Virus Recurrence Research Articles

Renal safety of entecavir and tenofovir with hepatitis B immunoglobulin in liver transplant patients

Introduction: Combination of potent nucleos(t)ide analougues (NAs) and hepatitis B immunoglobulin is recommended after liver transplantation for the prevention of hepatitis B virus (HBV) recurrence. Despite its proven efficacy, renal safety of NAs in liver transplant recipients has not been well defined. We aimed to assess the impact of entecavir and tenofovir on glomerular and tubular function. Method: We analyzed 201 liver transplant patients treated with entecavir (n=122) or tenofovir (n=79) with hepatitis B immunoglobulin between 2012 and 2016. Serum creatinine, phosphorus, and uric acid were measured, and estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Proximal tubular dysfunction was defined as the combination of hypophosphatemia (< 2 mg/dL) and hypouricemia (< 2 mg/dL). Result: Mean eGFR at start of NAs after liver transplant was 100.8 for entecavir, 102.7 mL/min/1.73 m2 for tenofovir group (P=0.554). Mean eGFR at the last on-treatment visit was 80.0 for entecavir and 82.5 mL/min/1.73 m2 for tenofovir group (P=0.491). During the 28 months of median follow-up, 30 patients experienced decrease of eGFR < 30 mL/min/1.73 m2 (20 [16.4%] of entecavir and 10 [12.7%] of tenofovir group, P=0.468). Serum phosphorus and uric acid in both groups were statistically not significant at start of NAs. A total of 37 patients developed renal tubular dysfunction (11 [9.0%] of entecavir and 26 [32.9%] of tenofovir group, P<0.001). Tenofovir (HR, 5.24; 95% CI, 2.25-12.19; P<0.001), decrease of eGFR < 30 mL/min/1.73 m2 (HR, 4.44; 95% CI, 1.67-11.85; P=0.003), and use of mTOR inhibitor (HR, 2.31; 95% CI, 1.04-5.11; P=0.04) were independent risk factors for proximal tubular dysfunction. Conclusion: The effect of tenofovir on glomerular function was comparable to that of entecavir in liver transplant patients. However, tenofovir increased the risk of proximal tubular dysfunction. Longitudinal studies are needed to assess the long-term outcomes.

Efficacy and safety of sofosbuvir-based therapy in hepatitis C virus recurrence post living donor liver transplant: A real life egyptian experience.

Direct acting antiviral has offered treatment of hepatitis C virus (HCV) recurrence post liver transplantation (LT) with an all-oral regimen for short duration, excellent safety profile, and high sustained virological response (SVR). The aim of this study was to evaluate the efficacy and safety of sofosbuvir (SOF)-based regimens in the real world among a cohort of Egyptian patients with recurrent HCV post living donor LT (LDLT). Patients with HCV-G4 recurrence post-LDLT were recruited from National Committee of Control of Viral Hepatitis, Egypt, from November 2014 to May 2017. They received different SOF-based regimens according to the treatment protocols available during this period. Patients' outcome and Adverse effects (AE) were evaluated. One hundred ninety patients (170 males, mean age 56.8 ± 7.9 years) were included. Calcineurin inhibitors were the main immunosuppression used (173 patients). Out of 190, 119 (62.6%) received SOF/ribavirin (RBV), 38 (20%) SOF/simeprevir (SMV), 22 (11.6%) SOF/daclatasvir (DSV)/ ± RBV, and 11 (5.8%) received SOF/LDV/ ± RBV. Overall SVR12 was 89.5%, 84.9% in SOF/RBV group, 94.7% in SOF/SMV, 100% in SOF/DCV, and 100% in SOF/LDV with no statistically significant difference ( P = 0.104). The AE reported were as follows: anemia (n = 65, 34.4%) mainly in SOF/RBV group, transient hyperbilirubinemia during SOF/SMV in 13 patients (34%), mild Acute cellular rejection in eight patients (4.2%), and hepatocellular carcinoma in two patients (1%) mainly driven by underlying liver condition. Two deaths were unlikely related to HCV therapy. Different SOF-based regimens were effective with high SVR12 rates in a difficult-to-treat population, recurrent HCV post LDLT.

Silencing HCV Replication in Its Reservoir.

BACKGROUND:HCV infection and its complications are among the leading public health challenges; the emergence of drug-resistant variants are expected to be a major problem. A novel combinatorial small interfering RNA (siRNA) could be a novel triple therapy that could be suitable for genotype 4. Although HCV is a hepatotropic virus, there is reliable evidence about its replication in peripheral blood mononuclear cells (PBMC) of chronically infected patients; these cells act as an extra-hepatic reservoir for viral recurrence and persistence. The patients with HCV-RNA in PBMC showed a significantly lower response to therapy that supports to be one of the factors influencing therapeutic response. Almost all regions of HCV show potential for siRNA target with relative efficiencies of individual siRNA sequences.AIM:This study aims to test the efficacy of siRNA against HCV-4 replication in PBMC in vitro, to introduce an alternative therapeutic option for HCV-4 suitable to eradicate it from both hepatic and extra-hepatic reservoirs.METHODS:Efficacy of synthesised siRNA molecule that targets 5/UTR of domain IIIC within IRES of HCV RNA to eradicate HCV intra-PBMC in vitro was tested and compared with IFN/RBV in vitro, by using both qRT-PCR and western blot. Sixty genotype-4 chronic HCV patients who are naïve for any HCV treatment were enrolled and tested for the presence of HCV intra-PBMC using qRT-PCR before and after siRNA treatment in vitro.RESULTS:Real-time PCR analysis showed a significant reduction of HCV RNA levels after 24hr post-HCV-positive-PBMCs treatment by siRNA with cell vitality reached up to 98%. Besides a complete inhibition of NS5A viral protein expression, that is functionally essential for viral assembly, replication and egress.CONCLUSION:So, Targeting HCV infection using RNA interference technology might be a reliable therapeutic option for chronic HCV patients with HCV minus strand within PBMCs.

Effect of valaciclovir on CD4 count decline in untreated HIV: an international randomized controlled trial.

ObjectivesTo determine the impact of valaciclovir on HIV disease progression in treatment-naive HIV-positive adults.MethodsIn this fully blind, multicentre, 1:1 randomized placebo-controlled trial, treatment-naive HIV-1-positive adults with CD4 counts 400–900 cells/mm3 and not meeting contemporaneous recommendations for combination ART (cART) were randomized to valaciclovir 500 mg or placebo twice daily, and followed quarterly until having two consecutive CD4 counts ≤350 cells/mm3 or initiating cART for any reason. The primary analysis compared the rate of CD4 count decline by study arm after adjusting for baseline CD4 count and viral load (VL). Secondary analyses compared the rate of CD4 percentage decline, HIV VL, herpes simplex virus (HSV) recurrences and drug-related adverse events. The trial closed after release of the START trial results in August 2015.ResultsWe enrolled 198 participants in Canada, Brazil, Argentina and the UK. Median (IQR) age was 35 (30–43) years. Baseline CD4 count was 592 (491–694) cells/mm3 and VL was 4.04 (3.5–4.5) log10 copies/mL. Over 276 person-years of follow-up, CD4 counts declined by 49 cells/mm3/year in the valaciclovir arm versus 58 cells/mm3/year in the placebo arm (P = 0.65). No differences were seen in the rate of change in CD4 percentage (−1.2%/year versus −1.7%/year, P = 0.34). VL was 0.27 log10 copies/mL lower in valaciclovir participants overall (P<0.001). Placebo participants had more HSV recurrences (62 versus 21/100 person-years, P < 0.0001) but similar rates of grade ≥2 drug-related adverse events.ConclusionsUnlike prior trials using aciclovir, we found that valaciclovir did not slow CD4 count decline in cART-untreated adults, although power was limited due to premature study discontinuation. Valaciclovir modestly lowered HIV VL.

