Polymorphisms in MT1a gene coding region are associated with longevity in Italian Central female population

Metallothioneins (MTs) play a pivotal role in zinc-related cell homeostasis because of their high affinity for zinc, which is in turn fundamental for immune response and antioxidant activity. MTs regulate zinc homeostasis by binding zinc and releasing zinc at the occurrence for immune response. The zinc release by MT is very limited in chronic inflammation and ageing. Some polymorphisms of MTs gene, in particular MT1a sub-isoform, may affect this release that is a problem still unresolved in ageing. The screening in the present paper of two polymorphisms in MT1a gene has revealed for the first time that the polymorphism corresponding to a A/C (Asp/Thr) transition at 647 nt position in the Mt1a coding region is the more involved in the longevity, at least in old women, rather than the other corresponding to A/G (Lys/Arg) transition at 1,245 nt position. Concomitantly, for the +647 MT1a polymorphism, old and very old female with Asp/Asp genotype (called C-carriers) display higher zinc release by MT (detected by Zinpyr-1 fluorescent probe in presence of NO donor), low MT levels and reduced IL-6 plasma concentrations, suggesting its involvement in longevity and in lower inflammatory status. This fact is confirmed by the analysis of haplotypes in which the allele Asp is more involved in longevity. Therefore the +647 MT1a polymorphism more affects MTs induction and zinc release, which are indispensable to undertake the inflammatory status under control and subsequently to reach healthy longevity.Presented at the ZincAge Conference, Madrid, February 10–13, 2006.     

Interaction between hepatic membrane type 1 matrix metalloproteinase and acireductone dioxygenase 1 regulates hepatitis C virus infection

Membrane type 1 matrix metalloproteinase (MT1‐MMP) binds to and regulates the function of tetraspanin‐enriched microdomains. It also physically interacts with claudin‐1 and acireductone dioxygenase 1 (ADI1), both associated with hepatitis C virus (HCV) cell entry. Here, we examined hepatic expression of MT1‐MMP, ADI1 and claudin‐1 as well as their physical interaction in relation to serum or intrahepatic HCV‐RNA levels. A total of 104 liver biopsies obtained from chronic hepatitis C patients and 84 liver tissues obtained from noncancerous parts of surgically removed HCV‐related hepatocellular carcinoma were analysed. Positive cytoplasmic ADI1 in liver biopsies was associated with higher serum HCV‐RNA levels (P = 0.009). Positive MT1‐MMP and ADI1 interaction assessed by co‐immunoprecipitation was associated with lower tissue HCV‐RNA levels (P = 0.009). Hepatic HCV‐RNA levels were positively associated with ADI1 levels in the MT1‐MMP and ADI1 co‐immunoprecipitates (P = 0.030). Overexpression of MT1‐MMP in Huh7.5 cells suppressed cell entry of HCV pseudoparticles as well as HCVcc infection. The suppression effect could be reversed by co‐expression of ADI1 in a dose‐dependent manner. In summary, clinical and cell‐based experiments suggested that physical interaction between MT1‐MMP and ADI1 led to suppression of HCV infection. This inhibitory effect could be reversed by ADI1 overexpression.     

Current Status of Hepatitis C Virus‐Infected Maintenance Hemodialysis Patients in Japan

Complete recovery using interferon therapy in Japanese hepatitis C virus (HCV)‐infected dialysis patients is difficult to achieve because >70 % of the HCV genotypes observed in Japan are type 1. In 2016, new direct‐acting antiviral drugs against HCV genotype 1 were reported to be effective and safe for HCV‐infected hemodialysis patients. Although new direct antiviral therapy has become available, no large‐scale studies evaluating the status of HCV infection in Japanese hemodialysis patients have been conducted since 2007. Therefore, we conducted a questionnaire survey to determine the current status of HCV infection in patients. Our results indicated that the HCV antibody prevalence was 5.02 %, and HCV RNA prevalence was 72.3 %. Genotype testing revealed that 62.1 % of patients had HCV genotype 1. New direct antiviral therapy may improve the survival of Japanese HCV‐infected dialysis patients.     

