Comparison of 208-week sequential therapy with telbivudine and entecavir in HBeAg-positive chronic hepatitis B patients with suboptimal responses to 24 weeks of Peg-IFNα-2a therapy: An open-labelled, randomized, controlled, "real-life" trial.

The purpose of the study was to compare the efficacy and safety of 208-week sequential therapy with telbivudine and entecavir in HBeAg-positive chronic hepatitis B (CHB) patients with suboptimal responses to 24 weeks of Peg-IFNα-2a therapy. This was an open-label, randomized, controlled, "real-life" trial. HBeAg-positive CHB patients with serum HBV DNA ≥5.0 lg IU/mL and a < 1 lg IU/mL decline of HBsAg level from baseline who underwent at least 24 weeks of Peg-IFNα-2a therapy were included. Enrolled patients were randomized to receive either telbivudine (600 mg/d, n = 95) or entecavir (0.5 mg/d, n = 95) for 208 consecutive weeks. Six patients were lost to follow-up (4 patients in the telbivudine group and 2 in the entecavir group). Treatment was combined with adefovir when week 24 HBV DNA levels declined to <2 lg IU/mL versus baseline, when viral breakthrough occurred during treatment,or when HBV DNA remained detectable at 52 weeks (HBV DNA ≥500 IU/mL). Responses and safety were assessed after 208 weeks of treatment. There were no significant differences among the baseline characteristics, including age, gender, and ALT, HBV DNA, HBsAg or HBeAg levels. After 208 weeks of treatment, there was no significant difference in the rates of undetectable HBV DNA (HBV DNA<500 IU/mL) between the telbivudine group and the entecavir group (84/91,92.31% vs 88/93,94.62%, respectively, P = .525). More patients in the telbivudine group than the entecavir group achieved HBeAg clearance (74.73% vs 46.24%, respectively, P < .001) and HBeAg seroconversion (64.84% vs 38.71%, respectively, P < .001). Univariate analysis (Enter, a = 0.05) of both groups showed that telbivudine, male gender and baseline HBeAg levels were significantly correlated with HBeAg seroconversion after 208 weeks of sequential therapy. Cox regression analysis (Enter, a = 0.05) of the telbivudine group showed that the HBeAg seroconversion rate at 208 weeks was significantly correlated with gender (male) (P = .006, HR=4.406), baseline HBeAg level (P = .005, HR=0.433) and 24 w-HBeAg level reduction of more than 0.5 lg IU/ml from baseline (P = .027, HR=0.487). All patients tolerated sequential telbivudine treatment; only slightly elevated creatine kinase levels were observed. Stratification analysis found that patients with baseline HBeAg levels less than 3 lg COI who switched to telbivudine may have had significantly improved HBeAg seroconversion rates. In conclusion, telbivudine promotes HBeAg seroconversion that merits investigation in HBeAg-positive CHB patients with suboptimal responses to 24 weeks of Peg-IFNα-2a therapy. We would suggest that patients with baseline HBeAg levels under 3 lg COI switch to telbivudine to achieve higher HBeAg seroconversion rates and use the early reductions in HBeAg levels (24 weeks) to guide treatment.

[Clinical effect of 156-week telbivudine sequential therapy in HBeAg-positive chronic hepatitis B patients with suboptimal response to pegylated interferon-α-2a therapy].

Objective: To investigate the clinical effect of 156-week telbivudine sequential therapy in HBeAg-positive chronic hepatitis B patients with suboptimal response to pegylated interferon-α-2a (Peg-IFN-α-2a) therapy. Methods: A total of 35 HBeAg-positive CHB patients with HBV DNA < 500 IU/ml who were treated with Peg-IFN-α-2a for 48 weeks and did not experience seroconversion of HBeAg were given telbivudine sequential therapy for 156 weeks. HBeAg clearance rate, HBeAg seroconversion rate, HBV DNA clearance rate, safety, and drug resistance rate were analyzed. The t-test was used for the analysis of continuous data and the chi-square test was used for the analysis of categorical data. A multivariate Cox regression analysis was used to identify the influencing factors for HBeAg seroconversion. Results: Telbivudine sequential therapy achieved an ideal HBeAg seroconversion rate of 87.88% with good tolerability and low drug resistance. The HBeAg clearance rate and HBeAg seroconversion rate increased over the time of treatment and were 45.45% and 45.45%, respectively, at 24 weeks and 93.94% and 87.88%, respectively, at 156 weeks. No patient had virologic breakthrough or HBsAg clearance during treatment. The multivariate Cox regression analysis showed that baseline HBsAg level (hazard ratio [HR] = 0.404, P = 0.003) and > 0.5 lg IU/ml reduction in HBeAg at 24 weeks (HR = 2.196, P = 0.048) were predictive factors for HBeAg seroconversion at 156 weeks. Conclusions: In HBeAg-positive CHB patients with suboptimal response to Peg-IFN-α-2a therapy, 156-week telbivudine sequential therapy has a good clinical effect and can be used as an optimal regimen for such patients.

[Optimal treatment regimen for patients with HBeAg-positive chronic hepatitis B after suboptimal response to 24 weeks of Peg-IFN α-2a].

