替诺福韦酯治疗慢性乙型肝炎的最新进展

1995年Dienstag等发现拉米夫定可抑制HBV DNA复制以来,以拉米夫定为代表的核苷（酸）类似物抗乙型肝炎病毒（HBV）的临床应用成为慢性乙型病毒性肝炎（CHB）治疗史上的里程碑,其问世推动了CHB治疗的进程。迄今为止,已有4种核苷（酸）类似物即拉米夫定（LMV）、阿德福韦酯（ADV）、恩替卡韦（ETV）和替比夫定（LdT）获得美国食品与药品管理局（FDA）批准用于慢性乙型病毒性肝炎的治疗。     

Causes and consequences of hypokalemia in patients on tenofovir disoproxil fumarate

To determine the spectrum of clinical manifestations of hypokalemia associated with tenofovir, we reviewed all reports of grades 3/4 hypokalemia received by Gilead Sciences Department of Safety and Public Health. Of 32 cases identified in 2001-2006, 23 were attributed to proximal renal tubular dysfunction, and medically significant conditions attributable to hypokalemia occurred in four, which all improved with medical management. In none of the six fatal cases did hypokalemia appear to contribute to death.     

Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients

Tenofovir disoproxil fumarate (TDF) has shown in vitro activity against both HIV and hepatitis B virus (HBV). We retrospectively evaluated the efficacy of TDF (300 mg/d), administered as a part of anti-retroviral therapy, in a large cohort of HIV/HBV-coinfected patients. Sixty-five HIV/HBV-coinfected patients who received TDF for at least 6 months with serum HBV DNA levels above 2.3 log10 copies/mL at TDF initiation and who had stored serum samples before and during TDF therapy were included. Serum HBV DNA was measured on stored samples. The median follow-up period was 12 (Q1-Q3: 8-17) months. Serum hepatitis B e antigen (HBeAg) was positive in 54 patients (83.1%). Fifty-two patients (80.0%) were receiving lamivudine (LAM) (150 mg twice a day), and 68.8% had documented LAM resistance at baseline. Among HBeAg-positive patients, the median reduction from baseline (8.17; Q1-Q3 = 7.30-8.30 log10 copies/mL) of serum HBV DNA was 4.56 log10 copies/mL (Q1-Q3 = 3.33-5.55) (P < .0001). In HBeAg-negative patients, serum HBV DNA decline from baseline (4.83; Q1-Q3 = 2.69-6.40 log10 copies/mL) was 2.53 log10 copies/mL (Q1-Q3 = 0.39-4.10). At the end of the study, HBV DNA became undetectable in 29.6% and 81.6% of the HBeAg-positive and HBeAg-negative patients, respectively. Serum HBeAg became negative in 4 patients, 2 of whom acquired serum hepatitis B e antibody. In conclusion, this retrospective analysis demonstrates the efficacy of TDF against wild-type, presumed precore mutants and LAM-resistant HBV when used as a part of anti-retroviral therapy in HIV-coinfected patients.     

HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate with or without switching to tenofovir alafenamide

Background/AimsThe incidence and relapse pattern in patients stopping tenofovir alafenamide (TAF), a prodrug of tenofovir which is more concentrated in hepatocytes, is unknown.MethodsHBeAg-negative CHB patients stopping tenofovir disoproxil fumarate (TDF) (off-TDF) or who had switched to TAF more than 3 months before discontinuation (off-TAF) were recruited. The propensity score-matching method (PSM) was used, creating a ratio of 1:3 between the off-TAF versus the off-TDF groups to adjust for associated factors.ResultsAfter PSM, 180 off-TDF and 60 off-TAF patients were analyzed. The cumulative rates of virological and clinical relapse at 52 weeks were 75.1% and 58.5% respectively in the off-TDF group and 91.1% and 61.6% in the off-TAF group. Patients in the off-TAF group had significantly higher rates of virological relapse than those in the off-TDF group (p = 0.021), but not clinical relapse (p = 0.785). Multivariate cox regression analysis showed that off-TAF group was an independent factor for virological relapse, but not clinical relapse. Severity of clinical relapse and hepatic decompensation rate were comparable between off-TDF and off-TAF groupsConclusionsThe off-TAF group had a higher virological relapse rate than the off-TDF group. The difference in clinical relapse pattern and severity was not clinically important between the two groups.     

