Hepatocellular Carcinoma Pattern after the Era of Direct-Acting Antiviral Agents: Does it Differ?

• Despite the advancement achieved in HCV treatment with DAAs, HCC remains a great risk for patients with liver cirrhosis.
• The available clinical data on patients receiving DAAs resulted in a debate regarding the impact of DAAs on the development of HCC.
• Patients with chronic HCV who developed HCC following DAA treatment showed a more advanced stage of HCC according to the BCLC staging and higher rates of lymph node metastasis compared to patients with chronic HCV who developed HCC not preceded by DAA treatment.

Hepatitis C virus (HCV) represents a major global and national health concern, causing around 400,000 deaths annually, primarily due to hepatocellular carcinoma (HCC) and chronic liver disease [9]. Direct-acting antivirals (DAAs) are reported to be highly effective in many countries, including Egypt [10]. However, even though direct-acting antivirals resulted in high rates of SVR, the risk of hepatocellular carcinoma development persists due to underlying liver cirrhosis [6].

This study compared the clinical presentation, laboratory data, and radiological findings in patients with de novo Hepatocellular carcinoma presented to our university hospital's HCC clinic. Participants were divided into two groups: group A involved 79 patients who received DAAs according to NCCVH guidelines, and group B included 117 patients who had not received direct-acting antivirals before. 

The current study showed a male predominance of 81% in group A and 70.1% in group B. Abdominal pain, lower limb edema and hepatic encephalopathy were significantly more frequent in group A in comparison to group B. Nevertheless, other non-significant variances have been observed among the two groups in general or abdominal examinations.

In addition, the current study reported no statistically significant variance in the median AFP level, Child-Pugh class, FIB-4 score, or ECOG Performance status among the two groups.

As regards the BCLC staging, the variance among the two studied groups was statistically significant (P=0.002). In group A, 21.5% of patients were stage Zero, 13.9% of patients were stage A, 31.6% of patients were stage B, 26.5% of patients were stage C and 6.3% of patients were stage D, while In-group B; 11.1% of patient were stage Zero, 20.5% of patients were stage A, 53.8% of patients were stage B, 12.8% of patients were stage C and 1.7% of patients were stage D. These results partially agree with the outcomes of the study conducted by El Fayoumie et al. in 2019 [11] which showed that in patients who developed HCC after DAA treatment, there were 5.9% of patients had stage Zero, 17.6% of patients had stage A, 13.7% of patients had stage B, 41.2% of patients had stage C and 21.6% of patients had stage D, while in HCC patients without DAA treatment, there were 7.4% of patients had stage Zero, 29.6% of patients had stage A, 24.1% of patients had stage B, 11.1% of patients had stage C and 27.8% of patients had stage D. The variance among the two groups was statistically significant (P=0.01).

Regarding PVT, cases of group A showed a higher rate of malignant PVT (27.8%) compared to group B (13.7%), but this variance was not statistically significant (P=0.083) which could be attributed to the smaller sample size of our study in comparison to the study conducted by Shiha et al. in 2020 [12] which showed that portal vein invasion was more common in patients who developed HCC before DAA treatment compared to those who developed HCC after DAA treatment (44.6% vs 7.3%, p<0.001).

Regarding lymphadenopathy, in group A, 25.3% of patients had abdominal lymphadenopathy mainly porta hepatis with malignant criteria by triphasic CT abdomen, while in group B, only 10.3% of patients had malignant abdominal lymphadenopathy, with a higher statistically significant difference in group A (p <0.005). This agrees with Abdelaziz et al, 2019 [13] who compared tumor aggression of HCV-related HCC patients in terms of the presence of lymph node metastasis and portal vein invasion which was reported in nine out of 89 patients (10.1%) in group I (DAA-treated patients) in comparison with eight out of 207 patients (3.9%) in group II patients (non-DAA treated patients), with a statistically significant variance among both groups (P=0.03). This could be due to the more aggressive pattern of hepatocellular carcinoma in patients who received DAAs in comparison to patients who had not received DAAs before.

On the other hand, a study at our university hospital, conducted between December 2017 and December 2018, examined 160 cirrhotic HCV patients with de novo HCC. Findings revealed that cases managed with Direct-Acting Antiviral agents had larger HCC lesions than untreated patients. Nevertheless, no differences were observed in BCLC staging or tumor aggressiveness among the two groups [14]. This difference from our results, which reported a more advanced stage of HCC according to the BCLC staging and higher rates of lymph node metastasis compared to chronic HCV patients who developed HCC not preceded by DAA treatment, could be attributed to our longer period of follow-up after receiving the DAAs because the current study included patients who developed HCC up to 5 years after receiving DAA treatment while the previous study included patients who developed HCC one to three years after receiving DAA treatment.

CONCLUSION

Despite the advancement achieved in HCV treatment with DAAs, HCC remains a great risk for patients with liver cirrhosis. In our study, patients with chronic HCV who developed HCC following DAA treatment showed more advanced stages of HCC according to the BCLC staging and higher rates of lymph node metastasis compared to patients with chronic HCV who developed HCC not preceded by DAA treatment. Further studies with larger sample sizes are still required to stand on the effect of DAA treatment on the pattern of de novo HCC following DAA treatment.

List of abbreviations:

HCC: Hepatocellular carcinoma

HCV: Hepatitis C Virus

DAAs: Direct-acting antiviral agents

NCCVH: National Committee for Control of Viral Hepatitis

AFP: Alpha-FetoProtein

BCLC: Barcelona Clinic Liver Cancer

Fib4: Fibrosis 4 index

HFL: Hepatic Focal Lesion

ECOG: Eastern Cooperative Oncology Group

PVT: Portal Vein Thrombosis

WHO: World Health Organization

SVR: Sustained Virologic Response

 Ethical approval:

This study was approved by the Research Ethics Committee (REC) of the Faculty of Medicine, Ain Shams University. The FMASU REC is organized and operated according to guidelines of the International Council on Harmonization (ICH) Anaesthesiology and the Islamic Organization for Medical Sciences (IOMS), the United States Office for Human Research Protections, and the United States Code of Federal Regulations and operates under Federal Wide Assurance No. FWA 000017585.

Authors’ contributions:

AM made the data collection and contributed to writing. HA, IF, and HK were involved in manuscript writing and revision. EG made the final revision and paraphrasing.

Competing interests:

The authors declare that they have no competing interests to disclose.

Funding:

The authors did not receive funding from any organization for the submitted work.