Baseline Plasma Metabotype Correlates With Direct-Acting Antiviral Therapy Nonresponse for HCV in HIV–HCV Coinfected Patients

Introduction: With the advent of direct-acting antiviral (DAA) therapy for HCV, the cure is achieved at similar rates among HIV–HCV coinfected patients as in HCV mono-infected patients. The present study evaluates host plasma metabolites as putative indicators in predicting the treatment response in baseline HIV–HCV patients.Methods: Non-cirrhotic HIV–HCV (N = 43) coinfected patients were treated with sofosbuvir and daclatasvir for 12 weeks. Plasma metabolite profiling of pre- and post-therapy was analyzed in 20/43 patients. Of the 20 selected, 10 (50%) attained the sustained viral response [(SVR) (responders)] as defined by the absence of HCV RNA at 12 weeks after the treatment, and 10 (50%) did not attain the cure for HCV (nonresponders).Results: A total of 563 features were annotated (metabolomic/spectral databases). Before therapy, 39 metabolites differentiated (FC ±1.5, p < 0.05) nonresponders from responders. Of these, 20 upregulated and 19 downregulated were associated with tryptophan metabolism, nicotinamide metabolism, and others. Post therapy, 62 plasma metabolites (12 upregulated and 50 downregulated, FC±1.5, p < 0.05) differentiated nonresponders from responders and highlighted a significant increase in the steroid and histidine metabolism and significant decrease in tryptophan metabolism and ascorbate and pyruvate metabolism in the nonresponders. Based on random forest and multivariate linear regression analysis, the baseline level of N-acetylspermidine (FC > 2, AUC = 0.940, Bfactor = −0.267) and 2-acetolactate (FC > 2, AUC = 0.880, Bfactor = −0.713) significantly differentiated between nonresponders from responders in HIV–HCV coinfected patients and was able to predict the failure of treatment response.Conclusion: Increased baseline levels of N-acetylspermidine and 2-acetolactate levels are associated with the likeliness of failure to attain the cure for HCV in HIV–HCV coinfected patients.

Regression of liver fibrosis and hepatocellular carcinoma development after HCV eradication with oral antiviral agents

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.Clinical trials registration: ClinicalTrials.gov (NCT02865369).

Late Recurrence of Hepatocellular Carcinoma in a Patient 10 Years after Liver Transplantation Unrelated to Transplanted Organ

Liver transplantation (LTx) is an accepted method of hepatocellular carcinoma (HCC) treatment in cirrhotic patients; however, it has many limitations, and there is a substantial risk of recurrence. Most relapses occur within the first 2 posttransplant years. We aimed to present a late extrahepatic recurrence of HCC 10 years after LTx, and we discuss the possible risk factors and ways to improve transplantation results. A 68-year-old patient with liver cirrhosis and HCC on the background of chronic HCV and past HBV infection was transplanted urgently due to the rapid decompensation. Anti-HCV treatment before surgery was unsuccessful. Pretransplant computed tomography showed 1 focal 4.5 cm lesion consistent with HCC. Histopathology of the explanted organ showed 2 nodules outside the Milan criteria. Angioinvasion was not found. The patient achieved a sustained viral response to pegylated interferon and ribavirin 2 years post-LTx. Eight years were uneventful. CT of the abdomen performed occasionally was normal. Ten years after LTx, the patient unexpectedly presented with shortness of breath, fatigue, and weight loss. Two metastatic nodules of HCC in the lungs and pelvis were found. Although late HCC recurrence post-LTx is rare, it should be always considered, especially when risk factors such as viral infections and underestimation of tumor advancement were identified. We advocate that oncological surveillance of HCC relapse has to be continued during the whole posttransplant period. High AFP levels, the unfavorable neutrophil to lymphocyte ratio, and better estimation of primary tumor size seem to be useful in the identification of good candidates for transplantation.

Depressive and Anxious Symptoms in Hepatitis C Virus Infected Patients Receiving DAA-Based Therapy

Hepatitis C virus (HCV) represents the most important etiologic factor for advanced fibrosis/cirrhosis and hepatocellular carcinoma associated with a psychological dimension. Our study aims to assess, on a sample comprising of 90 HCV-infected subjects (96.67% F3-F4 METAVIR), the relationship between Direct-Acting Antiviral (DAA) therapies and the psychological effects of the liver disease, focused on the anxious and depressive symptoms. The comprehensive evaluation was done before starting the DAA treatment (BSL), after 12 weeks (End of Treatment—EOT), respectively after another 12 weeks (Sustained Viral Response—SVR). Presumable depressive and/or anxious symptoms were evaluated by Hospital Anxiety and Depression Scale (HADS). The reported depressive symptoms decreased from 21.11% (BSL) to 1.11% (SVR) (p < 0.00001), while the anxious ones dropped from 43.34% (BSL) to 4.44% (SVR) (p < 0.00001), without a clear evolutionary pattern. We identified no statistically significant interaction between comorbidities (anemia, CKD, obesity) over HADS scores evolution (p > 0.05), while the DAAs side-effects (fatigue, headache, pruritus) significantly influenced the anxious and depressive symptoms (p < 0.05). During and after the DAA-based therapy, patients with HCV infection presented a significantly reduced rate of the associated depressive and anxious relevant symptoms.