Zinc, metallothioneins, immune responses, survival andageing

Zinc is required as a catalytic, structural (zincfingers) and regulatory ion. In this capacity, it isinvolved in many homeostatic mechanisms, includingimmune responses. Metallothioneins (MTs) may play keyroles because of their preferential binding to zincespecially in ageing. MTs protect from oxidativedamage during transient stress conditions atyoung-adult age. This protection no longer exists inageing and in age-related diseases (cancer andinfections) because the stress condition is constant.As such, MTs may constantly deplete zinc from plasmaand tissues. This phenomenon causes increased MTslevels on the one hand, but on the other hand induceslow zinc ion bioavailability for normal immuneresponses. This may be particularly relevant forthymic functions and natural killer activity.Therefore MTs which are protective in young-adults maybecome dangerous in immune responses during ageing.Physiological supplementation of zinc in ageingcorrects central and peripheral immune defects,resulting prolonged survival and decreased mortality (50%) frominfections and tumours, especially during middle age.Because of increased MT gene expression and proteinlevels in the liver and atrophic thymus of old mice,MTs are proposed as genetic markers of immunosenescence.     

Nurse case management to improve the hepatitis C care continuum in HIV co‐infection: Results of a randomized controlled trial

The opportunity to eliminate hepatitis C virus (HCV) is at hand, but challenges remain that negatively influence progress through the care continuum, particularly for persons co‐infected with HIV who are not well engaged in care. We conducted a randomized controlled trial to test the effect of nurse case management (NCM) on the HCV continuum among adults co‐infected with HIV compared to usual care (UC). Primary outcomes included linkage to HCV care (attendance at an HCV practice appointment within 60 days) and time to direct‐acting antiviral (DAA) initiation (censored at 6 months). Sixty‐eight participants were enrolled (NCM n = 35; UC n = 33). Participants were 81% Black/African American, 85% received Medicaid, 46% reported illicit drug use, 41% alcohol use, and 43% had an undetectable HIV viral load. At day 60, 47% of NCM participants linked to HCV care compared to 25% of UC participants (P = .031; 95% confidence bound for difference, 3.2%‐40.9%). Few participants initiated DAAs (12% NCM; 25% UC). There was no significant difference in mean time to treatment initiation (NCM = 86 days; UC = 110 days; P = .192). Engagement in HCV care across the continuum was associated with drinking alcohol, knowing someone who cured HCV and having a higher CD4 cell count (P < .05). Our results support provision of NCM as a successful strategy to link persons co‐infected with HIV to HCV care, but interventions should persist beyond linkage to care. Capitalizing on social networks, treatment pathways for patients who drink alcohol, and integrated substance use services may help improve the HCV care continuum.     

The Use of Cyclosporine for Recurrent Hepatitis C After Liver Transplant: A Randomized Pilot Study

Background  

Cyclosporine has antiviral activity in vitro against hepatitis C (HCV). We performed a pilot study to prospectively determine the antiviral effect of cyclosporine during therapy with PEGalfa-2a and ribavirin in liver transplant recipients with recurrent HCV infection.     

A randomized controlled trial adding fluvastatin to peginterferon and ribavirin for naïve genotype 1 hepatitis C patients

Fluvastatin or simvastatin has demonstrable antiviral activity against hepatitis C virus (HCV) as monotherapy. The safety and efficacy of adding fluvastatin or simvastatin to peginterferon/ribavirin for 48 weeks was tested in HCV genotype 1 naïve‐to‐treatment veterans. Thirty‐seven naïve‐to‐treatment genotype 1 HCV patients were randomized to either a control group (n = 20) to receive peginterferon alfa plus ribavirin or an experimental group (n = 18) to similarly receive peginterferon alfa plus ribavirin as well as fluvastatin 20 mg/day. In addition, seven patients who presented for HCV treatment already were on simvastatin and could not be withdrawn. These simvastatin users were not randomized but were entered into a concurrent prospective pilot arm. There were no unique safety issues with fluvastatin or simvastatin when these drugs were given with peginterferon/ribavirin for 48 weeks. Thirteen of 25 statin patients achieved sustained viral response (SVR), while 5 of 20 control patients achieved SVR. Analysis of SVR by intention‐to‐treat showed P = 0.078. In this phase 2 study, there were no safety issues with the addition of fluvastatin or simvastatin to peginterferon and ribavirin for 48 weeks. There was a trend towards improvement in SVR when fluvastatin or simvastatin was administered with peginterferon/ribavirin. The size of the groups did not reach the prestudy size thought needed to show significant difference (type II error). These results support the significant results of two other larger randomized controlled trials reported using the same dose of fluvastatin in naïve‐to‐treatment genotype 1 HCV patients.     

