Severe Hepatitis C Virus Research Articles

The Loss of a Great One.

The Loss of a Great One.

The Efficacy and Safety of Sofosbuvir/Daclatasvir Fixed-Dose Combination in Iranian Hemodialysis Patients with Hepatitis C Virus Infection

Background: Although several regimens have been approved for the treatment of hepatitis C virus (HCV) infection, sofosbuvir-based regimens are not approved for the treatment of HCV infection in patients with severe renal impairment. Methods: This study was conducted on hemodialysis patients infected with HCV. The patients received a constant dose of sofosbuvir/daclatasvir (SOF/DCV). Sustained virologic response (SVR) was evaluated 12 weeks after completion of treatment. Results: Fifty-one hemodialysis patients with HCV infection were selected and treated with a combination of SOF/DCV. Eleven patients expired during the anti-HCV treatment due to causes not related to liver disease or antiviral therapy. Finally, 40 patients finished the treatment, and 36 cases were evaluated for SVR. Among those tested for SVR, 35 (97.2%, 95% CI: 85.5 - 99.9%) achieved SVR and one (2.8%, 95% CI: 0.1 - 14.5%) relapsed. No patient reported severe adverse events. Conclusions: The combination of SOF/DCV showed great efficacy and safety in hemodialysis patients with severe renal impairment and chronic HCV infection.

Severe Hepatitis C Recurrence as a Risk Factor for Opportunistic Infections in Liver Transplant Recipients

ObjectiveThe aim of the study was to determine the clinical characteristics, frequency of opportunistic infections (OI), and the outcomes for liver transplant recipients with severe hepatitis C virus (HCV) recurrence. In addition, the objective was to evaluate HCV recurrence as a risk factor for developing an OI. MethodsWe conducted a retrospective observational study recording all liver transplant recipients from July 1, 2003, to December 31, 2012. Patients with liver disease due to HCV were selected. Active surveillance of infections was conducted periodically, and patients were classified according to presence of severe HCV recurrence. ResultsThree hundred seventy patients underwent liver transplantation because of chronic HCV. One hundred forty-seven patients presented severe recurrence (SR) (49%) and 50 (17%) of them had post–liver transplant cholestatic hepatitis C. Patients with SR presented OI, especially cytomegalovirus (CMV) infections and invasive fungal infections, more frequently than patients without SR (33% vs 13%; P < .001). From the diagnosis of SR to the presentation of OI, the median number of days was 169 (6–2083). Acute allograft rejection (OR 1.8 95% confidence interval [CI] 1.1–3.3) donor age ≥60 years (OR 2.9 95% CI 1.3–6.8), and SR (OR 2.8, 95% CI 1.6–5.1) were independently associated with the development of OI in liver transplant recipients. ConclusionA high index of suspicion of opportunistic infections must be maintained when faced with severe HCV recurrence in liver transplant recipients. Moreover, active surveillance against CMV infection and other prophylactic strategies against opportunistic infections should be considered.

Flavonoids from Pterogyne nitens Inhibit Hepatitis C Virus Entry

Hepatitis C virus (HCV) is one of the leading causes of liver diseases and transplantation worldwide. The current available therapy for HCV infection is based on interferon-α, ribavirin and the new direct-acting antivirals (DAAs), such as NS3 protease and NS5B polymerase inhibitors. However, the high costs of drug design, severe side effects and HCV resistance presented by the existing treatments demonstrate the need for developing more efficient anti-HCV agents. This study aimed to evaluate the antiviral effects of sorbifolin (1) and pedalitin (2), two flavonoids from Pterogyne nitens on the HCV replication cycle. These compounds were investigated for their anti-HCV activities using genotype 2a JFH-1 subgenomic replicons and infectious virus systems. Flavonoids 1 and 2 inhibited virus entry up to 45.0% and 78.7% respectively at non-cytotoxic concentrations. The mechanism of the flavonoid 2 block to virus entry was demonstrated to be by both the direct action on virus particles and the interference on the host cells. Alternatively, the flavonoid 1 activity was restricted to its virucidal effect. Additionally, no inhibitory effects on HCV replication and release were observed by treating cells with these flavonoids. These data are the first description of 1 and 2 possessing in vitro anti-HCV activity.