Assessment of Oral Shedding of Herpes Simplex Virus Before and After Endodontic and Fixed Partial Prosthodontics Treatment in Patients with Recurrent Herpes Simplex

Background: Herpes simplex virus type 1 (HSV-1) as a member of the herpes virus family recurs in 25% of infected patients 1 - 4 times a year. Reactivation of the virus in the oral mucosa is triggered by stress, sunray, menstruation and trauma to the face. Objectives: The current study aimed to evaluate the effect of fixed prosthetic treatment and root canal therapy on symptomatic and asymptomatic shedding of HSV-1 virus into the saliva. Methods: Twenty two patients with a history of recurrent herpes simplex infection were selected, 11 of whom underwent endodontic treatment and 11 received fixed prosthesis treatment. Saliva samples were obtained immediately before and three days after spitting method of collection. The samples were stored at -70°C and then examined via the polymerase chain reaction (PCR) technique in order to detect probable shedding of the virus. Results: In general, 72.7% (P = 0.09) and 63.6% (P = 0.09) of the samples were positive for HSV-1 in the endodontic and fixed prosthesis groups, respectively. Conclusions: The results of this study indicated that dental treatment could be considered as a risk factor for asymptomatic recurrence of HSV-1 virus in the oral cavity. Therefore, to prevent HSV infection, the use of infection control measures and prophylactic antiviral therapy is critical in immunocompromised patients.

'It's been a long haul, a big haul, but we've made it': hepatitis C virus treatment in post-transplant patients with virus recurrence: An interpretative phenomenological analysis.

The lived experience of both interferon-based and new interferon-free treatments in patients with hepatitis C virus remains understudied. To explore their journey through hepatitis C virus treatment, we interviewed seven post-transplant patients with recurrent hepatitis C virus. Three themes were identified using interpretative phenomenological analysis. Participants reported an ongoing sense of ontological uncertainty characterized by lack of control over their condition and treatment. Furthermore, an apposition of scepticism and hope accompanying each stage of hepatitis C virus treatment was described. A staged approach to psychological intervention tailored to the needs of the patient and their associated ‘stage’ of hepatitis C virus treatment was recommended.

Similar Low Rates of HCV Recurrence in HCV/HIV- and HCV-Infected Participants who Achieved SVR After DAA Treatment: Interim Results From the ACTG A5320 Viral Hepatitis C Infection Long-term Cohort Study (V-HICS).

Hepatitis C virus (HCV) recurrence rates were similar between those with HCV/HIV co-infection (0.35/100 person-years) and HCV infection (0.42/100 person-years). Low rates of recurrence likely represent enrollment of an HIV population at low risk for recurrence. Care should be taken not to label all HCV/HIV co-infected patients as being at high risk for HCV recurrence.

Improvement of liver stiffness measurement, acoustic radiation force impulse measurements, and noninvasive fibrosis markers after direct-acting antivirals for hepatitis C virus G4 recurrence post living donor liver transplantation: Egyptian cohort.

Progression of recurrent hepatitis C is accelerated in liver transplant (LT) recipients. Direct-acting antivirals (DAAs) have recently emerged as a promising therapeutic regimen for the treatment of hepatitis C virus infection. Rates of sustained virological response (SVR) have drastically improved since the introduction of DAAs. The aim is to elucidate the changes in liver stiffness measurement (LSM) by transient elastography (TE) as well as acoustic radiation force impulse (ARFI) elastography and fibrosis scores after DAA treatment in LT recipients with hepatitis C virus recurrence. A single-center, prospective study including 58 LT recipients with hepatitis C recurrence who received different sofosbuvir-based treatment regimens. Transient elastography and ARFI elastography values were recorded as well as fibrosis 4 score (FIB-4) and aspartate aminotransferase-to-platelet ratio index were calculated at baseline and SVR at week 24 (SVR24). The outcome was improvement in LSM and at least a 20% decrease in LSM at SVR24 compared with baseline. The sustained virological response was 98.1%. There was improvement of platelet counts, alanine aminotransferase, and aspartate aminotransferase, which in turn caused improvement in fibrosis scores at SVR24. LSM by TE and ARFI elastography decreased from the baseline median value of 6.3 kPa (interquartile range [IQR]; 4.6 to 8.8 kPa) and 1.28 m/s (IQR; 1.07 to 1.53 m/s) to an SVR24 median value of 6.2 kPa (IQR; 4.85 to 8.9 kPa) and 1.12 (IQR; 0.97 to 1.30 m/s), respectively. Logistic regression analysis showed that baseline viral load was the only significant predictor of improvement in LS after DAA therapy at SVR24. Sofosbuvir-based treatment resulted in an early improvement in parameters of liver fibrosis in post-LT patients with hepatitis C recurrence.

