Outcomes of patients with chronic hepatitis B who do not meet criteria for antiviral treatment at presentation.

BACKGROUND & AIMS: The availability of potent, well-tolerated, oral antivirals with low rates of resistance has led many experts to recommend liberalizing indications for the treatment of chronic hepatitis B (CHB). This study sought to determine the rate of transitions to an active phase of infection, the frequency of treatment initiation, and the clinical outcomes of patients with CHB who did not meet treatment criteria at presentation. METHODS: We reviewed medical records of patients with CHB, seen in the liver clinics at the University of Michigan Health System from 1999 through 2010, who did not receive antiviral treatment within 6 months of presentation. We collected data on transitions between different phases of CHB, hepatitis B e antigen (HBeAg) seroconversion, loss of hepatitis B surface antigen (HBsAg), and the development of hepatocellular carcinoma (HCC). Data analyses were censored or truncated at the time of treatment initiation or development of an outcome. RESULTS: Of the 234 patients analyzed, 52.1% were men (median age, 35 y), 72.2% were Asian, and 81.2% were HBeAg-negative. During a median follow-up period of 51 months, 19.2% of patients transitioned to a more active disease phase and 18.8% started antiviral therapy. Of the 44 HBeAg-positive patients, 4 patients (9%) had spontaneous HBeAg seroconversion. Nine HBeAg-negative patients but none of the HBeAg-positive patients lost HBsAg. The cumulative probability of HBsAg loss among HBeAg-negative patients was 1% at year 5 and 21% by year 10. No patients had flares of icteric hepatitis or hepatic decompensation. None of the HBeAg-positive patients developed HCC, whereas 2 HBeAg-negative patients developed HCC. CONCLUSIONS: Careful monitoring of patients with CHB who did not meet treatment criteria at presentation permits timely initiation of treatment, with a low risk of adverse clinical outcomes, based on a retrospective study with a median follow-up period of 4.3 years. These findings indicate that current guidelines for initiating treatment are appropriate.

Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice.

UNLABELLED: Virological breakthrough (VBT) is the first manifestation of antiviral drug resistance during nucleos(t)ide analogue (NUC) treatment of chronic hepatitis B (CHB), but not all VBTs are due to drug resistance. This study sought to determine the incidence of VBT and genotypic resistance (GR) in patients with CHB who were receiving NUCs in clinical practice. Records of patients with CHB who were receiving NUCs were reviewed. All patients with VBT were tested for drug resistance mutations. Of 148 patients included, 73% were men and mean age was 44.9 years. During a mean follow-up of 37.5 ± 20.1 months, 39 (26%) patients had at least 1 VBT. Of these 39 patients, 15 (38%) were not confirmed to have VBT on retesting, and 10 of these 15 had no evidence of GR. The cumulative probability of VBT, confirmed VBT, and GR at 5 years was 46.1%, 29.7%, and 33.9%, respectively. In multivariate analysis, failure to achieve undetectable hepatitis B virus (HBV) DNA was the only factor significantly associated with VBT. Among the 10 patients who had VBT but no confirmed VBT or GR and who were maintained on the same medications, serum HBV DNA decreased in all 10, and nine had undetectable HBV DNA at a mean of 6.8 months after the VBT. Four patients had persistently undetectable HBV DNA, six had transient increase in HBV DNA during follow-up, and none had GR. CONCLUSION: VBT was common in patients with CHB receiving NUCs in clinical practice, but nearly 40% of the VBTs were not related to antiviral drug resistance. Counseling of patients with CHB on medication adherence and confirmation of VBT and/or GR can avoid unnecessary changes in antiviral medications.

Sensitivity and accuracy of an updated line probe assay (HBV DR v.3) in detecting mutations associated with hepatitis B antiviral resistance.

BACKGROUND/AIMS: Early detection of antiviral drug-resistant mutations enables prompt initiation of rescue therapy. The aim of this study was to determine the accuracy and sensitivity of a new line probe assay in the detection of antiviral drug-resistant HBV mutations. METHODS: One-hundred samples from 54 patients with virologic breakthrough during entecavir, lamivudine or adefovir treatment and 21 samples from 21 nucleoside-naïve patients were tested by direct sequencing and an updated line probe assay (Innogenetics, HBV DR v.3) which incorporates probes that can detect mutations at 11 positions of the reverse transcriptase region of the HBV polymerase gene. RESULTS: Complete concordance between line probe and sequencing results was observed for 90/121 samples (74.3%) and 1291/1331 amino acid positions (96.9%). Testing of follow-up samples and clonal analysis of discordant samples confirmed the presence of mutations where line probe assay but not direct sequencing detected mutations. HBV DR v.3 assay consistently detected mutations present in > or = 5% of the virus population when HBV DNA concentration was > or = 4 log10copies/mL. CONCLUSIONS: The updated version of the line probe assay (HBV DR v.3) has high concordance with direct sequencing in detecting antiviral drug-resistant mutations but its sensitivity in detecting mutations at some positions needs to be improved.

Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations.

BACKGROUND/AIMS: We sought to identify mutations associated with treatment failure to adefovir (ADV) and to determine virologic response to tenofovir (TDF) alone and in combination with emtricitabine (FTC) in these patients. METHODS: Serum samples prior to and after the change in treatment to TDF/TDF+FTC from 13 patients were analyzed by direct sequencing and clonal analysis. RESULTS: ADV-resistant mutations, rtA181V and rtN236T, were detected on direct sequencing in 3 of 8 patients who had virologic breakthrough. Among patients with suboptimal virologic response, rtA181T, rtI233V, and rtN236T were present on clonal analysis in 3 patients. Ten patients received TDF, 8 achieved virologic response. One had ADV-resistance at baseline and persistence of ADV-resistant mutations during TDF treatment, addition of FTC resulted in a further decrease in HBV DNA. Another patient had no ADV-resistance at baseline, and selection of ADV-resistant mutations during TDF treatment. All 3 patients who received TDF+FTC had undetectable HBV DNA within 3-12 months including 2 who had ADV-resistance at baseline. CONCLUSIONS: TDF monotherapy is effective for patients with virologic breakthrough or suboptimal response to ADV, but combination therapy with a nucleoside analogue should be considered in patients with ADV-resistance. No novel mutations were detected.

Virologic response and resistance to adefovir in patients with chronic hepatitis B.

BACKGROUND: The incidence and risk factors for adefovir-resistant HBV have not been clearly defined. AIMS: To characterize the virologic response to adefovir, to determine the rate of adefovir resistance and to explore factors associated with initial virologic response (IVR) and adefovir resistance. METHODS: All hepatitis B patients who received adefovir for > or =6 months at our center were prospectively monitored for virologic response and adefovir resistance. RESULTS: Forty three patients were included; mean treatment duration was 18 months (range 6-45). Thirty four (79%) patients had prior lamivudine. IVR was observed in 44% patients and associated with higher pretreatment ALT (P = 0.05) and the absence of HBeAg (P = 0.02). Six (14%) patients were found to have adefovir-resistant mutations. The cumulative probability of genotypic resistance to adefovir at month 24 was 22%. Patients with adefovir resistance were more likely to have been switched from lamivudine to adefovir monotherapy (P = 0.01), to be older (P = 0.04), and to be infected with HBV genotype D (P = 0.02). CONCLUSIONS: Roughly 50% of patients failed to achieve IVR on adefovir. The cumulative probability of adefovir resistance at 2 years was 22%. Our data suggest that combination of lamivudine and adefovir may prevent emergence of adefovir resistance in patients with lamivudine-resistant HBV.

Effectiveness of interferon alpha-2b and ribavirin combination therapy in the treatment of naive chronic hepatitis C patients in clinical practice.

BACKGROUND & AIMS: Studies in many diseases have shown that efficacy in clinical trials often does not translate into effectiveness in clinical practice. The aims of this study were to determine the rate of sustained virological response (SVR) and the factors associated with SVR in therapy naive chronic hepatitis C patients treated with interferon alpha-2b and ribavirin combination therapy at a university outpatient clinic. METHODS: The medical records of 153 consecutive chronic hepatitis C patients treated between June 1998 and May 2001 were reviewed. RESULTS: The mean subject age was 44 years, 64% were men, 85% were white, 56% had HCV genotype 1, and 21% had cirrhosis on biopsy. The overall SVR rate was 42% (29% in genotype 1/4; 65% in genotype 2/3). Side effects resulted in interferon or ribavirin dose reductions in 22% of patients and premature termination of treatment in 10%. The SVR rate was significantly higher in the 102 patients who received >80% of the recommended dose and duration of therapy compared with the 51 patients who did not (53% vs. 20%, P = 0.00008). HCV genotype, subject race, and adherence were independently associated with SVR (P < 0.01). Although the incidence of side effects and medication adherence was similar in blacks and whites, adherent blacks had a significantly lower SVR rate (14% vs. 58%, P < 0.01). CONCLUSIONS: Despite the inclusion of a broader spectrum of patients and less frequent monitoring, combination antiviral therapy in our treatment-naive chronic hepatitis C patients was of similar efficacy to that reported in large multicenter trials. In addition, our data show that medication adherence is an important predictor of SVR in an academic clinical practice.