Effects of Tenofovir Disoproxil Fumarate in Hepatitis B e Antigen-Positive Patients With Normal Levels of Alanine Aminotransferase and High Levels of Hepatitis B Virus DNA

doi:10.1053/j.gastro.2014.01.044

Gastroenterology

Volume 146, Issue 5, May 2014, Pages 1240-1248

https://doi.org/10.1053/j.gastro.2014.01.044 Get rights and content

Background & Aims

Little is known about the benefit of antiviral therapy for hepatitis B e antigen (HBeAg)−positive patients with high viral load and normal levels of alanine aminotransferase. We evaluated the effects of single and combination therapies in immune-tolerant patients with chronic hepatitis B.

Methods

In a double-blind study, nucleos(t)ide-naïve patients with high levels of hepatitis B virus (HBV) DNA who were positive for HBeAg and had normal levels of alanine aminotransferase were randomly assigned to groups given either oral tenofovir disoproxil fumarate (TDF, 300 mg) and placebo (n = 64) or a combination of TDF (300 mg) and emtricitabine (200 mg, n = 62) for 192 weeks. The primary end point was proportion of patients with serum levels of HBV DNA <69 IU/mL at week 192.

Results

The study population (mean age was 33 years; 89% were Asian) was predominantly infected with HBV genotypes B and C (93%), 99% were HBeAg positive with a mean baseline level of HBV DNA of 8.41 log₁₀ IU/mL. At week 192, 55% of patients (35 of 64) in the TDF+placebo group and 76% of patients (47 of 62) in the TDF+emtricitabine group had levels of HBV DNA <69 IU/mL (P = .016). No patients were found to have viral resistance to therapy. HBeAg seroconversion occurred in 3 patients (5%), all in the TDF+placebo group; no patient had loss of hepatitis B surface antigen. In multivariate analysis, female sex (odds ratio = 7.05; P = .002) and TDF+emtricitabine treatment (odds ratio = 3.9; P = .01) were associated with a favorable response. Both regimens were well tolerated.

Conclusions

In HBeAg-positive patients with chronic HBV infection, high viral loads, normal levels of alanine aminotransferase, and therapy with the combination of TDF and emtricitabine provided better viral suppression than TDF alone, although rates of HBeAg seroconversion and hepatitis B surface antigen loss were low.

Section snippets

Study Design

This was a phase 2, randomized, double-blind, multicenter study in nucleos(t)ide-naïve patients with high HBV viral load (HBV DNA ≥1.7 × 10⁷ IU/mL) and ALT levels less than the upper limit of normal (ULN). Patients were randomized in a 1:1 ratio to receive TDF 300 mg orally once daily plus FTC 200 mg once daily, or TDF 300 mg once daily plus placebo once daily for 192 weeks. The initial protocol was for a 48-week study. The protocol was subsequently modified to extend treatment to 96 weeks, and

Patient Population

Of the 129 patients randomized at 34 sites in 11 countries, 126 received treatment with either TDF+placebo (n = 64) or TDF+FTC (n = 62) (Supplementary Figure 1). The baseline demographics and disease characteristics were similar between treatment groups (Table 1). The patients had a mean age of 33 years and were predominantly Asian (88% and 90% in the TDF and TDF+FTC groups, respectively) with approximately equal numbers of men and women (48% of patients in the TDF arm and 50% of patients in

Discussion

In this study, we examined the safety and efficacy of treating patients with CHB, high HBV DNA levels, and normal ALT levels with either TDF or a combination of TDF and FTC. Both regimens had a potent antiviral effect, but significantly more patients on the TDF+FTC combination therapy than patients on TDF monotherapy achieved the primary end point of viral suppression. Rates of HBsAg and HBeAg loss/seroconversion were low in both groups. No evidence of virologic resistance could be detected in

