Hepatitis: Sarin SK

Kumar M, Sarin SK. · Department of Gastroenterology, G.B. Pant Hospital, Affiliated to the University of Delhi, New Delhi, India. · Aliment Pharmacol Ther. · Pubmed #18373730 No free full text.

Abstract: BACKGROUND: There is a renewed interest in use of combination therapies in treatment-naïve chronic hepatitis B (CHB) because of limitations of monotherapies. AIM: To discuss the current status of combination therapies in treatment-naïve CHB. METHODS: PubMed search was done using 'combination', 'sequential' and 'chronic hepatitis B' as the search terms. RESULTS: The two most popular combination therapies include 'combination of nucleos(t)ide analogues' and 'combination of interferons and nucleos(t)ide analogues'. Combination therapies using two nucleos(t)ide analogues do not lead to higher long-term efficacy. However, addition of a nucleos(t)ide analogue with a good resistance profile to a nucleos(t)ide analogue with a lower genetic barrier to resistance decreases the risk of emergent resistance to the latter. Greater sustained virological, biochemical and seroconversion rates are observed with addition of lamivudine to conventional interferon, but pegylated-interferon monotherapy is equally effective as combination with lamivudine. Again, resistance to lamivudine is lower with its combination with interferons. CONCLUSIONS: The answer to the question whether hepatitis B can be treated better with combination or monotherapy remains largely unknown. Additional trials are warranted of combination therapies of peginterferon and potent nucleos(t)ide analogues or therapies with the combined use of nucleos(t)ide analogues or immunomodulators.

Sarin SK, Satapathy SK, Chauhan R. · Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India. · J Gastroenterol Hepatol. · Pubmed #12472956 No free full text.

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Agarwal S, Sarin SK. · Department of Gastroenterology, G B Pant Hospital, New Delhi. · Indian J Gastroenterol. · Pubmed #11293181 No free full text.

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Mishra A, Saigal S, Gupta R, Sarin SK. · Department of Gastroenterology, G. B. Pant Hospital, New Delhi, India. · Am J Gastroenterol. · Pubmed #10445566 No free full text.

Abstract: Association of hepatitis viruses with acute pancreatitis in the setting of nonfulminant viral hepatitis is rare. We report six cases of nonfulminant viral hepatitis complicated by acute pancreatitis, including the first documented case of hepatitis E virus (HEV) associated acute pancreatitis. The other five patients had acute viral hepatitis caused by hepatitis A infection. Besides features of viral hepatitis, the presence of typical abdominal pain, high serum amylase, and ultrasound or CT scan features suggested the diagnosis of acute pancreatitis. This complication generally developed in the initial phase of the hepatitic illness. All of the patients had mild to moderate pancreatitis that recovered uneventfully with conservative treatment.

Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. · Department of Gastroenterology, GB Plant Hospital, New Delhi, India. · J Gastroenterol Hepatol. · Pubmed #17444848 No free full text.

Abstract: BACKGROUND AND AIM: Inhibition of tumor necrosis factor (TNF)-alpha is a logical approach to manage patients with non-alcoholic steatohepatitis (NASH). Pentoxifylline reduces TNF-alpha and alanine aminotransferase (ALT) levels in patients with NASH. The aim of the present paper was to study if pentoxifylline can improve histological injury in patients with NASH. METHODS: Nine patients (mean age 31.6 +/- 7.2 years) with histologically proven NASH and with persistently elevated ALT (>1.5 times) were given pentoxyfylline at a dosage of 400 mg t.i.d. for 12 months. Besides biochemical assessment, a repeat liver biopsy was performed and the degree of inflammation and fibrosis was compared. RESULTS: After 12 months of therapy a significant reduction in ALT (111 +/- 53 IU/L vs 45 +/- 19 IU/L, P = 0.003) and aspartate aminotransferase (AST) (61 +/- 27 IU/L vs 33 +/- 12 IU/L, P = 0.005) levels was observed. Steatosis and lobular inflammation each reduced in 55% and six (67%) patients down-staged on Brunt's staging (P = 0.009). Four out of six patients with baseline fibrosis had reduction in their fibrosis stage. CONCLUSIONS: Long-term pentoxyfylline therapy effectively achieves sustained biochemical improvement. This correlates well with histological resolution of the disease.

Sarin SK, Sandhu BS, Sharma BC, Jain M, Singh J, Malhotra V. · Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India. · J Viral Hepat. · Pubmed #15500556 No free full text.

Abstract: Currently no therapy is given to patients with chronic hepatitis B virus (HBV) infection who are HBeAg positive with normal alanine aminotransferase (ALT) levels. Steroid priming has been shown to enhance T-helper-1 (Th-1) cell response. Lamivudine may restore immunologic competence against HBV by causing a sudden decline in the level of the virus. We examined the efficacy of lamivudine pulse therapy on the seroconversion from HBeAg to anti-HBe. This was a prospective single-blinded trial including 27 patients with chronic hepatitis B, HBeAg positive with ALT < or =1.5 times upper limit of normal (ULN). Lamivudine was administered initially for 4 weeks, then stopped for 2 weeks and later restarted and continued till 3 months after seroconversion or completion of 2 years of therapy. Twenty-six patients completed the study. Lamivudine withdrawal led to a rise in ALT levels above the ULN in 11 (42.3%) patients at 6 weeks; seven of them (63.6%) lost HBeAg compared with only two of the 15 patients (13.3%), in whom ALT levels did not rise (P = 0.011). As one patient showed a relapse, a total of eight (31%) patients responded to lamivudine pulse therapy over a mean period of 17.3 +/- 4.5 months. Responders had a higher serum albumin (P < 0.05), a lower fibrosis score (P < 0.05), and a relatively high baseline serum ALT levels (P = 0.024) than the nonresponders. YMDD mutations developed in three patients and none responded. No patient developed hepatic decompensation. Hence lamivudine pulse therapy has potential in converting HBeAg-positive, 'not-treat-worthy' (ALT < 1.5 ULN) patients to treat-worthy (ALT > 1.5 ULN) in 42%, with sustained HBeAg and HBV DNA loss in 31% patients. The effects are possibly because of a combination of antiviral and immunomodulating activities of lamivudine.

