High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma.

BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

Systematic review with meta-analysis: de novo non-alcoholic fatty liver disease in liver-transplanted patients.

BACKGROUND: De novo non-alcoholic fatty liver disease (NAFLD) in liver-transplanted patients for cirrhosis not due to non-alcoholic steatohepatitis (NASH) is becoming a growing phenomenon. AIMS: We performed a systematic review and evaluated the prevalence of this event and possible associated factors. METHODS: A literature search in medical databases (PubMed, MEDLINE/OVIDSP, Science Direct and EMBASE) was performed in March 2017. Relevant publications were identified in most important databases. We estimated the pooled prevalence of NAFLD and NASH in patients with liver transplant. The data have been expressed as proportions/percentages, and 95% confidence intervals (CI) were calculated, using the inverse variance method. Odd ratios (OR) and 95% confidence intervals (95% CI) were estimated. RESULTS: Twelve studies were selected, enrolling 2166 subjects overall undergoing post-liver transplant biopsy. The pooled weighted prevalence of de novo NAFLD was 26% (95% CI 20%-31%). The pooled weighted prevalence of NASH was 2% (95% CI 0%-3%). The highest prevalences of de novo NAFLD were found for patients transplanted for alcoholic cirrhosis (37%) and cryptogenic cirrhosis (35%) and for patients taking tacrolimus (26%). Tacrolimus showed a risk of NAFLD similar to ciclosporin (OR = 1.02, 95% CI 0.3-3.51). CONCLUSIONS: Patients undergoing liver transplant are more prone to experience diabetes, hypertension or dyslipidaemia, and NAFLD may be an important element in this context. In this study, we show how the prevalence of NASH tends to remain significant and similar to the general population. Moreover, this study suggests a possible association with specific transplant indications. Further studies are required to confirm these findings.

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.

De novo malignancies following liver transplantation: results from a multicentric study in central and southern Italy, 1990-2008.

OBJECTIVE: The objective of this study was to quantify incidence rates (IR) and risks of de novo tumors (except nonmelanoma skin cancers) in patients who underwent orthotopic liver transplantation (OLT) in central and southern Italy. METHODS: Data were collected on 1675 patients (75.5% males) who underwent OLT in six Italian transplantation centers in central and southern Italy (1990-2008). The time at risk of cancer (person years [PY]) was computed from OLT to the date of cancer diagnosis, death, or last follow-up, whichever occurred first. The number of observed cancer cases were compared with the expected one using data from population-based cancer registries. We computed gender- and age-standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: During 10,104.3 PYs (median follow-up, 5.2 years), 98 patients (5.9% of the total) were diagnosed with a de novo malignancy (for a total of 100 diagnoses). Twenty-two of these cancers were post-transplantation lymphoproliferative disorders (PTLD; 18 non-Hodgkin lymphoma [NHL] and 2 Hodgkin's lymphoma [HL]), 6 were Kaposi's sarcoma (KS), and 72 were solid tumors (19 head and neck [H&N], 13 lung, 11 colon-rectum, 6 bladder, and 4 melanoma). The overall incidence was 9.9 cases/10(3) PYs, with a 1.4-fold significantly increased SIR (95% CI, l.2-1.7). Significantly increased SIRs were observed for KS (37.3), PTLD (3.9), larynx (5.7), melanoma (3.1), tongue (7.1), and H&N (4.5) cancers. CONCLUSIONS: These results confirmed that OLT patients are at greater risk for cancer, mainly malignancies either virus-associated or related to pre-existent factors (eg, alcohols). These observations point to the need to improve cancer surveillance after OLT. The on-going enrollment of patients in the present cohort study will help to elucidate the burden of cancer after OLT and better identify risk factors associated with its development.

Peginterferon-Α_2B plus ribavirin is more effective than peginterferon-Α_2A plus ribavirin in menopausal women with chronic hepatitis C.