Lower tacrolimus trough levels in the late period after living donor liver transplantation contribute to improvements in long-term clinical outcomes

BackgroundPrevious studies have emphasized the need to reduce tacrolimus (TAC) trough levels in the early post-liver transplantation (LT) period. However, whether late-period TAC trough levels influence the long-term outcomes of liver recipients is not clear. MethodsWe enrolled 155 adult liver recipients survived more than 3 years after living donor liver transplantation because of non-malignant liver diseases. The maintenance immunosuppressive regimens were TAC monotherapy and combined therapy with mycophenolate mofetil. Patients were divided into three groups according to their late-period TAC trough levels: < 3 ng/mL group, 3–5 ng/mL group, and >5 ng/mL group. The complications and adverse effects of TAC were analyzed. ResultsEach group showed similar rejection, graft loss and mortality. Patients achieved the < 5 ng/mL state in less than 4 years had fewer new-onset diabetes, hyperlipidemia, de novo malignancies, and hepatitis B virus recurrence; the complications of renal dysfunction and hypertension rates were the same among these 3 groups. ConclusionsCollectively, our findings indicated that lower TAC trough levels in the late period of liver transplantation are safe, improve the long-term outcomes.

Shorter hepatitis B immunoglobulin administration is not associated to hepatitis B virus recurrence when receiving combined prophylaxis after liver transplantation.

The combination of hepatitis B immunoglobulin and a nucleos(t)ide analogues has markedly reduced the rate of hepatitis B virus recurrence after liver transplantation; however, the optimal duration of hepatitis B immunoglobulin has not been clarified. This lack of consensus perpetuates the use of different strategies. The aim of this study was to evaluate the risk factors associated to hepatitis B virus recurrence after liver transplantation in a large cohort of patients under different hepatitis B immunoglobulin regimens. Retrospective multicentre analysis of hepatitis B virus-related liver transplantation recipients receiving combined prophylaxis (hepatitis B immunoglobulin + nucleos(t)ide analogues). The strategy of short-term hepatitis B immunoglobulin was compared to lifelong administration. Hepatitis B virus recurrence was defined as positive HBsAg after liver transplantation. Three hundred and thirty-eight patients were analysed. After a median follow-up period of 72months, 37 patients (11%) developed hepatitis B virus recurrence. Hepatocellular carcinoma recurrence and lamivudine resistance after liver transplantation were the only factors independently associated to hepatitis B virus recurrence (HR 5.4 [2.3-12] and 9.3 [4.2-20] respectively P<.001). HBsAg reappearance after hepatitis B virus recurrence was transient (16 patients), persistent (15) or alternant (6). The hepatitis B immunoglobulin regimen did not have an impact on the rate or evolution of hepatitis B virus recurrence. Overall, patient survival was good and not influenced by hepatitis B virus recurrence (82% at 5years). Fulminant liver failure, hepatitis C coinfection or hepatocellular carcinoma at liver transplantation were independent risk factors for lower survival. Liver transplantation is an effective treatment for hepatitis B virus-related liver disease. Since the introduction of combined prophylaxis the rate of hepatitis B virus recurrence is very low. However, lifelong hepatitis B immunoglobulin administration does not seem necessary to reduce hepatitis B virus recurrence.

Combined Liver-Kidney Transplantation in Children: Single-Center Experiences and Long-Term Results

Combined liver-kidney transplantation (CLKT) is a rare procedure in pediatric patients in which liver and kidney from 1 donor are transplanted to a recipient during a single operation. The aim of our study was to analyze indications and results of CLKT in children. Materials and MethodsBetween 1990 and 2017 we performed 722 liver transplantations in children; we performed 920 kidney transplantations in children since 1984. Among them, 25 received CLKT. Primary diagnosis was fibro-polycystic liver and kidney disease in 17 patients, primary hyperoxaluria type 1 in 6 patients, and atypical hemolytic uremic syndrome-related renal failure in 2 children. Age of patients at CLKT was 3 to 23 years (median 16 years) and body mass was 11 to 55 kg (median 35.5kg). All patients received whole liver graft. Kidney graft was transplanted after liver reperfusion before biliary anastomosis. Cold ischemia time was 5.5 to 13.3 hours (median 9.4 hours) for liver transplants and 7.3 to 15 hours (median 10.4 hours) for kidney transplants. In 8 patients X-match was positive. We analyzed posttransplant (Tx) course and late results in our group of pediatric recipients of combined grafts. ResultsTx follow-up ranged from 1.5 to 17 years (median 4.5 years). Two patients died: 1 patient with oxalosis lost renal graft and died 2.6 years after Tx due to complications of long-term dialysis, and 1 died due to massive bleeding in early postoperative period. Twelve patients were transferred under the care of adult transplantation centers. Six patients were dialyzed after CLKT due to acute tubular necrosis, and time of kidney function recovery was 10 to 27 days in these patients. In 1 patient with aHUS, renal function did not recover. In children with oxalosis, hemodialysis was performed for 1 month after Tx as a standard, with the aim to remove accumulated oxalate. Primary immunosuppression consisted of daclizumab or basiliximab, tacrolimus, mycophenolate mofetil, and steroids. Acute rejection occurred in 4 liver and 3 kidney grafts. One patient required liver retransplantation due to hepatitis C virus recurrence and 2 patients required kidney retransplantation. Two patients required dialysis. ConclusionsCLKT in children results in low rate of rejection and high rate of patient and graft survival.

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9months, 3-9months and 4.5months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73m2 /month, P=0.03) independently of the pre-treatment eGFR (P=0.99), ribavirin administration (P=0.26), mycophenolate mofetil administration (P=0.51) and stage of fibrosis (F3 and F4 vs lower stages, P=0.18; F4 vs lower stages, P=0.08; F4 Child-Pugh B and C vs lower stages, P=0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P=0.34, 0.08, 0.73). The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Impact of Sofosbuvir-Based Regimens for the Treatment of Hepatitis C After Liver Transplant on Renal Function: Results of a Canadian National Retrospective Study.

We assessed the impact of sofosbuvir-based regimens on renal function in liver transplant recipients with recurrent hepatitis C virus and the role of renal function on the efficacy and safety of these regimens. In an expanded pan-Canadian cohort, 180 liver transplant recipients were treated with sofosbuvir-based regimens for hepatitis C virus recurrence from January 2014 to May 2015. Mean age was 58 ± 6.85 years, and 50% had F3/4 fibrosis. Patients were stratified into 4 groups based on baseline estimated glomerular filtration rate (calculated by the Modification of Diet in Renal Disease formula): < 30, 30 to 45, 46 to 60, and > 60 mL/min/173 m2. The primary outcome was posttreatment changes in renal function from baseline. Secondary outcomes included sustained virologic response at 12 weeks posttreatment and anemia-related and serious adverse events. Posttreatment renal function was improved in most patients (58%). Renal function declined in 22% of patients, which was more marked in those with estimated glomerular filtration rate < 30 mL/min/173 m2, advanced cirrhosis (P = .05), and aggressive hepatitis C virus/fibrosing cholestatic hepatitis (P < .05). High rates (80%-88%) of sustained virologic response at 12 weeks posttreatment were seen across all renal function strata. Cirrhotic patients with glomerular filtration rates < 30 mL/min/173 m2 had sustained virologic response rates at 12 weeks posttreatment comparable to the overall patient group. Rates of anemia-related adverse events and transfusion requirements increased across decreasing estimated glomerular filtration rate groups, with notably more occurrences with ribavirin-based regimens. Sofosbuvir-based regimens improved overall renal function in liver transplant recipients, with sustained virologic response, suggesting an association of subclinical hepatitis C virus-related renal disease. Sustained virologic response rates at 12 weeks posttreatment (80%-88%) were comparable regardless of baseline renal function but lower in cirrhosis.

