Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection.

UNLABELLED: Alisporivir is a cyclophilin inhibitor with pan-genotypic anti-hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL-1 study assessed alisporivir as interferon (IFN)-free therapy in treatment-naïve patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once-daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg-IFN); or arm 5, Peg-IFN and RBV. Patients receiving IFN-free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg-IFN from weeks 6 to 24. Overall, 300 patients received ALV-based regimens. In arm 1 to arm 4, the intent-to-treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg-IFN/RBV. Per-protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN-free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg-IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN-free regimens were numerically higher in genotype 3- than in genotype 2-infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN-free ALV treatment showed markedly better safety/tolerability than IFN-containing regimens. CONCLUSIONS: ALV plus RBV represents an effective IFN-free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN-free combination regimens with direct-acting antiviral drugs deserve exploration in future trials.

Interleukin-28b CC genotype predicts early treatment response and CT/TT genotypes predicts non-response in patients infected with HCV genotype 3.

Response to antiviral therapy for hepatitis C virus (HCV) depends upon the genotype and host immune response. IL28b gene mutations have been shown to modulate host antiviral immune response against genotype 1. However, the predictive value of IL28b polymorphism in genotype 3 HCV patients is largely unknown. The association of IL28b polymorphism with virological response was studied in 356 patients with genotype 3 chronic HCV undergoing treatment with peg-interferon and ribavirin and was compared with matched controls. IL28b genotyping followed by DNA sequencing was performed to identify the CC, CT, or TT genotypes. Two log reduction of HCV RNA at Day 7 (Quick Viral Response, QVR) and HCV RNA negativity at Day 28 (Rapid Viral Response, RVR) were analyzed with CC and non-CC genotypes in addition to other predictors of response. The associations of alleles with the response patterns were predicted. Sustained viral response was seen in 250 (70.2%) patients and the IL28b genotype CC/CT/TT distribution was 61.1%; 30.5%; and 8.4%, respectively. The non-CC genotypes were significantly higher in non-responders when compared to responders (67.6% vs. 38.9%, P < 0.001). Interestingly, the rapid viral response in responders was observed in 72.7% with the CC genotype and in 27.2% with the non-CC genotype (P < 0.001). Multivariate analysis showed CC genotype as an independent factor predicting the sustained viral response in patients infected with HCV genotype 3. In conclusion, the IL28b CT/TT genotype strongly correlates with treatment non-response in patients infected with HCV genotype 3 and CC genotype of IL28b is associated with higher quick viral response.

Unusual Facial Movements (Ictal Blinking, Oculogyric Crises, and Jaw Seizure) in Severe Liver Disease: A Case Series.

Background: Seizures are reported in about one-third of patients with severe liver disease in association with acute or chronic liver failure. The majority of the seizures are of focal type. Occasionally generalized tonic-clonic seizures are seen when there is ethanol withdrawal. Not much is known about ictal blinking (IB) in severe liver disease. IB is the rare form of seizures and was reported in severe liver disease recently from this institute. Oculogyric crisis (OGC) is rarely reported in relation to the severe liver disease. OGC was also noted first time in our intensive care unit. Methods: At the Institute of Liver and Biliary Sciences (ILBS), data on patients with IB and OGC were analyzed from October 2018 to January 2023 (52 months). All the patients had video electroencephalograph (video-EEG) recording after proper permission/consent. The patients were followed up later for the course of the illness. Results: A total of 16 (12M:4F) patients were seen. Majority 12 (75%) were IB and 3 OGC. EEG was abnormal in nine (75.0%) of IB patients. Brain imaging had nonspecific findings. The outcome was based on the severity and recovery of the underlying liver disease. Conclusions: Unusual facial movements in the form of IB and OGC are reported, which are most of the time missed. This report highlights the importance of recognition of these events and proper in time management to improve the outcome.

Treatment of patients with genotype 3 chronic hepatitis C--current and future therapies.