The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta‐analysis

Several studies investigating the role of statins and fibrates in chronic hepatitis C virus (HCV) infection offered so far conflicting evidence regarding the antiviral potency of these medications, whereas combination of these drugs with pegylated interferon and ribavirin improved in some trials therapeutic outcome. We conducted a literature search to identify trials that included monoinfected HCV patients, treated with statins or fibrates as monotherapy with the primary end point of our meta‐analysis being the quantitative change of HCV‐RNA induced by these medications. Logarithmic changes of the viral load (ΔlogVL) and confidence intervals (CIs) were calculated according to the DerSimonian‐Laird estimate. Statistical heterogeneity was assessed with the I² statistic. We identified eight observational studies that evaluated the potency of bezafibrate and different statins as monotherapy to induce a significant reduction of HCV‐RNA in HCV‐monoinfected patients (n = 281). Overall, a significant reduction of viral load with mean 0.19 [log₁₀ IU/mL] (95%‐confidence interval, (CI) 0.11–0.28) could be observed when antihyperlipidemic medications were administered. Bezafibrate featured the highest antiviral efficacy (0.45 log₁₀ reduction, 95%‐CI, 0.17–0.72) among all medications and fluvastatin (0.20 log₁₀ reduction, 95%‐CI, 0.09–0.31) among all statins tested. Based on meta‐analysis, fibrates and statins induce a reduction of HCV viral load. We suggest that the addition of statins and fibrates to antiviral regimes, especially in HCV patients with concomitant dyslipidemia, could beside the established reduction of cardiovascular risk increase the potency of antiviral therapy.     

The influence of immunosuppressants on direct‐acting antiviral therapy is dependent on the hepatitis C virus genotype

Background

Direct‐acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon‐based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified.

Methods

Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation‐related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real‐time polymerase chain reaction or luciferase assay.

Results

Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P ≤ .01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P ≤ .01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT.

Conclusion

For patients with HCV GT2a, GT3a, or GT4a infection, mTOR‐based immunosuppressive therapy may be beneficial. CNI‐based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection.     

Preclinical efficacy and immunogenicity assessment to show that a chimeric Plasmodium falciparum UB05‐09 antigen could be a malaria vaccine candidate

Although it is generally agreed that an effective vaccine would greatly accelerate the control of malaria, the lone registered malaria vaccine Mosquirix? has an efficacy of 30%‐60% that wanes rapidly, indicating a need for improved second‐generation malaria vaccines. Previous studies suggested that immune responses to a chimeric Plasmodium falciparum antigen UB05‐09 are associated with immune protection against malaria. Herein, the preclinical efficacy and immunogenicity of UB05‐09 are tested. Growth inhibition assay was employed to measure the effect of anti‐UB05‐09 antibodies on P. falciparum growth in vitro. BALB/c mice were immunized with UB05‐09 and challenged with the lethal Plasmodium yoelii 17XL infection. ELISA was used to measure antigen‐specific antibody production. ELISPOT assays were employed to measure interferon‐gamma production ex vivo after stimulation with chimeric UB05‐09 and its constituent antigens. Purified immunoglobulins raised in rabbits against UB05‐09 significantly inhibited P. falciparum growth in vitro compared to that of its respective constituent antigens. A combination of antibodies to UB05‐09 and the apical membrane antigen (AMA1) completely inhibited P. falciparum growth in culture. Immunization of BALB/c mice with recombinant UB05‐09 blocked parasitaemia and protected them against lethal P. yoelii 17XL challenge infection. These data suggest that UB05‐09 is a malaria vaccine candidate that could be developed further and used in conjunction with AMA1 to create a potent malaria vaccine.     

