antiviral therapy confer same benefit as host immune control of HBV?
Does suppression of HBV replication by antiviral therapy confer the same benefit as host immune control of HBV?
Suna Yapali, Anna S Lok
Approximately 50% of hepatocellular carcinoma (HCC) worldwide is attributed to chronic HBV infection.1 Data from the population-based Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV REVEAL-HBV study showed that high levels of serum HBV DNA are associated with increased risk of cirrhosis, HCC and liver-related mortality.2 The REVEAL-HBV study also demonstrated that among hepatitis B surface antigen positive persons with high levels of HBV DNA at enrolment, the risk of HCC was lower in those who had decline in HBV DNA levels during follow-up compared with those with persistently high levels of HBV DNA. These data suggest that antiviral therapy may decrease the risk of HCC through suppression of HBV replication.
There has been only one randomised controlled trial of nucleos(t)ide analogue (NUC) treatment in patients with chronic hepatitis B (CHB) with HCC as one of the predefined outcomes.3 This study comparing lamivudine versus placebo was terminated after a median of 32.4 months (range 1–42 months) because a significant difference in the composite outcome of disease progression which included HCC was observed between the two groups. At the time of study termination, HCC had occurred in 3.9% of the lamivudine-treated group and 7.4% of the placebo group with a HR of 0.49, and 95% CI 0.25 to 0.99 (p=0.047); however, this difference was no longer significant when the five cases of HCC diagnosed during the 1st year were excluded (p=0.052).
A systematic review and a meta-analysis found that patients with CHB who received NUC had a lower incidence of HCC compared with untreated patients with CHB.4 ,5 The difference between treated patients and untreated controls was greater in patients with cirrhosis, those with virological response and those who were hepatitis B e antigen (HBeAg)-positive. Similar results were observed in several individual studies that compared the risk of HCC between patients with CHB receiving NUC and untreated patients with CHB.3 ,6–8 However, these studies had one or more limitations: (1) inclusion of patients in various stages of HBV infection with small number of patients with cirrhosis and too few patients with HCC for meaningful analysis, (2) controls not well matched to treated patients, (3) duration of follow-up too short to observe a benefit of NUC therapy if any, or (4) inadequate data to examine effect of virological response to NUC therapy and HCC risk. One study of 818 HBeAg-negative Greek patients found that long-term NUC therapy did not reduce the risk of HCC even among those with virological remission; however, when the HCC cases diagnosed in the first 24 months were excluded, patients with virological remission had a marginally lower incidence of HCC than those without (p=0.062).9 These data suggest that an adequate period of virological remission is needed to improve clinical outcome. Indeed, analysis of the long-term outcomes of patients in the phase 3 trial of tenofovir found that the observed incidence of HCC was similar to the predicted risk up to year 3 but significantly lower than predicted at the last follow-up (median 5.5 years).10 Similarly, studies examining the effect of NUC therapy on liver fibrosis failed to show an improvement in liver biopsies obtained after 1 year of NUC therapy but a significant decrease in fibrosis and even reversal of cirrhosis was observed in liver biopsies obtained after 3–5 years of NUC therapy.11–13
The study by Cho et al14 is unique in that the incidence of HCC in 1378 patients with CHB (621 HBeAg-negative) treated with NUC was compared with 1014 inactive carriers to determine whether rendering patients with CHB to a state similar to inactive carriers through antiviral therapy can decrease the risk of HCC to a level comparable with patients who were in the inactive carrier state at presentation. Patients who received NUC for less than 24 weeks and those with HCC diagnosed within 24 weeks of treatment were excluded. Patients were classified as having continuous virological response if HBV DNA levels decreased to <2000 IU/mL and remained so during follow-up. Time to HCC development was calculated from the time patients with CHB achieved HBV DNA<2000 IU/mL. HCC incidence was significantly higher in the NUC-treated patients compared with the inactive carriers. This difference between the treated patients with CHB and inactive carriers remained when comparisons were stratified for presence or absence of cirrhosis, treated patients with or without continuous virological response, and HBeAg-status at the start of treatment. Compared with patients who were in the inactive carrier stage at presentation, 5-year cumulative incidence of HCC in NUC-treated patients with CHB was 7.2% vs 0.8% (p<0.001) for those without baseline cirrhosis and 17.4% vs 6% (p=0.015) for those with baseline cirrhosis. The high incidence of HCC in the NUC-treated patients with CHB with baseline cirrhosis corroborate the findings of a Greek study which showed that the 5-year cumulative incidence of HCC in patients with compensated cirrhosis receiving NUC was 20.9%.15 Cho et al concluded that the risk of HCC development in patients with CHB receiving NUC, and even those with continuous virological response, is significantly higher than in inactive HBV carriers.
The strengths of this study include the large number of patients with CHB receiving NUC and large number of inactive carriers permitting stratified analysis by HBeAg status, cirrhosis and virological response. However, there are limitations to this study. The short duration of follow-up (42 months) is a major limitation of this and other studies on this topic. HCC carcinogenesis is a multistep process which might have started before the initiation of antiviral treatment. Although the authors showed that HCC incidence remained higher in the treated group with continuous virological response after exclusion of patients diagnosed with HCC within 2 years of achieving virological response, one would not expect antiviral therapy to be a magical cure that can melt microscopic tumours or repair cells that had undergone malignant transformation. Thus, further studies with longer duration of follow-up are needed before we can conclude that patients with CHB with continuous virological response to NUC remained at higher risk of HCC than patients who presented as inactive carriers. These studies are important in clarifying whether inactive carrier stage induced by antiviral therapy has the same prognosis as inactive carrier stage achieved spontaneously via host immune control of HBV. Longer follow-up is also important to determine whether the risk of HCC declines with time in treated patients with continuous virological response such that HCC surveillance will no longer be cost-effective for selected group of virally suppressed patients such as those with no cirrhosis.
Excellent commentary by Professor Lok. Personally, I think if the results of the study were valid then it should tell us something about the the ways how our immune system naturally controls HBV and how oral antivirals control HBV. Maybe in the inactive carriers, their immune system controls the virus by maintaining control on the total number of infected cells, whereas with oral antivirals, HBV is controlled by inhibiting the viral load (hbvdna), but production of antigens, such as the notorious X-antigen, is not. I think, in the development of cancer, a larger pool of potential mutant cells can increase the risk.
Just my amateur opinion.
Sorry, I don't know the answer as I have not read the full paper by Cho et al. I would imagine in a truly inactive carriers, the qHBsAg would be very low. we also know that qHBsAg is lowest in the Immune Control (inactive) phase. I think there is a study that concluded for patients with low viral load, HCC risk is lower for those with lower qHBsAg.
i did not read the study but it is totally useless to think about any effect without hbsag getting to less than 1000iu/ml.
we know there is no immune control with higher hbsag and liver immune suppression, so it is obvious what nucs can do is extremely limited but i myself never thought they were such useless on hcc
true inactive carriers have hbsag less than 1000iu/ml and obvious immune control to keep hbvdna low/und, in this situation there is no liver immune suppression and of course better ability to fight/prevent hcc
if one was to study antioxidant therapy vs nucs to prevent fibrosis/cirrhosis i would not be surprised to see both therapies achieve similar results
anyway even if we have no proof from studies the best steps are: antivirals, healthy rich of antioxidants diet and pegintf add on after few years of nucs to achieve inactive carrier state (hbsag less than 1000iu/ml) as a minimum result....its a long (not easy) way but results are good
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