Genotype 3 is a common type of HCV infection, and standard therapy using pegylated interferon (PEG-IFN) and ribavirin (RBV) is quite effective in these patients. While a short course of 16 weeks may result in comparable end of therapy responses, relapse rates are often high. A 24-week course is therefore preferable, and is expected to result in sustained virological response (SVR) rates of more than 70%. The 24-week course is especially recommended in the presence of steatosis (often associated with Genotype 3 infection), fibrosis stage two or more, high BMI and high viral load. In patients who do not achieve a rapid viral response (RVR) with combination therapy, an extended course up to 48 weeks should be considered. While not as definite as for genotype 1 patients, the presence of the CC variant of IL28b could help in the initial prognosis and the need for additional treatment, if an RVR is not achieved. The role of directly acting antiviral agents (DAA) has not been fully evaluated in treatment naïve, non-responders and relapsers in genotype 3 patients. Initial results with the cyclophilin inhibitor Debio-025 are quite encouraging. There is an urgent need for large clinical trials using DAA and host modulators in patients with G3 infection.

Comparison of low-dose pegylated interferon versus standard high-dose pegylated interferon in combination with ribavirin in patients with chronic hepatitis C with genotype 3: an Indian experience.

BACKGROUND AND AIMS: In chronic hepatitis C virus (HCV) infection with genotype 3, therapy with pegylated interferon (peg-IFN) alfa-2b in a dose of 1.5 mug/kg/week and ribavirin (800-1000 mg/day) is recommended for 24 weeks. Reduced doses of peg-IFN may increase compliance and decrease cost and adverse events. This study aimed to assess the safety and efficacy of two different regimens of peg-IFN alfa-2b, in combination with ribavirin, in genotype 3 patients. METHODS: A total of 103 liver biopsy-proven chronic HCV patients with genotype 3, having alanine aminotransferase levels >1.2 x ULN and positive HCV-RNA were randomized into two groups: group I (n = 76; age, 43.1 +/- 11.4 years; male/female, 67/9) received peg-IFN 1.0 mug/kg/week + ribavirin 10.6 mg/kg/day, while group II (n = 27; age, 37.3 +/- 11.6 years; male/female, 21/6) received peg-IFN 1.5 microg/kg/week + ribavirin 10.6 mg/kg/day. Patients in both groups were treated for 24 weeks. End of treatment viral response (ETVR) and sustained viral response (SVR) after a 6-month follow-up period were assessed. RESULTS: In both groups I and II, one patient was lost to follow-up, while one patient in group II withdrew due to side-effects. ETVR was seen in 72/76 (94.7%) of patients in the low dose group and 24/27 (88.9%) of patients in the high dose group (P = 0.375). SVR was seen in 60/76 (78.9%) of patients in the low dose group and 25/27 (92.6%) of patients in the high dose group (P = 0.145). Age (Pearson correlation coefficient = 0.263; P = 0.008) and fibrosis (correlation coefficient, 0.263; P = 0.008) showed a significant correlation with the SVR. CONCLUSION: In patients with genotype 3, peg-IFN at 1.0 microg/kg/week with ribavirin is as effective as peg-IFN at 1.5 mug/kg/week with ribavirin.

Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support.

Conventionally, some bioartificial liver devices are used with separate plasmapheresis unit to separate out plasma from whole blood and adsorbent column to detoxify plasma before it passes through a hepatocytes-laden bioreactor. We aim to develop a hybrid bioreactor that integrates the separate modules in one compact design improving the efficacy of the cryogel based bioreactor as a bioartificial liver support. A plasma separation membrane and an activated carbon cloth are placed over a HepG2-loaded cryogel scaffold in a three-chambered bioreactor design. This bioreactor is consequently connected extracorporeally to a rat model of acute liver failure for 3 h and major biochemical parameters studied. Bilirubin and aspartate transaminase showed a percentage decrease of 20-60% in the integrated bioreactor as opposed to 5-15% in the conventional setup. Urea and ammonia levels which showed negligible change in the conventional setup increase (40%) and decrease (18%), respectively in the integrated system. Also, an overall increase of 5% in human albumin in rat plasma indicated bioreactor functionality in terms of synthetic functions. These results were corroborated by offline evaluation of patient plasma. Hence, integrating the plasmapheresis and adsorbent units with the bioreactor module in one compact design improves the efficacy of the bioartificial liver device.