Successful Treatment of Fibrosing Cholestatic Hepatitis With Daclatasvir and Asunaprevir After Liver Transplantation: A Case Report

BackgroundFibrosing cholestatic hepatitis (FCH) is an aggressive form of hepatitis C virus (HCV) recurrence after liver transplantation (LT). Most FCH cases are fatal, occurring as a secondary disease following rapidly progressive liver dysfunction and graft failure. We report a case of early-onset FCH after LT that was successfully treated using daclatasvir and asunaprevir. Case reportA 59-year-old woman underwent living donor LT for HCV-related liver cirrhosis. However, liver function was not improved after LT and gradually worsened. A liver biopsy was performed at 30 and 47 days after the living donor LT to identify the cause of the liver dysfunction. The first biopsy result showed no specific finding. However, combined treatment with pegylated interferon and ribavirin was started because of a high HCV viral load (> 8.0 log IU/mL). Nevertheless, liver function and HCV viral load deteriorated, and the second biopsy performed on postoperative day 47 revealed FCH. We converted the antiviral agents into daclatasvir and asunaprevir and performed plasmapheresis twice. Since then, the liver dysfunction and HCV viral load gradually improved, and HCV RNA clearance occurred at week 11 after treatment. The patient achieved a sustained virologic response at week 24 after completion of the treatment. ConclusionDaclatasvir combined with asunaprevir can be a useful treatment option in potentially fatal FCH after LT.

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.

Hepatitis B and liver transplantation

Chronic Hepatitis B (CHB) infection remains a common cause for liver cirrhosis and hepatocellular carcinoma. Orthotopic liver transplantation (OLT) has been a treatment modality for CHB patients with decompensated cirrhosis and or hepatocellular carcinoma. Previously early outcomes of transplantation for CHB patients were associated with rapid recurrence of the virus and loss of the allograft. Development of hepatitis B immunoglobulin (HBIG) and its use in prophylaxis of CHB patients after liver transplantation resulted in significant improvement in patient and allograft survival. Continued use of HBIG mono-therapy however has been complicated by development of viral resistance. With the development of nucleos(t)ide (NA) inhibitors for treatment of CHB, liver transplant outcomes continued to improve. One of the most important risk factors for viral recurrence in post liver transplant setting is the HBV DNA level. Use of NAs prior to liver transplantation to reduce the viral load has been an important way to prevent recurrence of CHB in post liver transplant patients. Addition of NAs to HBIG was the standard of therapy for liver transplant patients for many years and reduced the development of viral resistance. Long-term use of HBIG however is expensive and inconvenient for patients. Development of more potent NAs, with low viral resistance, has allowed for reduction and in some cases elimination of use of HBIG in post liver transplant prophylaxis of patients with CHB.

Daclatasvir and sofosbuvir treatment of decompensated liver disease or post-liver transplant hepatitis C virus recurrence in patients with advanced liver disease/cirrhosis in a real-world cohort.

