Interferon Alfa-2b Alone or in Combination with Ribavirin for the Treatment of Relapse of Chronic Hepatitis C

BACKGROUND Interferon alfa is the only effective treatment for patients with chronic hepatitis C. Forty percent of patients have an initial response to this therapy, but most subsequently relapse. We compared the effect of interferon alone with that of interferon plus oral ribavirin for relapses of chronic hepatitis C. METHODS We studied 345 patients with chronic hepatitis C who relapsed after interferon treatment. A total of 173 patients were randomly assigned to receive standard-dose recombinant interferon alfa-2b concurrently with ribavirin (1000 to 1200 mg orally per day, depending on body weight) for six months, and 172 patients were assigned to receive interferon and placebo. RESULTS At the completion of treatment, serum levels of hepatitis C virus (HCV) RNA were undetectable in 141 of the 173 patients who were treated with interferon and ribavirin and in 80 of the 172 patients who were treated with interferon alone (82 percent vs. 47 percent, P\u3c0.001). Serum HCV RNA levels remained undetectable 24 weeks after the end of treatment in 84 patients (49 percent) in the combinationtherapy group, but in only 8 patients (5 percent) in the interferon group (P\u3c0.001). Sustained normalization of serum alanine aminotransferase concentrations and histologic improvement were highly correlated with virologic response. Base-line serum HCV RNA levels of 2¬106 copies per milliliter or less were associated with higher rates of response in both treatment groups. Viral genotypes other than type 1 were associated with sustained responses only in the combination-therapy group. Combined therapy caused a predictable fall in hemoglobin concentrations but otherwise had a safety profile similar to that of interferon alone. CONCLUSIONS In patients with chronic hepatitis C who relapse after treatment with interferon, therapy with interferon and oral ribavirin results in higher rates of sustained virologic, biochemical, and histologic response than treatment with interferon alone

Evolution of hepatic steatosis in patients with advanced hepatitis C: Results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial

Hepatic steatosis is a common histologic feature in patients with chronic hepatitis C (CHC) but there are no large longitudinal studies describing the progression of steatosis in CHC. We examined changes in steatosis on serial biopsies among CHC patients participating in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All 1050 patients in the trial had advanced fibrosis at baseline biopsy and were documented not to have had a sustained virological response to peginterferon and ribavirin. Most (94%) patients had genotype 1 infection. At least one protocol follow-up biopsy was read on 892 patients, and 699 had the last biopsy performed 3.5 years after randomization. At enrollment, 39% had cirrhosis and 61% had bridging fibrosis; 18%, 41%, 31%, and 10% had steatosis scores of 0, 1, 2, and 3 or 4, respectively. The mean steatosis score decreased in the follow-up biopsies in both the interferon-treated patients and controls with no effect of treatment assignment ( P = 0.66). A decrease in steatosis score by ≥1 point was observed in 30% of patients and was associated with both progression to cirrhosis and continued presence of cirrhosis ( P = 0.02). Compared to patients without a decrease in steatosis, those with a decrease in steatosis had worse metabolic parameters at enrollment, and were more likely to have a decrease in alcohol intake, improvement in metabolic parameters, and worsening liver disease (cirrhosis, esophageal varices, and deterioration in liver function). Conclusion: Serial biopsies demonstrated that in patients with CHC, steatosis recedes during progression from advanced fibrosis to cirrhosis. Decreased alcohol intake and improved metabolic parameters are associated with a decline in steatosis and may modulate hepatitis C progression. (H EPATOLOGY 2009.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63058/1/22865_ftp.pd

Prognostic value of Ishak fibrosis stage: Findings from the hepatitis C antiviral long-term treatment against cirrhosis trial

Studies of the prognostic value of Ishak fibrosis stage are lacking. We used multi-year follow-up of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial to determine whether individual Ishak fibrosis stages predicted clinical outcomes in patients with chronic hepatitis C. Baseline liver biopsy specimens from 1050 patients with compensated chronic hepatitis C who had failed combination peginterferon and ribavirin were reviewed by a panel of expert hepatopathologists. Fibrosis was staged with the Ishak scale (ranging from 0 = no fibrosis to 6 = cirrhosis). Biopsy fragmentation and length as well as number of portal tracts were recorded. We compared rates of prespecified clinical outcomes of hepatic decompensation and hepatocellular carcinoma across individual Ishak fibrosis stages. Of 1050 biopsy specimens, 25% were fragmented, 63% longer than 1.5 cm, 69% larger than 10 mm 2 , and 75% had 10 or more portal tracts. Baseline laboratory markers of liver disease severity were worse and the frequency of esophageal varices higher with increasing Ishak stage ( P < 0.0001). The 6-year cumulative incidence of first clinical outcome was 5.6% for stage 2, 16.1% for stage 3, 19.3% for stage 4, 37.8% for stage 5, and 49.3% for stage 6. Among nonfragmented biopsy specimens, the predictive ability of Ishak staging was enhanced; however, no association was observed between Ishak stage and outcomes for fragmented biopsy specimens because of high rates of outcomes for patients with noncirrhotic stages. Similar results were observed with liver transplantation or liver-related death as the outcome. Conclusion : Ishak fibrosis stage predicts clinical outcomes, need for liver transplantation, and liver-related death in patients with chronic hepatitis C. Patients with fragmented biopsy specimens with low Ishak stage may be understaged histologically. (H EPATOLOGY 2010;51:585–594.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64929/1/23315_ftp.pd

Venting of a separate CO2-rich gas phase from submarine arc volcanoes: Examples from the Mariana and Tonga-Kermadec arcs

Submersible dives on 22 active submarine volcanoes on the Mariana and Tonga-Kermadec arcs have discovered systems on six of these volcanoes that, in addition to discharging hot vent fluid, are also venting a separate CO2-rich phase either in the form of gas bubbles or liquid CO2 droplets. One of the most impressive is the Champagne vent site on NW Eifuku in the northern Mariana Arc, which is discharging cold droplets of liquid CO2 at an estimated rate of 23 mol CO2/s, about 0.1% of the global mid-ocean ridge (MOR) carbon flux. Three other Mariana Arc submarine volcanoes (NW Rota-1, Nikko, and Daikoku), and two volcanoes on the Tonga-Kermadec Arc (Giggenbach and Volcano-1) also have vent fields discharging CO2-rich gas bubbles. The vent fluids at these volcanoes have very high CO2 concentrations and elevated C/3He and δ 13C (CO2) ratios compared to MOR systems, indicating a contribution to the carbon flux from subducted marine carbonates and organic material. Analysis of the CO2 concentrations shows that most of the fluids are undersaturated with CO2. This deviation from equilibrium would not be expected for pressure release degassing of an ascending fluid saturated with CO2. Mechanisms to produce a separate CO2-rich gas phase at the seafloor require direct injection of magmatic CO2-rich gas. The ascending CO2-rich gas could then partially dissolve into seawater circulating within the volcano edifice without reaching equilibrium. Alternatively, an ascending high-temperature, CO2-rich aqueous fluid could boil to produce a CO2-rich gas phase and a CO2-depleted liquid. These findings indicate that carbon fluxes from submarine arcs may be higher than previously estimated, and that experiments to estimate carbon fluxes at submarine arc volcanoes are merited. Hydrothermal sites such as these with a separate gas phase are valuable natural laboratories for studying the effects of high CO2 concentrations on marine ecosystems

Relationship between karstification and burial dolomitization in Permian platform carbonates (Lower Khuff - Oman)

Large breccia fabrics associated with karst constitute an important structure in massive limestone successions. The dimensions and shapes of breccia structures are controlled by the initial fracture pattern of the limestone and preferential pathways of the karstifying fluids, but subsequently breccia fabrics can also govern the migration of later fluids. Therefore, breccias are highly relevant features to capture for reservoir characterisation. Outcrop analogues for Lower Khuff units in the Middle East present in the Central Oman Mountains reveal brecciated fabrics up to 10’s of meters in diameter. These brecciated units are closely associated with dolomite bodies of late diagenetic origin. Based on an integrated set of data, the breccias are interpreted as collapsed karst cavities either formed by meteoric or hypogenic fluids. The exact origin of the fluids could not be constrained due to an overprint by later dolomitizing fluids. Based on the composition of the clasts and matrix in the breccias, two dolomitization events are interpreted to have affected the succession, one prior to (early diagenetic [ED] dolomite) and one after brecciation (late diagenetic [DT2] dolomite). Dolomite of shallow burial origin (ED dolomite) was only observed as clasts within breccia and is much more frequent than late diagenetic (medium to deep burial) dolomite clasts. Thus, the timing of the brecciation and collapse is assumed to postdate shallow burial early diagenetic dolomitization. Late diagenetic replacive dolomite (DT2 dolomite) forms 90% of the matrix in the breccia fabrics with the exception of a small area that was not affected by dolomitization, but is rarely present as clasts. Stable isotope measurements [δ18O: − 2.5‰ to − 6‰ VPDB and δ13C: 2.9‰ to 4.8‰ VPDB] suggest a burial origin for the late diagenetic dolomite potentially with the participation of hydrothermal fluids. The dolomitized matrix indicates a migration of late dolomitizing fluids subsequent to or postdating the collapse of the karstic cavities. Thus, early karstification processes seem to have played a big role in controlling subsequent loci of late dolomitization in the Oman Mountains, and potentially in other similar settings elsewhere

A Collaborative Epidemiological Investigation into the Criminal Fake Artesunate Trade in South East Asia

Paul Newton and colleagues' international, collaborative study found evidence that counterfeit artesunate was being manufactured in China, which prompted a criminal investigation

Clinical Presentation of Hepatocellular Carcinoma (HCC) in Asian-Americans Versus Non-Asian-Americans

The incidence of HCC is rising worldwide. Studies on ethnicity-based clinical presentation of HCC remain limited. The aim is to compare the clinical presentation and stage of HCC between Asian-Americans and non-Asian-Americans. This retrospective study assessed ethnicity-based differences in HCC presentation, including demographics, laboratory results, diagnosis of underlying liver disease, and stage of HCC. Of 276 patients, 162 were Asian-Americans and 114 were non-Asian-Americans. Compared to non-Asian-Americans, Asian-Americans had a significantly higher incidence of history of hepatitis B virus (HBV) infection (55.0% vs. 4.9%, P < 0.001), family history of HBV infection (12.5% vs. 0.0%, P < 0.001) and HCC (15.2% vs. 2.9%, P = 0.002), but lower incidence of history of hepatitis C virus (HCV) infection (37.5% vs. 61.6%, P < 0.001). At diagnosis of HCC, Asian-American patients had a significantly lower frequency of hepatic encephalopathy (8.9% vs. 29.3%, P = 0.001), and ascites (26.7% vs. 57.3%, P < 0.001). Asian-Americans had lower Child-Pugh scores (class A: 62.0% vs. 31.4%, P < 0.001), and MELD scores (9.2 ± 4.4 vs. 12.0 ± 6.4, P = 0.02), and presented with a lower stage of HCC by Okuda staging (I: 43.8% vs. 22.8%, P = 0.001). Asian-American patients with HCC presented with a higher incidence of history and family history of HBV infection, lower incidence of hepatic decompensation, lower Child and MELD scores, and an early stage HCC disease

Global temperature calibration of the alkenone unsaturation index (UK′37) in surface waters and comparison with surface sediments

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 7 (2006): Q02005, doi:10.1029/2005GC001054.In this paper, we compile the current surface seawater C37 alkenone unsaturation (UK′37) measurements (n=629, −1 to 30°C temperature range) to derive a global, field-based calibration of UK′37 with alkenone production temperature. A single nonlinear “global” surface water calibration of UK′37 accurately predicts alkenone production temperatures over the diversity of modern-day oceanic environments and alkenone-synthesizing populations (T=−0.957 + 54.293(UK′37) − 52.894(UK′37)2 + 28.321(UK′37)3, r2=0.97, n=567). The mean standard error of estimation is 1.2°C with insignificant bias in estimated production temperature among the different ocean regions sampled. An exception to these trends is regions characterized by strong lateral advection and extreme productivity and temperature gradients (e.g., the Brazil-Malvinas Confluence). In contrast to the surface water data, the calibration of UK′37 in surface sediments with overlying annual mean sea surface temperature (AnnO) is best fit by a linear model (AnnO=29.876(UK′37) − 1.334, r2=0.97, n=592). The standard error of estimation (1.1°C) is similar to that of the surface water production calibration, but a higher degree of bias is observed among the regional data sets. The sediment calibration differs significantly from the surface water calibration. UK′37 in surface sediments is consistently higher than that predicted from AnnO and the surface water production temperature calibration, and the magnitude of the offset increases as the surface water AnnO decreases. We apply the global production temperature calibration to the coretop UK′37 data to estimate the coretop alkenone integrated production temperature (coretop IPT) and compare this with the overlying annual mean sea surface temperature (AnnO). We use simple models to explore the possible causes of the deviation observed between the coretop temperature signal, as estimated by UK′37, and AnnO. Our results indicate that the deviation can best be explained if seasonality in production and/or thermocline production as well as differential degradation of 37:3 and 37:2 alkenones both affect the sedimentary alkenone signal.C.R. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG)