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HCC after DAAs.pptx
1. Rising HCC in the era of DAAS:
A fact or an artifact ?
Sameh Lashen, MD
Lecturer Of Internal Medicine, Hepatology Unit
University Of Alexandria
2. The new DAA yield outstanding results with >90% of patients with
HCV achieving SVR.
However, the impact of DAA therapy on the incidence of HCC in patients
with cirrhosis (particularly HCC recurrence) has emerged as a
controversial issue.
Previously, It has been known that interferon therapy resulted in an
approximately four-fold reduction of HCC risk.
7. Median time from HCC treatment and start of DAA therapy was 376 days.
Risk factors for HCC occurrence/recurrence were:
Low platelet, CTP: B, Liver stiffness > 21.3 kPa
Neither HCV genotype nor DAA regimen correlated to HCC occurrence
May 2016
344 patients DAAs
24 wk follow up
8. Similarly, Another study of 59 patients in Spain with HCC remission
at start of DAA therapy reported a 29% rate of early HCC
recurrence within 6 months of DAAs therapy.
Buonfiglioli F, Conti F, Andreone P, Crespi C, Foschi G, Lenzi M, et al. Development of hepatocellular carcinoma
in HCV cirrhosis patients treated with direct acting antivirals. J Hepatol 2016;64:LB506
9. Rapid HCV eradication leads to sudden withdrawal in immune
surveillance, which in turn might favor the proliferation of isolated
neoplastic cells.
Why, What is possible explanation
Another hypothesis to explain a potential risk of HCC recurrence after SVR
by these drugs entails a direct effect of DAAs on cancer cells that favors
their rapid expansion and dissemination.
liver-specific microRNA 122, which reduces tumourigenesis,
angiogenesis and intrahepatic metastasis, and is downregulated
by DAA therapy
10. On the other side
In the same year, another paper…
406 cirrhotic patients ( 317 with no previous HCC and 29 with treated
HCC) DAAS therapy……with follow up 15 months
15 denovo (4.7%)…….vs 4.2% in untreated
2 cases had recurrence (6.8%)
15. Were observational/retrospective studies, With short follow-up of ~1 year
TACE is non curative and satellites may be missed in pre treatment evaluation.
Time variability between HCC treatment and DAAS initiation.
an increased aggressiveness and rate of recurrence in 1st 6-month following
a curative resection or ablation of a HCC is likely to reflect a biological
process of cancer cell dissemination rather than metachronous
tumorigenesis.
Criticism of initial reports which support
DAAs tumerogenicity
17. Prospective cohort/ 58 patients
patients with HCV and complete radiologic response for HCC treated by
ablation, resection or TAE.
CR by dedicated imaging
Any hepatic nodule regardless size or enhancement pattern, excluded
DAAs started
Recurrence 16/58 (27%)…
In those who started DAAs before 4 months (41.2%)
Time from CR to start DAAs 11.2 months(3.6-23)
Time from stat DAAS to 1st HCC 3.5 (1.1-8m)
18. Pattern of recurrence:
3/16 regrowth of primary HCC mass
10/16 denovo metachronous 3-5 foci, 3-4 cm
3/16 infiltrative HCC with vascular invasion
Predictors were :
Duration between CR and DAAs start, Child Pugh and Histologic evidence of tumor
(microvascular invasion and satellites)
19. Another prospective study 2016
Results
8/280 (2.8%) Occurrence rate and , 1/15 (6.6%) recurrence
22. Retrospective
IFN-RBV (244 pts) vs DCV/ASUN (154 pts)
Follow up period 96 months vs. 23 months
HCC occurrence 5.3% vs. 4.5%
No difference in Risk
23. Prospective multicenter study
Inclusions: 47 pts with HCC of BCLC stage 0, A or B.
HCC treated with surgical resection, ablation or TACE before DAAs.
Radiological complete response before starting DAA treatment.
Radiological assessment after DAA therapy.
24. Prospective multicenter study
The mean follow-up times were 21.5 months after HCC treatment and 9.6
months after DAA therapy
There was no statistically significant difference in recurrence rate between the
resection (35.3%), ablation (52.4%) and TACE/TAE (33.3%) groups (p = 0.470).
In this study, the time between HCC
treatment and the start of DAA therapy
was a significant time-dependent
predictor of recurrence.
25.
26. 1. More advanced liver fibrosis (biochemical or imaging surrogates of
histological fibrosis e.g., serum albumin, platelet count, FIB-4 index, APRI, liver
stiffness) before and/or after antiviral treatment are the most prominent
features associated with higher post-SVR HCC risk.