We report the findings of an early access program providing treatment for chronic hepatitis C virus infection (any genotype) with daclatasvir and sofosbuvir with/without ribavirin to patients with Child‐Pugh class C cirrhosis or prior liver transplant recipients with recurrent hepatitis C virus infection and advanced fibrosis/cirrhosis. Patients had <12‐month life expectancies per the local investigator. Patients received daclatasvir 60 mg and sofosbuvir 400 mg once daily, with/without ribavirin, for 24 weeks. Sustained virologic response (SVR) at posttreatment week 12 (SVR12) was measured. Assessments adhered to local standards. One patient (prior Child‐Pugh class C who improved to class B) enrolled by exemption was included in the overall data but not the class C cohort efficacy/safety data. Of the 77 treated patients, including 62 liver transplant recipients (genotype 1, n = 43, 69%; genotype 3, n = 16, 26%) and 14 patients with Child‐Pugh class C cirrhosis (genotype 1, n = 4, 29%; genotype 3, n = 10, 71%), 63 (82%) completed treatment. SVR12 rates by modified intention‐to‐treat analysis (excluding nonvirologic failures lost to follow‐up and withdrawal [consent/no reason]) in the overall, liver transplant, and Child‐Pugh class C cohorts were 84% (n = 64/76), 90% (n = 56/62), and 62% (n = 8/13), respectively. Rates increased to 96% (n = 64/67), 97% (n = 56/58), and 89% (n = 8/9), respectively, in patients with available virologic data (including early discontinuations); 22/23 patients with genotype 3 (96%) achieved SVR12. Single cases of virologic nonresponse and relapse (both in liver transplant recipients with genotype 1) and viral breakthrough (Child‐Pugh class C; genotype 3) occurred. Six patients died, 10 had adverse events leading to discontinuation, and 30 experienced serious adverse events. Conclusion: Daclatasvir plus sofosbuvir, with/without ribavirin, provided high SVR12 rates and was generally well tolerated in patients with life‐threatening disease and high unmet needs. (Hepatology Communications 2018;2:354‐363)

Deep anterior lamellar keratoplasty combined with antiviral therapy in the treatment of severe herpes necrotizing stromal keratitis

Objective: To evaluate the efficacy of modified deep lamellar keratoplasty (DLKP) combined with antiviral medications for severe herpes necrotizing stromal keratitis. Methods: Retrospective case series study. Modified DLKP was performed in combination with antiviral medications in fifty patients (50 eyes) with severe necrotizing stromal keratitis, which was unresponsive to systemic and topical antiviral treatment for 1 week, at Shandong Eye Hospital. Before surgery, the operated eyes were examined using slit-lamp microscopy. The size of corneal ulceration and inflammatory infiltration and the depth of ulceration were observed in all of the patients. Corneal scraping and microbial culture and confocal laser scanning microscopy were used to exclude fungal, bacterial, Acanthamoeba, or other infections, and check the number of corneal endothelial cells. Anterior segment optical coherence tomography was used to examine the depth of infiltration, especially the thickness of the remaining cornea below the deepest ulceration. Antiviral drugs were used topically and systemically to control the infection and inflammation. Postoperatively, both antiviral drugs and low-dose corticosteroids were used. The ocular inflammation, corneal graft status and viral recurrence were monitored intraoperatively and postoperatively. Results: All of the fifty patients showed obvious inflammatory infiltration and stromal ulcers, and the corneal stroma in 23 patients (46%) remained less than 1/5 of the corneal thickness. Nine (18%) of the patients presented with descemetocele. The depth of infiltration ranged from 128 μm to 519 μm [mean, (265±84) μm]. The depth of corneal ulcers was deeper than 2/3 of the corneal thickness in 36 eyes (72%). The endothelial cells were visible in 26 eyes. The density of endothelial cells ranged from 1 275 cells/mm(2) to 2 994 cells/mm(2) [mean, (2 053±507) cells/mm(2)]. No fungal or bacterial infection was detected by corneal scraping. The microbial culture results were negative. All the inflammations in patients with severe herpes necrotizing stromal keratitis were under control by DLKP. No intraoperative corneal perforation occurred, and 6 eyes (12%) healed following amniotic membrane transplantation due to slow corneal epithelial healing. The infection was exacerbated two days following the surgery in two eyes (4%). These infections were controlled with enhanced antiviral medications in addition to the immediate withdrawal of corticosteroids. The corneal grafts returned to transparency at 1-2 weeks in 42 eyes (84%). Ten eyes (20%) exhibited recurrence due to medication withdrawal without the doctors' advice and a lack of regular visit during 2-year follow-up. Two patients (4%) developed stromal graft rejection for the same reasons. Conclusions: DLKP can achieve the results of ulcer healing for severe herpes necrotizing stromal keratitis. Combined antiviral therapy and close follow-up can reduce the viral recurrence. (Chin J Ophthalmol, 2018, 54: 97-104).