Direct-acting antivirals for hepatitis C virus in patients on maintenance dialysis.

The frequency of hepatitis C virus (HCV) infection remains high in patients with chronic kidney disease (CKD) and plays a detrimental role in mortality in this population. According to the latest survey, the adjusted hazard ratio for HCV-positive versus HCV-negative patients on long-term dialysis was 1.12 (95% CI, 1.05 to 1.20) and 1.10 (95% CI, 0.98 to 1.22) for all-cause and cardiovascular mortality, respectively. An impairment on quality of life has also been documented in HCV-infected patients undergoing regular dialysis. Most clinicians have been so far reluctant to treat hepatitis C in patients with advanced CKD, due to concerns regarding low efficacy and safety of interferon-based regimens. The advent of all-oral, direct-acting antivirals (DAAs) has revolutionized treatment paradigms for HCV, including patients with other comorbidities such as CKD. Two combinations of DAAs have been recently approved for the treatment of HCV in advanced CKD: elbasvir/grazoprevir (evaluated in 1 randomized controlled trial) and ombitasvir/paritaprevir/ritonavir/dasabuvir with or without ribavirin (examined in some observational, single-arm studies). These antiviral combinations have provided high safety and efficacy (SVR12 rates >90%) in HCV-infected patients with stage 4-5 CKD. Sofosbuvir, a nucleotide analogue inhibitor of the HCV NS5B polymerase, is the cornerstone of most anti-HCV current regimens but is not currently recommended for patients with severe renal insufficiency (eGFR <30 mL/min per 1.73 m2). However, several small-sized studies have been published on the safety and efficacy of sofosbuvir-based regimens for patients with hepatitis C on maintenance dialysis; overall, the viral response was satisfactory (SVR12 rates ranging between 58% and 100%) with a few drug-related drop-outs. Studies are in progress to assess whether ribavirin-free antiviral combinations with novel DAAs are a viable option for patients with severe renal impairment and chronic HCV infection.

Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

Mechanism of Hepatitis C Virus-Induced Diabetes Mellitus.

The hepatitis C virus (HCV), the most predominant cause of liver failure worldwide, is associated with the development of diabetes mellitus (DM) and insulin resistance (IR), both in vivo and in vitro. DM and IR aggravate the rate of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most studies have revealed that patients with HCV are at a greater risk of developing type 2 diabetes (T2D), compared with controls or patients with hepatitis B. In the same way, patients with T2D are highly prone to severe HCV clinical outcomes and increased progression to fibrosis and cirrhosis, ultimately leading to HCC. HCV interferes with the insulin-signaling pathway by modulating cellular gene expression such as up-regulation of inflammatory cytokine tumor necrosis factor-α, hypophosphorylation of insulin receptor substrate-1 and -2, phosphorylation of protein kinase B (Akt), up-regulation of gluconeogenic genes, accumulation of lipids, and targeting of lipid storage organelles. Owing to the pathological association between HCV and DM, the possibility of HCV eradication, resulting in reduced morbidity and mortality rate due to T2D, cannot be ruled out. HCV diabetes-associated IR can be targeted for HCV therapy. However, few such studies have revealed that IR minimizes (interferes with) the response rate of interferon/ribavirin treatment.

Early Acute Severe HCV Recurrence After Transplantation: From Universal Mortality to Cure

Acute severe recurrence of hepatitis C virus (HCV) after solid organ transplant is associated with high mortality. Pegylated interferon and ribavirin are suboptimal in treatment of this severe form of recurrence. We report 4 cases of acute severe HCV recurrence (within 6 months after transplant), including 3 cases with fibrosing cholestatic hepatitis treated with sofosbuvir and ribavirin. All four patients achieved a rapid suppression of HCV RNA with a normalization of liver function tests within 4 weeks of starting therapy. All patients were HCV RNA negative at 12 weeks after stopping therapy. The combination was found to be safe as anemia was the only adverse effect, which developed in 2 patients (1 patient required blood transfusion, while another managed with erythropoietin). Sofosbuvir and ribavirin appear to be safe and efficacious in treatment of acute severe HCV recurrence after organ transplant.

Early non-invasive selection of patients at high risk of severe hepatitis C recurrence after liver transplantation.