CCR5Delta32 mutation does not influence the susceptibility to HCV infection, severity of liver disease and response to therapy in patients with chronic hepatitis C.

AIM: To study whether CCR5Delta32 mutation was associated with viral infection and severity of liver disease. METHODS: Two hundred and fifty two histologically proven, chronic HCV patients (mean age: 41 +/- 14 years; M/F: 164/88) were genotyped. PCR based genotyping of 32 bp deletion at the CCR5 locus was done. Four-hundred and eight matched healthy controls were studied to assess susceptibility to HCV infection. To assess correlation of immune gene polymorphism with severity of HCV related liver disease, patients with chronic HCV infection were divided into those with a fibrosis score of <= 2 (mild) or > 2 (severe) and histological activity index (HAI) of <= 5 or > 5. For correlation between CCR5Delta32 mutations and response to therapy, 129 patients who completed therapy were evaluated. RESULTS: The majority (89.4%) of the patients were infected with genotype 3. The frequency of homozygous CCR5Delta32 mutants was comparable to HCV patients as compared to the healthy controls (0.7% vs 0%, P = 0.1). Further more, the frequency of CCR5Delta32 mutation was comparable in patients with mild or severe liver disease. (P = NS). There was also no association observed with response to therapy and CCR5Delta32 mutation. CONCLUSION: CCR5Delta32 mutation does not have a role in disease susceptibility, severity or response to therapy in patients with chronic hepatitis C infection.

Combination of pegylated interferon and lamivudine for patients with chronic hepatitis B who have failed treatment.

BACKGROUND: Treatment of chronic hepatitis B (CHB) alone with interferon or lamivudine alone or in combination is effective in only a small proportion of patients. Treatment of patients in whom antiviral therapy fails is challenging. This study was made to determine the efficacy of combined pegylated interferon alpha (peg-IFN) and lamivudine in patients with CHB who had failed to respond to antiviral treatment. METHODS: Twenty patients with CHB proven by liver biopsy, with ALT levels >1.5 X ULN, HBV DNA levels>141,500 copies/ml, and previous treatment failure with an adequate regimen were treated with a combination of peg-IFN 1.5 microg/kg and lamivudine 100 mg/day for 52 weeks and followed up for a further 24 weeks. Biochemical response was defined as normalization of ALT and DNA response as HBV DNA<141,500 copies/ml. Secondary efficacy measures included HBsAg loss, HBeAg loss and appearance of anti-HBe (in cases of HBeAg-positive patients). RESULTS: Twenty patients were treated, of whom 16 were HBeAg positive. At 52 weeks, normal ALT was seen in 10 (50%) (8 of 16 HBeAg+ and 2 of 4 HBeAg-), HBV DNA response in 5 (25%) (5 of 16 in HBeAg+ and none in HBeAg-), and HBeAg loss with appearance of anti-HBe in 5 (31.3%) of the 16 HBeAg positive patients. At 76 weeks, 8 (80%) of the 10 patients with normal ALT at 52 weeks relapsed, with normal ALT only in 2 (10%) (1 of 16 HBeAg+ and 1 of 4 HBeAg-), and all 5 patients who had a DNA response at 52 weeks relapsed at 76 weeks and had no DNA response. HBeAg loss with appearance of anti-HBe was seen in 1 (6.3%) of 16 HBeAg-positive patients. None of the patients lost HBsAg. CONCLUSIONS: The combination of peg-IFN and lamivudine for 52 weeks is not effective for treatment of CHB patients with a failed treatment. New treatment strategies need to be developed.