Effects of deep lamellar keratoplasty on severe necrotizing stromal keratitis

Objective: This study is to investigate the application of deep lamellar keratoplasty (DLKP) in the treatment of necrotizing stromal keratitis (NSK). Methods: Corneal confocal microscopy and histopathological examination were performed before surgery. DLKP and penetrating keratoplasty (PKP) were performed on 14 and 20 NSK subjects, respectively, followed by proper drug administration. In the follow-up period, the pathological features were evaluated and compared. Results: Significant corneal neovascularization and inflammatory cell infiltration were observed in NSK patients before surgery. After proper drug treatments, PKP and DLKP were performed. In the followup period, the visual acuity was elevated in the PKP and DLKP groups at 1 y after surgery. Moreover, corneal opacity was observed in 2 corneal grafts in the PKP group, while all the corneal grafts were transparent in the DLKP group. Furthermore, compared with the PKP group, corneal endothelial cell numbers at 6 and 12 months after surgery were significantly higher in the DLKP group. On the other hand, there were 2 eyes reporting virus recurrence in the PKP group, while no virus recurrence was reported in the DLKP group. Moreover, 4 eyes were accompanied with neovascularization at the corneal graft edge in the PKP group, while there was only 1 eye associated with neovascularization in the DLKP group. Furthermore, 5 cases in the PKP group reported graft rejection, while no rejection case was reported for DLKP. Conclusion: DLKP provides superior outcomes to PKP in treating NSK, which might be an ideal alternative option for the disease treatment.

Shear-wave elastography for the assessment of liver fibrosis in liver transplant recipients treated for hepatitis C virus recurrence.

Direct-acting antiviral agents have revolutionized hepatitis C therapy, and are also found to be effective in the liver transplant setting. The extent of liver fibrosis influences patient management and is used to monitor therapeutic effects. Shear-wave elastography (SWE) is a relatively new imaging-based method that has not yet been studied extensively in liver transplant patients. Our aim was to study the effect of direct-acting antivirals in heaptitis C recurrence on liver stiffness determined by SWE. A total of 23 liver transplant patients with hepatitis C recurrence were enrolled in this prospective study. The patients underwent 24 weeks of ombitasvir/paritaprevir/ritonavir+dasabuvir±ribavirin combination therapy. Elastographic examinations, serological tests and laboratory tests were performed, and serum biomarkers of liver fibrosis were calculated the day before treatment (baseline) and at the end of the treatment. All our patients became hepatitis C virus RNA negative by the end of the treatment. Median liver stiffness values decreased significantly after treatment compared with baseline (8.72±3.77 vs. 7.19±2.4 kPa; P<0.001). Among the studied laboratory values, a significant decrease was observed in the levels of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase, whereas international normalized ratio levels increased. Serum biomarkers, namely aspartate aminotransferase-to-platelet ratio index and Fibrosis-4, decreased significantly after treatment compared with baseline. In the present study, SWE was succesfully used to monitor the beneficial therapeutic effects of direct-acting antivirals in hepatitis C recurrence following liver transplantation. We believe that SWE is a useful noninvasive diagnostic tool in the follow-up of hepatitis C treatment in liver transplant patients.