B. Möller

Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy†‡§

Incomplete virological response to adefovir dipivoxil (ADV) has been observed in patients with lamivudine‐resistant hepatitis B virus (HBV) infection and may be associated with developing resistance and disease progression. We therefore investigated whether the efficacy of viral suppression could be improved by replacing ADV with tenofovir disoproxil fumarate (TDF). Twenty patients with chronic HBV infection (18 HBeAg+), viral breakthrough during lamivudine therapy, and persistent viral replication (>10 4 copies/mL) after 15 months of ADV monotherapy (range 4‐28 months) were treated with TDF 300 mg daily and were retrospectively analyzed. A screening for nucleoside/nucleotide analogue resistance mutations within the HBV polymerase gene was performed in all patients by direct sequencing. Within a median of 3.5 months, application of TDF led to undetectable HBV DNA in 19 of 20 patients, as demonstrated by suppression of HBV DNA below the detection limit of 400 copies/mL. Initially elevated ALT levels had normalized in 10 of 14 patients by the end of follow‐up (median 12 months, range 3‐24 months). Four patients lost HBeAg, after 3, 4, 5, and 16 months, and one patient seroconverted to anti‐HBs after 16 months of TDF therapy. Lamivudine‐associated mutations (rtV173L, rtL180M, rtM204V/I) could be detected in 6 patients at baseline of TDF, but this obviously did not influence the response. ADV‐resistant mutations were not detected. No side effects were reported. In conclusion, these preliminary observations strongly suggest that TDF might be a highly effective rescue drug for HBV‐infected patients with altered responsiveness to treatment with lamivudine and ADV. (HEPATOLOGY 2006;44:318–325.)

Long‐term efficacy of tenofovir monotherapy for hepatitis B virus‐monoinfected patients after failure of nucleoside/nucleotide analogues

Tenofovir disoproxil fumarate (TDF) has demonstrated high antiviral efficacy in treatment‐naive patients with chronic hepatitis B virus (HBV) infection but experience in nucleoside/nucleotide analogue (NA)‐experienced patients is limited. In this retrospective multicenter study we therefore assessed the long‐term efficacy of TDF monotherapy in patients with prior failure or resistance to different NA treatments. Criteria for inclusion were HBV DNA levels >4.0 log10 copies/mL at the start and a minimum period of TDF therapy for at least 6 months. In all, 131 patients (mean age 42 ± 12 years, 95 male, 65% hepatitis B e antigen [HBeAg]‐positive) were eligible. Pretreatment consisted of either monotherapy with lamivudine (LAM; n = 18), adefovir (ADV; n = 8), and sequential LAM‐ADV therapy (n = 73), or add‐on combination therapy with both drugs (n = 29). Three patients had failed entecavir therapy. Resistance analysis in 113 of the 131 patients revealed genotypic LAM and ADV resistance in 62% and 19% of patients, respectively. The mean HBV DNA level at TDF baseline was 7.6 ± 1.5 log10 copies/mL. The overall cumulative proportion of patients achieving HBV DNA levels <400 copies/mL was 79% after a mean treatment duration of 23 months (range, 6–60). Although LAM resistance did not influence the antiviral efficacy of TDF, the presence of ADV resistance impaired TDF efficacy (100% versus 52% probability of HBV DNA <400 copies/mL, respectively). However, virologic breakthrough was not observed in any of the patients during the entire observation period. Loss of HBeAg occurred in 24% of patients and HBsAg loss occurred in 3%. No significant adverse events were noticed during TDF monotherapy. Conclusion: TDF monotherapy induced a potent and long‐lasting antiviral response in NA‐experienced patients with previous treatment failure. Our data may have implications for current add‐on strategies. (HEPATOLOGY 2009.)

Long-term follow-up of posttransfusion and sporadic chronic hepatitis non-A, non-B and frequency of circulating antibodies to hepatitis C virus (HCV)

The natural course of chronic hepatitis non-A, non-B (HNANB) was documented for 3-20 yr (mean 8 yr) in 86 patients, who attended our special ambulance between 1981 and 1988. Sixty five of the 86 patients (75%) were positive for circulating antibodies against hepatitis C virus (HCV) (anti-HCV). Twenty four patients had chronic posttransfusion (PT)-HNANB (18 anti-HCV-positive; 75%), and 62 patients had sporadic (S)-HNANB (47 anti-HCV-positive; 75%). Twenty nine per cent of patients with chronic PT-HNANB had sustained normalization of aminotransferases after a period up to 5 yr, 55% demonstrated chronic persistent hepatitis (CPH) and 16% progressed to chronic active hepatitis (CAH) with transition to cirrhosis. In the group with chronic S-HNANB, 2% of patients showed remission, 43% had stable CPH and 55% progressed to CAH or cirrhosis. However, development of cirrhotic complications required many years. Transition from CAH to CPH or remission was not observed. The results indicate that 75% of both patients groups with chronic PT- and S-HNANB are infected with the same agent, of which antibodies are detected by the new anti-HCV assay. There was no statistical association between the severity of the disease and the presence of anti-HCV. The different proportions of progressive courses in chronic PT- and S-HNANB might be explained by the patient recruitment.

ARE ANTIMITOCHONDRIAL ANTIBODIES IN PRIMARY BILIARY CIRRHOSIS INDUCED BY R(ROUGH)-MUTANTS OF ENTEROBACTERIACEAE?

Antimitochondrial antibody (AMA)-positive serum samples from 45 patients with primary biliary cirrhosis (PBC) and AMA-negative serum samples from patients with chronic liver diseases, systemic lupus erythematosus, or rheumatoid arthritis were studied by an immunoblot technique with mitochondria from bovine heart and pig kidney and with several strains of gram-negative bacteria as antigens after separation by sodiumdodecylsulphate polyacrylamide gel electrophoresis. Serum from patients with PBC recognised up to three mitochondrial antigens with molecular weights of 70 kD, 50 kD, and 42 kD. Equivalent patterns were found with bands at 70-80 kD and 50-52 kD with Enterobacteriaceae as antigens. AMA-reactive polypeptides were localised in the ribosomal and membrane fractions from Enterobacteriaceae but differed from known outer membrane proteins. Conversely, PBC-specific mitochondrial antigens at 70 kD and 50 kD were recognised by rabbit antisera against Salmonella minnesota Rb and Rc mutants but not by antisera against wild-type Enterobacteriaceae. Absorption experiments and two-dimensional immunoblotting studies confirmed that mitochondria and gram-negative bacteria share identical PBC-specific determinants. It seems that PBC-specific antigens are expressed in gram-negative bacteria and that these antigens may be immunogenic in mutants with defective polysaccharide synthesis. The data support the hypothesis of a bacterial aetiology for PBC.

Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients.

Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type 1–infected patients represents one possible strategy. Four hundred thirty‐three patients were randomly assigned to receive either 1.5 μg/kg peginterferon alfa‐2b weekly plus 800‐1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18‐48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription‐mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P< 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of >80% obtained in patients treated for only 18 or 24 weeks. Conclusion: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia. (HEPATOLOGY 2009.)

Improved Responses to Pegylated Interferon Alfa-2b and Ribavirin by Individualizing Treatment for 24–72 Weeks

BACKGROUND & AIMS Guidelines recommend that patients with chronic hepatitis C virus (HCV) infection be treated with pegylated interferon and ribavirin for 24, 48, or 72 weeks, based on their virologic response to treatment. We investigated the effects of treating patients for individualized durations. METHODS We treated 398 treatment-naïve patients who had HCV genotype 1 infections with pegylated interferon alfa-2b and ribavirin for 24, 30, 36, 42, 48, 60, or 72 weeks (mean of 39 weeks, termed individualized therapy); the duration of therapy was determined based on baseline viral load and the time point at which HCV RNA levels became undetectable (measured at weeks 4, 6, 8, 12, 24, and 30). Results were compared with those of 225 patients who received standard treatment for 48 weeks (mean of 38 weeks). RESULTS Rates of sustained virologic response (SVR) were 55% among patients who received individualized treatment and 48% among those who received standard treatment (P < .0001 for noninferiority). SVR rates, according to the time point at which HCV RNA levels became undetectable, did not differ significantly between groups. Patients with a rapid virologic response (undetectable levels of HCV RNA at week 4) who were treated for 24 to 30 weeks achieved high rates of SVR (86%-88%). Rates of SVR increased among slow responders who first tested negative for HCV RNA at week 24 and were treated for 60 to 72 weeks compared with those treated for 48 weeks (60%-68% vs 43%-44%). The CC polymorphism at IL28B rs129797860 was associated with an increased rate of SVR compared with the CT/TT polymorphism (P < .0001) at baseline but not among patients who had undetectable levels of HCV RNA following treatment. CONCLUSIONS Individualizing treatment of patients with chronic HCV genotype 1 infections for 24 to 72 weeks results in high rates of SVR among rapid responders and increases SVR among slow responders.

Epidemiologie der chronischen Hepatitis C in Deutschland - Eine Analyse von 10 326 Hepatitis-C-Virus-Infizierten aus Schwerpunktpraxen und -ambulanzen

Little is known about the epidemiology of chronic hepatitis C (CHC) in Germany and especially about the importance of transmission, duration of infection, genotypes, symptoms and quality of life of the patients. The current study prospectively evaluates epidemiological and clinical data of patients infected with the hepatitis C virus (HCV). Using online data entry, various characteristics of 10,326 untreated patients with CHC were documented from March 2003 until May 2006 in 352 centres all over Germany. Mean age of patients was 43.4 years. Patients infected by i.v. drug abuse were considerably younger (36.5 years) than the remaining patients (49.2 years). As indicated by their native language, 64.4% of the patients came from Germany and 19.2% from Russia. 61.7% were infected with genotype 1 and 34.9% with genotype 2 or 3. 45.5% of the patients had been infected by i.v. drug abuse. In at least 5.4% of the patients liver cirrhosis had been proved by biopsy. 63.5% of the patients felt an impairment of quality of life caused by CHC. In many patients infected with hepatitis C socio-economic issues are existent. This is reflected, i.e., in very high rates of unemployment in special subpopulations. Coinfections with hepatitis B and HIV occurred in 1.5% and 4.7%, respectively. Nearly 80% of patients were managed near their homes. The data of the 10 326 patients represent about 2% of all German patients with CHC. This database is up to now the largest of its kind and gives a representative insight into the epidemiological situation of CHC in Germany.

Hepatocellular clearance function of bacterial lipopolysaccharides and free lipid A in mice with endotoxic shock

Hepatic uptake of bacterial lipopolysaccharides (LPS) in defined salt forms and free lipid A was studied in C3H mice. Extracts of 14C-labeled and unlabeled LPS from Salmonella abortus equi and lipid A from Salmonella minnesota R 595 (Re) were administered intravenously in doses sufficient to induce endotoxic shock. Sixty minutes after administration of 14C-LPS, 40% of the total activity was found in the liver tissue, 10% was in the isolated nonparenchymal cells, and only 1% was in the isolated hepatocytes. However, at this time only one third of the hepatocytes could be isolated; the other two thirds were obviously damaged. After 240 minutes, 55% of the total activity was measured in the liver tissue. The nonparenchymal cells had 8% of the activity, and all hepatocytes were damaged. By use of immunofluorescence, LPS S abortus equi was localized in sinusoidal cells 5 to 10 minutes after administration, and LPS S minnesota R 595 and lipid A were found in both nonparenchymal and parenchymal liver cells. All toxins were localized in both cell populations 60 and 240 minutes after injection. After application of LPS or lipid A, the third complement component (C3) was detectable in sinusoidal cells. In decomplemented mice the hepatic deposits of LPS and lipid A were unaffected, without demonstration of C3. The data indicate that LPS and lipid A interact in vivo with Kupffer cells and hepatocytes. Hepatic clearance of endotoxin seems to be independent of complement.

Chronic hepatitis C: Treat or wait? Medical decision making in clinical practice

AIM To analyzes the decision whether patients with chronic hepatitis C virus (HCV) infection are treated or not. METHODS This prospective cohort study included 7658 untreated patients and 6341 patients receiving pegylated interferon α 2a/ribavirin, involving 434 physicians/institutions throughout Germany (377 in private practice and 57 in hospital settings). A structured questionnaire had to be answered prior to the treatment decision, which included demographic data, information about the personal life situation of the patients, anamnesis and symptomatology of hepatitis C, virological data, laboratory data and data on concomitant diseases. A second part of the study analyzes patients treated with pegylated interferon α2a. All questionnaires included reasons against treatment mentioned by the physician. RESULTS Overall treatment uptake was 45%. By multivariate analysis, genotype 1/4/5/6, HCV-RNA ≤ 520,000 IU/mL, normal alanine aminotransferase (ALT), platelets ≤ 142,500/μL, age > 56 years, female gender, infection length > 12.5 years, concomitant diseases, human immunodeficiency virus co-infection, liver biopsy not performed, care in private practice, asymptomatic disease, and unemployment were factors associated with reduced treatment rate. Treatment and sustained viral response rates in migrants (1/3 of cohort) were higher than in German natives although 1/3 of migrants had language problems. Treatment rate and liver biopsy were higher in clinical settings when compared to private practice and were low when ALT and HCV-RNA were low. CONCLUSION Some reasons against treatment were medically based whereas others were related to fears, socio-economical problems, and information deficits both on the side of physicians and patients.

Treatment of naive patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA.

Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10–20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.