Under-enrolment of women to randomized clinical trials, including chronic hepatitis C, has long been recognized. The aim of this study was to identify factors predictive of sustained virological response (SVR) to PEG IFN/Ribavirin antiviral therapy in relation to gender and reproductive status of female patients involved. Seven hundred and forty-six treatment-naïve patients (431 men, 315 women) treated with Peg-IFNα-2a (180 µg/week) or Peg-IFNα-2b (1.5 µg/kg/week) plus ribavirin (800-1400 mg/day) for 24 or 48 weeks were studied between 2006 and 2010. Differences in SVR rate, overall and by gender were assessed after adjustment and propensity score matching. SVR was obtained in 44.2% of Peg-IFNα-2a-treated patients and in 51.2% of Peg-IFNα-2b-treated patients (intention-to-treat; P = 0.139). Age, fibrosis stage and genotype 2 and 3 were independently associated with SVR by multivariate analysis. Analysing by gender, the difference in SVR between PEG-IFNα types was not significant in men but highly significant in women (Peg-IFNα-2a:39.1%vs Peg-IFNα-2b:54.4%, P = 0.007). This was attributable to a higher SVR rate with Peg-IFNα-2b in the difficult postmenopausal population (26.9% Peg-IFNα-2a vs 46.0% Peg-IFNα-2b, P = 0.040). In women, absence of menopause, genotype 2 hepatitis C virus infection and use of Peg-IFNα-2b were independently associated with SVR. In conclusion, predictive factors for SVR are different in men and women. Factors differing between genders are menopause, severe steatosis and peg-interferon used. The higher SVR rate with Peg-IFNα-2b in menopausal women is likely attributable to more favourable pharmacokinetics that allows Peg-IFNα-2b to reach visceral fat and oppose the increased cytokine production and enhanced inflammatory status in menopause.

Campylobacter fetus bacteremia in an immunocompromised patient: case report and review of the literature.

A 33-year-old woman underwent a liver transplantation and splenectomy in 1985 and had followed immunosuppressive therapy until 1995. Afterwards a non-Hodgkin lymphoma was diagnosed and chemotherapy was started. In January 2000, because of suspect transplantation rejection she was treated with steroid and immunosuppressive therapy. Fever occurred after two months and Cytomegalovirus (CMV) infection was diagnosed. Ganciclovir was started with clinical remission. In November 2000 fever recurred without clinical symptoms. Lymphoma recurrence was excluded and CMV was detected by PCR in several biological fluids. Blood cultures were positive for a bacterium that was identified as Campylobacter fetus. The patient was successfully treated with intravenous ciprofloxacin. For persistent CMV viremia therapy with gancyclovir was stopped and foscarnet was used (60mg/Kg/tid i.v. for two weeks). Bacteremia due to C. fetus is rare, occurring mainly in immunocompromised patients. In our patient the immunosuppressive therapy, chemotherapy for lymphoma and CMV infection had made the patient susceptible to bacteremia with this infrequently found bacterium. The clinical microbiologist should be aware of this infection in immunocompromised hosts.

Mycophenolate mofetil in the treatment of autoimmune HCV-associated haematological disorders showing steroid resistance or dependence.

We report two cases of hepatitis C virus (HCV) associated autoimmune haematological disorders successfully treated with an unusual protocol (mycophenolate mofetil: MMF). The first case was a male patient with chronic HCV infection who developed, during interferon (IFN)/ribavirin therapy, severe autoimmune thrombocytopenia unresponsive to steroids. MMF was then administered and, simultaneously, the steroid dose was gradually reduced until withdrawal. Following this strategy, a progressive increase in platelet count and complete negativity of anti-PLT antibodies were achieved without changes in HCV-RNA quantitative determination. The second case was a woman with HCV liver cirrhosis with severe anaemia and Coombs test positivity partially responsive to continuous administration of steroid high doses. However, this treatment unmasked a severely painful vertebral osteoporosis. For this reason we introduced MMF and simultaneously steroid therapy was progressively reduced until withdrawal. Haemoglobin reached a normal value and the Coombs test became negative within 60 days. These case reports suggest that MMF may represent an interesting therapeutic approach for autoimmune HCV associated haematological disorders.

A logit model for the effect of telecardiology on acute newborn transfers.

UNLABELLED: The deregionalization of neonatal intensive care in the United States has shifted the site of care for many newborn infants away from academic medical centers where subspecialty support is available. OBJECTIVE: To investigate the effect of immediate echocardiogram interpretation via telemedicine on rates of neonatal transfer to academic medical centers. METHODS: A logit model was developed to predict the probability of transfer from two regional level 3 neonatal intensive care units to academic medical centers. One of these units implemented a telecardiology program and the other acted as a comparison institution with on-site cardiology expertise. The telecardiology intervention began 18 months into the 36-month study period. SUBJECTS: Infants (n = 2,142) admitted to neonatal intensive care at either of the two institutions during calendar years 1994 through 1996. RESULTS: A statistically significant reduction in the rate of transfer to academic medical centers was observed. Telecardiology was associated with a 58% reduction of such transfers (p = .001, 95% CI = 30%, 75%). No such reduction was noted at the comparison institution. It is estimated that approximately 30 transfers were eliminated during the study period, resulting in the elimination of approximately $150,000 in hospital charges. In addition, the infants that were transferred after the adoption of telemedicine were more often transferred to their telemedicine partner institution (p < .02).

Oral tacrolimus long-term therapy in patients with Crohn's disease and steroid resistance.

AIM: To report the results of a prospective, open-label, uncontrolled study in 13 patients affected by Crohn's disease with resistance to steroids. METHODS: The patients were treated long-term with oral tacrolimus, aiming to both resolve acute attacks and maintain remission. Tacrolimus was administered at the dose of 0.1--0.2 mg.day/kg and adjusted in order to achieve levels of 5--10 ng/mL; only mesalazine was continued concomitantly. Steroids and total parenteral nutrition were tapered when appropriate. RESULTS: Median treatment was 27.3 months. Only one patient dropped out due to adverse events. Crohn's disease activity index score significantly decreased after 6 months in 11 patients; for 1 year in nine of them, and 7 years in two of them. The inflammatory bowel disease life-quality questionnaire score significantly increased over the same periods. A marked drop in hospitalizations was recorded. In three out of six patients complete closure of fistulas occurred. Tacrolimus allowed total parenteral nutrition to be withdrawn in three out of five patients. Supplementation with low-dose steroids was required in five patients. Two patients underwent surgery. CONCLUSIONS: Tacrolimus therapy appears to be associated with both short- and long-term benefits, and may represent a therapeutic option in Crohn's disease when conventional therapies fail. This study encourages its use in controlled trials.

Patients following their echoes: the effect of telemedicine on institutional referral patterns.

UNLABELLED: Increasing market share by attracting patient referrals has long been cited as a justification for implementing telemedicine. METHODS: At the onset of this study, there were two level III NICUs in North Carolina that did not have on-site cardiology support. During the study period, both institutions set up telemedicine links to the University of North Carolina Health Care System for the provision of rapid cardiology support. OBJECTIVE: This paper tests the hypothesis that telemedicine was associated with an increase in the percentage of newborn referrals transferred to UNC instead of the other academic medical centers. RESULTS: Analysis of a total of 201 transfers over a three and a half year period shows that the percentage of acute transfers to UNC increased from 58 % during the pre-intervention phase to 86 % in the post-intervention phase (p = 0.001). An increase in transfers to UNC was observed from both of the level III centers. CONCLUSION: Telemedicine was an effective tool to attract patient referrals in a competitive tertiary care environment.

Oral tacrolimus (FK 506) in Crohn's disease complicated by fistulae of the perineum.

We describe the cases of two patients with Crohn's disease affected by severe perineal fistulae resistant to conventional therapies, successfully treated with FK 506, a new immunomodulatory drug. It is well absorbed from diseased bowel and preliminary experiences have indicated its short-term use in complicated Crohn's disease. The first patient was a 24-year-old male with perineal fistula and severe skin ulceration (8 cm of external opening diameter). He had undergone colectomy and ileostomy because of severe pancolitis refractory to medical treatment and had been treated with azathioprine and metronidazole. Two months after starting FK 506, a dramatic improvement made further surgical operation unnecessary. Local and general benefit was observed during the following 26 months, until FK 506 was withdrawn. The second patient was a 28-year-old male with a diagnosis of ulcerative pancolitis changed to Crohn's disease two months after the onset of a perineal fistula, recurring despite drainage procedures, steroid therapy, and total parenteral nutrition. FK 506 was administered for two months with a complete healing of fistula. Successively, it was stopped and corticosteroids (associated to enteral nutrition) were given because of recurrent rectal bleeding. Our experience encourages the use of oral FK 506 in complicated Crohn's disease and suggests the possibility of a long-term primary therapy other than the use as a "bridge" to other treatments.

Liver graft infection by HBV S-gene mutants in transplant patients receiving long-term HBIg prophylaxis.

