Completion Of Antiviral Therapy Research Articles

Lymphocyte counts predict optimal timing of chemotherapy reinitiation after antivirus treatment for herpes zoster in children with leukemia.

Herpes zoster (HZ) is rare in healthy children, but more prevalent in those with leukemia. Optimal timing of chemotherapy reinitiation after HZ treatment is challenging because chemotherapy suppresses immunity and increases risk of HZ relapse. We aimed to optimize the timing of chemotherapy reinitiation after HZ therapy in children with leukemia. The study included 31 children with acute leukemia and HZ infection. General information, clinical symptoms, laboratory test results, duration of HZ treatment, and prognosis were compared with those of children with leukemia alone. Correlation analysis was performed for 20 children who restarted chemotherapy after HZ treatment. Of 31 children with leukemia and HZ, 67.74% had lesions at multiple sites. The median time from chemotherapy initiation to HZ onset was 14.1 (1.5-29.5) months. Among 27 children included in the follow-up, there was one case of HZ relapse. After excluding children who did not continue chemotherapy after HZ treatment, the median interval between completion of HZ therapy and chemotherapy reinitiation in the remaining 20 children was 8.00 (-3 to 27) days. Lymphocyte counts (LY#) on restarting chemotherapy correlated inversely with HZ lesion healing time (p < 0.05). LY# at the time of HZ onset were lower than those pre- and post-onset, and lower than those in the control group (p < 0.05). In conclusion, children with leukemia have a good HZ prognosis, but an increased risk of HZ recurrence. LY# at the time of chemotherapy reinitiation may be a useful indicator for selecting the optimal interval between antiviral therapy completion and chemotherapy reinitiation.

The Fixed Dose Combination of Sofosbuvir and Velpatasvir is Safe and Effective in Patients of Chronic Hepatitis C With End-stage Renal Disease

The burden of hepatitis C virus (HCV) in India is alarming, with a major share of this virus being witnessed in patients with end-stage renal disease (ESRD). A pan-genotypic combination of sofosbuvir and velpatasvir is found to be safe, effective, and economical in resource-constraint countries such as ours. However, there are scanty data on the efficacy and safety of sofosbuvir and velpatasvir combination in patients with ESRD. Hence, we performed this study to evaluate the safety and efficacy of the combination of sofosbuvir and velpatasvir in patients of chronic hepatitis C (CHC) with ESRD. This is an observational study comprising of 40 CHC patients with ESRD on maintenance hemodialysis. All patients were treated with a fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks in case of non-cirrhotic or compensated cirrhosis and 24 weeks in case of decompensated cirrhosis. The efficacy was assessed by sustained virological response defined by negative HCV RNA at 12 weeks (sustained virological response [SVR] 12) post treatment, and safety was assessed by recording any side-effects of all patients. Out of the 40 patients enrolled in our study, majority were non-cirrhotic (77%), and all were treatment-naive. The mean age was 49.87±12.13 years, and 80% patients were male. The mean baseline HCV RNA was 2.61±7.83×106 IU/ml. All the 40 patients (100%) achieved undetectable HCV RNA at the end of treatment; however, 39 patients (97.5%) achieved SVR 12. There was no significant deterioration of estimated glomerular filtration rate (eGFR) after completion of antiviral therapy as compared to the baseline eGFR (13.27±10.32 vs13.54±11.38, P= 0.54). None of the patients reported any serious adverse effects during treatment. The fixed-dose combination of sofosbuvir and velpatasvir is effective and has showed excellent safety profile in patients of CHC with ESRD.

DYNAMICS IN MAIN CLINICAL AND IMMUNOLOGICAL INDICATORS IN PATIENTS WITH COMORBIDITY OF CHRONIC HEPATITIS C AND CHRONIC PANCREATITIS FOLLOWING INTEGRATED THERAPY INCLUDING VITAMIN D

