Hepatitis B—management of acute infection and active inflammation in pregnancy—a hepatologist's perspective

Women at childbearing age and pregnant ladies living in the areas of high or intermediate prevalence of hepatitis B virus (HBV) remain at risk of getting the infection and passing the infections to their offspring via mother-to-child transmission (MTCT) of HBV. HBV infection may affect the mothers by active hepatitis, very occasionally liver cirrhosis and rarely fulminant hepatitis and liver failure. The virus may be transmitted to the babies despite immunoprophylaxis in the setting of very high maternal viral load. Tenofovir disoproxil fumarate (TDF) has been shown to be efficacious to reduce MTCT of HBV, which contributes to the elimination of chronic HBV infection by 2030, the goal set by World Health Organization.     

Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide analogue-na?ve and nucleos(t)ide analogue-experienced chronic hepatitis B patients

Background/Aims

This study investigated the antiviral effects of tenofovir disoproxil fumarate (TDF) monotherapy in nucleos(t)ide analogue (NA)-naive and NA-experienced chronic hepatitis B (CHB) patients.

Methods

CHB patients treated with TDF monotherapy (300 mg/day) for ≥12 weeks between December 2012 and July 2014 at a single center were retrospectively enrolled. Clinical, biochemical, and virological parameters were assessed every 12 weeks.

Results

In total, 136 patients (median age 49 years, 96 males, 94 HBeAg positive, and 51 with liver cirrhosis) were included. Sixty-two patients were nucleos(t)ide (NA)-naïve, and 74 patients had prior NA therapy (NA-exp group), and 31 patients in the NA-exp group had lamivudine (LAM)-resistance (LAM-R group). The baseline serum hepatitis B virus (HBV) DNA level was 4.9±2.3 log IU/mL (mean±SD), and was higher in the NA-naïve group than in the NA-exp and LAM-R groups (5.9±2.0 log IU/mL vs 3.9±2.0 log IU/mL vs 4.2±1.7 log IU/mL, P<0.01). The complete virological response (CVR) rate at week 48 in the NA-naïve group (71.4%) did not differ significantly from those in the NA-exp (71.3%) and LAM-R (66.1%) groups. In multivariate analysis, baseline serum HBV DNA was the only predictive factor for a CVR at week 48 (hazard ratio, 0.809; 95% confidence interval, 0.729-0.898), while the CVR rate did not differ with the NA experience.

Conclusions

TDF monotherapy was effective for CHB treatment irrespective of prior NA treatment or LAM resistance. Baseline serum HBV DNA was the independent predictive factor for a CVR.     

替诺福韦酯阻断乙型肝炎病毒母婴传播不同停药时间的安全性评价

目的探讨采用替诺福韦酯（TDF）阻断乙型肝炎病毒（HBV）母婴传播的高HBV DNA载量孕妇分娩后不同停药时间对母婴安全性的影响。 方法招募2015年1月至2017月12月于深圳市第三人民医院就诊的免疫耐受期HBsAg阳性孕妇109例，均于孕24～28周开始服用TDF治疗，根据简单随机化方法将入组患者分为分娩时停药组（58例）和分娩后4～12周停药组（51例）。定量检测两组孕妇抗病毒治疗后4周、8周、12周、停药时与停药后4周、8周、12周、24周的HBV DNA载量和ALT水平，并定量检测新生儿产后4周HBsAg和HBsAb水平。 结果所有孕妇分娩前HBV DNA载量均显著降低，较基线水平差异有统计学意义（分娩时停药组：Z = 8.459、P < 0.001；分娩后4～12周停药组：Z = 7.760、P < 0.001）。停药时两组产妇HBV DNA载量差异有统计学意义（Z = 2.242、P = 0.025）。停药后4周两组产妇HBV DNA载量差异无统计学意义（Z = 1.041、P = 0.298），且较基线水平差异均无统计学意义（分娩时停药组：Z = 0.155、P = 0.877；分娩后4～12周停药组：Z = 0.376、P = 0.707）。随访至停药后24周，两组产妇产后ALT升高的发生率差异无统计学意义（χ² = 1.319、P = 0.251），两组产妇ALT升高的中位时间点均在停药后4周，差异无统计学意义（Z = 0.196、P = 0.844）。孕期ALT升高可能引起分娩停药后ALT升高，但并非独立危险因素。20例新生儿在产后4周行外周血HBsAg、HBsAb定量检测，HBsAg均为阴性，均产生保护性抗体。 结论妊娠中晚期使用替诺福韦酯能有效阻断HBV母婴传播；随访24周发现分娩后停药与延后停药对产后安全性的无显著影响，新生儿4周龄即能产生保护性抗体并有效发挥作用，母乳喂养是安全的。     