The early identification of patients at high risk of severe post liver transplant hepatitis C recurrence is relevant, as these patients may be treated using interferon (IFN)-free regimens. In a retrospective study with prospectively collected data, we investigated whether the use of several non-invasive methods (fibrosis 4 index [FIB-4], AST-to-platelets ratio index [APRI], enhanced liver fibrosis test [ELF], IFN-γ-inducible protein 10 [IP-10], and transient elastography by Fibroscan) and their combinations 6 months after transplantation could identify those recipients at higher risk of severe recurrence, defined by the presence of significant fibrosis (F ≥2) and/or portal hypertension (hepatic venous pressure gradient ≥6 mmHg) 12 months after transplant. Seventy-two hepatitis C virus (HCV)-infected liver transplant patients and 10 recipients in whom HCV was eradicated before transplantation were included in the study. The levels of all biomarkers were significantly higher in HCV-infected recipients than in controls. Among HCV recipients, levels of biomarkers were significantly higher in patients with severe recurrence. Although there were no statistically significant differences between biomarkers, APRI, ELF, and FIB-4 obtained the highest area under the ROC curve values. The combination of serum biomarkers with Fibroscan increased the negative and positive predictive values, although diagnostic accuracy of individual tests was not significantly improved. Patients at higher risk of severe HCV recurrence can be identified early, 6 months after transplantation, using readily available non-invasive methods.

Rapidity of fibrosis progression in liver transplant recipients with recurrent hepatitis C is influenced by toll-like receptor 3 polymorphism.

Liver transplantation activates the innate immune system through toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single-nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two-center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real-time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (-1237T/C and -1486C/T). The CC genotype of TLR3 Leu412Phe in liver recipients was associated with severe recurrence (odds ratio (OR) = 2.01, 95% confidence interval (95% CI) = 1.02-3.93, p = 0.04). We also analyzed this polymorphism in 72 of their donors but no association was found with severity of HCV recurrence (p = 0.89). Multivariate analysis showed donor age older than 40 yr (OR=2.93; 95% CI = 1.49-5.8, p = 0.002) and the TLR3 Leu412Phe CC genotype (OR=2.02, 95%CI=1.01-4.05, p = 0.046) were independently associated with severe HCV recurrence. Our results show that the TLR3 Leu412Phe CC genotype is independently associated with severity of hepatitis C recurrence after LT.

Increased hepatic progenitor cell response and ductular reaction in patients with severe recurrent HCV post-liver transplantation.

Post-liver transplant (LT) hepatitis C virus (HCV) patients may develop allograft cirrhosis and rarely fibrosing cholestatic hepatitis (FCH), while others have a stable course. Hepatic progenitor cells (HPC) may be implicated in liver injury and fibrogenesis through ductular reaction (DR). We studied HPC response and DR in three distinct post-LT patterns of HCV: stable recurrence, allograft cirrhosis, and FCH. We identified 52 patients with untreated recurrent HCV and longitudinal liver biopsies (20 stable/23 cirrhosis/9 FCH) and eight healthy controls. Archived liver biopsy specimens for three time points (LT; initial recurrence; and clinical outcome) were stained for cytokeratin-7. Manual HPC counts and DR quantification using image analysis were performed. HCV counts and DR at LT did not differ across groups. At initial recurrence, HPC expansion occurred only in patients who developed cirrhosis, while prominent DR was present in those who developed FCH vs. stable and controls (p < 0.05). At outcome biopsies, HPC response and DR were increased in cirrhosis and FCH vs. stable and controls (p < 0.05). HPC response and DR did not differ in stable vs. These findings suggest that an altered HPC response assessed by cytokeratin-7 stain after LT may predict severity of HCV recurrence.

Daclatasvir combined with sofosbuvir or simeprevir in liver transplant recipients with severe recurrent hepatitis C infection.

Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV-based all-oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years; 93% had genotype 1 HCV and 31% had biopsy-proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End-Stage Liver Disease (MELD) score was 13.0 ± 6.0, and the proportion with Child-Turcotte-Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3 × 6 log10 IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n = 77), DCV+SMV (n = 18), and DCV+SMV+SOF (n = 2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels <43 IU/mL. CTP and MELD scores significantly improved between DCV-based treatment initiation and last contact. Three virological breakthroughs and 2 relapses occurred in patients treated with DCV+SMV with or without RBV. None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy. In conclusion, DCV-based all-oral antiviral therapy was well tolerated and resulted in a high sustained virological response in LT recipients with severe recurrent HCV infection. Most treated patients experienced stabilization or improvement in their clinical status.

Impact of Cytomegalovirus Infection on Severe Hepatitis C Recurrence in Patients Undergoing Liver Transplantation.

The influence of cytomegalovirus (CMV) on recurrent hepatitis C virus (HCV) in liver grafts is controversial. Our aim was to investigate the association between CMV infection and disease and severe HCV recurrence (composite variable of presence of stage 3 to 4 fibrosis, need for retransplantation or death due to liver disease) in the first year after transplantation. An observational, prospective, multicenter study was performed. The CMV replication was monitored by determining CMV viral load weekly during hospitalization after transplantation, twice monthly in the first 3 months after discharge, and at each follow-up visit until month 12. Liver fibrosis was assessed histologically by liver biopsy or transient elastometry. Pretransplant, intraoperative, and posttransplant variables were recorded. Multiple logistic regression was performed to study the impact of CMV on severe HCV recurrence. Ninety-eight patients were included. The CMV infection was detected in 48 patients (49%) in the first year posttransplant, of which 11 patients (22.9%) had CMV disease. Twenty-three patients (23.5%) had severe HCV recurrence. Of these, 17 (73.9%) developed stage 3 to 4 fibrosis, 4 (17.4%) died, and 2 (8.7%) underwent retransplantation. Only 7 of 12 (58.3%) seronegative recipients of a seropositive donor (positive donor/negative recipient [D+/R-]) received universal prophylaxis, and 10 of 12 (83.3%) D+/R- patients developed CMV replication. In the multivariate analysis, the presence of CMV D+/R- serodiscordance (odds ratio, 6.87; 95% confidence interval, 1.89-24.99; P = 0.003), and detection of a higher peak HCV viral load (odds ratio, 3.85; 95% confidence interval, 1.49-9.94; P = 0.005) were associated with severe HCV recurrence. Our results support an association between CMV D+/R- serodiscordance and severe HCV recurrence in patients undergoing liver transplantation for HCV liver disease.

Liver Support With Albumin Dialysis Reduces Hepatitis C Virus Viremia and Facilitates Antiviral Treatment of Severe Hepatitis C Virus Recurrence After Liver Transplantation.

Patients with severe hepatitis C virus (HCV) recurrence after liver transplantation (LT) present an ominous prognosis, rarely achieving sustained virological response (SVR). Dialysis procedures may transiently decrease the HCV viral load, but the effect of albumin dialysis is currently unknown. Here, we evaluated the impact of albumin dialysis using the Molecular Adsorbent Recirculating System (MARS) used as a co-adjuvant antiviral treatment for severe HCV recurrence after LT. Thirteen patients (11 males, median age 48 years) with fibrosing cholestatic hepatitis or METAVIR fibrosis score ≥ F3 with severe portal hypertension underwent three consecutive MARS sessions. Antiviral therapy was initiated in 11 patients within 24 h after the MARS sessions. A contemporary cohort of seven patients who did not follow the MARS protocol is shown for comparison. MARS treatment resulted in consistent decreases of viral load from 7.59 log10 IU/mL [6.15-8.90] to 6.79 log10 IU/mL [5.18-7.84] (P = 0.003) as well as in decreases of serum bilirubin, gamma-glutamyl transpeptidase, alanine aminotransferase and aspartate aminotransferase (all P < 0.05). The overall rate of SVR was 0% in the Control group and 54.6% in patients initiating antiviral therapy within 24 h after MARS. Survival at 1 and 3 years was, respectively, 93% and 70% in patients undergoing MARS, compared with 29% and 14% in the Control group (P = 0.001). No major adverse events related to MARS treatment were observed. In conclusion, the use of MARS may facilitate the achievement of SVR and improve the prognosis of patients with severe HCV-recurrence after LT by reducing viral load and improving liver function prior to antiviral therapy.

Increased Risk of Intracerebral Hemorrhage Among Patients With Hepatitis C Virus Infection.