The aim of this study is to evaluate the impact of integrated therapy including vitamin D on the clinical and immunological parameters of patients with chronic hepatitis C combined with chronic pancreatitis.&#x0D; Materials and methods. 52 patients with chronic hepatitis C and chronic pancreatitis with exocrine pancreatic insufficiency who had an insufficient level of vitamin D were under observation. They were divided into 2 groups depending on the treatment prescribed. All patients received antiviral therapy and sofosbuvir 400 mg + daclatasvir 60 mg once a day for 12 weeks and rabeprazole 20 mg once a day for a month. Depending on the scheme of taking enzyme preparations and vitamin D, all patients were divided into 2 groups. Group 1 (n=24) received Creon 25,000 according to the scheme and vitamin D 4,000 IU/day for 12 weeks of antiviral therapy and 12 weeks after the completion of antiviral therapy. Group 2 (n=28) took only Creon 10,000 according to the scheme. Analysis of findings obtained and their processing were carried out in Jamovi 2.3.2.1, Microsoft Office Excel for Windows 2016 programs using the Mann-Whitney, Wilcoxon U-test. The difference was considered statistically significant at p&lt;0.05.&#x0D; Results: The administration of complex therapy, supplemented with vitamin D, resulted in a 100% achievement of sustained virological response (SVR) in patients belonging to group 1, while group 2 exhibited an SVR rate of 82.1%. It has been found out the treatment in group 1 demonstrated a significantly more pronounced reduction in ALT, AST, and total bilirubin levels compared to group 2. Furthermore, patients in group 1 exhibited more substantial changes in the cytokine profile, including a decrease in the levels of IL-6, TNF-б, neopterin, IL-4, IL-10, and TGF-в. Three months after the completion of antiviral therapy, the average FE-1 level in group 1 normalized, whereas in group 2, it only displayed a tendency toward normalization.&#x0D; Conclusion: The integration of a polyenzyme drug with minimal lipase activity (25,000 units) and vitamin D (4,000 IU/day) into the therapy for patients with comorbidity of chronic hepatitis C and chronic pancreatitis enhances the efficacy of antiviral therapy. This combination facilitates the rapid normalization of ALT, AST, and total bilirubin, mitigates cytokine imbalances, and improves exocrine pancreas function.

Treatment of chronic hepatitis C virus infection to increase access to cancer clinical trials in patients with hematologic malignancies: A prospective observational study.

3142 Background: Most cancer patients with chronic hepatitis C virus (HCV) infection are excluded from cancer clinical trials (CCTs). The use of direct-acting antivirals (DAAs) to eradicate HCV and allow access to CCTs in HCV-infected cancer patients has not been studied. We aimed to evaluate the efficacy and safety of DAA treatment to increase access to CCTs in patients with chronic HCV infection and hematologic malignancies (HM). Methods: HCV-infected patients with HM seen at MD Anderson Cancer Center between 01/01/2016 and 01/31/2023 were enrolled in a prospective observational study. Those initially excluded from CCTs and then treated with DAAs to allow that cancer treatment were further analyzed (cases). HCV-infected cancer patients treated with DAAs but never enrolled in CCTs were used as controls. The 1:1 matching between cases and controls was based on the cancer type and stage, history of &gt; 3 types of chemotherapy, and presence of cirrhosis. The primary outcomes were the efficacy and safety of DAAs. The secondary outcomes were overall survival (OS) and progression-free survival (PFS). Results: Twenty-four patients with HM initially excluded from CCTs because of HCV were enrolled. Twelve of them (50%) received DAAs to have access to CCTs and they were matched to 12 controls. Most of the cases were men (10; 83%), white (6; 50%), non-cirrhotic (10; 83%), and with HCV genotype 1 (9; 75%). Most patients in the control group were men (7; 58%), white (9; 75%), non-cirrhotic (8; 67%), and with HCV genotype 1 (9; 75%). Among the entire study group, adverse events occurred in 6 of the 24 patients (25%), and all were grade 1-2. No HCV-associated liver failure or death occurred. The overall sustained virologic response (microbiologic cure) after completion of antiviral therapy was 92%. Median OS was 74 months in the cases vs 52 months in the controls, median PFS was 30 months in the cases vs 33 months in the controls. When compared to controls in multivariate analysis, cases had significantly better OS (hazard ratio = 0.23, 95% CI = 0.06 to 0.85, p = 0.027). No significant differences were noted in PFS (p=0.13). Death due to progressive HM occurred in all 12 controls (100%) but only in 4 cases (33%) (p=0.001). Conclusions: DAA treatment increases access to CCTs and improves OS in patients with chronic HCV infection and HM. HCV infection should not be considered a contraindication to investigational cancer treatment. The use of DAAs to facilitate access CCTs could become one of the most common indications for DAAs in HCV-infected cancer patients.

Molnupiravir for Treatment of COVID-19 in Solid Organ Transplant Recipients.

