Treatment With Direct-acting Antivirals for HCV Decreases But Does Not Eliminate the Risk of Hepatocellular Carcinoma

Federico Piñero; Manuel Mendizabal; Ezequiel Ridruejo; Fernando Herz Wolff; Beatriz Ameigeiras; Margarita Anders; María Isabel Schinoni; Virginia Reggiardo; Ana Palazzo; María Videla; Cristina Alonso; Luisa Santos; Adriana Varón; Sebastián Figueroa; Cecilia Vistarini; Raúl Adrover; Nora Fernández; Daniela Perez; Federico Tanno; Nelia Hernández; Marcela Sixto; Silvia Borzi; Andres Bruno; Daniel Cocozzella; Alejandro Soza; Valeria Descalzi; Claudio Estepo; Alina Zerega; Alexandre de Araujo; Hugo Cheinquer; Marcelo Silva; LALREAN


Liver International. 2019;39(6):1033-1043. 

In This Article


From a total of 1749 HCV patients prospectively followed and enrolled in LALREAN's registry, 1400 received at least one pill of DAA and were therefore included in the analysis (Figure 1). Baseline characteristics of the study population are shown on Table 1.

Figure 1.

Flow chart describing the study population

Overall, 91.4% (n = 1280) completed DAA regimen (Figure 1). SVR outcomes were available in 1,149 patients with a SVR rate of 96.9% (CI 95.8%-97.9%). The most frequently used antiviral regimen was sofosbuvir (SOF) + daclatasvir (DCV) in 80.5% of the patients (n = 1127), followed by paritaprevir-r/ombitasvir/dasabuvir (PrOD) 13.4% (n = 188), SOF/ledipasvir 2.3% (n = 32), Grazoprevir/Elbasvir 1.6% (n = 22), DCV +Asunaprevir (ASV) 1.6% (n = 21), SOF/Simeprevir 0.4% (n = 6), SOF/Velpatasvir and paritaprevir-r/ombitasvir in two patients each respectively. Sixty-three patients initiated DAAs during 2015 as part of different compassionate use programmes during 2015 and were also prospectively followed. Median treatment duration was 12 weeks (IQR 11–23 weeks). Adverse events were described in 370 patients (28.3%); mostly mild. The most common DAA regimen was SOF+DCV across all genotypes: genotype 1a (85.4%), genotype 1b (59.6%), genotype 2 (98.4%), genotype 3 (98.8%) and genotype 4 (82.3%). Ribavirin was frequently associated in genotype 3 (74.9%) and less frequently in genotype 1b (33.1%). SVR rates were not significantly different among genotypes (Table S1).

Cumulative Incidence of HCC in the Overall Population

Median follow-up since DAAs initiation was 16 months (IQR 8.9-23.4 months). During follow-up, 30 de novo HCC cases were diagnosed within a median time of 7.9 months (IQR 5.1-15.4 months) since DAA initiation (2 patients had F3 fibrosis and 28 patients fibrosis grade 4). None of the patients with grades 1-2 fibrosis developed HCC. Figure 2 shows the cumulative incidence of HCC at 12 months (0.02 [CI 0.01; 0.03]) and at 24 months (0.04 [CI 0.03; 0.06]) since DAA initiation. At HCC diagnosis, median largest tumour diameter was 25.5 mm (IQR 18–40 mm), 78% had only 1 HCC nodule and median serum AFP at diagnosis was 6.4 ng/mL (IQR 4.2-10 ng/mL). According to BCLC staging, 63.3% were within BCLC 0-A (n = 19), 20% were BCLC-B (n = 6) and 16.7% were BCLC C-D stages (n = 5). Three patients presented tumour macrovascular invasion, two patients had extrahepatic metastasis and one patient had both extrahepatic metastasis and vascular invasion. There was no association between the type of tumour burden and SVR.

Figure 2.

Kaplan-Meier cumulative incidence curve of hepatocellular carcinoma in the overall population

Baseline Risk Factors for de Novo Hepatocellular Carcinoma

In univariate analysis, a higher risk of de novo HCC was observed in individuals with CSPH with a HR of 13.5 (CI 4.72; 38.81) (Figure 3A), cirrhosis HR 8.9 (CI 2.11; 37.4) (Figure 3B), platelets count ≤100 000 per mm3 HR 4.1 (CI 1.88; 9.14) and in patients with AFP >20 ng/mL HR 3.2 (CI 1.20; 8.35). A stratified analysis among patients with advanced fibrosis grades with or without CSPH showed that the highest risk of HCC development was observed in patients with F4 and CSPH with a HR of 13.3 (1.81; 98.7) (Figure 3C). None of the DAA regimens were associated with a higher risk of HCC development (Table 2). Although genotypes 1b and 3 had the highest incidence of de novo HCC (2.5% and 2.4% respectively), genotype 2 and 4 had the lowest incidence of HCC (0.79% and 0% respectively), these differences did not reach statistical significance (Table S2).

Figure 3.

Univariate Cox regression analysis and Kaplan-Meier cumulative incidence curves showing the effect of different covariates and the incidence of de novo HCC: Panel A, clinically significant portal hypertension; Panel B, Fibrosis grade; Panel C, fibrosis grade stratified by the presence of portal hypertension

Not achieving SVR was also significantly associated with a higher risk of de novo HCC (HR of 5.7 [CI 1.71; 18.80]). Overall cumulative incidence of HCC for patients with and without SVR at 12 months was 0.02 (CI 0.01-0.03) and 0.04 (CI 0.02-0.06) respectively (Figure 4). Achieving SVR presented a relative risk reduction for de novo HCC of 73% (CI 15%-91%), with an absolute risk difference of −0.06 (CI −0.15; 0.0.03) when compared with antiviral failure. This represented a number needed to treat (NNT) of 17 patients to prevent one case of de novo HCC.

Figure 4.

Kaplan-Meier cumulative incidence curve of hepatocellular carcinoma (HCC) according to achievement of SVR12

A multivariable model describing the adjusted effect of SVR is shown on Table 2. Non-SRV patients presented a HR of 4.9 (CI 1.44; 17.32; P = 0.011) for developing HCC after DAAs initiation, adjusted for the presence of diabetes mellitus, previous non-responders to PegIFN-based regimens, CTP class and the presence of CSPH. The presence of CSPH was the strongest predictor of HCC development with a HR of 9.1 (CI 2.69; 30.89; P < 0.0001). Not achieving SVR was independently associated with HCC development, adjusted for other covariates including diabetes mellitus, non-responders to PegIFN-based regimens, CTP class and the presence of CSPH (Figure S1) in the competing risk regression analysis (Table 3) and in the propensity score matching, assessing the probability of SVR (Table S2 and Figure S2).

Supplementary Figure 1.

Competing risk regression and cumulative incidence of HCC.

Supplementary Figure 2.

Receiving operating curve (ROC) for the propensity score assessing the probability of SVR12.

Sensitivity Analysis: Risk of HCC Among Cirrhotic Patients

A sensitivity analysis including only patients with F4 or cirrhosis (n = 784) showed that cumulative incidence of HCC at 12 months was 0.03 (CI 0.02-0.05) and 0.06 (CI 0.04-0.08) at 24 months of follow-up respectively. As expected, a higher incidence of de novo HCC was observed with increasing Child-Pugh score (Table 4). From a multivariable Cox regression analysis, non-SVR and the presence of CSPH were independently associated variables with HCC development among patients with cirrhosis (Table 4).