Role of PNPLA3 in the Assessment and Monitoring of Hepatic Steatosis and Fibrosis in Patients with Chronic Hepatitis C Infection Who Achieved a Sustained Virologic Response

Background and Objectives: Hepatic diseases are an important public health problem. All patients with chronic hepatitis C virus (HCV) infection receive treatment, regardless of hepatic fibrosis severity. However, evaluation of hepatic fibrosis and steatosis is still useful in assessing evolution, prognosis and monitoring of hepatic disease, especially after treatment with direct-acting antivirals (DAAs). The aim of this study was to assess the link between patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism and the degree of hepatic steatosis and fibrosis in patients with chronic HCV infection, as well as changes in steatosis and fibrosis three monthsafter obtaining a sustained viral response (SVR). Materials and Methods:Ourstudy included 100 patients with chronic hepatitis C (CHC) infection and compensated cirrhosis who received DAA treatment and who were evaluated using Fibromax prior to and 3 months after SVR. The influence of PNPLA3 (CC, CG, GG) genotype among these patients on the degree of post-treatment regression of steatosis and fibrosis was assessed. Results: Regression was noticed in the degree of both hepatic steatosis and hepatic fibrosis post-DAA treatment (three months after SVR). Analysis of the correlation between PNPLA3 genotype and fibrosis indicated that the average level of fibrosis (F) before DAA treatment was higher in patients with the GG genotype than in patients with the CC or CG genotype. Three months after SVR, the average level of fibrosis decreased; however, it remained significantly increased in GG subjects compared to that in CC or CG patients. The degree of hepatic steatosis before treatment was not significantly different among patients with different PNPLA3 genotypes, and no significant correlations were observed three months after SVR. Conclusions: The genetic variants of PNPLA3 influence the evolution of hepatic fibrosis. The GG subtype plays an important role in the degree of hepatic fibrosis both before and after treatment (three months after SVR)and could be a prognostic marker for assessment of post-SVR evolution.

Regression of Liver Fibrosis and Hepatocellular Carcinoma Development After HCV Eradication With Oral Antiviral Agents; A Prospective Multi-center Study

Purpose: We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years.Method: LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN).Result: Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks.Conclusion: HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.

Acute hepatitis C virus infection and direct-acting antiviral drugs: Perfect combination to eliminate the epidemic?

Early diagnosis and treatment of incident cases of hepatitis C virus (HCV) infection is fundamental to eliminate HCV in HIV-positive patients. From January 2016 to December 2019, we attended 40 episodes of acute HCV infection (AHC) in 35 subjects (9 reinfections) who were coinfected with HIV. The patients were treated with direct-acting antiviral agents (DAAs) in seven hospitals in Andalusia, Spain. All were men who have sex with men (MSM), mean age was 42.9 (±8.3) years and median time of HIV infection was 46.6 months (IQR: 20.4–67.2). All received antiretroviral therapy and had undetectable HIV viral load (except 2 with 65 and 68 copies/mL); median CD4 count was 632 cells/mm3 (IQR: 553–896). Over half (74.3%) also had another concomitant sexually transmitted infection, syphilis (48.6%) being the most common. AHC was asymptomatic in 32 cases (80%). Genotypeic distribution was G1a 65%, G4 32.5% and G1b 3%. Median time to DAA was 6 weeks (IQR: 4.3–18.3) and median baseline HCV RNA was 6.1 Log (IQR: 5.6–6.5). DAA regimens were SOF/LDV (19 episodes), SOF/VEL (14), ELB/GZV (5) and GLP/PIB (2). All presented sustained viral response and none discontinued due to adverse effects. In conclusion, early treatment with DAA in AHC patients proved effective and safe. It could be an excellent strategy to eliminate HCV infection in HIV-coinfected MSM.

Effectiveness and safety of orally administered silymarin (milk thistle) for pegylated interferon unresponsive chronic delta hepatitis patients

Objective: Silymarin is a natural extract from milk thistle (Silybum marianum), a natural herb that contains flavonoids. Silymarin also has anti-inflammatory properties and lipid peroxidation effects on human hepatocytes. It has also been used for the treatment of acute alpha-amanitin poisoning and chronic hepatitis C infection. Chronic Hepatitis D virus (HDV) infection is a severe health problem leading to fibrosis and hepatocellular carcinoma. Patients with chronic HDV infection can be treated with Peg-IFN with lower treatment success. Most patients with chronic HDV are unable or unwilling to use interferon (IFN)-based treatment due to liver cirrhosis. Our objective was to establish the long-term clinical outcomes with silymarin for interferon-experienced chronic HDV patients. Materials and Methods: We studied ten patients from one centre with interferon who experienced chronic HDV, of which 8 had cirrhosis, and 2 had chronic hepatitis who received HDV treatment with silymarin 600 mg/day after a median period of 12 months. Information collected included demographic, clinical, virologic, and outcomes data. MELD and Child-Pugh (CP) scores were also obtained. Friedman test was used to evaluate the laboratory parameters during the study period. Results: 10 chronic HDV patients (median age 54 yrs, six female, all of them previous null responders to Peg-IFN with mildly decompensated cirrhosis [CP 7 (range 6-11), MELD 11 (range 6-20] were followed for 12 months from the start of silymarin 600 mg/day. There was no decompensation of both MELD and CP scores among patients at the end of therapy. In addition, no patients stopped silymarin treatment early due to side effects. At the end of treatment, there was no significant change in prothrombin time (p= 0.949), AST (p=0.662) and AFP (p=0.983) levels and platelets counts (p=0.988) compared to the pre-treatment period (all p>0.005). Finally, HDV-RNA suppression was seen in all patients at the end of treatment (p=0.009). Conclusions: In the light of the presented data, silymarin seems to be effective in treating chronic HDV infection. Further research is needed for validation. The study is ongoing with a collection of data on sustained viral response.