Solid organ transplant recipients (SOTRs) are at a higher risk of progression of coronavirus disease 2019 (COVID-19).1,2 With the emergence of new viral-variants, the currently available antisevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies are losing their efficacy.3 Outpatient treatment of COVID-19 in SOTRs is limited by complicated logistics of administration of Remdesivir and drug–drug interactions with Nirmatrelvir/ritonavir. Molnupiravir acts as a substrate for SARS-CoV-2 RNA polymerase and impairs SARS-CoV-2 replication and infection.4 It retains antiviral activity against all known variants of SARS-CoV-2.3 In a recent clinical trial, patients treated with molnupiravir resulted in faster time to recovery and reduced viral detection and load.5 We present our data regarding the characteristics and outcomes of adult SOTRs with mild-to-moderate COVID-19 who were treated with oral dosage of 800 mg of molnupiravir twice a day for 5 d during the period from June 2022 to October 2022 and with at least 14 d of follow-up. During the study period, 98 SOTRs were diagnosed with COVID-19 in our institution. They received Bebtelovimab 54 (55%), molnupiravir 23 (23%), and no treatment for asymptomatic illness 21 (21%). Among 23 patients who received molnupiravir, they were at a mean of 5.5 y (range, 0.3–17.2) away from the transplant, with median duration of symptoms of 1.9 d (range, 1–4) and had variable vaccination status. Seven patients (30%) had received Tixagevimab/Cilgavimab, given at a mean of 170 d (range, 82–256) before the current diagnosis of COVID-19. Nine (39%) had a remote history of previous COVID-19. Eleven (48%) patients were on Tacrolimus monotherapy, and in the rest 12 (52%), mycophenolate was stopped for duration of COVID-19 symptoms. Considerations for use of molnupirivir were inability/unwilling to be scheduled for SARS-CoV-2 monoclonal antibodies infusion, 3 (13%); prior use of Tixagevimab/Cilgavimab prophylaxis, 7 (30%) and more recently starting October 2022; and less predictable activity of Bebtelovimab, 13 (57%) (Table 1). Pregnancy status of all women in childbearing age was reviewed before prescribing molnupiravir, and all recipients were advised on the use of barrier contraception. TABLE 1. - Characteristics and outcomes of solid organ transplant recipients treated with molnupiravir (N = 23) Age, mean (range), y 60 (41–73) Male sex, N (%) 13 (56%) Race Caucasian 14 (61%) African American 5 (22%) Hispanic 2 (8.6%) Asian 2 (8.6%) Type of organ transplant, N (%) Kidney 9 (39%) Heart 6 (26%) Liver-kidney 4(17%) Liver 3(13%) Heart-kidney 1 (4%) Time from transplant, mean (range), y 5.5 (0.3–17.2) Duration of symptoms before treatment, mean (range), d 1.9 (1–4) COVID-19 vaccination status, N (%) Unvaccinated 2 (8.7%) 1- 1-dose 1 (4%) 2- 2-doses 10 (43%) 3- 3-doses 9 (39%) Induction immunosuppression T-cell depletion 14 (61%) Steroids 7 (30%) Basiliximab 2 (8.6%) Lowered/stopped mycophenolate 12/12 (100) of eligible patients Follow-up period, mean (range), d 69 (15–178) Resolution of acute symptoms excluding cough, mean (range), d 3.6 (3–7) Progression of COVID-19 symptoms, N (%) 0 (0%) Hospitalizations not related to COVID-19 within 14 d of treatment, N (%) 1 (4%) arm swelling Associated graft rejection/dysfunction during the follow-up period, N (%) 0 (0%) Need for intensive care, N (%) 0 (0%) Death during at least 14-d follow-up, N (%) 0 (0%) Rebound of COVID-19 symptoms 0 (0%) COVID-19, coronavirus disease 2019. During the mean follow-up period of 69 d (range, 16–178), none of the patients reported progression of symptoms, and 1 patient (4%) was hospitalized for non-COVID illness. Molnupiravir was tolerated in all the patients with none of the recipients requiring discontinuation of therapy secondary to intolerance. No rebound COVID-19 symptoms were noted. No episodes of organ rejection associated with alteration of immunosuppression and COVID-19 were noted after completion of antiviral therapy during the study period. These acceptable outcomes are likely associated with very early initiation of antiviral therapy, overall lower immune suppression in setting of time away from transplant, and no recent treatment of allograft rejection, along with previous variable natural and acquired immunity. Limitations of our retrospective results include no comparator arm, diversity of patient population, and a small sample size. Although there is a chance these patients may have improved without any therapeutic intervention, but based on the unknown risk of progression and associated morbidity, all symptomatic SOTRs with COVID-19 are currently offered treatment along with optimization of immunosuppression. In the current setting of uncertain and limited choices, when initiated early in the disease course, molnupiravir may offer a safe and efficacious therapeutic option for the treatment of mild-to-moderate COVID-19 in certain SOTRs. To attain desired outcomes in the outpatient management of COVID-19, transplant centers should devise mechanisms for early diagnosis, prompt treatment, and mitigation strategies to provide equitable access to treatment for all transplant recipients.

Persistent cryoglobulinemia after antiviral treatment is associated with advanced fibrosis in chronic hepatitis C patients.

