Journal of Hepatology
Volume 37, Issue 2 , Pages 277-279, August 2002

Hepatitis B virus viral dynamics: effects of drug dose and baseline alanine aminotransferase

Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM 87545, USA

Accepted 5 June 2002.

See Article, pages 253–258

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1. Principles of viral dynamics 

The use of mathematical models to enhance our understanding of the dynamics of chronic viral infections has proven fruitful. Analyzes of viral load changes during antiviral therapy have provided critical insights into the pathogenesis of chronic infection with human immunodeficiency virus (HIV) [1], [2], [3], [4], [5], [6], [7] and hepatitis C virus (HCV) [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. These methods have lead to increased quantitative understanding of the dynamics of virus replication, viral clearance, and infected cell turnover [18], which have provided a rational framework for the design of treatment strategies. Moreover, in the case of HCV infection these methods have provided insights into the mechanisms of interferon action [10], a new means of quantifying drug effectiveness [10], and generated correlations between the outcome of treatment and viral kinetic factors [10], [17], [19].

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2. Hepatitis B virus (HBV) viral dynamics 

The study of HBV using viral kinetic methods has followed approaches used in HIV and HCV [20]. Nowak et al. [21] in 1996 introduced the use of viral dynamics principles into the field of HBV. Using a standard viral dynamic model, which had been developed for HIV [2], and fitting that to data obtained from patients treated with lamivudine, they estimated that free virus was cleared from the plasma with a half-life of about 1 day, implying a total viral turnover of about 1011 per day. They also used the rebound in plasma viral load after the end of treatment to estimate that the half-life of infected hepatocytes is variable ranging between 10 and 100 days. They were able to estimate the efficacy of the drug in blocking virion production and noticed that this was dependent on the lamivudine treatment dose. They reported that daily doses of 20, 100, 300 and 600 mg blocked 87, 97, 96 and 99% of production, respectively. However, the analysis was limited by the assay technology in place at the time. In this study, the Abbott Genostics solution hybridization assay was used, which has a lower limit of detection of 106 copies/ml. Zeuzem et al. [22], also analyzed HBV viral kinetic data using a somewhat different model but the same HBV DNA quantification technique, and reached a similar conclusion about the HBV half-life.

These initial estimates of HBV and infected cell half-lives have been extended in other studies, with different assays, therapies and patient populations. Tsiang et al. [23] analyzed the outcome of HBV treatment with 30 mg of adefovir dipivoxil daily in 13 patients enrolled in a phase II clinical trial. They used the Roche Amplicor HBV Monitor assay, with a lower limit of detection of 400 copies/ml and an upper limit (without dilution) of 4×107 copies/ml. They observed that the decay of plasma HBV DNA levels was biphasic, with a fast initial phase reflecting the clearance of free virus with an estimated the half-life of 1.1 days, followed by a slower second phase reflective of the rate of infected cell loss. The infected cell half-lives they reported, between 11 and 27 days, was less variable than those reported by Nowak et al. [21]. They also estimated that the mean efficacy of adefovir to be 99.3%. Lau et al. [24] used viral dynamics to compare 150 mg lamivudine daily with lamivudine 150 mg daily plus famciclovir 500 mg three times a day combination therapy in a group of HBV-infected Chinese patients. They used the Digene Hybrid-Capture II assay, with a lower limit of detection of 5000 copies/ml. They found a significant lower efficacy in the lamivudine monotherapy group (94%) versus combination therapy (99%). Their estimates of free virion and infected cell half-lives were in line with previous results, and were similar for both treatment groups.

Recently, Lewin et al. [25] used a new real-time polymerase chain reaction (PCR) assay using molecular beacon hybridization probes to compare HBV dynamics between lamivudine monotherapy and lamivudine in combination with famciclovir. This new assay has a broader dynamic range and increased sensitivity, down to 100 copies/ml. The average free virion half-life was also estimated to be about 1 day, but there was one patient with a very rapid free virus half-life of only 1 h, indicating that at least in some instances HBV half-life can be as fast as seen in HCV [7], [10] and HIV [3], [7]. The study also reported great variation between individual patients in the infected cell half-life, but it was possible to divide patients into two groups: those patients with infected cell half-lives between 2 and 12 days; and those with infected cell half-lives longer than 120 days. In addition, in this study, the decay of HBV DNA was found to be biphasic for most patients, but some patients also showed more complex patterns of decay. In these, the viral load decayed initially, leveled off for a period of days and then decayed again, generating a ‘staircase’ pattern of viral decay. The authors speculated that these complex patterns could be due to the importance of the immune system in controlling HBV infection. Indeed, Nowak et al. [21] had found a correlation between the infected cell half-life and baseline alanine aminotransferase (ALT). If ALT is a surrogate for hepatocyte damage, and potentially for the strength of the immune response against HBV, this result supports the role of the immune system in this infection.

In this issue, Wolters et al. [26] present a study analyzing the influence of lamivudine dose and baseline ALT on the dynamics of HBV infection. They analyze two groups of chronically infected HBV patients, one treated with 150 mg lamivudine daily, and the other treated with 600 mg lamivudine daily. After 4 weeks both group received 150 mg daily. In this study HBV DNA was quantified using the Digene Hybrid Capture assay and reassessed with quantitative PCR if the measurements were below the detection limit of the Digene assay. The patients were sampled more frequently during the first 48 h than in any previous study. They used two mathematical methods to estimate parameters characterizing the viral declines observed over the first 4 weeks after the start of therapy, a viral dynamic model [10] and a phenomenological model that simply assumed that the logarithm of the viral load declined in a piecewise linear manner. Both models fitted the data equally well. The fits indicated a higher therapy efficacy (96 versus 92%) and a shorter infected cell half-life (125 versus 186 h) in the high dose lamivudine regimen [26]. They also confirmed that higher baseline ALT levels were associated with shorter infected cell half-lives [21], [27]. However, when both baseline ALT and dose were taken into account the association between baseline ALT and second-phase slope was no longer significant. Moreover, the relationship between higher drug dose and shorter infected cell half-life was also no longer significant. Together, these results suggest that baseline ALT needs to be carefully controlled in future studies. They also found that patients previously treated with lamivudine had a slower initial decline of HBV DNA. In these pre-treated patients no drug resistant virus was found at baseline, although the authors do not exclude the hypothesis of low-level resistance. Finally, it is interesting to note that the more frequent initial sampling of HBV DNA, led to estimates of the half-life of free virus that were shorter (12–15 h) than in previous studies that had suggested a half-life of approximately 1 day.

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3. Future directions 

The results presented in Wolters et al. [26] describe the mean behavior of groups of patients. The dynamics of individual patients are not given and thus it is impossible to assess the existence of non-biphasic patterns of viral decay as observed by Lewin et al. [25]. Similarly, the variability between patients is only hinted at in the present paper, with their analysis methodology that involves a random effects model. Thus, whether some patients can clear HBV from blood as rapidly as HIV and HCV, as was observed in a few patients in [25], remains unanswered. Indeed, in this type of study, a better understanding of viral dynamics can be gleaned from the individual patient data and fits, rather than by showing the average only. In addition, by examining data on individual patients one can assess the ability of the model to explain data on that patient. For reasons that are not yet clear, possibly involving drug resistance or immune response differences, some patients do not exhibit biphasic viral decay profiles. In the present paper, one patient showed viral rebound and analyses were done with and without this patient. Another approach would be to provide viral kinetic data and analysis on each patient, so that as a community we have a continually enlarging body of knowledge about viral kinetics that if need be can be reanalyzed as new ideas and models enter this exciting new field. HBV being a DNA virus with a covalently closed circular DNA (ccc-DNA) replication template may indeed require a different set of models than those developed for HIV and HCV. So far, analyzes based on HIV/HCV dynamic models have dominated the field. Whether more can be understood by using HBV specific models that take into consideration the dynamics of ccc-DNA, replication of infected cells, non-cytolytic loss of the infected state and other novel features remains to be seen.

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References 

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PII: S0168-8278(02)00210-6

Journal of Hepatology
Volume 37, Issue 2 , Pages 277-279, August 2002

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