2. Older age, alcohol abuse, metabolic disorders (especially diabetes), and
persisting hepatic inflammation, e.g., high AST, were also associated with HCC
risk.
3. Serum AFP levels pre- and post-SVR have also been implicated as a risk
indicator.
Risk factors for HCC occurrence/ Recurrence
after DAAS “Host factors”
27. 1. Pre-treatment viral factors have been identified, suggesting that
HCV leads to irreversible changes in cellular signaling via
mechanisms such as epigenetic activation or imprinting, which
continue to drive carcinogenesis even after viral clearance.
2. Variant in GT1b HCV core protein, (His70), and GT3 were
associated with increased HCC incidence post-SVR.
Risk factors for HCC occurrence/ Recurrence
after DAAS “viral factors”
28. Italy against
Recurrence rate was 3.2% (1/31 cases)
Time from HCC cure to DAAs start 1.7 months (1.05.-2.4)
Follow up period after the start of DAA was 8 months( 5-10.9).
the longer this interval between HCC therapy and
DAAs initiation, the lower the risk that any residual
tumor is present at start of DAAs and so, the risk
of recurrence
30. After a median 12.4 month follow-up, following treatment with DAAs,
the rate of HCC recurrence was 31.2% with aggressive course in the
immediate 6-month follow-up.
Degree of liver scarring and failure to achieve SVR were predicting
factors for liver cancer.
31. A total of 41 studies Including (n= 13,875 patients)
26 study on HCC occurrence and 15 study on HCC recurrence.
In studies assessing HCC occurrence, average follow up was shorter and
average age was higher in DAA studies compared to IFN studies.
incidence was lower with longer follow-up and younger age.
32. In studies assessing HCC recurrence, average follow up was shorter.
Ultimately, in the meta-regression analysis, no evidence in favor of a
differential HCC occurrence or recurrence was found between DAA and
interferon regimens, after adjusting for study follow-up and age.
35. 2279 patients were treated with approved DAAs regimens and monitored
monthly.
At the time of this analysis, mean follow-up from initiation of DAA therapy was
months. During this period, 27 patients developed HCC, and the overall
incidence was 2.1/100 patients/year
Multivariate analysis indicated that only baseline AST and Platelets count were
statistically associated with HCC risk,
while gender, Age, HCV genotype and DAA regimen were not.
36. conclusions
Post-SVR HCC is an emerging problem, with urgent unmet needs for the clinical
strategy of early tumor detection and intervention.
Molecular mechanisms of carcinogenesis after DAAs are not yet finally clarified,
further research is needed.
Biomarker discovery for prediction of HCC occurrence/Recurrence is required.
Prolonged clinical observation should be further accumulated to determine the
impact of DAA-induced SVR on HCC development and recurrence as well as on
other cancer types.
In tumours arising in the context of chronic inflammation, such as HCC, the net effect of the immune system is stimulation
of tumour growth and progression. However, cancer cells express ‘‘non-self” antigens, and tumour clones may be subject
to immune surveillance and killing by activated T and natural killer (NK) cells [25]. Therefore, an effective cancer immune surveillance process may prevent cancer development. It is not known whether this is the case for HCC arising in HCV-related cirrhosis, but it is known that DAA therapy is associated with a
rapid decrease in NK cell activation and a normalization of NK cell cytotoxic effector functions…..
---------------------------
2-Additional findings emerging from our study are that patients who experienced HCC recurrence were younger and had a more
severe liver stiffness. This may corroborate the hypothesis of a less efficient immunosurveillance associated with a more advanced liver fibrosis.
If this immunosurveillance is further reduced after DAA therapy, this could allow the growth of liver cancer, especially in younger patients, in whom neoplastic lesions
are generally more aggressive.
In tumours arising in the context of chronic inflammation, such as HCC, the net effect of the immune system is stimulation
of tumour growth and progression. However, cancer cells express ‘‘non-self” antigens, and tumour clones may be subject
to immune surveillance and killing by activated T and natural killer (NK) cells [25]. Therefore, an effective cancer immune surveillance process may prevent cancer development. It is not known whether this is the case for HCC arising in HCV-related cirrhosis, but it is known that DAA therapy is associated with a
rapid decrease in NK cell activation and a normalization of NK cell cytotoxic effector functions…..
---------------------------
2-Additional findings emerging from our study are that patients who experienced HCC recurrence were younger and had a more
severe liver stiffness. This may corroborate the hypothesis of a less efficient immunosurveillance associated with a more advanced liver fibrosis.
If this immunosurveillance is further reduced after DAA therapy, this could allow the growth of liver cancer, especially in younger patients, in whom neoplastic lesions
are generally more aggressive.
