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4. Can current DAAs be curative?
Given enough time, treatment with DAAs might produce a “virological” cure of chronic hepatitis B. Indeed, despite the limitations of current therapies, up to 10% of patients, and in some studies up to 17%, appear to achieve stable off-drug suppression of viremia, and even the loss of HBsAg or anti-HBs seroconversion (Perrillo, Gish et al. 2006; Lok and McMahon 2009). It is therefore possible for DAAs, alone to eliminate all virological markers and achieve the clinical and biological benefits that, borrowing from HIV nomenclature, we have defined as a “functional” cure (Cohen 2011), in at least a sub-set of patients.
Hepatocytes are self-renewing, with a half-life in the healthy liver of approximately 6 months (Mason, Jilbert et al. 2005; Mason, Low et al. 2009; Mason, Liu et al. 2010). In HBV-infected individuals, in contrast, the half-life is dramatically shortened to only 3-30 days (Nowak 1996; Ciupe, Ribeiro et al. 2007). Therefore, as illustrated in Figure 1, if DAA therapy alone could absolutely block HBV replication, then inhibition at any step of the life cycle should eventually eliminate all viral replicative intermediates, resulting in a stable SVR once the treatment period has exceeded 10 hepatocyte half-lives (Fig. 2). Such an outcome should therefore be achieved by the currently used DAAs, even though they target the viral polymerase and have no direct effect on cccDNA. However, the reality appears to be more complicated (Fig. 2). Substantial HBsAg antigenemia may persist even after 5-10 years of DAA therapy, indicating the persistence of significant numbers of productively infected cells or virus reservoirs, making it impossible to discontinue treatment without a risk of rebound viremia (Lok 2011). This has certainly been the experience with monotherapy.
Figure 1
Figure 1
Inhibition of the HBV replication cycle
Figure 2
Figure 2
Reduction of the number of infected hepatocytes in treated HBV infection
The reason for the inability of current DAAs to reliably achieve a stable SVR, and thus “virologically” cure chronic hepatitis B (Table 1), may be due to their failure to completely suppress viral replication in vivo. Consistent with this notion is the observation that, while antiviral therapy often lowers the serum viral load by more than 6 logs, it only reduces intracellular HBV cccDNA and core DNA by 1 or 2 logs, respectively (Werle-Lapostolle, Bowden et al. 2004; Wursthorn, Lutgehetmann et al. 2006; Sung, Tsoi et al. 2008; Takkenberg, Terpstra et al. 2011). The reason for this disconnection between the reduction in circulating and intracellular forms of HBV DNA is unclear. One possibility is that the maturation of viral genomes to produce secreted virions is much more sensitive to the current polymerase inhibitor DAA therapy than the intracellular generation of immature virions. Alternatively, there might be drug-refractory viral “reservoirs,” with two possible scenarios. In the first, a subpopulation of infected cells is “off limits” to the current DAAs, creating sanctuaries from drugs. In the other, a percentage of HBV-infected cells are long-lived, and their nuclear cccDNA is quiescent and stable, serving as a persistent source of virus reactivation.
Understanding why current polymerase inhibitor DAA therapy fails to resolve chronic HBV infection holds the key to achieving a “virological cure” For example, if the incomplete suppression of HBV replication results from the failure of metabolic activation of nucleoside/nucleotide analogues in a small percentage of infected hepatocytes, then combination therapy with drugs that target both the viral DNA polymerase and other steps in DNA synthesis might be beneficial.
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5. How great a decline in viral load is needed for clinical benefit?
Kinetic studies have shown that HBV viremia declines in a multistep, at least biphasic manner in most patients treated with DAAs (Nowak 1996; Ciupe, Ribeiro et al. 2007). Based on such reports (Tsiang, Rooney et al. 1999; Lewin, Ribeiro et al. 2001; Wang, Holte et al. 2004), we have graphed some ”hypothetical” effects of the current polymerase inhibitor DAAs on viral and HBsAg load (Fig. 3). The responses can be divided into four groups. Unless an individual is infected with a drug-resistant virus, all four response groups show an initial, rapid drop in viral load (circulating viral DNA), usually within the first 4 weeks, followed by a slower decline which varies among patients. In some, the second period of decline is gradual but steady, ending up below the level of detection (Fig. 3a). In others, although the viral load declines, it either does not go below (Fig. 3b) or stabilizes just above (Fig. 3c) or significantly above (Fig. 3d) the level of detection.
Figure 3
Figure 3
Hypothetical kinetics of HBV viremia and HBs antigenemia during DAA therapy
In marked contrast to the HBV DNA level, which may drop more than 5 logs during the first year of nucleoside/nucleotide analogue therapy, the level of HBsAg rarely falls more than 1 log (Fig. 3). (An apparent exception is telbivudine, which can produce a >1 log decline in HBsAg after 4 years of treatment (Wursthorn, Jung et al. 2010; Chan, Thompson et al. 2011)). Even though DNA polymerase inhibitors do not directly suppress viral transcription or HBsAg synthesis, a decline in the number of infected cells should cause a decrease in HBsAg. It thus appears that, even after virus production has been inhibited for a year by current DAA therapy, a significant number of infected cells remain. This observation is consistent with previously cited reports of the continued presence of intracellular replicative forms of viral DNA and cccDNA, long after the viral load has fallen near the level of detection (Werle-Lapostolle, Bowden et al. 2004; Sung, Wong et al. 2005; Wursthorn, Lutgehetmann et al. 2006; Pan, Hu et al. 2012). In this regard, it should be noted, as illustrated in the graphs of hypothetical outcomes in Fig. 4, that pegIFN-α therapy may cause a more rapid decline in circulating HBsAg, associated with the loss of HBeAg and the eventual loss of detectable HBsAg, or even anti-HBs seroconversion, producing a stable off-drug benefit (Moucari, Mackiewicz et al. 2009; Ma, Yang et al. 2010; Thompson, Nguyen et al. 2010; Liaw 2011; Chen, Jeng et al. 2012). These data suggest that long-term efficacy is related to the kinetics of the drug-induced reduction in viral gene products. In chronic hepatitis C, a rapid reduction in viral load is an excellent predictor of a beneficial outcome (Poordad, Reddy et al. 2008). Perhaps the same is true for HBV infection.
Figure 4
Figure 4
Hypothetical kinetics of HBV viremia and HBs antigenemia during therapy with pegIFN-α |
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发表于 2015-7-9 18:52