Sarin SK, Goyal A, Kumar S, Guptan RC, Hashmi AZ, Sakhuja P, Malhotra V. · Department of Gastroenterology, G.B. Pant Hospital, New Delhi 110002, India. · Hepatobiliary Pancreat Dis Int. · Pubmed #14969836 links to  free full text

Abstract: BACKGROUND: Standard combination-therapy of ribavirin with alternate day interferon (IFN) in patients with chronic hepatitis C (CHC) has been reported to achieve 30%-55% sustained viral response. Early reduction of viral load by daily dosage of IFN could enhance viral clearance. However, the duration of daily dosage protocol and the likely side-effects have not been well studied. We compared the efficacy and safety of a 4- vs 12-week daily IFN dosage in patients with CHC. METHODS: Fifty-nine, histologically proven CHC patients having ALT levels >1.5 x ULN were divided randomly into 2 groups, group I was given IFN 3 MIU daily for 4 weeks, followed by tiw up to 12 months and group II was given IFN 3 MIU daily for 12 weeks, followed by tiw up to 12 months. Ribavirin was given in a dose of 800-1200 mg/d for 12 months. RESULTS: Fifty-two of the 59 patients (group I=28; group II=24) completed the study. The pretreatment variables and the prevalence of HCV genotype 1 were comparable between the groups. Nine patients (29%) in group I and 6 (25%) in group II had stage 3, 4 fibrosis. At the end of 4, 12, 24 and 52 weeks, HCV RNA negativity was observed in 27%, 54%, 65% and 71% in group I and 38%, 54%, 71% and 75% in group II, respectively (P=ns). Four of the eight (50%) patients with genotype 1 and 30 (69.8%) of 43 patients with genotype non-1 responded to therapy (P=ns). Sustained viral response was achieved in 61% and 71% in groups I and II, respectively. None of the variables predicted non-response precisely. No serious adverse effects were observed and they were comparable between the two groups. CONCLUSION: Daily IFN dosage with ribavirin is safe and can achieve response in up to 65% patients. Since the efficacy of a 4-week daily dosage of IFN is comparable to a 12-week schedule, we recommend the former regimen.

Guptan RC, Thakur V, Kazim SN, Sarin SK. · Department of Gastroenterology, GB Pant Hospital, New Delhi, India. · J Gastroenterol Hepatol. · Pubmed #12121506 No free full text.

Abstract: BACKGROUND AND AIMS: Non-response to interferon (IFN) monotherapy is a major therapeutic problem in the management of chronic hepatitis B infection. The efficacy of combination therapy to enhance the immunomodulatory effect of IFN by combining granulocyte-macrophage colony-stimulating factor (GMCSF) or decreasing viral load by adding an antiviral agent such as lamivudine was evaluated prospectively. METHODS: Twenty-four patients with chronic hepatitis B who were non-responders to previous IFN therapy were randomized to receive an IFN and GMCSF (group A, n = 10) or IFN and lamivudine (group B, n = 14) combination for 6 months. The end-of-treatment response was assessed by hepatitis B virus (HBV)-DNA and hepatitis B e antigen (HBeAg) determination. RESULTS: All patients successfully completed both the treatment schedules. The mean age, alanine aminotransferase (ALT) levels, liver histology, HBV-DNA levels and distribution of HBV genotypes were comparable between the two groups. At the end of treatment there was a significant decrease in mean ALT levels. The HBV-DNA and HBeAg loss was seen in six of 10 (60%) patients in group A and in seven of 14 (50%) patients in group B. During a mean follow-up of 15 +/- 3 months, two of six (33%) patients in group A and three of seven (43%) patients in group B relapsed with HBV-DNA and HBeAg positivity, which meant an overall sustained response of 40% and 28%, respectively. None of the factors such as HBV viral load, ALT levels or liver histology could predict the non-response to combination therapy or occurrence of relapse. There was a trend in patients with genotype A compared with genotype D towards non-response to therapy, although the difference was not significant. CONCLUSIONS: The combination of IFN plus GMCSF or lamivudine was effective in non-responders to IFN monotherapy. Larger studies using such combination therapies would be helpful in improving treatment strategies for chronic hepatitis B.

Guptan RC, Thakur V, Safary A, Sarin SK. · Department of Gastroenterology, GB Pant Hospital, New Delhi, India. · Vaccine. · Pubmed #11972979 No free full text.

