Hugo E. Vargas

An Interferon-free Antiviral Regimen for HCV after Liver Transplantation

BACKGROUND Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection. METHODS We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigators discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study. CONCLUSIONS Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).

Search for Hepatitis C Virus Negative-Strand RNA Sequences and Analysis of Viral Sequences in the Central Nervous System: Evidence of Replication

ABSTRACT Patients with chronic hepatitis C are more likely to have significant changes in their physical and mental well-being than patients with liver disease of other etiology, and hepatitis C virus (HCV) has been occasionally implicated in diseases of the central nervous system. We analyzed the presence of the HCV negative-strand RNA sequence, which is the viral replicative intermediary, in autopsy brain tissue samples from six HCV-infected patients. Negative-strand HCV RNA was searched for by a strand-specific Tth-based reverse transcriptase PCR, and viral sequences amplified from brain tissue and serum were compared by single-strand conformational polymorphism analysis and direct sequencing. HCV RNA negative strands were detected in brain tissue in three patients. In two of these patients, serum- and brain-derived viral sequences were different and classified as belonging to different genotypes. In one of the latter patients, HCV RNA negative strands were detected in lymph node and, while being different from serum-derived sequences, were identical to those present in the brain. The results of the present study suggest that HCV can replicate in the central nervous system, probably in cells of the macrophage/monocyte lineage.

Liver transplantation for hepatocellular carcinoma: The MELD impact

The new allocation policy of the United Network of Organ Sharing (UNOS) based on the model for end‐stage liver disease (MELD) gives candidates with stage T1 or stage T2 hepatocellular carcinoma (HCC) a priority MELD score beyond their degree of hepatic decompensation. The aim of this study was to determine the impact of the new allocation policy on HCC candidates before and after the institution of MELD. The UNOS database was reviewed for all HCC candidates listed between July 1999 and July 2002. The candidates were grouped by two time periods, based on the date of implementation of new allocation policy of February 27, 2002. Pre‐MELD candidates were listed for deceased donor liver transplantation (DDLT) before February 27,2002, and post‐MELD candidates were listed after February 27, 2002. Candidates were compared by incidence of DDLT, time to DDLT, and dropout rate from the waiting list because of clinical deterioration or death, and survival while waiting and after DDLT. Incidence rates calculated for pre‐MELD and post‐MELD periods were expressed in person years. During the study, 2,074 HCC candidates were listed for DDLT in the UNOS database. The DDLT incidence rate was 0.439 transplant/person years pre‐MELD and 1.454 transplant/person years post‐MELD (P < 0.001). The time to DDLT was 2.28 years pre‐MELD and 0.69 years post‐MELD (P < 0.001). The 5‐month dropout rate was 16.5% pre‐MELD and 8.5% post‐MELD (P < 0.001). The 5‐month waiting‐list survival was 90.3% pre‐MELD and 95.7% post‐MELD (P < 0.001). The 5‐month survival after DDLT was similar for both time periods. The new allocation policy has led to an increased incidence rate of DDLT in HCC candidates. Furthermore, the 5‐month dropout rate has decreased significantly. In addition, 5‐month survival while waiting has increased in the post‐MELD period. Thus, the new MELD‐based allocation policy has benefited HCC candidates. (Liver Transpl 2004;10:36–41.)

Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon α2b and ribavirin: An open-label series

Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence. Methods. Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 &mgr;g/kg per week and titrated toward a maximum dose of 1.5 &mgr;g/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks. Results. Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P =0.05) in nonresponders versus 6.8 to 2.6 (P <0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P <0.05 for both). Conclusions. Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.

Outcome of liver transplantation in hepatitis C virus–infected patients who received hepatitis C virus–infected grafts

BACKGROUND & AIMS The present organ shortage has brought into question the suitability of hepatitis C virus (HCV)-positive grafts. This study reviewed the outcome of such transplantations in our institution. METHODS Twenty-three HCV-positive patients who underwent orthotopic liver transplantation (OLT) for end-stage liver disease with HCV-positive grafts in 1992-1995 were studied. Only patients who survived more than 30 days were included in the analysis. Control group included 169 patients who underwent transplantation for HCV-related cirrhosis and received HCV-negative organs. RESULTS Patients who received HCV-infected organs had a cumulative survival rate of 89% and 72% at 1 and 5 years, respectively, vs. 88% and 73% for the control group (NS). There was no difference in graft survival, incidence of cirrhosis, mean hepatitis activity index score, fibrosis, or mean activity of serum transaminases. There was a trend toward lower incidence of recurrent hepatitis C in the study group compared with control (21% vs. 23% at 1 year and 47% vs. 64% at 5 years; NS). Patients in whom the donor strain became predominant after transplantation had significantly longer disease-free survival than patients who retained their own HCV strain (P < 0.003). CONCLUSIONS HCV-infected livers transplanted into HCV-infected recipients do not appear to convey a worse outcome in the initial years after OLT than HCV-negative grafts.