Objective: To investigate the optimal treatment regimen for patients with HBeAg-positive chronic hepatitis B (CHB) after suboptimal response to 24 weeks of pegylated interferon (Peg-IFN) α-2a. Methods: A total of 188 patients with HBeAg-positive CHB who had suboptimal response to 24 weeks of Peg-IFN α-2a were randomly divided into entecavir group (n = 93) and telbivudine group (n = 95). The two groups received entecavir 0.5 mg/d and telbivudine 0.6 g/d, respectively, for 208 weeks. After 208 weeks of treatment, the following indices were assessed: HBeAg clearance rate and seroconversion rate, hepatitis B virus (HBV) DNA clearance rate (HBV DNA < 500 IU/ml), safety, and drug resistance rate. The data were subjected to intention-to-treat (ITT) analysis and per protocol (PP) analysis. Univariate and multivariate logistic regression analyses were performed for the drugs used and baseline characteristics in patients with or without HBeAg seroconversion, and stratification analysis was performed based on the baseline HBeAg level. Results: Six cases in the entecavir group and four cases in the telbivudine group did not complete the treatment. Sequential entecavir and telbivudine were well tolerated and safe for all patients. There was a significant difference in HBV DNA clearance rate at 52 weeks of treatment between the entecavir group and the telbivudine group (ITT analysis: 93.55% [87/93] vs 77.89% [74/95], χ (2) = 9.363, P = 0.002; PP analysis: 93.10% [81/87] vs 76.92% [70/91], χ (2) = 9.049, P = 0.003). The suppression rates of HBV DNA at 208 weeks of treatment were 95.70% (89/93) vs 92.63% (88/95) (ITT analysis) and 95.40% (83/87) vs 92.31% (84/91) (PP analysis). There was a significant difference in HBeAg seroconversion rate at 208 weeks of treatment between the entecavir group and the telbivudine group (ITT analysis: 38.71% [36/93] vs 62.11% [59/95], χ (2) = 10.290, P = 0.001; PP analysis: 41.38% [36/87] vs 64.84% [59/91], χ (2) = 9.833, P = 0.002). Univariate and multivariate logistic regression analyses suggested that sequential use of telbivudine, male sex, and the baseline level of HBeAg were significantly associated with HBeAg seroconversion at 208 weeks of treatment (P = 0.003, hazard ratio [HR] = 0.386; P = 0.009, HR = 0.303; P = 0.001, HR = 3.502). Conclusion: For patients with HBeAg-positive CHB after suboptimal response to 24 weeks of Peg-IFNα-2a, sequential use of telbivudine is the optimal treatment regimen according to the baseline level of HBeAg (baseline guidance). The incidence of HBeAg seroconversion during 208 weeks of sequential treatment can be significantly increased according to the HBeAg decline curve in early treatment (24 weeks) and 104 weeks (response guidance).

Does Increasing Treatment Frequency Address Suboptimal Responses to Ivermectin for the Control and Elimination of River Blindness?

BACKGROUND: Several African countries have adopted a biannual ivermectin distribution strategy in some foci to control and eliminate onchocerciasis. In 2010, the Ghana Health Service started biannual distribution to combat transmission hotspots and suboptimal responses to treatment. We assessed the epidemiological impact of the first 3 years of this strategy and quantified responses to ivermectin over 2 consecutive rounds of treatment in 10 sentinel communities. METHODS: We evaluated Onchocerca volvulus community microfilarial intensity and prevalence in persons aged ≥20 years before the first, second, and fifth (or sixth) biannual treatment rounds using skin snip data from 956 participants. We used longitudinal regression modeling to estimate rates of microfilarial repopulation of the skin in a cohort of 217 participants who were followed up over the first 2 rounds of biannual treatment. RESULTS: Biannual treatment has had a positive impact, with substantial reductions in infection intensity after 4 or 5 rounds in most communities. We identified 3 communities-all having been previously recognized as responding suboptimally to ivermectin-with statistically significantly high microfilarial repopulation rates. We did not find any clear association between microfilarial repopulation rate and the number of years of prior intervention, coverage, or the community level of infection. CONCLUSIONS: The strategy of biannual ivermectin treatment in Ghana has reduced O. volvulus microfilarial intensity and prevalence, but suboptimal responses to treatment remain evident in a number of previously and consistently implicated communities. Whether increasing the frequency of treatment will be sufficient to meet the World Health Organization's 2020 elimination goals remains uncertain.

Diagnosis and management of autoimmune hepatitis.

Autoimmune hepatitis is characterized by increased serum aminotransferase levels, autoantibodies, hypergammaglobulinemia, and interface hepatitis. Presentation can be acute, severe (fulminant), asymptomatic, or chronic. Diagnosis requires multiple findings and exclusion of similar diseases. Treatment with prednisone or prednisolone with azathioprine is recommended. Budesonide with azathioprine has normalized laboratory test with few side effects, but histologic resolution, durability of response, and target population are uncertain. Progressive worsening, incomplete improvement, drug intolerance, and relapse after drug withdrawal are suboptimal outcomes. Calcineurin inhibitors and mycophenolate mofetil are salvage agents in small series and liver transplantation is effective for liver failure.