BACKGROUND/AIMS: HBV reinfection of transplant livers occurs frequently even in the presence of high doses of anti-HBs immunoglobulins. We analyzed, retrospectively, whether and which type of S-gene variants were selected by long-term polyclonal anti-HBs (HBIg) treatment leading to reinfection of patients transplanted because of chronic HBs-positive end-stage liver disease. METHODOLOGY: The preS2/S gene of the viral genomes obtained from sera before transplantation and during HBV reinfection was amplified by PCR and directly sequenced. RESULTS: According to transaminase and HBV DNA hybridization analysis, 3/18 (17%) liver transplant patients had HBV and hepatitis recurrence during anti-HBs therapy. A HBV S-gene mutant containing a G to A nucleotide mutation at position 587, converting Glycine to Arginine (G145A), was identified in all three patients as the dominant population at reinfection but not pre-transplantation. Contrary to the S-gene, no consistent nucleotide changes were found in the pre-S2 region of HBV genomes when comparing the reinfection and pre-transplantation samples. CONCLUSIONS: These data demonstrate that long-term polyclonal anti-HBs immunoprophylaxis selected the most commonly described G145R S-gene escape HBV variant which became the dominant virus population and was responsible for graft infection. Therefore, immunoglobulins with high affinity for the G145R HBs variant should be included in HBIg to prevent recurrent HBV infection in transplant patients.

The effect of a neonatal telecardiology system on respiratory therapy in very low birthweight infants.

Factors in the U.S. healthcare system have shifted the site of care of many newborns to hospitals where subspecialty services are unavailable. This study examines whether a more rapid turn-around of echocardiogram interpretations and availability of interactive video during neonatal consultations reduces the morbidity of very low birthweight (VLBW) infants. The two groups (n = 21 and n = 28) were similar on the basis of known risk factors. A composite index of respiratory therapy intensivity and duration was used to measure the utilization of respiratory therapies. The index was similar in both groups, 89.6 +/- 12.6 before versus 89.5 +/- 13.0 with telemedicine. These results show little evidence of a reduction in RT utilization.

Effect of telemedicine on health outcomes in 87 infants requiring neonatal intensive care.

OBJECTIVE: This is an evaluation of a telemedicine system for the rapid interpretation of neonatal echocardiograms from a regional, level III neonatal intensive care unit (NICU). The use of telemedicine to support the cardiology needs of NICUs is increasing. However, there is very little published objective information regarding health outcomes or costs resulting from such telemedicine systems. The primary hypothesis tested was that the utilization of a telemedicine system for the interpretation of neonatal echocardiograms reduces the intensive care length of stay of low birthweight (LBW) infants. STUDY DESIGN: All infants who were admitted to neonatal intensive care at New Hanover Regional Medical Center during the first six months of the system were studied by the use of echocardiograms. They were compared with infants who were born in the same period of the previous year. The outcome measures were the intensive care length of stay, rate of transfer to academic medical centers, and mortality rate. RESULTS: A statistically non-significant reduction of 5.4 days in the intensive care length of stay (LOS) of low birthweight infants was observed (p = 0.37). The cost per echocardiogram transmitted was calculated at $33 compared to previous method of sending videotapes via overnight courier. CONCLUSIONS: While the sample size was inadequate to demonstrate improvements in health outcomes, the magnitude of the change and the low costs of the system suggest that this intervention is practical for obtaining rapid diagnostic and treatment support. Larger studies are warranted to confirm these findings and determine whether faster diagnosis and earlier initiation of treatment improve health outcomes of newborn infants.

The effect of telemedicine on neonatal intensive care unit length of stay in very low birthweight infants.

OBJECTIVE: This study addresses the effect of the installation and use of a telecardiology system on the intensive care length of stay of very low birthweight (VLBW) newborn infants. DESIGN: A retrospective comparison of 314 VLBW infants admitted to one of two neonatal intensive care units for a three year period from calendar years 1994 through 1996. A regression model was constructed to predict the intensive care length of stay while controlling for known risk factors. RESULTS: Telemedicine's effect is to reduce the intensive care length of stay and it both statistically significant (p < 0.05) and practically significant, reducing the intensive care length of stay by over 17%. The reduction in length of stay is greater at lower birthweights. CONCLUSIONS: Under the circumstances present in this study, telemedicine has been an effective intervention to reduce the intensive care length of stay.

Effect size and experimental power analysis in a paediatric cardiology telemedicine system.

A telemedicine system was installed between the University of North Carolina Hospitals and the New Hanover Regional Medical Center. It allowed the transmission of neonatal echocardiograms for immediate reporting. During a six-month study period the system was used for the interpretation of 110 echocardiograms from 48 babies. There were 38 babies studied in a retrospective control period. Hospital length of stay decreased by an average of six days in the telemedicine group, representing an annual saving of some $1.3 million. However, these apparent differences were not significant (P = 0.2) and a power analysis suggested that a sample size of some 600 would have been necessary.