Endoscopic treatment of anastomotic biliary strictures after living donor liver transplantation: outcomes after maximal stent therapy

BACKGROUND The optimal endoscopic treatment for anastomotic biliary strictures after deceased donor liver transplantation is undefined. Endoscopic therapy with conventional methods of biliary dilation and stent placement has been successful but often requires prolonged therapy. OBJECTIVE To determine the outcomes of an aggressive endoscopic approach that uses endoscopic dilation followed by maximal stent placement. SETTING Tertiary-care academic medical center. PATIENTS Of 176 patients who underwent deceased donor liver transplantation between June 1999 and July 2004, 25 were diagnosed with anastomotic biliary strictures. INTERVENTIONS Patients were treated endoscopically with a combined technique of balloon dilation and maximal stent placement. MAIN OUTCOME MEASUREMENTS Treatment outcomes, including bile-duct patency, a need for surgical intervention, morbidity, and mortality, were evaluated retrospectively. RESULTS Endoscopic dilation followed by maximal stent placement was performed until resolution of strictures in 22 of 25 patients (88% immediate success on intent-to-treat analysis). Persistent resolution of strictures was achieved in 18 of these 22 patients. Re-treatment was successful in 2 of 4 patients with recurrent strictures. Overall, 20 of 22 patients who completed endoscopic therapy (91%) avoided surgical intervention. Median duration of endoscopic treatment was 4.6 months. Patients with early onset strictures required a significantly shorter duration of endoscopic therapy (3 vs 9 months; P<.01). Multiple stent placement was not technically difficult, and no major complications were encountered. CONCLUSIONS Aggressive endoscopic therapy with combined biliary dilation and maximal stent placement allows resolution of anastomotic biliary strictures after deceased donor liver transplantation in a relatively short period, with sustained success and minimal complications.

Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension

Bleeding from esophageal varices (EV) is a serious consequence of portal hypertension. Current guidelines recommend screening patients with cirrhosis with esophagogastroduodenoscopy (EGD) to detect varices. However, the unpleasantness and need for sedation of EGD may limit adherence to screening programs. Pilot studies have shown good performance of esophageal capsule endoscopy in detecting varices. This multicenter trial was designed to assess the diagnostic performance of capsule endoscopy in comparison with EGD. Patients undergoing EGD for screening or surveillance of EV underwent a capsule study previously. The study was designed as an equivalence study, assuming that a difference of ≤10% between capsule endoscopy and EGD in diagnosing EV would demonstrate equivalence. Two hundred eighty‐eight patients were enrolled. Endoscopy was for screening in 195 patients and for surveillance of known EV in 93. Overall agreement for detecting EV between EGD and capsule endoscopy was 85.8%; the kappa score was 0.73. Capsule endoscopy had a sensitivity, specificity, positive predictive value, and negative predictive value of 84%, 88%, 92%, and 77%, respectively. The difference in diagnosing EV was 15.6% in favor of EGD. There was complete agreement on variceal grade in 227 of 288 cases (79%). In differentiating between medium/large varices requiring treatment and small/absent varices requiring surveillance, the sensitivity, specificity, positive predictive value, and negative predictive value for capsule endoscopy were 78%, 96%, 87%, and 92%, respectively. Overall agreement on treatment decisions based on EV size was substantial at 91% (kappa = 0.77). Conclusion: We recommend that EGD be used to screen patients with cirrhosis for large EV. However, the minimal invasiveness, good tolerance, and good agreement of capsule endoscopy with EGD might increase adherence to screening programs. Whether this is the case needs to be determined. (HEPATOLOGY 2008;47:1595–1603.)

Detection and Analysis of Hepatitis C Virus Sequences in Cerebrospinal Fluid

ABSTRACT Hepatitis C virus (HCV) sequences were detected in cerebrospinal fluid (CSF) in 8 of 13 HCV-positive patients. In four patients harboring different virus strains in serum and peripheral blood mononuclear cells (PBMC), CSF-derived virus was similar to that found in PBMC, which suggests that PBMC could carry HCV into the brain.

Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant.

Treatment with an all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events in non–liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3‐F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV‐based regimens) received treatment and were followed for a median of 30 weeks (range 12‐53 weeks). The median time from LT to treatment was 32 months (range 2‐317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval 84%‐96%). In patients with genotype 1a infection, the SVR12 rate was significantly lower in those with METAVIR F3‐F4 (71%) compared to those with F0‐F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4, and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA (83%). Treatment was very well tolerated with mild degrees of adverse events, except for one death possibly due to drug‐induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. Conclusion: An all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection. (Hepatology 2015;61:1880–1886)

Effectiveness of Simeprevir Plus Sofosbuvir, with or Without Ribavirin, in Real-World Patients with HCV Genotype 1 Infection

BACKGROUND & AIMS The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.