替诺福韦酯治疗慢性乙型肝炎的最新进展

在众多核苷和核苷酸类药物（NAs）中,替诺福韦（TDF）以其强效、低耐药性及对多种 NAs治疗失败的慢性乙型肝炎（CHB）患者有效的特点脱颖而出,使其在临床HBV感染治疗中被广泛应用。介绍了TDF对CHB初治患者和经治患者的疗效,并分析了其对肝硬化患者治疗的效果,同时也对TDF治疗的安全性进行了评估。认为TDF耐药率低、安全性好,为目前CHB治疗的一线药物。     

Cost-effectiveness analysis of tenofovir disoproxil fumarate for treatment of chronic hepatitis B in China

Background

Tenofovir disoproxil fumarate (TDF) is newly available for treatment of chronic hepatitis B patients in China. To date, no study has been conducted to examine the cost-effectiveness of this treatment. The aim of this study was to estimate the cost-effectiveness of TDF versus four oral nucleos(t)ide analogs [lamivudine (LAM), adefovir (ADV), telbivudine (LdT), and entecavir (ETV)] and from a pharmacoeconomic perspective to assess current drug pricing for TDF.

Methods

Based on Chinese healthcare perspectives, a Markov model was applied to simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for five different monotherapy strategies. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: directly using ETV + ADV) were separately considered for treatment of patients refractory to monotherapy. Model parameters (including disease transition, cost, and utility) were obtained from previous Chinese population studies. Both branded and generic drugs were separately analyzed. Study model uncertainties were assessed by one-way and probabilistic sensitivity analyses. Two-way sensitivity analysis was used to explore uncertainties between efficacy and price of TDF.

Results

In the base-case analysis, the lowest lifetime cost and the best cost-effectiveness ratio were obtained by ETV, which was considered the reference treatment. LAM, ADV, and LdT treatments had significantly greater costs and lower efficacies. Compared to ETV, TDF was more effective but also more expensive. The incremental cost-effectiveness ratios of TDF versus ETV were much higher than the willing-to-pay threshold of $20,466 US dollars (USD) per QALY gained (3 × gross domestic product per capita of China, 2014). TDF would be the most cost-effective strategy if the annual cost did not exceed $2260 USD and $1600 USD for branded and generic drugs, respectively.

Conclusions

For Chinese chronic hepatitis B patients, ETV is still the most cost-effective strategy over TDF and other nucleos(t)ide analogs, with a threshold of $20,466 USD/QALY gained.

     

Histopathological evaluation of long-term tenofovir disoproxil fumarate treatment in patients with hepatitis be antigen-negative chronic hepatitis B

BACKGROUND Hepatitis B virus is a universal health problem.There are approximately 250 million people living with hepatitis B worldwide,and approximately 600000 of these people die every year due to the virus.AIM To compare the pretreatment and post-treatment histopathological results of patients with hepatitis be antigen(HBeAg)-negative chronic hepatitis B(CHB)who had been receiving tenofovir disoproxil fumarate(TDF)treatment at our clinic for at least 5 years.METHODS Patients with HBeAg-negative CHB who were being treated with TDF(245 mg/d)were included in the study.Liver biopsies of patients before TDF treatment and liver biopsies after 5 years of TDF treatment were retrospectively compared.RESULTS A total of 50 HBeAg-negative CHB patients were included in the study(mean age:47.9±10.4 years,men:27.54%).Histological improvement was observed in 78%(39)of the patients after 5 years of treatment.After the 5 years of treatment,the mean Ishak score of the patients was 1.3±1.3,and the mean histologic activity index score was 4.1±2.8.A 1.53 point reduction in Ishak fibrosis score was detected after long-term TDF treatment.CONCLUSION Liver biopsies after 5 years of TDF treatment revealed a significant histological response and a regression of the necroinflammatory score compared to pretreatment liver biopsies.To better understand the effects of antiviral treatments on the improvement of liver histology,long-term studies involving larger numbers of patients are needed.     

替诺福韦酯对阿德福韦酯应答不佳患者的挽救治疗研究进展

阿德福韦酯(adefovir dipivoxil,ADV)作为常用抗HBV治疗药物,与拉米夫定(lamivudine,LAM)、替比夫定和恩替卡韦无交叉耐药,且价格相对低廉,长期以来用于初治患者和LAM耐药患者的挽救治疗。然而由于ADV耐药基因屏障较低且临床用药剂量较低,临床长期应用累积了较多ADV应答不佳患者。替诺福韦酯(tenofovir disoproxil fumarate,TDF)作为ADV应答不佳患者的挽救治疗方案之一,对ADV初治应答不佳患者和LAM耐药的ADV应答不佳患者的临床疗效略有差异。然而多项体外研究显示TDF对ADV耐药病毒株抑制作用减弱。ADV应答不佳的患者换用TDF是否会引起或加重肾损害值得临床关注。本文就TDF对ADV应答不佳患者挽救治疗的国内外研究进展作综述,为提高耐药HBV感染防治的管理提供帮助。     

替诺福韦酯治疗慢性乙型肝炎的最新进展

核苷(酸)类似物抗病毒药物已广泛应用于慢性乙型肝炎的治疗,其中替诺福韦酯作为一种新型药物,以其良好的抗病毒作用及低耐药性成为目前研究的热点.本文概述了近年来替诺福韦酯的体内外研究进展及其在临床应用的前景.     

