second hepatitis C replication compartment indicated by viral dynamics during liver transplantation

Dahari, Harel; Feliu, Anna; García–Retortillo, Montserrat; Forns, Xavier; Neumann, Avidan U.

doi:10.1016/j.jhep.2004.12.017

Cited by 81 publications

(79 citation statements)

References 48 publications

(60 reference statements)

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“…Thus, the rate of decrease was more heterogeneous in DDLT patients. As suggested by Dahari et al, 33 this variability may reflect an extrahepatic compartment that is larger in some patients than in others. Other factors that varied over a wider range in our DDLT patients than in our LDLT patients, such as donor age and the extent of ischemia-reperfusion injury, also may contribute to variability in the rate of viral load decrease in DDLT patients.…”

Section: Discussionmentioning

confidence: 64%

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

et al. 2005

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This study tested the hypothesis that hepatitis C virus (HCV) RNA and core antigen levels rise more rapidly after liver transplantation (LT) in recipients of grafts from living donors (LD) versus deceased donors (DD). Eleven consecutive LD and 15 DD recipients were followed prospectively. Before LT, median HCV RNA levels were similar: 5.42 (LDLT) and 5.07 (DDLT) log 10 IU/mL (P ‫؍‬ NS). During the first 7 hours after LT a trend toward a greater HCV RNA decrease in LDLT patients was seen, although they received fewer blood replacement products during surgery. HCV RNA levels rose more rapidly in LDLT patients between days 1 and 3 (P ‫؍‬ .0059) and were higher in this group on days 2, 3, 4, and 5. Core antigen levels were significantly higher in LDLT patients on days 3 and 5, although they were similar before LT (P ‫؍‬ NS). Alanine aminotransferase (ALT) values were higher among LDLT patients from 8 to 14 days and from 4 to 24 months. Two-year graft and patient survival were 73% for LDLT patients and 80% for DDLT patients (P ‫؍‬ NS). In conclusion, viral load rose more rapidly in LD recipients and reached higher levels shortly after surgery. Greater ALT elevations were evident in the LDLT group, but survival rates were similar. The trend toward a greater initial viral load decrease in patients with LD grafts and the significantly sharper increase suggest that the liver plays a predominant role in both HCV clearance and replication. ( A fter transplantation of hepatitis C virus (HCV) patients, viral infection of the graft is nearly universal, providing a unique opportunity to examine interactions between the human liver and HCV. Grafts from living donors (LDs) differ from grafts from deceased donors (DDs) in characteristics such as the rapid increase in volume that occurs in LD grafts during the first week after surgery. 1 Several studies have compared outcomes of LD liver transplantation (LDLT) and DDLT in HCV patients. [2][3][4][5][6][7][8][9][10][11] Results have been inconsistent, in part, because of differences in experimental design and small sample sizes. 12-17 Concerning survival, no short-term difference was observed in a study of 65 DD versus 35 LD patients, 6 and analysis of the United Network for Organ Sharing liver transplant database showed that the 2-year survival of 279 LD and 3,955 DD recipients was virtually identical. 5 Other analyses of the same database, however, showed that graft survival was lower in LD recipients. 4,8 Studies of biopsy specimens have yielded conflicting results regarding the severity of recurrent hepatitis and the rate of progressive graft injury. 7,10,11 HCV may interact differently with LD grafts than with DD grafts, and this difference may lead to greater LD graft injury. Exceptionally high HCV RNA levels in the early postoperative period are associated with greater long-term liver damage in DDLT patients, 18,19 and a similar association may exist in LDLT patients. The popula-

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Section: Discussionmentioning

confidence: 64%

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

et al. 2005

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“…25 Models of HCV kinetics during and after liver transplantation also have been developed. 53 These models have expanded the set of HCV RNA patterns that can be explained to include the end of the week rebounds seen with PEG IFN and triphasic responses, as well as offering suggestions of how treatment works 1,25 and why some people, such as African Americans, do not respond. 14 Nevertheless, patterns such as the hump in the viral load curve seen between 32 and 120 hours by Bekkering et al 13 in hard-to-treat patients have not yet been explained, and even when patterns are "explained" by models, the underlying hypotheses still need to be confirmed experimentally.…”

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confidence: 99%

New kinetic models for the hepatitis C virus

et al. 2005

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K inetic models of hepatitis C virus (HCV) RNA decay induced by interferon (IFN) therapy have been developed by us and others. [1][2][3][4][5][6] The models, inspired by previous work on HIV and hepatitis B virus kinetics, 7-9 stimulated the collection of frequent viral loads and alanine aminotransferase (ALT) measurements after the initiation of therapy that revealed previously unknown kinetic patterns of HCV RNA change. The models have successfully summarized much of these new kinetic data and have given insights into features of HCV biology in vivo, such as the rate of virion clearance and the daily rate of virion production. More importantly from a clinical perspective, the models have allowed quantification of the antiviral effects of therapy and thus have made comparison of the antiviral effectiveness of different drug regimens possible using data collected over short intervals.

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“…This finding indicates that a virion-clearing compartment, which does not depend on T-and B-cell responses, may exist in this mouse model. One possible explanation is that viral kinetics after liver transplantation in humans may play a role in HCV clearance under immunosuppressed conditions (Dahari et al, 2005;Powers et al, 2006;Schiano et al, 2005). This observation suggests that this mouse model is capable of evaluating 'first-phase' HCV clearance after drug treatment.…”

Section: Discussionmentioning

confidence: 99%

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

Kamiya¹,

Iwao²,

Hiraga

et al. 2010

Journal of General Virology

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A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA +/+ /SCID +/+ mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11-0.17 log 10 h "1 . During the initial phase of treatment, the log 10 reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10 8 virions per day, and this may be comparable to HCV production in the human liver. INTRODUCTIONHepatitis C virus (HCV) is a major cause for concern worldwide. More than 3 % of the world's population is chronically infected with HCV and 3-4 million people are newly infected each year (Wasley & Alter, 2000). Chronic HCV infection is relatively mild and progresses slowly; however, about 20 % of chronic hepatitis C (CHC) carriers progress to serious end-stage liver disease (Lauer & Walker, 2001;Liang et al., 2000;Poynard et al., 2003). The current standard treatment for HCV infection is administration of pegylated alpha interferon (PEG-IFN) in combination with ribavirin (RBV) for 48 weeks. The overall cure rates with this intervention are 40-50 % for patients with genotype 1 and more than 75 % for patients with genotypes 2 and 3 (Fried et al., 2002;Manns et al., 2001). Several compounds that inhibit specific stages of the virus life cycle have been clinically evaluated (Manns et al., 2007;Pereira & Jacobson, 2009). Telaprevir is a novel peptidomimetic slow-and tight-binding inhibitor of HCV NS3-4A protease, which was discovered using a structure-based drug design approach (Perni et al., 2006). A rapid decline in viral RNA was observed in CHC patients treated with telaprevir (Reesink et al., 2006) and an increased antiviral effect of a combination of telaprevir and PEG-IFN has been reported (Forestier et al., 2007). Recent clinical trials of telaprevir in combination with PEG-IFN and RBV have indicated a promising material advance in therapy for CHC patients (Hézode et al., 2009;McHutchison et al., 2009). Firstgeneration HCV-specific agents have been...

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Second hepatitis C replication compartment indicated by viral dynamics during liver transplantation

Cited by 81 publications

References 48 publications

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors

New kinetic models for the hepatitis C virus

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

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