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Citation Excerpt :
This suggests that long-term therapy will be required in this subset to ensure viral suppression. Immune tolerant CHB patients who are HBeAg-positive with normal or near-normal ALT levels have a lower HBeAg seroconversion rate receiving either PEG IFN or NA treatment.39 Tseng et al focused on-treatment response of TDF in IT CHB patients.
Chronic hepatitis B (CHB) remains a public health burden, with more than 257 million persons living with hepatitis B virus globally. Despite the availability of a safe and efficacious vaccine, access to immunization remains poor. As per current estimates, if Asian countries rely only on immunization to reduce the burden of disease, the timelines for HBV elimination will be extended to 2060–2090, a far cry from the World Health Organization’s clarion call for viral hepatitis elimination by 2030.
Currently, all practice guidelines lay stress on immunization, prevention of mother-to-child transmission and treatment of immune active disease or cirrhosis. In this review, we critically examine the data from the Asian cohorts, clinical and public health rationale of early treatment, risk of HCC, and assess the need for revision of guidelines.
Patients in the immune tolerant phase (IT) remain untreated till they meet variable age, transaminase, or fibrosis criteria, are often lost to follow up and continue transmitting the infection. With global migration patterns, immunization programmes alone cannot prevent the complications of HBV like cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). In addition, data from Asian cohorts from Taiwan and Korea suggest that HBV DNA levels are directly associated with increased risk of HCC. Histological evidence of advanced fibrosis or immune reactive T cell subsets in the IT phase also raises doubts about the viability of current guidelines that focus on age, alanine transaminase levels, and liver stiffness as markers of risk of inflammation and fibrosis. Current practice does not take into account the histological subsets with minimal inflammation, HBV genome integration or risk of HCC with high viral loads.
New data from Asian cohorts argue the case of expanding access to care to IT-CHB from public health and clinical perspective.

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: Conflicts of interest These authors disclose the following: Henry L. Y. Chan has received grants and done research for Roche; consulted for Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Novartis, and Roche; been a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Roche. Fred Poordad has received grants and done research for Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, Human Genome Sciences, Idenix, Inhibitex, Janssen, Merck, Novartis, Pharmasset, Salix, and Vertex; consulted for Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, Idenix, Inhibitex, Janssen, Kadmon, Merck, Novartis, Salix, and Vertex; been a speaker for Genentech, Gilead Sciences, Kadmon, Merck, Salix, and Vertix. Philippe Mathurin serves on advisory boards at Abbott, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme, Novartis, and Roche; consulted for Abbott, Bayer Healthcare, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohm, Novartis, and Roche; been a speaker for Abbott, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme, Novartis, and Roche. Sam Lee has received grants and done research for AbbVie, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, and Vertex; consulted for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, and Vertex; been a speaker for Bristol-Myers Squibb, Gilead Sciences, Merck, Roche, and Vertex. Edward J. Gane serves on advisory boards for AbbVie, Gilead Sciences, Janssen, Novartis, and Roche; been a speaker for Gilead Sciences and Roche. John F. Flaherty, Lanjia Lin, Amy Corsa, Anuj Gaggar, G. Mani Subramanian, and John G. McHutchison are current or former employees of Gilead Sciences. The remaining authors disclose no conflicts.

: Funding This trial was supported by Gilead Sciences.

: Author names in bold designate shared co-first authorship.

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Original ResearchFull Report: Clinical—LiverEffects of Tenofovir Disoproxil Fumarate in Hepatitis B e Antigen-Positive Patients With Normal Levels of Alanine Aminotransferase and High Levels of Hepatitis B Virus DNA

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Design

Patient Population

Discussion

Lancet

Clin Gastroenterol Hepatol

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Gastroenterology

Hepatitis B virus infection

N Engl J Med

Immune tolerant hepatitis B: a clinical dilemma

Gastroenterol Hepatol (N Y)

Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase

Hepatology

Natural history and clinical management of chronic hepatitis B virus infection in children

Hepatol Int

EASL clinical practice guidelines: management of chronic hepatitis B virus infection

J Hepatol

Chronic hepatitis B: update 2009

Hepatology

Original Research
Full Report: Clinical—Liver
Effects of Tenofovir Disoproxil Fumarate in Hepatitis B e Antigen-Positive Patients With Normal Levels of Alanine Aminotransferase and High Levels of Hepatitis B Virus DNA