Quality of life in adolescents with hepatitis C treated with sofosbuvir and ribavirin

Chronic HCV infection has been associated with impairment of HRQL in both adults and paediatric patients. Our aim was to assess the HRQL of HCV‐positive children treated with SOF + RBV. The data for this post hoc analysis were collected in a phase 2 open‐label multinational study that evaluated safety and efficacy of SOF (400 mg/day) plus RBV (weight‐based up to 1400 mg/day) for 12 or 24 weeks in adolescents with chronic HCV (GS‐US‐334‐1112). Patients and their parents/guardians completed the PedsQL‐4.0‐SF‐15 questionnaire at baseline, at the end of treatment and in post‐treatment follow‐up. We included 50 adolescents with HCV genotype 2 and 3 without cirrhosis (14.8 ± 1.9 years; male: 58%; treatment‐naïve: 82%; vertically transmitted HCV: 70%). After treatment, 100% of patients with HCV genotype 2 and 95% with genotype 3 achieved SVR‐12. During treatment with SOF + RBV, there were no significant decrements in any of patients’ self‐reported or parent‐proxy‐reported PRO scores regardless of treatment duration (all P > .05). After treatment cessation, we recorded a statistically significant improvement in patients’ self‐reported Social Functioning score by post‐treatment week 12: on average, +4.8 points on a 0‐100 scale (P = .02). By post‐treatment week 24, parent‐proxy‐reported School Functioning score increased by, on average, +13.0 points (P = .0065). In multivariate analysis, history of abdominal pain and psychiatric disorders were predictive of impaired HRQL in adolescents with HCV (P < .05). Adolescents with HCV do not seem to experience any HRQL decrement during treatment with SOF + RBV and experience some improvement of their HRQL scores after achieving SVR.     

Hepatitis C diagnosis and treatment,impact on engagement and behaviour of people who inject drugs,a service evaluation,the hooked C project

There is emerging evidence that Hepatitis C (HCV) treatment engagement is associated with change in drug behaviours and reduced drug‐related death rates among people who inject drugs (PWID). The project aims to investigate whether HCV diagnosis and treatment engagement reduces all‐cause mortality and drug‐related death, and whether any effect is dependent on treatment regimen and intensity of engagement with staff. Case‐control studies comparing: PWID with active HCV infection (PCR positive) to PWID HCV infected but spontaneously resolved (PCR negative); PCR‐positive patients who engaged with treatment services to nonengagers; and patients who received interferon vs direct‐acting antiviral (DAA) based treatment. No differences in risk of all‐cause mortality or drug‐related death between PCR‐negative controls and PCR‐positive cases were detected. The odds of all‐cause mortality was 12.2 times higher in nonengaging persons compared to treatment engaging cases (aOR 12.15, 95% CI 7.03‐20.99, P < .001). The odds of a drug‐related death were 5.5 times higher in nonengaging persons compared with treatment engaging cases (aOR 5.52, 95% CI 2.67‐ 11.44, P < .001). No differences in risk of all‐cause mortality or drug‐related death between interferon‐treated cases and DAA‐treated controls were detected. HCV treatment engagement is significantly protective against all‐cause mortality and drug‐related death. This engagement effect is independent of treatment regimen, with the introduction of DAA therapies not increasing risk of drug‐related death, suggesting intensity of HCV therapy provider interaction is not an important factor.     

Antiviral therapy (pegylated interferon and ribavirin) of hepatitis C in dialysis patients: meta‐analysis of clinical studies

Information on the antiviral treatment (pegylated interferon plus ribavirin) of chronic infection by hepatitis C virus (HCV) in patients on long‐term dialysis is extremely limited. We evaluated the efficacy and safety of combination antiviral therapy (pegylated interferon plus ribavirin) in patients on long‐term dialysis with chronic hepatitis C by performing a systematic review of the literature with a meta‐analysis of clinical studies. The primary outcome was sustained virological response (SVR) (as a measure of efficacy); the secondary outcome was dropout rate (as a measure of tolerability). We used the random‐effects model of DerSimonian and Laird, with heterogeneity and sensitivity analyses. We identified eleven clinical studies (287 unique patients), two of them being controlled clinical trials. The summary estimate for SVR and dropout rate was 0.60 (95% Confidence Intervals, 0.47; 0.71) and 0.18 (95% CI, 0.08; 0.35), respectively; studies being heterogeneous with regard to both the outcomes. Stratified analysis reported a higher SVR rate in controlled trials, 0.86 (95% CI, 0.27; 0.99). The most common sources of dropout were anaemia (11/46 = 23%) and infections (6/46 = 13%). Meta‐regression analysis showed a detrimental impact of HCV genotype 1 (P = 0.036) and dropout (P = 0.0001) rate upon the frequency of SVR. Antiviral therapy based on pegylated interferon plus ribavirin for HCV gives encouraging results in terms of efficacy and safety among patients on long‐term dialysis; such approach should be considered the current standard of care for HCV‐infected individuals on regular dialysis.     

Genetic variations in host IL28B links to the detection of peripheral blood mononuclear cells–associated hepatitis C virus RNA in chronically infected patients

Hepatitis C virus (HCV) is mainly hepatotropic; however, several reports document the presence of genomic viral RNA in extrahepatic sites including peripheral blood mononuclear cells (PBMCs). In this study, the presence of HCV RNA was initially evaluated in the plasma and peripheral blood mononuclear cells (PBMCs) of 53 HCV‐infected patients who were treated per protocol. PBMC‐associated HCV RNA was detectable in 79% of patients. Early virological response to combined pegylated interferon‐α (PegIFN) and ribavirin (RBV) therapy in patients with undetectable levels of PBMCs‐associated HCV RNA was 100%, while it was 60% (P = 0.003) in those who had detectable levels of PBMC‐associated HCV RNA. A sustained virological response was observed in 35% of patients with detectable PBMC‐associated HCV RNA, but was 70% in patients with undetectable levels of PBMC‐associated HCV RNA (P = 0.07). In a multivariate analysis incorporating parameters such as HCV genotype, viral load, presence of cirrhosis and absence of PBMC‐associated HCV RNA, a significant relationship was observed between the detection of PBMC‐associated HCV RNA and the sustained virological response (OR 19.4, 95% CI: 2.1–486.2, P = 0.0061). The association between single nucleotide polymorphism (SNP) in IL28B, known predictor of antiviral therapy outcome, and the occurrence of HCV RNA in PBMC in 84 chronically infected patients was then evaluated. Results suggest that the presence of a G allele in rs8099917, known to associate to a poor response to PegIFN/RBV therapy, also predicts an increased association of HCV RNA with PBMC (OR: 3.564; 95% CI: 1.114–11.40, P = 0.0437).     

Changes in liver fibrosis in HIV/HCV‐coinfected patients following different outcomes with peginterferon plus ribavirin therapy

There is scarce information about the impact of antiviral treatment on subsequent progression of liver fibrosis in HIV‐infected patients with chronic hepatitis C who experience different outcomes following peginterferon‐ribavirin therapy. We conducted a retrospective study of a cohort of HIV/HCV‐coinfected patients with longitudinal assessment of liver fibrosis using elastometry. Patients were split out into four groups according to the prior peginterferon‐ribavirin response: sustained virological response (SVR), relapse (R), partial response (PR) and null response (NR). A group of untreated, coinfected patients was taken as control. Significant liver fibrosis progression (sLFP) was defined as a shift from baseline Metavir estimates ≤F2 to F3‐F4, or by >30% increase in liver stiffness in patients with baseline F3‐F4. Conversely, significant liver fibrosis regression (sLFR) was defined as a shift from baseline Metavir estimates F3‐F4 to ≤F2, or by >30% reduction in liver stiffness in patients that kept on F3‐F4. A total of 498 HIV/HCV‐coinfected patients were examined. They were classified as follows: 138 (27.7%) SVR, 40 (8%) R, 61 (12.2%) PR, 71 (14.3%) NR and 188 (37.8%) naive. After a mean follow‐up of 53.3 months, sLFP occurred less frequently in patients with SVR (7.2%) compared with R (25%; P = 0.002), PR (23%; P = 0.002), NR (29.6%; P < 0.001) and naïve (19.7%; P = 0.002). Conversely, sLFR was 26.1% in SVR compared with 10% in R (P = 0.03), 14.8% in PR (P = 0.06), 16.9% in NR (P = 0.07) and 10.6% in naïve (P < 0.001). Sustained clearance of serum HCV‐RNA following a course of antiviral treatment is the major determinant of liver fibrosis regression in HIV/HCV‐coinfected patients.     

Oral anti‐CD3 immunotherapy for HCV‐nonresponders is safe,promotes regulatory T cells and decreases viral load and liver enzyme levels: results of a phase‐2a placebo‐controlled trial

Orally administered anti‐CD3 antibodies are biologically active in the gut through induction of regulatory T cells, exert an immune‐modulatory effect, and alleviate insulin resistance and liver damage in patients with NASH. Aims: To determine the safety of oral anti‐CD3 monoclonal antibody (MAb) immunotherapy in chronic HCV patients with associated immune dysfunction. Methods: Four groups (n = 9) of chronic HCV patients who were nonresponders to interferon plus ribavirin therapy received oral placebo (group A) or anti‐CD3 MAb at one of three dosage levels for 30 days. Patients were followed for safety parameters and serum levels of liver enzymes, virus, cytokines and regulatory T cells. Results: Oral anti‐CD3 immunotherapy was safe and well tolerated; no treatment‐related adverse events were noted. The following improvements were noted relative to pretreatment levels: HCV viral load and AST and ALT levels decreased in the low‐ and high‐dose groups following 30 days of therapy. In two of the treated groups, an increase in regulatory T cells (CD4⁺ CD25⁺) was noted. The positive effects were somewhat more apparent in subjects with initially elevated liver enzyme levels. Conclusions: Oral anti‐CD3 MAb immunotherapy for nonresponder HCV patients was safe and well tolerated. Trends and statistically significant improvements were observed as reductions in viral load and liver enzyme levels, along with an increase in regulatory T‐cell levels. These data support a role for the immune system in the pathogenesis of HCV infection and suggest that this immunotherapy is worthy of evaluation in combination with HCV antiviral drugs.     

Improved liver transplant waitlist mortality and lower risk of disease progression among chronic hepatitis C patients awaiting liver transplantation after the introduction of direct‐acting antiviral therapies in the United States

Direct‐acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection achieve high cure rates, reducing HCV‐related disease progression to cirrhosis and hepatocellular carcinoma. We aim to evaluate the impact of DAAs on US liver transplant (LT) waitlist outcomes. We retrospectively evaluated US adults (age ≥18) with and without chronic HCV listed for LT before and after the widespread use of sofosbuvir, allowing a 6‐month period after approval (Era 1: 1/1/2002‐5/31/2014 vs Era 2: 6/1/2014‐12/31/2016) using the United Network for Organ Sharing registry. Overall, LT waitlist survival and likelihood of receiving LT were evaluated with multivariate Cox regression models. From 2002 to 2016, 158 045 patients were listed for LT. While the number of patients listed for HCV has been decreasing since 2012, the proportion of HCV patients with concurrent HCC is increasing by 3.33% per year (R²: 0.99, P < 0.001 by simple linear regression). While there was no difference in likelihood of LT between HCV and non‐HCV patients, those listed in Era 2 had lower likelihood of LT (HR: 0.91, P < 0.001), more pronounced in the HCV cohort (HR: 0.83, P < 0.001) compared to the non‐HCV cohort (HR: 0.93, P < 0.001). Compared to non‐HCV patients, higher waitlist mortality was seen in HCV patients in Era 1 (HR: 1.08, P < 0.001) but not in Era 2 (HR: 1.02, P = 0.75). Since the introduction of DAAs for HCV treatment, number of patients with HCV listed for LT has declined. In the post‐DAA era, HCV patients on the LT waitlist had improved waitlist mortality.     

HCV E1E2‐MF59 vaccine in chronic hepatitis C patients treated with PEG‐IFNα2a and Ribavirin: a randomized controlled trial

Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV‐specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy‐eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon‐(IFN)/ribavirin‐(RBV)] were randomly assigned to vaccine (V:23), Peg‐IFNα2a‐180‐ug/qw and ribavirin 1000–1200‐mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0‐4‐8‐12‐24‐28‐32‐36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2‐specific‐CD4 + T cells were performed at week 0‐12‐16‐48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and <0.001, respectively). Among the 22 patients with the strongest direct antiviral effects of IFN (ε ≥ 0.800), those treated with P/R + V (10) reached lower HCV‐RNA levels (P = 0.026) at week 16. HCV E1E2MF59 vaccine in combination with Peg‐IFNα2a + RBV was safe and elicited E1E2 neutralizing antibodies and specific CD4 + T cell proliferation. Upon early response to IFN, vaccinations were associated with an enhanced second phase viral load decline. These results prompt phase II trials in combination with new antiviral therapies.