替诺福韦DF治疗慢性乙型肝炎和HIV感染的研究动态

1替诺福韦DF（TDF）抗病毒作用机制 替诺福韦是5’-单磷酸腺苷（脱氧腺苷）类似物,已经被美国、澳大利亚和欧洲数个国家批准用于治疗HIV感染,但是口服吸收差,替诺福韦DF（TDF）能提高口服吸收和细胞对其摄取。TDF是核苷酸逆转录酶抑制剂（NRTI）替诺福韦的酯类前体药,与其他NRTI一样,TDF为DNA的天然底物的衍生物,口服后很快就水解为替诺福韦,替诺福韦被细胞激酶磷酸化生成具有药理活性的代谢产物替诺福韦二磷酸,     

Renal safety of tenofovir disoproxil fumarate and entecavir with hepatitis B immunoglobulin in liver transplant patients

Potent nucleos(t)ide analogues and hepatitis B immunoglobulin combinations are recommended after liver transplantation to prevent the recurrence of hepatitis B virus (HBV). Despite its proven efficacy, the renal safety of tenofovir disoproxil fumarate (TDF) has not been well established in liver transplant recipients. We aimed to assess the impacts of TDF and entecavir (ETV) on tubular and glomerular functions. We analysed 206 liver transplant patients treated with TDF (n = 102) or ETV (n = 104) plus hepatitis B immunoglobulin. Serum creatinine, phosphate and uric acid levels were measured. Proximal tubular dysfunction was defined as the presence of hypophosphatemia (<2 mg/dL) and hypouricemia (<2 mg/dL). Glomerular dysfunction was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m² accompanied by a ≥25% eGFR decline from baseline. During a median follow‐up of 42.5 months, 48 patients developed proximal tubular dysfunction (30.4% and 16.3% in the TDF and ETV groups; P = .017). Serum levels of phosphate and uric acid were significantly lower in the TDF group post‐LT. TDF (OR, 2.34; 95% CI, 1.16‐4.69; P = .017) and low body mass index (OR, 2.11; 95% CI, 1.06‐4.21; P = .034) were independent risk factors for proximal tubular dysfunction. The prevalence of glomerular dysfunction was not significantly different between the two groups (TDF 51.0% and ETV 54.8%; P = .582). TDF significantly increased the risk of proximal tubular dysfunction. Although the effect of TDF on glomerular function was comparable to that of ETV, glomerular dysfunction was common after liver transplant.     

Long-term hepatitis B virus dynamics in HIV-hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate

BACKGROUND: The long-term impact of tenofovir disoproxil fumarate (TDF) on hepatitis B virus (HBV) replication has not yet been studied in HIV-HBV-co-infected patients. METHODS: We conducted a prospective study of HBV-DNA decay kinetics in 28 HIV-HBV-co-infected patients treated by TDF. HBV dynamics were studied using mixed linear models, and baseline factors affecting them were analysed using Cox models. RESULTS: The HBV-DNA load declined by a mean of 4.6 log copies/ml during follow-up (mean 71 weeks), and fell below the detection limit (200 copies/ml) in 21 patients. Inhibition of viral replication by TDF was associated with a decrease in alanine aminotransferase levels (125 versus 68 IU, P < 0.05). HBV-DNA decay was biphasic, with an rapid fall followed by a gradual decline. Baseline factors associated with a steeper first slope in the HBV-DNA decrease were high HBV load, positive hepatitis B e antigen (HBeAg) and YMDD mutations. Baseline factors increasing the time to reach an HBV-DNA level less than 200 copies/ml were high HBV load (150 days when HBV-DNA < 10 log, 316 days when HBV-DNA > 10 log) and positive HBeAg. Previous exposure to lamivudine or TDF-lamivudine did not modify HBV-DNA decrease under therapy in this population with a high prevalence of YMDD mutations. CONCLUSION: The long-term decline in HBV DNA under TDF is biphasic and is primarily influenced by the initial HBV load. However, the clinical significance of such an association remains moderate, and TDF can be efficiently included in the highly active antiretroviral therapy regimen of HIV-HBV-co-infected patients, regardless of HBV strains and their degree of replication.