This research explored whether hepatitis C virus (HCV) infection leads to the development of intracerebral hemorrhage (ICH).Using Taiwan National Health Insurance claims data, 9023 patients newly diagnosed with HCV infection between 2000 and 2010 were identified, and 36,092 age- and sex-frequency-matched patients without HCV infection were selected randomly as the control group. The risk of ICH for patients with HCV infection and comorbidities of diabetes, hypertension, ischemic heart disease, hyperlipidemia, atrial fibrillation, alcoholic liver disorder, and head injury was evaluated at the end of 2011.The risk of ICH was higher in the HCV cohort than in the control group, with an adjusted hazard ratio (aHR) of 1.60 (95% confidence interval [CI]: 1.24–2.06), estimated using a multivariate Cox regression model. Age-specific analysis revealed that the risk of ICH in the HCV patients was higher in the younger groups, with aHRs of 1.92 (95% CI: 1.18–3.11) and 2.45 (95% CI: 1.52–3.98) in the ≤55 and 56 to 64 years age groups, respectively. The risk of ICH increased with the severity of HCV infection, from an aHR of 1.66 (95% CI: 1.21–2.30) in mild HCV patients to 2.12 (95% CI: 1.47–3.06) in severe HCV patients. For patients without comorbidities, the risk of ICH was 2.33 (95% CI: 1.36–3.98) higher in the HCV cohort than in the control group.We found that HCV infection is associated with an increased risk to develop ICH, particularly in the patients with relatively younger ages.

Multicenter Experience with Boceprevir or Telaprevir to Treat Hepatitis C Recurrence after Liver Transplantation: When Present Becomes Past, What Lessons for Future?

Background and aimsFirst generation protease inhibitors (PI) with peg-interferon (PEG-IFN) and ribavirin (RBV) have been the only therapy available for hepatitis C virus (HCV) genotype 1 infection in most countries for 3 years. We have investigated the efficacy and tolerance of this triple therapy in transplanted patients experiencing a recurrence of HCV infection on the liver graft.PatientsThis cohort study enrolled 81 liver transplant patients (Male: 76%, mean age: 55.8±9.7 years) with severe HCV recurrence (F3 or F4: n = 34 (42%), treatment experienced: n = 44 (54%)), treated with boceprevir (n = 36; 44%) or telaprevir (n = 45; 56%). We assessed the percentages of patients with sustained virological responses 24 weeks after therapy (SVR24), and safety.ResultsThe SVR24 rate was 47% (telaprevir: 42%; boceprevir: 53%, P = ns). At baseline, a normal bilirubin level (p = 0.0145) and albumin level >35g/L (p = 0.0372) and an initial RBV dosage of ≥800 mg/day (p = 0.0033) predicted SVR24. During treatment, achieving an early virological response after 12 weeks was the strongest independent factor to predict SVR24 (p<0.0001). A premature discontinuation of anti-HCV therapy due to a serious adverse event (SAE) was observed in 22 patients (27%). Hematological toxicity, infections and deaths were observed in 95%, 28% and 7% of patients, respectively. A history of post-LT antiviral therapy and thrombocytopenia (<50G/L) during treatment were both independent predictors of the occurrence of infections or SAE (p = 0.0169 and p = 0.011).ConclusionsThe use of first generation PI after liver transplantation enabled an SVR24 rate of 47% in genotype 1 patients, but induced a high rate of SAE. The identification of predictive factors for a response to treatment, and the occurrence of SAE, have enabled us to establish limits for the use of this anti-HCV therapy in the transplant setting.

Immunologic Predictors of Liver Transplantation Outcomes in HIV-HCV Co-Infected Persons.

