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Discussion
To date, most of the evidence pertaining to PEG-IFN efficacy has been derived from large controlled trials.[7,12–15] Outcomes from such studies are often better than what can be achieved in routine clinical practice as a consequence of the increased monitoring, support and improved compliance. Given the relatively low rates of viral suppression following PEG-IFN, even in these controlled circumstances, and the expectation of poor tolerability, the level of response that can be expected in a non-trial setting is unclear. Therefore, we studied a cohort of patients treated in the setting of routine clinical care in order to address these concerns. This multicentre study provides a number of valuable insights relating to the use of PEG-IFN for CHB in an everyday clinical setting.
In HBeAg[+] disease, we identified a PEG-IFN induced HBeAg seroconversion rate of 32% that compared well with the rates of 21% to 32% in controlled studies. ALT normalization occurred in 46%, which was also consistent with the published rates of 35–48%.[7,12,14,15] The definition of optimal viral suppression has evolved with increasingly sensitive assays to measure viral load, the degree of suppression now achievable with oral antivirals and evidence suggesting viral load as an independent predictor of adverse outcomes.[16] We evaluated viral load suppression below 351 IU/mL (lower limit of detection of our assay) and 2000 IU/mL, which is a widely accepted cutoff for inactive disease.[9–11] Six months after completing treatment, 16% and 22% of HBeAg [+] patients remained below these respective thresholds. The combined response of viral load suppression plus HBeAg seroconversion was seen in 13% and 19% of patients, an even more desirable result as the combined outcome is more likely to decrease the risk of long term complications.[17,18]
PEG-IFN has typically been used less frequently in HBeAg[−] disease, largely due to low response rates, the absence of an endpoint such as HBeAg seroconversion and the high rates of relapse previously seen following conventional interferon.[10] The sustained viral suppression rate (< 351 IU/mL) of 36% that we observed in this group appears encouraging, though difficult to compare to other controlled studies, which used a lower cutoff of 400 copies/mL (approximately 50 IU/mL) and achieved suppression rates of 9–19%.[19,20] In relation to the threshold of < 2000 IU/mL, our viral suppression rate of 50% compared favorably with a rate of 20% for a comparable cutoff in a recent controlled trial and a rate of 43% below 4000 IU/mL observed in a large phase 3 registration study.[19,20]
Another advantage of IFN based therapy is the durability of the response. Three-year follow-up data from the large registration studies revealed PEG-IFN induced HBeAg seroconversion was sustained in over 80% of responders, with 60% also maintaining a viral load less than 2000 IU/mL. Similarly, in HBeAg negative patients the initial rates of viral suppression were also effectively well maintained over the 3 years.[21,22] Though not part of the initial study design, we were able to follow the majority of viral responders for up to 2 years post-treatment. In both HBeAg positive and negative patients with initial viral suppression below 2000 IU/mL (and HBeAg seroconversion in the HBeAg[+] group) the response was maintained in approximately 60% over the 2 years. For those with initial suppression below 351 IU/mL the durability ranged from 50% in the HBeAg [−] group to 75% in the HBeAg[+] group. Given the small number of patients involved, further studies are required to definitively assess durability of response in a non-controlled setting. The potential benefit of such long term IFN induced viral suppression is shown in studies involving standard IFN-α in which HBsAg clearance rates in both HBeAg positive and negative patients displaying an initial response to IFN-α exceeded 60% over 15 years.[3,4,6,23–25] Most importantly, these studies also show that successful IFN-α therapy reduces the risk of developing cirrhosis, hepatic decompensation and HCC.[3,25–27]
Concerns relating to AEs and poor tolerability are often cited as a barrier to the use of PEG-IFN. However, observational studies demonstrate that when used in CHB, PEG-IFN is associated with significantly less AEs, treatment withdrawals and impact on health related quality of life compared with when used as monotherapy in chronic hepatitis C.[28] Although our cohort included a significant proportion with advanced fibrosis, we found PEG-IFN to be well tolerated, with 94% of all patients able to complete 48 weeks of therapy. Nevertheless, given the potential AEs and lower antiviral potency compared with the nucleos(t)ide analogues, identifying and treating patients that are more likely to respond to PEG-IFN is important in defining its optimal use in CHB therapy. Multiple studies have demonstrated that female sex, high serum ALT, low HBV viral load and genotype A are among these factors.[29–31] Apart from the negative predictive value of a high viral load in HBeAg negative patients, our study was unable to confirm the predictive value of the other baseline variables, which may be related to our sample size. The predictive value of "on treatment" markers such as the week 12 HBV viral load has also been studied.[32] We found that the failure to suppress viral load to below 6log IU/mL by week 12 of therapy was an indicator of poor outcome in HBeAg[−] patients. Recently, the emergence of quantitative HBsAg and HBeAg measurements as both pre- and on-treatment predictors of outcome has been another encouraging development that is likely to improve results.[33–37] Not only can these measurements contribute to better patient selection but in future may also form the basis of on-treatment stopping rules similar to that used in HCV therapy.
There are some limitations to our study due to retrospective data collection that restrict its comparability to data from prospective controlled studies. HBV genotype, a factor shown to influence PEG-IFN induced HBeAg seroconversion rates was only tested in 41% of the cohort. Nevertheless it is unlikely that our outcomes were skewed by genotype given that over 80% of our patients were from East Asia where genotypes B and C predominate. These two have a modest influence on outcome compared with genotypes A and D, which are the most and least favorable genotypes, respectively.[31] The upper limit of normal range of 55 U/L for ALT was also higher than that used in the majority of controlled trials as well as current guidelines. We elected to use this limit in assessing biochemical response given it formed part of the range used by the majority of the centers in clinical decision making. This may, however, have led to an overestimation of ALT normalization rates in our study when compared with the existing literature. Similarly, differences in the viral load detection limits of assays used in our study (< 351 IU/mL) and previous trials (50 IU/mL) made direct comparisons difficult.
In conclusion, our study provides a "real world" perspective to data obtained from controlled studies. Evaluating over 90 patients, we found that both HBeAg positive and negative patients treated in a clinical setting can expect efficacy and safety outcomes equivalent to those seen in those large trials. In addition, our cohort was principally of Asian ethnicity, in which genotypes B and C, typically associated with poorer outcomes than genotype A, predominated. Combined with the existing literature these results should engender a greater sense of confidence regarding the use of PEG-IFN. It is also likely that the availability of well characterized pretreatment and on treatment predictors will allow greater individualization of therapy in future to maximize beneficial patient outcomes.
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发表于 2012-9-20 14:19