BackgroundHigh dosage and longer duration of antiviral treatment has been suggested to treat cryoglobulinemia patients. We aimed to investigate the efficacy of antiviral treatment in cryoglobulinemia patients and analyze the associated factors of persistent cryoglobulinemia.MethodsTotally 148 patients after completion of anti-HCV treatment were enrolled in our study. Serum cryoglobulinemia precipitation was assessed and analyzed for the associated factors after antiviral therapy.ResultsFifty-one (34.5%) out of 148 patients were positive for serum cryoglobulinemia after completion of antiviral therapy. In multivariate analysis, advanced fibrosis (Odds Ratio [OR]– 4.13, 95% Confidence Interval [95% CI]– 1.53–11.17, p = 0.005) and platelet counts (OR-0.98, 95% CI– 0.97–0.99, p = 0.010) were independently and significantly associated with persistent cryoglobulinemia. The factors associated with the persistent cryoglobulinemia in SVR patients were advanced fibrosis (OR-1.93, 95% CI– 1.02–3.65, p = 0.041) and platelet count (OR-0.98, 95% CI– 0.96–0.99, p = 0.041) by multivariate analysis. Multivariate logistic regression analysis showed persistent (OR-4.83, 95% CI– 1.75–13.36, p = 0.002) was significantly associated with advanced fibrosis in patients with cryoglobulinemia follow up after antiviral therapy.ConclusionsThe prevalence of the persistent cryoglobulinemia is 34.5% after completing antiviral therapy and it is associated with advanced fibrosis, also HCV clearance.

Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication.

BACKGROUNDChronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.AIMTo investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.METHODSOne hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.RESULTSHCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively.CONCLUSIONDownregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.

Weight Gain after Interferon-Free Treatment of Chronic Hepatitis C-Results from the German Hepatitis C-Registry (DHC-R).

Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (−0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.

Effect of Sofosbuvir based antiviral treatment for eradication of hepatitis C virus on clinical and laboratory parameters of HCV cirrhosis patients.

HCV infects nearly 10 million patients in Pakistan, genotype 3 is the predominant genotype. Liver transplant used to be the only option in patients with decompensated cirrhosis before the emerging role of DAAs. Clinical trials have suggested that successful treatment of HCV in this group results in early improvement in liver function although long term benefit is not yet known. Objectives: To measure clinical and laboratory parameter improvement after successful eradication of hepatitis C in cirrhotics. To study any events of decompensation while on treatment. To measure incidence of HCC on/after treatment. Study Design: A retrospective, observational study. Setting: Fatima Memorial Hospital, Lahore. Period: July 2015-April 2017. Material &amp; Methods: We included patients with compensated and decompensated cirrhosis with a CTP score ranging from A5 to C12, treated with sofosbuvir and ribavirin or pegylated interferon sofosbuvir and ribavirin. Data analyzed at the initiation, at the end, 12 weeks and 24 weeks post treatment. Results: A total of 191 (98 male and 93 female) patients were included in our study. There was statistically significant improvement in albumin, bilirubin, AFP, platelet count, CTP and MELD scores but not in INR. One patient developed ascites and another developed hepatic encephalopathy. Four patients developed HCC during follow up after completion of antiviral therapy. Conclusions: 1) Successful treatment of cirrhotic patients leads to improvement in clinical and laboratory parameters. 2) Need for continued surveillance for HCC in patients with cirrhosis remains after successful antiviral treatment.

Long-Term Results of the Etiotropic Therapy of Subcompensed Liver Cirrhosis in the Outcome of Chronic Hepatitis C

Aim . The evaluation of long-term results of antiviral therapy (AVT) with ombitasvir/paritaprevir/ritonavir and dasabuvir in patients with noncompensated liver cirrhosis (LC) in the outcome of chronic hepatitis C. Material and methods . A retrospective analysis included the data from patients with subcompensated liver cirrhosis (LC) of HCV etiology (genotype 1b) (7–9 points of the Child-Pugh score) having received interferon-free antiviral therapy (AVT) with ombitasvir/paritaprevir/ritonavir and dasabuvir during 12 weeks from September to December 2015. In total, 66 patients (27 men and 39 women) received such a therapy, the median age was 56.4 years. Results. 147 weeks (IQR 56–156) following AVT completion, the long-term results were evaluated. At that time, 27 patients were available for observation. The assessment of liver function compensation using the Child-Pugh score showed improvement in 25 (93 %) patients. The assessment of laboratory data revealed a decrease in the median of total bilirubin by 13.6 μmol/l, as well as an increase in the median of serum albumin by 9.7 g/L and the median of platelets by 41,700/μl. Two deaths were reported due to hepatocellular cancer (HCC) and bleeding from esophageal varices. HCC was detected in 8 patients. Two patients underwent liver transplantation. Conclusion . AVT in patients with LC of HCV etiology is associated with a high frequency of virologic response. Longterm follow-up results indicate a significant improvement of liver function, but also a continuing high risk of developing complications of underlying disease, primarily HCC.