Liver disease is a leading cause of mortality among HIV-infected persons in the highly active anti-retroviral therapy (HAART) era. Hepatitis C Virus (HCV) co-infection is prevalent in, and worsened by HIV; consequently many co-infected persons require liver transplantation (LT). Despite the need, post-LT outcomes are poor in co-infection. We examined predictors of outcomes post-LT. Immunologic biomarkers of immune activation, microbial translocation, and Th1/Th2 skewing were measured pre-LT in participants enrolled in a cohort of HIV infected persons requiring solid organ transplant (HIVTR). Predictive biomarkers were analyzed in Cox-proportional hazards models; multivariate models included known predictors of outcome and biomarkers from univariate analyses. Sixty-nine HIV-HCV co-infected persons with available pre-LT samples were tested: median (IQR) CD4+ T-cell count was 286 (210–429) cells mm-3; 6 (9%) had detectable HIV RNA. Median (IQR) follow-up was 2.1 (0.7–4.0) years, 29 (42%) people died, 35 (51%) had graft loss, 22 (32%) were treated for acute rejection, and 14 (20%) had severe recurrent HCV. In multivariate models, sCD14 levels were significantly lower in persons with graft loss post-LT (HR 0.10 [95%CI 0.02–0.68]). IL-10 levels were higher in persons with rejection (HR 2.10 [95%CI 1.01–4.34]). No markers predicted severe recurrent HCV. Monocyte activation pre-LT may be mechanistically linked to graft health in HIV-HCV co-infection.

Costs and absence of HCV-infected employees by disease stage

Objectives:Quantify the costs and absenteeism associated with stages of the Hepatitis C virus (HCV).Study design:Retrospective analysis of the HCMS integrated database from multiple geographically diverse, US-based employers with employee information on medical, prescription, and absenteeism claims.Methods:Employee data were extracted from July 2001–March 2013. Employees with HCV were identified by ICD-9-CM codes and classified into disease severity cohorts using diagnosis/procedure codes assigning the first date of most severe claim as the index date. Non-HCV employees (controls) were assigned random index dates. Inclusion required 6-month pre-/post-index eligibility. Medical, prescription, and absenteeism cost and time were analyzed using two-part regression (logistic/generalized linear) models, controlling for potentially confounding factors. Costs were inflation adjusted to September 2013.Results:All direct costs comparisons were statistically significant (p ≤ 0.05) with mean medical costs of $1813 [SE = $3] for controls (n = 727,588), $4611 [SE = $211] for non-cirrhotic (n = 1007), $4646 [SE = $721] for compensated cirrhosis (CC, n = 87), $12,384 [SE = $1122] for decompensated cirrhosis (DCC, n = 256), $33,494 [SE = $11,753] for hepatocellular carcinoma (HCC, n = 17) and $97,724 [SE = $32,437] for liver transplant (LT, n = 19) cohorts. Mean short-term disability days/costs were significantly greater for the non-cirrhotic (days = 2.03 [SE = 0.36]; $299 [SE = $53]), DCC (days = 6.20 [SE = 1.36]; $763 [SE = $169]), and LT cohorts (days = 21.98 [SE = 8.21]; $2537 [SE = $972]) compared to controls (days = 1.19 [SE = 0.01]; $155 [SE = $1]). Mean sick leave costs were significantly greater for non-cirrhotic ($373 [SE = $22]) and DCC ($460 [SE = $54]) compared to controls ($327 [SE = $1]).Conclusions:Employees with HCV were shown to have greater direct and indirect costs compared to non-HCV employee controls. Costs progressively increased in the more severe HCV disease categories. Slowing or preventing disease progression may avert the costs of more severe liver disease stages and enable employees with HCV to continue as productive members of the workforce.

Recipient female gender is a risk factor for graft loss after liver transplantation for chronic hepatitis C: Evidence from the prospective Liver Match cohort

BackgroundFemale gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. AimsTo investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. MethodsWe performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. ResultsFive-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03–2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03–1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20–4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05–1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. Conclusions. This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts.

Therapy with boceprevir or telaprevir in HIV/hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation.

Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation. All patients had severe HCV recurrence [fibrosis stage ≥F2 or acute hepatitis ≥A2 (n = 5) or fibrosing cholestatic hepatitis (n = 2)] associated with genotype 1a (n = 4) or 1b (n = 3). Patients were treated with Peg-interferon/ribavirin and boceprevir (n = 2) or telaprevir (n = 5) immediately (n = 3) or after a 4-week lead-in phase (n = 4). Immunosuppression included either cyclosporine (n = 5) or tacrolimus (n = 2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug-drug interactions. At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (n = 2), infection (n = 2), acute rejection (n = 1) and myocardial infarction (n = 1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients.Average cyclosporine doses were reduced by 50-84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir. Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug-drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy.