HCV resistance compartmentalization within tumoral and non‐tumoral liver in transplanted patients with hepatocellular carcinoma

Abstract

Background & aims:We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. Methods:Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated. Results: At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193).The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCVcompartmentalization resulted to be associated with HBcAb-positivity (P = 0.013).UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCVclusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related. Conclusions:Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. | 1987 SORBO et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Sorbo MC, Carioti L, Bellocchi MC, et al. HCV resistance compartmentalization within tumoral and non-tumoral liver in transplanted patients with hepatocellular carcinoma.

Cure With Interferon‐Free Direct‐Acting Antiviral Is Associated With Increased Survival in Patients With Hepatitis C Virus‐Related Hepatocellular Carcinoma From Both East and West

“…In fact, our data could be further supported by findings that 60% of the patients with SVR who died in our study actually died of non‐liver‐related causes, which is also consistent with the fact that the majority of these patients had lower (<10) MELD scores, CTP class A, and small tumors without metastasis. IFN‐free DAA treatment should not be withheld from patients with HCC who are eligible for HCC therapies because the improved survival benefit of HCV treatment may outweigh the cost of the care factor …”

Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b

“…Finally, in a dataset of NS5A sequences specifically isolated from plasma, tumoral, and peritumoral liver tissue samples of seven cirrhotic HCV genotype-1b infected patients with HCC [ 26 ], ≥1 mutation associated with HCC was detected in 43% (3/7) in all the three compartments. Furthermore, an enrichment of amino acid mutations at positions 133 and 181 was also observed in two other patients, again in all the compartments analyzed.…”

Genetic Variability in Patients with HCV-Related Hepatocellular Carcinoma

“…There are few studies that analyze the genetic and aa variability of HCV in the cancerous and non-cancerous tissue of HCC patients, with equivocal results. [30][31][32][33][34] In the study by Perez et al, 31 core and E2 regions were amplified, cloned and sequenced in four patients with HCC who underwent liver transplantation, showing in all the patients a compartmentalization in the three compartments Interesting are the results of Sorbo et al 35 who investigated the prevalence of resistance-associated aa substitutions (RASs) in plasma, liver tumoral and non-tumoral tissue samples in 18 patients undergoing liver transplant or hepatic resection due to HCC and/or cirrhosis: 6 of 18 patients had at least one RAS in at least one of the compartments analyzed, and nucleotide variability assessed by genetic distance analysis showed higher median values for NS3 and NS5A sequences compared to NS5B in the tissue compartments.…”