Atorvastatin in Combination with Pegylated Interferon and Ribavirin Provided High Rate of Sustained Virological Response in Patients with Genotype 3 Hepatitis C Virus

BACKGROUND:Chronic hepatitis C virus infection represents a more frequent cause of liver cirrhosis and hepatocellular carcinoma. Statins, inhibit HCV replication in vitro, enhance the antiviral effect of the already known antiviral drugs and reduce their resistance.AIM:To determine the impact of additional therapy (treatment with Atorvastatin 20 mg) to the standard antiviral therapy (pegylated interferon alpha-peg-IFN α and ribavirin) on achieving sustained virological response (SVR).MATERIAL AND METHODS:In the study which is comparative, open-label, prospective-retrospective, 70 patients diagnosed with chronic hepatitis C virus infection who met criteria for treatment with standard antiviral therapy combined with anti-lipemic therapy (Atorvastatin 20 mg) were included. Patients in the study were divided into two groups: one group of 35 patients receiving combination therapy (Atorvastatin + peg-IFN α + Ribavirin) and another group of 35 patients received only standard antiviral therapy. Those parameters were followed in all patients: genotyping, quantification of the virus, histological assessment of liver inflammation and fibrosis degree (before starting treatment), the presence of steatosis, laboratory analysis: hematology, liver, lipid and carbohydrate status, insulin blood level (the calculation of HOMA-IR) and body mass index (BMI) calculation. The overall treatment of the patients depends from the virus genotype, thus, patients with genotype 1 and 4 received 48 weeks standard antiviral therapy, but patients with genotypes 2 and 3 received 24 weeks of antiviral therapy. SVR was considered an undetectable level of HCV RNA levels 24 weeks after completion of antiviral therapy. The results were statistically analysed, and all results for p < 0.05 were considered statistically significant.RESULTS:Combination therapy leads to a slightly higher percentage of SVR (85.71%) in patients with chronic hepatitis C versus standard therapy (74.29%), but in a group of patients with genotype 3 this rate of SVR amounting to 95.83%. Combination therapy leads to significant improvement of lipid and glucose status after treatment, and in terms of side effects, there was no appearance of serious adverse events that would be a reason for discontinuation of the therapy.CONCLUSION:Combination therapy Atorvastatin + pegylated interferon alpha + Ribavirin leads to high rate of SVR of 95.83% in patients with chronic hepatitis C, genotype 3. Statins can be used safely in patients with chronic hepatitis C.

Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients

BackgroundHearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection.MethodsWe conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir–velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation.ResultsA total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders.ConclusionsIn patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.)

Does interferon-free direct-acting antiviral therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC? A multicenter study by the Japanese Red Cross Hospital Liver Study Group.

Background and aimThis study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort.MethodsThis multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively.ResultsAFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients.ConclusionsThere were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.

The use of sofosbuvir for the treatment of recurrent hepatitis C after liver transplantation

The article presents the experience of direct-acting antiviral (DAA) drug treatment for hepatitis C in the patients after liver transplantation. The end-stage liver disease caused by hepatitis C is the main indication for orthotopic liver transplantation (OLT). In 2013, the first agent in the class of antiviral drugs directly acting on hepatitis C virus (HCV) was introduced into clinical practice. That was sofosbuvir, a HCV polymerase inhibitor, that could be used without interferon alfa. Materials and methods . The study enrolled 33 liver transplant recipients with recurrent hepatitis C. Thirty-five courses of antiviral therapy (AT) were conducted with sofosbuvir being one of AT components. Results. By the time of analysis, 21 patients had completed the antiviral therapy. All the patients showed an initial response to the antiviral therapy, HCV aviremia was achieved. In 3 patients, with the evaluable sustained virologic response (SVR), a renewed HCV replication was observed in the first weeks after the AT completion. Conclusion. The new direct-acting antiviral drugs offer an effective antiviral therapy to all liver graft recipients with recurrent HCV.

Sustained Viral Response May Halt the Progression of Hepatic Fibrosis in Patients with Recurrent Hepatitis C Infection after Liver Transplant