Tenofovir gel for HIV prevention for women: Perspectives of Key Opinion Leaders from India

ObjectivesCountry decision-making regarding adoption of new health technologies is a lengthy process that is informed by scientific, public health, and policy analyses. Key Opinion Leaders (KOLs), who include a range of influential individuals (e.g., Ministry of Health officials, leaders of medical and pharmacy associations, civil society representatives, donors), play a critical role in country decision-making around adoption and availability of new HIV-prevention tools. Their perspectives can shape public opinion and influence policy, programming, and procurement decisions.MethodsIn-depth face-to-face interviews with a dozen purposefully selected national KOLs in India were conducted to gain their perspectives around ARV-based prevention for women, focusing on microbicides in general and tenofovir vaginal gel specifically. Theme-based content emerged and was analyzed using ATLAS.ti software.ResultsWhile generally supportive, KOLs expressed caveats regarding the role tenofovir gel might play in the overall HIV-prevention program. Key outstanding issues that would need to be addressed include product effectiveness, potential for resistance, product cost, feasibility of HIV testing and re-testing, and effective targeting of key populations for public health impact.ConclusionsAs new HIV-prevention technologies advance through clinical trials, there is a concomitant necessity to engage in policy analysis exercises. Formative research with stakeholders early in the process is an important yet often overlooked step. The potential role that the tenofovir gel could play in India will depend in large part on epidemiological, public health, and economic factors. Understanding target populations' perspectives on the product will also be critical for its successful introduction.     

替诺福韦酯在乙型病毒性肝炎合并肝硬化患者挽救治疗中的应用

目的探讨替诺福韦酯在乙型病毒性肝炎合并肝硬化患者挽救治疗中的应用效果。方法收集2014-2017年沈阳市第六人民医院收治的乙肝合并肝硬化拉夫米定抗病毒治疗失败的患者89例,以替诺福韦酯进行挽救治疗%周。分别依据挽救治疗前患者HBV定量和谷丙转氨酶(ALT)水平将患者进行分组,比较不同分组情况下HBV累积应答率、乙型肝炎E抗原(HBeAg)累积转换率和ALT累积复常率。结果本组89例患者中,HBV累积应答64例,占71.91%;HBeAg累积转换32例,占35.96%;ALT累积复常74例,占83.15%。低定量组与高定量组HBV累积应答率、HBeAg累积转换率、ALT累积复常率差异均有统计学意义(P值均<0.05)。低转氨酶组与高转氨酶组HBV累积应答率、HBeAg累积转换率、ALT累积复常率差异均无统计学意义(P值均>0.05)。结论替诺福韦酯作为挽救治疗用药,可有效抑制乙型肝炎病毒复制,改善转氨酶和肝炎抗体指标,尤其是对病毒定量水平较低的患者,效果更为明显。     

Advances in Nucleotide Antiviral Development from Scientific Discovery to Clinical Applications: Tenofovir Disoproxil Fumarate for Hepatitis B

