New therapeutic options for persistent low-level viremia in patients with chronic hepatitis B virus infection:Increase of entecavir dosage

Chronic hepatitis B virus(HBV)infection(CHB)is a public health concern worldwide.Current therapies utilizing nucleos(t)ide analogs(NA)have not resulted in a complete cure for CHB.Furthermore,patients on long-term NA treatment often develop low-level viremia(LLV).Persistent LLV,in addition to causing the progression of liver disease or hepatocellular carcinoma,may shed light on the current plight of NA therapy.Here,we review the literature on LLV,NA treatment,and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent.For LLV patients,three therapeutic options are available,switching to another antiviral monotherapy,interferon-αswitching therapy,and continuing monotherapy.In real-world clinical practice,entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV,which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies.The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety,and has great potential in inhibiting HBV replication,in all of the NAs.In the particular section of the drug approval package published by the United States Food and Drug Administration,entecavir doses 2.5-20 mg/d do not increase adverse events,and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy.The literature survey led us to two suggestions:(1)Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA>2×106 IU/mL is feasible and would provide better prognosis;and(2)Further research is needed to assess the long-term toxic effects of higher entecavir doses(2.5 and 5.0 mg/d),which may prove beneficial in treating patients with prior NA treatment,partial virological response,or LLV state.

恩替卡韦经治慢性乙肝患者低病毒血症的临床研究进展

目前临床上广泛使用恩替卡韦、富马酸替诺福韦酯等核苷(酸)类似物作为一线抗乙肝病毒药,部分患者经此类药物治疗后,其血清HBV DNA虽然降低到2000 IU/mL以下,但仍持续或间歇性地高于检测下限,即处于低病毒血症(low-level viremia,LLV)状态。持续存在的LLV会导致慢性乙肝患者出现耐药风险增加、病毒学突破、促进肝纤维化、肝硬化进展、肝癌风险增加、影响生存率等一系列临床危害。本文重点综述恩替卡韦治疗下LLV的相关临床研究,总结了LLV的规范定义和诊断标准,阐述恩替卡韦相关LLV的临床危害和管理策略,并讨论LLV的发生机制,为此类患者的治疗和管理提供参考。

Low-level viremia in nucleoside analog-treated chronic hepatitis B patients

Low-level viremia(LLV)was defined as persistent or intermittent episodes of detectable hepatitis B virus(HBV)DNA(<2000 IU/mL,detection limit of 10 IU/mL)after 48 weeks of antiviral treatment.Effective antiviral therapies for chronic hepatitis B(CHB)patients,such as entecavir(ETV),tenofovir disoproxil fumarate(TDF),and tenofovir alafenamide(TAF),have been shown to inhibit the replication of HBV DNA and prevent liver-related complications.However,even with long-term antiviral therapy,there are still a number of patients with persistent or intermittent LLV.At present,the research on LLV to address whether adversely affect the clinical outcome is limited,and the follow-up treatment for these patients is open to question.At the same time,the mechanism of LLV is not clear.In this review,we summarize the incidence of LLV,the association between LLV and long-term outcomes,possible mechanisms,and management strategies in these patient populations.

Risk factors for very low-level viremia in patients with chronic hepatitis B virus infection: A single-center retrospective study