Introduction: Sustained viral response (SVR) can be achieved in a significant proportion of patients with recurrent hepatitis C virus (HCV) infection following orthotopic liver transplantation (OLT). However, the impact of SVR on regression/progression of hepatic fibrosis post-OLT is controversial. Our aim was to study the impact of SVR on regression versus progression of hepatic fibrosis in patients with recurrent HCV post-OLT. Methods: We used the retrospective liver biopsy database of all OLTs performed at Cleveland Clinic for only HCV-related liver disease between Jan 2009 and Dec 2014. Post OLT patients with at least one liver biopsy before and one after HCV treatment were included. Batts and Ludwig scoring system was used for staging and grading of the liver biopsies. SVR was defined as undetectable HCV RNA 12 weeks after completion of anti-viral therapy. Multivariable analysis was used to assess the impact of SVR on the regression versus progression of hepatic fibrosis. Results: 189 consecutive patients (21% female; average age of 54 ± 9 years) underwent OLT due to only HCV-associated liver disease. Median follow-up post-OLT was 3 years. To the date of this study, 177 patients (63%) received HCV treatment after liver transplant. 134 patients (75%) achieved SVR; data was not available for 25 patients (14%). Among all patients who received HCV treatment, 53 patients (30%) had at least one liver biopsy before the initiation of treatment and one liver biopsy after achieving SVR. Genotype 1a &1b were the most common genotype (85%), followed by genotype 2a & 2b (8%) and other genotypes (7%). Mean baseline viral RNA was 7.84 ± 9.19 million IU/ml prior to treatment. After achieving SVR, there was an improvement in stage of fibrosis in pre and post treatment biopsies (mean stage of 0.8 vs. 1.2; P value 0.004), also there was an improvement in the grade of inflammation (mean grade of 1.3 vs. 1.9; P value 0.001). Age was a significant predictor of improvement in stage of fibrosis after achieving SVR, with older patients having a 14% lower chance of experiencing improvement in their fibrosis stage for each one year increase in their age (OR=0.86; P value=0.036) Conclusion: This study suggests that achieving SVR may have an impact on the regression of hepatic fibrosis post-liver transplantation; however this impact was not seen in all the patients.Figure 1Figure 2

Recurrence of Hepatocellular Carcinoma Following Eradication of Hepatitis C Infection

Introduction: With the widespread use of novel, well-tolerated, and effective therapeutic modalities for the treatment of Hepatitis C (HCV), concern has been raised regarding the recurrence of hepatocellular carcinoma (HCC) after completion of antiviral therapy. In our experience treating HCV infected patients with direct-acting antivirals (DAA), among some of those with a history of HCC, we observed a relapse of the malignancy after DAA therapy. However, there is no substantial data available on the rate of recurrence amongst this population of patients. We aim to compare demographic and clinical characteristics of HCC patients treated for HCV who subsequently developed recurrence of HCC as compared to those who remain in clinical remission.Table 1: Clinical characteristics between those patients with recurrence and non recurrenceTable 2: Treatment modalities used for treatment of HCC in both groups.Methods: We conducted a retrospective analysis on a cohort of patients treated with DAAs within our hospital network. Those with active hepatitis C as well as hepatocellular carcinoma who remained without evidence of active malignancy for approximately one year were included in the study. Those who had evidence of relapse of HCC after therapy were compared to those who remained disease free. We used descriptive statistics to compare the two groups. Continuous variables were analyzed using measures of central tendencies and dispersion. We used frequency of distributions to interpret categorical variables. Results: Of the 10 HCC patients treated for HCV who were in remission prior to initiation of therapy, four patients were found to have recurrence and six patients did not have recurrence of their HCC. Those with recurrence tended to be younger with a higher post treatment AFP level. Patients were treated with either ledipasvir+sofosbuvir, ledipasvir+sofosbuvir+ribavirin or sofosbuvir+simeprevir+ribavirin. One patient was treated for eight weeks, eight patients were treated for 12 weeks and one patient was treated for 24 weeks. 75% had Barcelona stage A disease at relapse. Recurrence of HCC occurred as early as 41 days after completion of therapy (range 41-186 days). Conclusion: Our preliminary results suggest a 40% recurrence rate of HCC amongst those treated with DAA therapy, with relapse occurring as early as 41 days after eradication of the virus. HCC relapse was associated with higher AFP levels and younger age. However, additional studies are needed to confirm our findings and to further characterize the implication of eradication of hepatitis C in HCC and the underlying pathogenic mechanisms involved.