Exploration of naturally occurring chemical structures for medicinal uses has received significant interest in drug discovery and development research in the past few decades. None have had more success or products of greater clinical efficacy than synthetic analogs of nucleosides and nucleotides, especially as antiviral drugs. Nucleos(t)ide antivirals are synthetic analogs of the natural building blocks of DNA or RNA. This review focuses on the developmental path of tenofovir disoproxil fumarate (TDF), a prodrug of a nucleotide analog and its clinical applications as a first-line antiviral for chronic hepatitis B (CHB).Tenofovir is a potent antiviral compound, but has poor oral availability. The disoproxil fumarate (DF) prodrug moiety greatly enhances intestinal absorption allowing it to become an oral medication. Tenofovir is activated intracellularly, and the incorporation into HBV DNA prevents further elongation thus terminating replication. In patients with CHB, TDF has demonstrated broad, potent and sustained virologic response. Maintenance of viral suppression for up to 5 years resulted in regression of fibrosis and cirrhosis. No tenofovir-resistant HBV variants have been detected in patients after long-term use. The efficacy and safety profiles reported from cohort studies of clinical practices were consistent with those observed in registration trials.Continuous development includes a new oral prodrug, tenofovir alafenamide fumarate (TAF), which has enhanced delivery of tenofovir to target cells compared to TDF.     

Combination treatment in HBeAg-negative chronic hepatitis B

Chronic hepatitis B (CHB) represents an important public health problem. HBeAg-negative CHB is frequently associated with advanced liver disease and its prevalence is increasing. Monotherapy with either interferon (conventional or pegylated) or nucleoside/nucleotide analogues has its limitations. It has been suggested that a combination of these agents might increase antiviral efficacy. However, existing data do not support this hypothesis, even though combination treatment appears to reduce the risk for emergence of lamivudine resistance. Nevertheless, most existing combination studies are small, and it is possible that they have not been designed to detect significant differences between combination treatment and monotherapies. Another limitation of these studies is that, in most of them, lamivudine treatment was discontinued after 1 year, a strategy that is not followed in clinical practice. It was thought to be interesting to evaluate the combination of a short course of interferon (particularly pegylated) with the long-term administration of nucleotide or nucleoside analogues. The efficacy of combining pegylated interferon with the newer nucleotide or nucleoside analogues or of nucleotide with nucleoside analogues could also be evaluated. However, findings show that until more data are available, combination therapy cannot be recommended as first-line treatment in patients with CHB. On the other hand, add-on therapy with adefovir or tenofovir is the treatment of choice in patients who develop resistance to lamivudine. In patients with cirrhosis, a combination of lamivudine/adefovir may also be used as initial treatment; another option would be to add tenofovir in patients with an insufficient response to entecavir.     

Does tenofovir gel or do other microbicide products affect detection of biomarkers of semen exposure in vitro?

Objectives

There is currently no information on whether products evaluated in HIV microbicide trials affect the detection of the semen biomarkers prostate-specific antigen (PSA) or Y chromosome DNA.

Study Design

We tested (in vitro) dilutions of tenofovir (TFV), UC781 and the hydroxyethylcellulose (HEC) placebo gels using the Abacus ABAcard and the quantitative (Abbott Architect total PSA) assays for PSA and Y chromosome DNA by real-time polymerase chain reaction.

Results

TFV gel and the HEC placebo adversely affected PSA detection using the ABAcard but not the Abbott Architect total PSA assay. UC781 adversely affected both the ABAcard and Abbott Architect total PSA assays. While there were some quantitative changes in the magnitude of the signal, none of the products affected positivity of the Y chromosome assay.

Conclusions

The presence of TFV or HEC gels did not affect quantitative PSA or Y chromosome detection in vitro. Confirmation of these findings is recommended using specimens obtained following use of these gels in vivo.

Implications

Researchers should consider the potential for specific microbicides or any products to affect the particular assay used for semen biomarker detection. The ABAcard assay for PSA detection should not be used with TFV UC781, or HEC.