In tumours arising in the context of chronic inflammation, such as HCC, the net effect of the immune system is stimulation
of tumour growth and progression. However, cancer cells express ‘‘non-self” antigens, and tumour clones may be subject
to immune surveillance and killing by activated T and natural killer (NK) cells [25]. Therefore, an effective cancer immune surveillance process may prevent cancer development. It is not known whether this is the case for HCC arising in HCV-related cirrhosis, but it is known that DAA therapy is associated with a
rapid decrease in NK cell activation and a normalization of NK cell cytotoxic effector functions…..
---------------------------
2-Additional findings emerging from our study are that patients who experienced HCC recurrence were younger and had a more
severe liver stiffness. This may corroborate the hypothesis of a less efficient immunosurveillance associated with a more advanced liver fibrosis.
If this immunosurveillance is further reduced after DAA therapy, this could allow the growth of liver cancer, especially in younger patients, in whom neoplastic lesions
are generally more aggressive.
Natural history of HCV-related HCC development and modulation by anti-HCV therapies. Progressive liver fibrosis along with aging gradually
increases the risk of hepatocarcinogenesis, which could be further accelerated by several host and viral risk factors. Annual incidences of HCC
development and recurrence after DAA-based SVR were estimated from retrospective and prospective studies summarized in Table 1. SVR induced by
interferon- or DAA-based anti-HCV therapies may result in distinct post-SVR HCC risk
الرد علي ادعاءات ارتفاع النسب انه
Indeed, the recent Spanish study suggesting an high risk of HCC recurrence have included patients with noncurative therapies such as chemoembolization, characterized by high early recurrence rates
Time from HCC response to DAAS start 6m-67 month
Time of 1st recurrence 3.4 month -37 months
NB: Normally, it is important to consider that the HCC recurrence rate at 1 year is 19% after liver resection and 20.1% after radiofrequency ablation
الرد علي ادعاءات ارتفاع النسب انه
Indeed, the recent Spanish study suggesting an high risk of HCC recurrence have included patients with noncurative therapies such as chemoembolization, characterized by high early recurrence rates
Time from HCC response to DAAS start 6m-67 month
Time of 1st recurrence 3.4 month -37 months
NB: Normally, it is important to consider that the HCC recurrence rate at 1 year is 19% after liver resection and 20.1% after radiofrequency ablation
الرد علي ادعاءات ارتفاع النسب انه
Indeed, the recent Spanish study suggesting an high risk of HCC recurrence have included patients with noncurative therapies such as chemoembolization, characterized by high early recurrence rates
Time from HCC response to DAAS start 6m-67 month
Time of 1st recurrence 3.4 month -37 months
NB: Normally, it is important to consider that the HCC recurrence rate at 1 year is 19% after liver resection and 20.1% after radiofrequency ablation
الرد علي ادعاءات ارتفاع النسب انه
Indeed, the recent Spanish study suggesting an high risk of HCC recurrence have included patients with noncurative therapies such as chemoembolization, characterized by high early recurrence rates
Time from HCC response to DAAS start 6m-67 month
Time of 1st recurrence 3.4 month -37 months
NB: Normally, it is important to consider that the HCC recurrence rate at 1 year is 19% after liver resection and 20.1% RFA
Reig et al. (19) has reported a high percentage of 27.6% HCC recurrence rate 6 months after DAA. However, the median disease free time from initiating DAA treatment was 11.2 months. And 7 (43.8%) of the recurrent HCC happened <4 months between HCC treatment and last assessment of complete response. Similarly, Conti et al. (14) have noted an identical percentage of 28.8% recurrence rate sooner after DAA. The median observation period before DAA was 446 (range, 50–1,301) days in HCC patients. However, 35% and 73% of the recurrent HCC happened within 1 and 2 years after primitive HCC treatment, respectively. Both studies had short follow-up period after antiviral therapy. Given that we are talking about the risk of HCC, the comparison could only count on incidence rather than the percentage of HCC, which was lacking in both studies.
Second, patients who were treated with PEG-IFN/RBV and those treated with DCV/ASV
differ with respect to many host and viral factors that potentially affect HCC development.
Previous studies have shown that advanced liver fibrosis, male gender, older age, high AFP
levels, greater alcohol intake, complications from diabetes mellitus, and obesity were risk factors
for HCC development after HCV eradication by IFN treatment [17,18, 31±34]. The present
study showed that male gender and AFP levels 10 ng/mL were associated with HCC
development after HCV eradication by DCV/ASV therapy; however, no factor was identified
for independent risk for HCC development
Another hypothesis
involves the liver-specific microRNA 122, which reduces
tumourigenesis, angiogenesis and intrahepatic metastasis,10 and
is downregulated by DAA therapy.1