IMPACT OF ANTIVIRAL THERAPY FOR CHRONIC HEPATITIS C ON CYTOKINE SYNTHESIS AND HEPATIC FIBROSING PROCESSES

Objective: to estimate the time course of changes in the levels of tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, and the hepatic fibrosis indicators hyaluronic acid (HA) and liver elasticity index during combined antiviral therapy (AVT) with interferon alpha-2b and ribavirin in patients with chronic hepatitis C (CHC). Subjects and methods. Fifty patients with CHC were examined. Serum TNF-α, IL-6, IL-4, and HA were estimated using an enzyme immunoassay. The stage of hepatic fibrosis was determined by fibroelastography with the liver elastic index being measured; the time course of changes in the indicators was assessed in 20 patients at the end of AVT. A virological response was monitored at therapy completion and 6 months later. Results. The patients with CHC in the reactivation phase were found to have enhanced TNF-α, IL-6, and IL-4 activities in 84, 60, and 100 % of the cases, respectively (р < 0.001, р = 0.01, р < 0.001, respectively). The median serum concentration of HA in CHC was 1.8-fold higher than that in the control group (p = 0.03); the liver elastic index averaged 6.5 kPa. TNF-α and IL-6 levels correlated with viremia, transaminases, and hepatic fibrosis indicators. At combined AVT completion, the virological response rate was as high as 85 %, which was attended by a considerable reduction in cytolysis, HA concentrations, and liver density index to 5.4 kPa (3.6–6.8 kPa) (p < 0.04), and in the activity of the examined cytokines. The sustained virological response rate was 80 %. Only IL-4 levels decreased and TNF-α and IL-6 concentration remained at the baseline level in patients unresponsive to AVT. Conclusion. It is expedient to monitor TNF-α, IL-4, IL-6, and HA to evaluate the severity of liver involvement in CHC and to predict the efficiency of AVT.

Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients.

Recurrent hepatitis C virus (HCV) infection occurs universally in the allograft in the absence of effective antiviral therapy before liver transplantation (LT). Antiviral therapy with sofosbuvir and simeprevir has proven to be highly effective and well tolerated in the nontransplant setting for treatment of HCV genotype 1 infection; therefore, we sought to evaluate the efficacy and safety of this regimen in LT recipients with recurrent HCV infection. This was a retrospective analysis of a single-center treatment protocol of patients with HCV genotype 1 infection who received a 12-week combination regimen of sofosbuvir and simeprevir. Sixty-one patients (35 with genotype 1a and 26 with genotype 1b) completed treatment with simeprevir and sofosbuvir. Three patients received additional ribavirin. Laboratory data and clinical assessments performed at the baseline, on treatment, at the end of treatment, and 12 weeks after the completion of antiviral therapy [sustained virological response at 12 weeks (SVR12)] were analyzed. The median time after LT was 5.4 years [interquartile range (IQR), 1.9-8.4 years], and tacrolimus was the most commonly used immunosuppressive agent (80.3%). Overall, SVR12 was achieved in 93.4% [95% confidence interval (CI), 84%-97%] of LT recipients treated with 12 weeks of sofosbuvir and simeprevir. When they were analyzed according to the HCV subtype, LT recipients with genotype 1b had a 100% SVR12 rate (95% CI, 87%-100%), whereas SVR12 was 89% (95% CI, 74%-95%) for those with genotype 1a. Advanced fibrosis (METAVIR F3-F4) was associated with diminished antiviral efficacy in LT recipients with genotype 1a [SVR12, 67% (95% CI, 39%-86%); P = 0.01]. Overall, the incidence of adverse events (AEs) was low, and no severe AEs occurred during treatment. In conclusion, treatment with a 12-week regimen of sofosbuvir and simeprevir was well tolerated and resulted in a high SVR12 rate for LT recipients with recurrent HCV genotype 1 infection. Genotype 1a patients with advanced fibrosis of the allograft were more likely to relapse.

Incidence and Management of Hematological Toxicities Associated with Treatment of Hepatitis C Virus Infection in Cancer Patients

▪BackgroundHematologic toxicity is a common treatment complication of chronic hepatitis C virus (HCV) infection, especially when interferon (IFN) and ribavirin are used. The side effects of treatment are often augmented in cancer patients due to baseline cytopenias. These adverse events often lead to dose reduction or discontinuation of antivirals. Hematopoietic growth factors (GF) and blood transfusions are used to counteract toxicities allowing patients to complete treatment. We aimed to evaluate the incidence and management of hematological toxicity associated with different types of HCV treatment in cancer patients.MethodsMedical records of cancer patients treated for HCV infection at MD Anderson Cancer Center between 2009 and 2014 were reviewed. Those seen from 8/2009 to 10/2012 were analyzed retrospectively, whereas those seen from 11/2012 to 7/2014 were prospectively studied. Patients who received combination treatment with peg-IFN and ribavirin (PR), telaprevir or boceprevir plus PR (TBPR), sofosbuvir plus PR (SPR), sofosbuvir with simeprevir (SS) and sofosbuvir with ribavirin (SR) were included in the study. Data regarding treatment interventions (dose reductions and/or discontinuation of antivirals), use of GFs or blood transfusions in the management hematological side effects were analyzed. Categorical variables were analyzed using the χ2 or Fischer’s exact test.ResultsSixty-five patients were identified (Table). The need for treatment interventions, GFs or blood transfusions was comparable between patients with hematologic malignancies and solid tumors. Seventeen (81%) of the PR group, 13 (93%) of the TBPR group, 6 (67%) of the SPR group, 9 (64%) of the SR group and 0 of the SS group required treatment interventions (p <0.001) (Figure). Twelve (57%) of the PR group, 9 (64%) of the TBPR group, 3 (33%) of the SPR group, 2 (14%) of the SR group and 0 of SS group required the use of GFs (p <0.01). Six (29%) patients of the PR group, 9 (64%) from the TBPR group, 1 (11%) from the SPR group, 1 (7%) from the SR group and 0 from the SS group received blood transfusions (p <0.01). From patients who received GFs (N=26), 2 received epoetin alfa, 11 darbepoetin alfa, 2 filgrastim, 17 pegfilgrastim, 4 eltrombopag and 1 romiplostim. Ten of them (39%) required multiple GFs, with darbepoetin alfa and pegfilgrastim being the most common combination. Combined use of GFs was only needed in those receiving TBPR (56%), PR (33%) or SPR (33%). Overall, 82% of the patients who received treatment interventions, 77% of those who received GFs and 47% of those who received blood transfusions were able to complete HCV treatment. Thirteen patients (62%) from the PR group, 12 (86%) from the TBPR group, 3 (33%) from the SPR group, 2 (14%) from the SR group and 0 from the SS group developed grade 3 or 4 hematologic toxicities (p <0.001). One (25%) of 4 patients receiving eltrombopag developed portal vein thrombosis. No other patients developed side effects attributed to GF support.ConclusionsHematologic toxicity during HCV treatment in cancer patients is common. The use of GFs helps manage such toxicity, allowing completion of antiviral therapy. The newer HCV direct-acting antiviral agents are associated with less hematological toxicity, requiring fewer interventions, GFs and blood transfusions. No hematologic side effects were seen with the IFN-free, ribavirin-free combination of SS.Abstract 4126. TableCharacteristics of HCV-infected cancer patients treated with different antiviral regimensPR (N=21)%TBPR (N=14)%SPR (N=9)%SR (N=14)%SS (N=7)%Age, median (range)54.3 (45-68)59.7 (49-69)54.7 (35-75)62.7 (33-82)60.9 (46-64)Male gender13 (62)6 (43)4 (44)8 (57)4 (57)Type of cancer Solid Hematologic16 (76)5 (24)10 (71)4 (29)4 (44)5 (56)6 (43)8 (57)4 (57)3 (43)Cirrhosis5 (24)7 (50)2 (22)3 (21)6 (86)Baseline labs, median (range) Hemoglobin (g/dL) Platelets (x1,000 K/uL) Absolute Neutrophil count (K/uL)12.8 (10-15.9)165 (83-408)1385 (940-6120)13.5 (9.6-16.3)112 (52-397)2360 (800-4900)13.8 (8.8-14.2)183 (121-268)2680 (1650-5810)13.1 (9.8-15.5)179 (57-390)2490 (1040-4040)13.8 (12.3-16.1)141 (59-239)3000 (1390-5030)FDA-recommended duration of antiviral treatment, weeks24-4824-481212-2412Duration of antiviral treatment, median (range)24 (2-48)19 (3-52)12 (1-12)*12 (3-24)*6 (3-12)**Patients may still be on treatment. [Display omitted] DisclosuresTorres:Genentech,: Consultancy; Vertex Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc. : Consultancy, Research Funding; Gilead Sciences: Consultancy.

Eltrombopag: a review of its use in the treatment of thrombocytopenia in patients with chronic hepatitis C.

Eltrombopag (Revolade(®); Promacta(®)) is an orally bioavailable, small-molecule, thrombopoietin receptor agonist that selectively binds to thrombopoietin receptors on megakaryocyte precursors and megakaryocytes leading to increased platelet production. It is approved in a number of countries for the treatment of thrombocytopenia, including adult patients with chronic hepatitis C virus (HCV) infection to allow for the initiation and maintenance of peginterferon-based therapy, which is the focus of this review. In two, well-designed, randomized controlled trials in adults with chronic HCV infection and thrombocytopenia (ENABLE-1 and ENABLE-2), eltrombopag increased platelet counts to sufficient levels to allow for the initiation of peginterferon-based antiviral therapy in 95 % of patients whose baseline platelet counts would have made them ineligible or marginal candidates for peginterferon therapy. Moreover, a significantly higher proportion of eltrombopag recipients than placebo recipients achieved a sustained virological response (primary endpoint) 24 weeks after the completion of antiviral therapy. Of note, the additional benefit over placebo was relatively small (<10 %). Compared with placebo, eltrombopag was associated with fewer patients discontinuing antiviral therapy early and a numerically greater proportion of patients not requiring antiviral dose reduction. Oral eltrombopag had an acceptable tolerability profile; however, there is an increased risk of adverse events, including potentially fatal hepatic decompensation and thromboembolic events. Eltrombopag provides a new treatment option for thrombocytopenia in patients with chronic HCV infection to allow for optimal antiviral therapy.