Fabrication of macroporous cryogels as potential hepatocyte carriers for bioartificial liver support.

Two different cryogels composed of copolymer of acrylonitrile (AN) and N-vinyl-2-pyrrolidone (NVP) (poly(AN-co-NVP)) and interpenetrated polymer networks (IPN) of chitosan and poly(N-isopropylacrylamide) (poly(NiPAAm)-chitosan) were fabricated by gelation at sub-zero temperatures. The two cryogels possess an interconnected network of macropores of size 20-100 µm and efficient transport properties as determined by physiochemical analysis. Both cryogels support in vitro growth and function of fibroblasts (COS-7) and human liver hepatocarcinoma cells (HepG2). The cryogels are hemocompatible as demonstrated by low albumin adsorption and platelet adherence. Furthermore, in vivo implantation of poly(NiPAAm)-chitosan cryogel in mice shows its biocompatibility with the surrounding tissue. Primary rat hepatocytes grown on poly(NiPAAm)-chitosan cryogel for 96 h formed cellular aggregates and maintained their functions in terms of, ammonia removal, ureagenesis and drug detoxification. Cryogel-based closed continuous bioreactor systems could maintain HepG2 cells at high density for 7 days. Off-line clinical evaluation of these cryogel-based bioreactors showed the ability of immobilized cells to detoxify circulating plasma obtained from patients with acute on chronic liver failure (ACLF). Altogether, the presented data suggests cryogels as a potential bioreactor matrix for bio-artificial liver support system.

Endoscopic treatment of gastric varices.

Gastric varices (GV) are present in one in 5 patients with portal hypertension and variceal bleeding. GV bleeds tend to be more severe with higher mortality. High index of suspicion, early detection and proper locational diagnosis are important. An algorithmic approach to the management of GV bleeding prevents rebleeds and improves survival. Vasoactive drugs should be started with in 30 minutes (door to needle time) and early endotherapy be done. Cyanoacrylate injection in experienced hands achieves hemostasis in >90% patients. A repeat session is sometimes needed for complete obturation of GV. Transjugular intrahepatic portosystemic shunt and balloon retrograde transvenous obliteration are effective rescue options. Secondary prophylaxis of GV bleeding is done with beta-blocker and endotherapy.

A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices.

OBJECTIVE: Treatment of bleeding gastric varices (GVs) is still controversial, mainly because of anecdotal studies or inclusion of patients with GVs located at different sites that have variable incidences of bleeding. A prospective study was undertaken to compare the efficacy and safety of GV sclerotherapy using alcohol and GV obturation using cyanoacrylate glue. METHODS: Thirty-seven consecutive patients with portal hypertension and endoscopic evidence of isolated GVs, 17 presenting with histories of active bleeding, were randomized to receive endoscopic intervention either with alcohol (n = 17) or with cyanoacrylate glue (n = 20) injection. Variceal obliteration, rebleeding, or death was the endpoint. RESULTS: The glue was significantly more effective in achieving variceal obliteration than alcohol (100% vs 44%, p < 0.05). Furthermore, this could be achieved in a significantly shorter period (2.0 +/- 1.6 vs 4.7 +/- 3.2 wk, p < 0.05) and with a smaller volume of the agent. Cyanoacrylate glue injection could achieve arrest of acute GV bleeding more often than alcohol (89% vs 62%), and the need for rescue surgery was less; the difference was, however, not significant. Six patients died from uncontrolled GV bleeding, four being in the alcohol group. During a mean follow-up of 15.4 +/- 3.7 months there was no recurrence of GVs in either group. CONCLUSIONS: Our results show that cyanoacrylate is more effective and achieves GV obliteration faster than injection sclerotherapy with alcohol. It also appears to be more useful in controlling acute GV bleeding, with less of a need for rescue surgery.