Lamivudine is a potent inhibitor of human immunodeficiency virus reverse transcriptase and hepatitis B virus (HBV) DNA polymerase. Its overall efficiency is clearly hampered by relapse at ...discontinuation and by risk of genotypic resistance. We describe herein the first cases of HBV resistance to lamivudine in kidney recipients and hemodialyzed patients.
We analyzed 26 HBV-infected kidney recipients and five hemodialyzed patients treated with lamivudine who became serum HBV DNA-negative (by Digene test). The biological and virological follow-up identified breakthrough as defined by the reappearance of serum HBV DNA. In two cases of breakthrough, HBV DNA was amplified and sequenced through the polymerase domain, including the YMDD motif, before the beginning of treatment and at time of breakthrough to determine genotypic mutations.
Ten breakthroughs (reappearance of serum HBV DNA) were observed after a median follow-up of 11 months in eight kidney recipients and two hemodialyzed patients after a median duration of treatment of 16.5 (from 4 to 31) months of treatment. Previous HBe/anti-HBe seroconversion was not observed in the patients who escaped. In two kidney recipients, the comparison of HBV-DNA sequences before the treatment and after the breakthrough identified in one case a mutation of the highly conserved YMDD motif (YVDD), whereas in the second case, no genotypic mutation was observed in the sequenced region.
We report the first cases of HBV genotypic resistance to lamivudine in kidney recipients and hemodialysis patients. Genotypic resistance is observed after 4-31 months of therapy. The YMDD mutation does not account for all cases of virological escape.
In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind ...trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment.
We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12–16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury.
Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p >0.05). The proportion of patients with ALP <1.67×ULN, a ≥15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p <0.05, each). In contrast to placebo, budesonide reduced mean ALP and 35% of budesonide-treated patients achieved normalisation of ALP (placebo 9%; p = 0.023). Serious adverse events occurred in 10 patients receiving budesonide and 7 patients receiving placebo.
Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses.
Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests.
NCT00746486.
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•In patients with PBC at high-risk of disease progression, budesonide in addition to UDCA did not improve liver histology.•Addition of budesonide was associated with improved biochemical markers of PBC disease activity.•Future trials of new therapies in PBC will benefit from the use of a variety of clinical endpoints.
Liver steatosis is a common histopathological finding in patients infected with hepatitis C virus. Patients with chronic hepatitis C having both steatosis and factors causing oxidative stress may be ...at a higher risk of fibrogenesis. In a subset of patients with a definite date of contamination, our study aimed to assess the potential synergistic interaction between steatosis and factors likely to induce oxidative stress-namely, alcohol intake, iron overload, and drugs.
Out of 700 anti-HCV-positive screened patients, 142 untreated patients with liver biopsy and with one known risk factor were selected. Liver fibrosis, inflammation, and necrosis were graded according to the Knodell score, and steatosis as moderate to severe if more than 30% of hepatocytes were affected. Drinkers were defined as having daily mean alcohol intakes of more than 30 g in men and 20 g in women.
In multivariate analysis, two factors were independently associated with extensive fibrosis: the degree of severity of piecemeal necrosis (OR = 3.27, CI = 1 .17-9.16) and a combination of moderate to severe steatosis and alcohol intake (OR = 7.02, CI = 1.12-44). The median progression rate of fibrosis was about twice as high among drinkers with steatosis than among drinkers without steatosis or nondrinkers with or without steatosis (0.25 vs 0. I vs 0.13 vs 0.08, respectively; p = 0.02). Independent parameters significantly associated with moderate to severe steatosis were body mass index (OR = 1.13, CI = 1.02-1.26) and infection with genotype 3 (OR = 5.5, CI = 1.88-16), but not alcohol consumption.
As well as the key role of the severity of piecemeal necrosis, the study underlines the synergistic interaction between steatosis and even low alcohol consumption as a contributory factor in extensive liver fibrosis.
Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cirrhosis (PBC). The long-term administration of UDCA might indirectly favor colon carcinogenesis by increasing the fecal ...excretion of secondary bile acids or, in contrast, it might inhibit colon carcinogenesis, as demonstrated in animal models. In patients with PBC, we examined the effect of prolonged UDCA administration on the prevalence and recurrence of colorectal adenoma and on the proliferation of colon epithelial cells. One hundred fourteen patients (103 women, 11 men; mean age, 55 years) with PBC, were enrolled in a colonoscopic surveillance program. The prevalence of colon adenoma was compared in patients already treated with UDCA (mean duration 46 months) at the time of colonoscopy (treated group, n = 52) and in patients undergoing colonoscopy just prior to treatment initiation (untreated group, n = 62). The recurrence of adenoma following removal (mean follow-up, 35 months) was compared between UDCA-treated patients and appropriate age- and gender-matched controls (2/1) selected from a cohort of 205 patients undergoing polypectomy. Epithelial cell proliferation was assessed using anti-Ki67 antibodies on colon biopsies from both treated and untreated patients. Treated and untreated patients displayed similar demographic characteristics. The prevalence of colorectal adenomas was 13% in the treated group versus 24% in the untreated group (
P = .16). The colon epithelial cell proliferation index was significantly lower in treated patients than in untreated patients (
P = .001). Following removal of the adenoma, the probability of recurrence was significantly lower in patients treated with UDCA than in controls (7% vs. 28% at 3 years,
P = .04). In conclusion, this study suggests that, in patients with PBC, the prolonged administration of UDCA (1) is not associated with an increased prevalence of colorectal adenomas, and (2) significantly decreases the probability of colorectal adenoma recurrence following removal. These results are strengthened by the significant reduction in colon epithelial cell proliferation seen in patients treated with UDCA. (H
epatology 2003;38:203-209.)
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