Abstract: BACKGROUND AND AIMS: Hepatitis A virus (HAV) and hepatitis B virus (HBV) are vaccine preventable important childhood acquired infectious diseases in developing countries. In the changing epidemiology of HAV, the utility of such a vaccine in India needs urgent attention. Further, the efficacy of two versus three dose schedule needs to be assessed to improve compliance. SUBJECTS AND METHODS: One hundred healthy school children, aged 1-15 years were recruited in a randomised open study to receive either vaccination schedule: Group I: combined high-dose hepatitis A and B vaccine to be administered on a 0, 6 month schedule intramuscularly; Group II: to be administered on 0, 1, 6 month Twinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) schedule intramuscularly. The seroconversion (> or =1MIU/ml for anti-HBs antibodies and > or =33MIU/ml for anti-HAV antibodies) and seroprotection (anti-HBs > or =10MIU/ml after the third dose of vaccine) rates were determined at months 1, 2, and 7. RESULTS: The mean age and gender was similar between groups: 7.9+/-2.6 years (range 3-15 years). At month 7 all subjects (100%) in both groups were seropositive for anti-HAV antibodies, Group I had higher anti-HAV titres at months 1 or 2 compared to Group II (P=0.025, P=0.040). Group II developed higher seroprotection rates (month 2, P=0.002, month 6, P=0.003) compared to Group I and higher titres (month 2, P=0.001, month 6 P=0.001) compared to Group I. At month 7, the geometric mean titres (GMTs) were comparable between groups and seroprotection reached 100% in both the groups. The incidence of any symptom per dose analysis reported during a 4-day follow-up period was significantly higher in Group I, 53% (52/98) of the documented doses compared to 37% (54/146) in Group II (P=0.018). CONCLUSION: Twinrix vaccine is safe and highly immunogenic in Indian children. Further study of the high dose vaccine would determine if its two dose regimen is a feasible advantage.

Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. · Department of Gastroenterology, Govind Ballabh Pant Hospital, New Delhi, India. · J Gastroenterol Hepatol. · Pubmed #11595068 No free full text.

Abstract: BACKGROUND AND AIMS: Hepatotoxicity is a major side-effect of antitubercular drugs (ATD). As these drugs are metabolized in the liver, there is a theoretical risk of increased hepatotoxicity in patients with underlying chronic liver disease (CLD). Ofloxacin has antitubercular activity and has exclusive renal clearance. The aim was to study the efficacy and safety of an ofloxacin-based antitubercular regimen for treating tuberculosis in patients with underlying CLD. METHODS: Thirty-one cases were randomly assigned to two drug regimens using WHO dosage schedules: (i) regimen A (n = 15): isoniazid, rifampicin and ethambutol for 2 months, followed by isoniazid and rifampicin for a further 7 months; and (ii) regimen B (n = 16): isoniazid, pyrazinamide, ethambutol and ofloxacin for 2 months, followed by isoniazid, ethambutol and ofloxacin for a further 10 months. Hepatotoxicity was diagnosed if alanine aminotransferase/aspartate aminotransferase increased > fivefold from the baseline or to > 400 IU/L, or if bilirubin increased by > 2.5 mg/dL from the baseline. RESULTS: The response to ATD was achieved in all the patients who completed the therapy. Four (26.6%) patients on regimen A developed hepatotoxicity as compared to none on regimen B (P = 0.043). None of these patients could be restarted on ATD using the same regimen A because of the persistently deranged liver functions. CONCLUSIONS: In patients with tuberculosis who have underlying CLD: (i) an ofloxacin-based antitubercular regimen without rifampicin is as effective as a rifampicin-based regimen; and (ii) a combination of isoniazid with rifampicin is more hepatotoxic than a combination with ofloxacin and pyrazinamide.

Kapoor D, Aggarwal SR, Singh NP, Thakur V, Sarin SK. · Department of Gastroenterology, G.B. Pant Hospital, New Delhi-2, India. · J Viral Hepat. · Pubmed #10607257 No free full text.

Abstract: The response to vaccination with recombinant hepatitis B virus (HBV) vaccine is poor in haemodialysis patients. A defect in the antigen-presenting cells may be responsible for this hyporesponsiveness. To overcome this and to improve the response to HBV vaccine in dialysis patients, we used granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant. Fifteen consecutive patients with chronic renal failure (CRF), commenced on dialysis, were stratified to receive either 40microg HBV vaccine (Engerix-B) at 0, 1, 2 and 6 months (group A, n=9) or 3microg kg-1 GM-CSF (Leucomax) on day 1 followed by the vaccination schedule described above (group B, n=6). All patients were negative for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV) and human immunodeficiency virus (HIV) serology. Titres of antibody to HBsAg (HBsAb) were quantitatively assayed, using enzyme-linked immunosorbent assay (ELISA), at 1, 2, 6 and 7 months from the first dose of vaccination. Only 44% of the patients in group A developed protective antibody levels (mean HBsAb: 22 IU l-1) Fifty per cent of responders developed protective antibody levels (HBsAb >10 IU l-1) only after the fourth dose of vaccination. In contrast, all six patients (100%) in group B developed protective levels of HBsAb (mean HBsAb: 70 IU l-1) (P<0.02). Sixty-seven per cent of the responders were protected after only the second dose of vaccination (P=0.046). No serious adverse effects of GM-CSF were observed in group B. Hence, haemodialysis patients respond poorly to HBV vaccine. GM-CSF is a safe vaccine adjuvant capable of stimulating an earlier and a stronger antibody response to HBV vaccine in haemodialysis patients.

Guptan RC, Thakur V, Raina V, Sarin SK. · Department of Gastroenterology, GB Pant Hospital, New Delhi, India. · J Gastroenterol Hepatol. · Pubmed #10535471 No free full text.

Abstract: BACKGROUND: Nearly 14% of non-alcoholic chronic liver disease in India is related to hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection. There are no clear data available from the literature on the therapeutic management of these patients who often suffer an unfavourable course. METHODS: Fourteen consecutive cases of biopsy-proven chronic liver disease fulfilling the following criteria were included: Child's A or B liver disease, hepatitis B surface antigen positive, HBV-DNA positive, antibody to HCV positive and HCV-RNA positive. Seven patients had chronic liver disease (group I), while the remaining seven patients (group II) had additional disorders (non-Hodgkin's lymphoma (two), acute leukaemia (two), thalassaemia (two), chronic renal failure (one). Interferon alpha-2b (IFN) was given in a dose of 6 MIU thrice weekly for 6 months. Complete response was defined as loss of HBV-DNA and HCV-RNA at 6 months and sustained response (SR) as the sustained loss of HBV-DNA and HCV-RNA for more than 6 months during the follow-up period. RESULTS: At the end of 6 months, alanine aminotransferase (ALT) levels remained unchanged (120 +/- 40 vs 136 +/- 64 IU/L), but six of the seven (86%) patients in group I lost HBV-DNA. All three hepatitis Be antigen (HBeAg)-positive patients lost HBeAg with an early flare of ALT (at 45 +/- 12 therapy days). Two of these patients (29%) lost HCV-RNA. Thus, SR was seen in 29%, while HBV-DNA loss was found in 100% during the follow-up period. In group II patients, there was a significant decrease in ALT (308 +/- 14 vs 65 +/- 25 IU/L, P < 0.001), but only three (43%) patients lost HBV-DNA and two (29%) lost HCV-RNA. One patient with acute leukaemia and another with renal failure had a complete response to IFN, but none of the lymphoma patients showed any antiviral response. CONCLUSIONS: In chronic hepatitis due to dual infection with HBV and HCV, interferon therapy is: (i) safe; (ii) effective (more so in clearing HBV); (iii) often associated with early ALT flare; and (iv) may be less effective if non-Hodgkin's lymphoma is present.

Saxena R, Thakur V, Sood B, Guptan RC, Gururaja S, Sarin SK. · Department of Social and Preventive Medicine, Lady Hardinge Medical College and Department of Gastroenterology, and Blood Bank, G.B. Pant Hospital, New Delhi, India. · Vox Sang. · Pubmed #10474084 No free full text.

Abstract: BACKGROUND AND OBJECTIVES: In Indian blood banks, screening for hepatitis B virus (HBV) is currently done by the EIA method, but no routine screening is done for hepatitis C virus (HCV). MATERIALS AND METHODS: To determine the incidence of transfusion-associated HCV hepatitis, and of any residual transfusion-associated hepatitis (TAH) after HBsAg screening, we prospectively studied 182 patients who underwent surgery and received blood transfusion. These recipients had normal alanine aminotransferase (ALT) and were negative for HBsAg (monoclonal EIA), and anti-HCV (third-generation EIA) before receiving transfusion. RESULTS: Of the 818 blood units transfused after routine screening (average 4.49+/-3.3 U/patient, range 1-14), 14 (1.7% of units) were found to be infected. Of the 182 recipients, 14 (7.69%) developed TAH during a follow-up of 6 months, 3 (21.4%) from HBV, 10 (71.5%) from HCV, and 1 (1.7%) from a coinfection of HBV and HCV. All patients with TAH due to HCV were asymptomatic. One patient with TAH due to HBV (33%) and 5 with TAH due to HCV (50%) developed chronic infection with persistently elevated ALT at 6 months. CONCLUSIONS: With the current screening practices, the incidence of TAH remains high in India and is mainly due to HCV infection. Furthermore, the screening methods for HBV also need to be improved.

Kumar M, Chauhan R, Gupta N, Hissar S, Sakhuja P, Sarin SK. · Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India. · Gastroenterology. · Pubmed #19208347 No free full text.

Abstract: BACKGROUND & AIMS: No information is available about the frequency or factors that predict spontaneous increases in alanine aminotransferase (ALT) levels in asymptomatic Indian patients with chronic hepatitis B virus (HBV) infection who are HB e antigen (HBeAg) negative and have normal ALT levels. METHODS: We followed 217 asymptomatic patients with chronic HBV who were HBeAg negative, anti-HBe antigen (anti-HBe) positive, and had normal ALT levels. Spontaneous increases in ALT levels (ALT flares) were considered to be >2-fold the upper limit of normal (ULN) and were accompanied by HBV DNA levels>or=10(5) copies/mL or a 100-fold increase from the previously measured level. RESULTS: During a median follow-up period of 69.0 months, spontaneous ALT flares occurred in 43 patients (an annual rate of 4.3%), with cumulative probabilities of 10.8% and 47.3% after 5 and 10 years, respectively. Based on multinomial logistic regression, the probability of an ALT flare correlated with age>or=30 years at presentation (odds ratio [OR], 5.31; 95% confidence interval [CI]: 1.53-18.39; P=.008), male sex (OR, 4.54; 95% CI: 1.01-20.76; P=.05), and presence of a precore mutation (OR, 10.99; 95% CI: 3.67-32.92; P<.001). The median time to spontaneous ALT flare after enrollment was 25 months (range, 1-128 months; 10th percentile=3.4 months). CONCLUSIONS: In asymptomatic patients with chronic HBV infection who have normal ALT levels and are HBeAg negative, the annual rate of ALT flares was 4.3%. Precore mutants, male sex, and age>or=30 years at presentation are independent predictors for an ALT flare. A follow-up every 3 months can capture up to 90% of flares and would help identify patients who require antiviral therapy.

Kumar GT, Kazim SN, Kumar M, Hissar S, Chauhan R, Basir SF, Sarin SK. · Department of Gastroenterology, G. B. Pant Hospital, New Dehli 110002, India. · J Gastroenterol Hepatol. · Pubmed #19207682 No free full text.

Abstract: BACKGROUND: The association and profile of surface gene mutations with viral genotypes have been studied in patients with chronic hepatitis B virus (HBV) but not in subjects with occult HBV infection. AIM: This study aimed to investigate the association of surface gene mutations with viral genotypes in occult HBV infection. MATERIALS & METHODS: Of 293 family contacts of 90 chronic HBV index patients, 110 consented for the study. Of 110 subjects, 97 were hepatitis B surface antigen (HBsAg) negative. HBV genotyping was done using direct DNA sequencing. The S-gene was also sequenced in 13 chronic hepatitis B patients to serve as controls. RESULTS: Twenty-eight (28.8%) of the 97 subjects had occult HBV infection. Bidirectional sequencing of partial S-gene was successful in 13 of them. Seven (53.8%) of the viral sequences are genotype A1, two (15.3%) each having genotypes D5&D2 and one each (7.6%) having D1&G genotypes. Seven (53.8%) of the 13 HBsAg positive patients, had genotype D&6 (46.1%) genotype A. A128V & T143M mutations were observed in 5 of 13 (38.4%) subjects and A128V & P127S in 2 of 13 (15.3%) patients (P = 0.385). A128V mutation was seen in two (15.3%) subjects with D2 genotype, while T143M mutation was seen in three (23.07%) subjects with A1genotype. At aa125, three (23.07%) subjects with D5 genotype had methionine instead of threonine. There were wild type sequences in five (38.4%) subjects, one each of D1, G genotypes (20%) and four A1 (80%) genotypes. None of the subjects had G145R mutation. CONCLUSIONS: Occult HBV infection may be common in household contacts of chronic HBV infected patients. Equal prevalence of A&D sub-genotypes was present in occult HBV subjects and in chronic HBV patients. Mutations of the S-gene are genotype specific in both occult as well as chronic HBV infection.

TrehanPati N, Geffers R, Sukriti, Hissar S, Riese P, Toepfer T, Buer J, Kumar M, Guzman CA, Sarin SK. · Department of Gastroenterology, GB Pant Hospital, New Delhi, India. · Hepatology. · Pubmed #19185001 No free full text.

Abstract: CD4+ T and regulatory T cells (Tregs) seem to play a key role in persistence of hepatitis B virus (HBV) infection. However, the molecular events by which Tregs exert their modulatory activity are largely unknown. The transcriptional profiles of CD4+ T cells of healthy controls (HCs) and patients affected by acute hepatitis B (AVH-B) or chronic hepatitis B (CHB) infection were established using a custom expression array consisting of 350 genes relevant for CD4+ T cell and Treg function. These studies were complemented by real-time reverse-transcription polymerase chain reaction. Peripheral blood mononuclear cells (PBMCs) were also analyzed for the presence of Tregs, which were more abundant in the acute stage of the disease (7%) than in HCs and CHB infection (HCs versus AVH-B, P = 0.003; AVH-B versus CHB, P = 0.04). One hundred eighteen genes (34%) intrinsically differentiate HBV-infected patients from HCs. Using gene ontology, we identified T cell receptor signaling and clusterization, mitogen-activated protein kinase kinase signaling, cell adhesion, cytokines and inflammatory responses, cell cycle/cell proliferation, and apoptosis as the most prominent affected modules. A higher expression of CCR1, CCR3, CCR4, CCR5, and CCR8 was seen in AVH-B than in CHB-infected patients and HCs. Annotation of the interconnected functional network of genes provided a unique representation of global immune activation during acute infection. Almost all genes were down-regulated in patients with CHB infection. Conclusion: The fingerprints enable clear discrimination between patients suffering from AVH-B or CHB infection. The observed profiles suggest accumulation of effector T cells with a potential role in necro-inflammation during the acute stage. Subsequent down-regulated effector functions support the hypothesis of suppressed CD4+ effector T cells favoring viral persistence in the chronic infection stage.

Sharma P, Kumar A, Sharma BC, Sarin SK. · Department of Gastroenterology, G B Pant Hospital, University of Delhi, New Delhi, India. · J Hepatol. · Pubmed #19155081 No free full text.

Abstract: BACKGROUND/AIMS: Severe alcoholic hepatitis (AH) is associated with very high mortality. Tumor necrosis factor-alpha (TNF-alpha) contributes to the progression of AH and TNF-alpha antagonists like infliximab may help in ameliorating the severity and complications of AH. There is a scarcity of data regarding the safety and efficacy of infliximab monotherapy in the treatment of AH. We evaluated infliximab monotherapy in patients with severe AH. METHODS: Patients with severe AH (Maddrey's score>32) received a single dose of infliximab 5 mg/kg IV. The primary endpoint was survival assessed at one and two months. The secondary endpoints were reduction of the Maddrey's DF and development of any bacterial infections. Predictors of survival were assessed at admission and at day 7. RESULTS: Nineteen patients were enrolled in the study and received infliximab. By the end of one month two patients died resulting in 1-month survival of 17/19 (89%). By the end of two months four additional patients died resulting in 2-month survival of 68%. At the end of one and two months, compared to baseline, there was significant improvement in median values of Maddrey's DF (p<0.05). Median serum TNF-alpha levels decreased from 45 (range 11-19,880) at baseline to 20 (range 4-8600) pg/mL at 4 weeks (p=0.001). CRP levels, MELD score, and absolute neutrophil count decreased significantly. Five patients (26%) developed infection: three of them had pneumonia, while two developed a flare of pulmonary tuberculosis. Three patients recovered with treatment but two patients (10%) died (one with pneumonia leading to sepsis and the other of disseminated tuberculosis). Absence of hepatic encephalopathy at admission significantly predicted survival. Among patients who survived only 1/13 (8%) had hepatic encephalopathy at admission while among patients who died 4/6 (67%) had hepatic encephalopathy (p=0.017). Lille score and delta bilirubin at day 7 (DBD7) (defined as [baseline serum bilirubin minus serum bilirubin at day 7] x 100/baseline serum bilirubin), also predicted 2-month mortality. The area under ROC curve of DBD7 values for predicting survival was 0.77 (95% CI 0.55-0.99). DBD7 of >7.5% best predicted survival in the patients (sensitivity 85%, specificity 67%, PPV 85%, NPV 67%, and overall accuracy 79%). CONCLUSIONS: In severe AH, single dose infliximab is associated with improvement in parameters of severity and survival. However, infection remains a concern. Hepatic encephalopathy at admission, Lille score and DBD7 predicted 2-month mortality. Large randomized controlled trials are needed before infliximab can be recommended for AH.

Suneetha PV, Schlaphoff V, Wang C, Stegmann KA, Fytili P, Sarin SK, Manns MP, Cornberg M, Wedemeyer H. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · J Immunol Methods. · Pubmed #19135447 No free full text.

Abstract: Peptide pools are routinely used to study antigen specific T cell responses, both in epitope discovery as well as immune monitoring. However, optimal assay conditions such as concentration of peptides or the best possible number of peptides per pool have not been defined. Thus, we examined whether different peptide concentrations or varying number of peptides per pool influence effector functions of antigen-specific human T-cells. PBMC isolated from HLA-A2-positive individuals with known responses to frequently recognised dominant CD8+ T cell epitopes derived from four different viruses (influenza virus, CMV, EBV, or HCV) were studied. PBMC were cultured with one of these HLA-A2 restricted peptides and varying concentrations of overlapping peptide pools derived from unrelated viruses specific for the hepatitis D and E viruses, the subjects have not been exposed to. Importantly, unrelated peptide pools inhibited the proliferation of IV-M1(58), CMVpp65(495-503), EBV-BMLF(1259-267) and HCV NS3(1073)-specific CD8 T-cells in a dose dependent manner. Similarly, an increase in the number of peptides per pool also impaired antigen specific CD8+ T cell proliferation. In contrast, secretion of cytokines such as IL-2, IL-10, IFN-gamma, TNF-alpha or IP-10 as well as cytotoxicity was not affected by these unrelated peptide pools. The inhibition of proliferation could be restored by blocking PD-1/PDL-1 interaction and was not dependent on DMSO when DMSO concentration was <or=0.5%. Thus, peptide-specific CD8 T-cell proliferation but not cytokine production may be largely underestimated when using a peptide pool which warrants caution in immunomonitoring during clinical trials and in epitope discovery studies.

Kumar M, Choudhury A, Manglik N, Hissar S, Rastogi A, Sakhuja P, Sarin SK. · Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India. · Am J Gastroenterol. · Pubmed #19098853 No free full text.

Abstract: OBJECTIVES: Chronic hepatitis C virus infection is associated with insulin resistance (IR), and both host and viral factors are important in its development. The association and the predictors of IR in chronic hepatitis B virus (CHBV) infection remain unclear. METHODS: A total of 69 CHBV-infected subjects were examined to study the relationship between histological findings and anthropometric and biochemical data, including IR determined by the homeostasis model assessment (HOMA-IR). To assess the influence of CHBV infection on IR independent of any effect of hepatic fibrosis, overweight, or sex we also compared fasting serum insulin, C-peptide, HOMA-IR, HOMA-beta (measure of beta-cell function) and C-peptide-insulin ratio (to distinguish impaired insulin degradation (low ratio) from insulin hypersecretion (normal ratio)) levels between the subset of 14 male normal weight (body mass index, BMI<23) CHBV patients with stage 0 or 1 hepatic fibrosis and 50 male normal weight healthy controls matched by age and anthropometry (BMI and waist circumference). RESULTS: A total of 31 (44.9%) CHBV-infected patients were overweight (BMI>23 kg/m(2)) and 18 (26.1%) were obese (BMI>25 kg/m(2)). IR was seen in 34 (49.3%) patients. BMI (Spearman's coefficient=-0.436; P<0.001) and serum triglyceride levels (Spearman's coefficient=-0.307; P=0.010) were univariate predictors of IR. In multiple linear regression analysis, only BMI (P<0.001) was an independent predictor of HOMA-IR. The subgroup of CHBV-infected patients and the controls had comparable levels of all markers of IR, including fasting glucose, insulin, C-peptide, and HOMA-IR. CONCLUSIONS: IR in CHBV-infected patients is a reflection of the host metabolic profile and CHBV infection is not in itself correlated with IR.

Kumar M, Sarin SK. · Department of Gastroenterology, Academic Block, GB Pant Hospital, New Delhi-110002, India. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072396 No free full text.

Abstract: Lamivudine was the first nucleoside analog for the treatment of chronic hepatitis B (CHB). It is well-tolerated and induces a decrease in serum HBV DNA levels associated with normalization of serum alanine aminotransferase levels. However, a sustained response with hepatitis B 'e' antigen to anti-hepatitis B e seroconversion is obtained in a smaller proportion of patients and hepatitis B surface antigen loss is exceptional. The response is maintained during therapy, and needs to be continued indefinitely in the majority of patients since withdrawal of treatment is generally followed by a rapid reappearance of the virus. However, mutations can be induced in long-term treatment.

Hissar SS, Kumar M, Tyagi P, Goyal A, Suneetha PV, Agarwal S, Rastogi A, Sakhuja P, Sarin SK. · Department of Gastroenterology, G.B. Pant Hospital, New Dehli 110002, India. · J Gastroenterol Hepatol. · Pubmed #19032460 No free full text.

Abstract: BACKGROUND AND AIM: The rate of fibrosis progression per year can predict the time for the development of cirrhosis in chronic hepatitis C (CHC). We assessed the rate of fibrosis progression and the predictors of disease severity in Indian CHC patients. METHODS: Of the 355 treatment-naïve, histologically-proven CHC patients, the precise duration of infection (from the time of exposure to HCV until liver biopsy) could be determined in 213 patients (age = 41.6 +/- 14.7 years, male : female = 139 : 74, genotype 3 = 75%). The rate of fibrosis progression per year was calculated. The correlation of the advanced degree of fibrosis and age, duration of infection, age at the onset of infection, sex, mode of infection, hepatitis C virus (HCV) genotype, histological activity index (HAI), and the presence of diabetes mellitus were studied. RESULTS: The median rate of fibrosis progression per year was 0.25 (0.0-1.5) fibrosis units. The fibrosis progression rate was higher in patients who acquired infection at > 30 years of age, those < 30 years (0.33 vs 0.15; P < 0.001), and those who acquired HCV infection with a history of blood transfusion than with other modes of transmission (0.25 vs 0.19; P = 0.04). The median time to progress to cirrhosis was 16 years. The multivariate analysis found that the HAI score (odds ratio [OR]= 14.03; P < 0.001) and the duration of infection > 10 years (OR = 4.83; P < 0.001) correlated with severe liver disease (fibrosis > or = 3). CONCLUSION: The median rate of fibrosis progression per year in Indian CHC patients is 0.25 fibrosis units. A higher HAI and longer duration of infection are associated with a significant risk of advanced liver disease, and merit early therapeutic interventions.

Chauhan R, Kazim SN, Kumar M, Bhattacharjee J, Krishnamoorthy N, Sarin SK. · Department of Gastroenterology, G. B. Pant Hospital, Delhi University Affiliated, Room No. 201, Academic Block, New Delhi 110002, India. · World J Gastroenterol. · Pubmed #18985816 links to  free full text

Abstract: AIM: To confirm the presence of recombination, full-length hepatitis B virus (HBV) from chronic patients was sequenced and analyzed. METHODS: Full-length HBV genomes from 12 patients were amplified and sequenced in an automated sequencer. Phylogenetic analysis was carried out on full-length, Core and preS2/Surface regions using MEGA software. SimPlot Boot Scanning and amino acid sequence analysis were performed for confirmation of recombination. RESULTS: Eight patients were infected with genotype D strain; one patient with genotype A and three patients had genotype A and D recombination; two of them had cirrhosis and one had hepatocellular carcinoma. Phylogenetic analysis of core and preS2/surface regions separately showed evidence of genotype A and D recombination. The breakpoints of recombination were found to be at the start of preS2 and at the end of surface coding regions. CONCLUSION: We identified and characterized recombinant A and D genotype HBV in hepatitis B surface antigen (HBsAg)-positive patients.

Sukriti, Pati NT, Sethi A, Agrawal K, Agrawal K, Kumar GT, Kumar M, Kaanan AT, Sarin SK. · Department of Gastroenterology, G.B. Pant hospital, New Dehli, India. · J Gastroenterol Hepatol. · Pubmed #18761556 No free full text.

Abstract: BACKGROUND AND AIM: The risk of acquiring hepatitis B virus (HBV) infection through exposure to blood or its products is highest amongst health care workers (HCWs). Despite potential risks, a proportion of HCWs never get vaccinated. India is second to China in the numbers of people with chronic HBV. This study aimed to investigate the vaccination practices and the prevalence of HBV infection in HCWs in India. METHODS: A total of 2162 HCWs were screened for the presence of serological markers of HBV and hepatitis C virus (HCV). Occult HBV infection was tested by detection of HBV-DNA for surface and core regions by nested polymerase chain reaction in HBsAg-negative and IgG anti-hepatitis core antigen-positive subjects. RESULTS: Only 1198 (55.4%) of the 2162 HCWs screened had been vaccinated; and 964 (44.6%) were not vaccination-status conscious; of these HCWs, 600 (27.7%) had never been vaccinated and 364 (16.4%) were unaware of their vaccination status. Protective (> 10 IU/mL) anti-hepatitis B surface (anti-HBs) antigen titers were seen in only 61.7%. The anti-HBs titers were found to be lower with the passage of time; the median anti-HBs titers in subjects who were vaccinated > 10 years ago were significantly lower than those who had been vaccinated < 5 years ago (P < 0.001). One percent of HCWs were HBsAg-positive, and 24.7% of 700 HCWs screened had past exposure (IgG-anti-HBc-positive). Occult HBV was detected in 5% of 120 positive subjects with past exposure; all had anti-HBs titers > 10 IU/mL. CONCLUSIONS: Even today, 28% HCWs in India are unvaccinated and 17% are unaware of their vaccination status. This data suggests that use of hepatitis B immune globulin be mandatory in needle-pricked HCWs in India, and that implementation of awareness strategies is urgent. Since the anti-HBs titers decline in a fair proportion, there is justification for giving a booster dose of vaccine 10 years after primary vaccination to HCWs in India.

Sharma P, Sharma BC, Tyagi P, Kumar M, Sarin SK. · Department of Gastroenterology, G. B. Pant Hospital, New Delhi, India. · Liver Int. · Pubmed #18710429 No free full text.

Abstract: BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis may have prognostic significance with regard to the development of clinical hepatic encephalopathy (HE) and deterioration in patient quality of life. Its prevalence in acute viral hepatitis (AVH) is not known. PATIENTS AND METHODS: Consecutive 20 AVH patients (age, 29.9+/-7.9 years; M:F 18:2, hepatitis A:B:E: 2:16:2) without overt encephalopathy were evaluated for MHE and followed up. All patients underwent number connection tests - A and B, figure connection tests - A and B, digit symbol test and object assembly test and critical flicker frequency (CFF) at baseline and after the resolution of icterus. MHE was diagnosed if two or more psychometric tests were abnormal. RESULTS: Prevalence of MHE (n=5) was 25%, which resolved on follow-up during the anicteric resolution phase. Five (25%) patients had greater than two abnormal psychometry tests and four (20%) had CFF <38 Hz. CFF alone had sensitivity and specificity of 80 and 100%, respectively, in the diagnosis of MHE. There was significant difference in the performance of CFF during the icteric and resolution phase of AVH (40.6+/-3.4 vs 41.8+/-2.1 Hz, P=0.04). Arterial ammonia level were higher in patients with MHE compared with patients without MHE (88.2+/-23.5 vs 53.8+/-10.9 micromol/L, P=0.001). On univariate analysis fasting ammonia level at baseline was significantly associated with all the psychometric tests (P=0.001). None of the patients developed HE either in MHE group or in those who did not had MHE at baseline. CONCLUSIONS: MHE occurs in 25% of patients with AVH and resolves on follow up with recovery of AVH. Raised arterial ammonia during the icteric phase is associated with development of MHE.

Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R, Bose S. · Department of Gastroenterology, G. B. Pant Hospital, New Delhi, India. · Gastroenterology. · Pubmed #18471514 No free full text.

Abstract: BACKGROUND & AIMS: There is a paucity of data on hepatitis B virus (HBV) DNA levels and histologic lesions in patients with chronic HBV (CHBV) infection and persistently normal alanine aminotransferase (ALT) levels (PNALT). We studied the ALT, HBV DNA levels, and spectrum of histologic lesions in such patients. METHODS: One thousand three hundred eighty-seven incidentally detected asymptomatic hepatitis B surface antigen (HBsAg)-positive patients with >/=1-year follow-up and either PNALT (n = 189; hepatitis B e antigen [HBeAg(+)], 73; HBeAg(-), 116) or persistently or intermittently elevated ALT (PIEALT; n = 1198; HBeAg(+), 530; HBeAg(-), 668) were included. RESULTS: In the PIEALT and PNALT patients, baseline DNA >/=5-log copies/mL was seen in 73.8% and 60.3% in HBeAg(+) (P = .018) and 76% and 35.3% in HBeAg(-) (P < .001) patients and histologic fibrosis stage >/=2 in 65.5% and 40.2% in HBeAg(+) (P < .001) and 63.9% and 13.8% in HBeAg(-) (P < .001) patients, respectively. Approximately 21% of HBeAg(-) patients with PNALT and HBV DNA <5-log copies/mL had histologically active liver disease (histologic activity index >/=3 and/or fibrosis stage >/=2). CONCLUSIONS: A fair proportion of patients with CHBV infection with PNALT have HBV DNA >/=5-log copies/mL and significant histologic fibrosis. Use of ALT and HBV DNA levels without resorting to liver biopsy to define "inactive carrier state" in HBeAg(-) PNALT patients may miss histologically significant disease in a proportion of patients.