Background and aim:Several effective antiviral drugs are now available;however,the risk of liver-related complications is still present.Low-level viremia(LLV),defined as a hepatitis B virus(HBV)deoxy-ribonucleic acid(DNA)load lower than 2000 IU/mL,is one of the major factors responsible for these complications.It has been reported that 22.7e43.1%of patients with HBV experience LLV.Herein,we aimed to explore the risk factors for very LLV(VLLV)during antiviral treatment.Methods:We collected data of patients with chronic hepatitis B(CHB)who received nucleos(t)ide analog treatment from October 2016 to April 2021.VLLV was defined as an HBV DNA load of 9e20 IU/mL.A total of 139 patients with LLV were matched with 139 patients with a sustained virological response at a 1:1 ratio according to age and gender.Results:Seropositivity rates for hepatitis B e antigen(HBeAg)(45.3%vs.17.3%,P<0.001)and hepatitis B surface antigen(HBsAg,3.11±0.68 lg IU/mL vs.2.54±1.04 lg IU/mL,P<0.001)and alanine amino-transferase levels(30.34±15.08 U/L vs.26.15±16.66 U/L,P¼0.040)in the two groups were significantly different.The multivariate analysis showed that both HBeAg seropositivity(adjusted odd ratio(aOR),3.63;95% confidence interval(CI):1.98±6.64;P<0.001)and HBsAg levels(aOR,2.21;95% CI:1.53±3.20;P<0.001)are independent risk factors for VLLV.During the multivariate analysis in the subgroup of HBeAg-positive patients,male gender(aOR,3.68;95% CI:1.23±10.76;P=0.017)and high HBsAg(aOR,4.86;95%CI:1.73e13.64;P¼0.003)levels were significantly correlated with VLLV.However,this was not the case in HBeAg-negative patients(P>0.050).HBeAg seropositivity(aOR,5.08;95% CI:2.15±12.02;P<0.001 vs.aOR,2.78;95% CI:1.16±7.00;P=0.022)and HBsAg levels(aOR,2.75;95% CI:1.41e5.37;P=0.003 vs.aOR,2.10;95% CI:1.27±3.46;P=0.004)significantly increased the risk of VLLV,irrespective of the age group.Both HBsAg(area under the receiver operating characteristic curve(AUC),0.681;95% CI:0.623±0.736;P<0.001)and HBeAg(AUC,0.640;95% CI:0.581±0.697;P<0.001)had certain pre-dictive value for VLLV.Conclusion:HBeAg seropositivity and higher HBsAg levels were not only risk factors for VLLV but also predicted its occurrence.When a patient with CHB remains HBeAg seropositive with high HBsAg levels after antiviral treatment for 48 weeks,emphasis should be placed on the potential occurrence of VLLV,warranting the use of highly sensitive HBV DNA detection methods.

Transcriptome analysis of CD4^(+)T cells from HIV-infected individuals receiving ART with LLV revealed novel transcription factors regulating HIV-1 promoter activity

Some HIV-infected individuals receiving ART develop low-level viremia(LLV),with a plasma viral load of 50-1000 copies/mL.Persistent low-level viremia is associated with subsequent virologic failure.The peripheral blood CD4^(+)T cell pool is a source of LLV.However,the intrinsic characteristics of CD4^(+)T cells in LLV which may contribute to low-level viremia are largely unknown.We analyzed the transcriptome profiling of peripheral blood CD4^(+)T cells from healthy controls(HC)and HIV-infected patients receiving ART with either virologic sup-pression(VS)or LLV.To identify pathways potentially responding to increasing viral loads from HC to VS and to LLV,KEGG pathways of differentially expressed genes(DEGs)were acquired by comparing VS with HC(VS-HC group)and LLV with VS(LLV-VS group),and overlapped pathways were analyzed.Characterization of DEGs in key overlapping pathways showed that CD4^(+)T cells in LLV expressed higher levels of Th1 signature transcription factors(TBX21),toll-like receptors(TLR-4,-6,-7 and-8),anti-HIV entry chemokines(CCL3 and CCL4),and anti-IL-1βfactors(ILRN and IL1R2)compared to VS.Our results also indicated activation of the NF-κB and TNF signaling pathways that could promote HIV-1 transcription.Finally,we evaluated the effects of 4 and 17 tran-scription factors that were upregulated in the VS-HC and LLV-VS groups,respectively,on HIV-1 promoter activity.Functional studies revealed that CXXC5 significantly increased,while SOX5 markedly suppressed HIV-1 tran-scription.In summary,we found that CD4^(+)T cells in LLV displayed a distinct mRNA profiling compared to that in VS,which promoted HIV-1 replication and r+eactivation of viral latency and may eventually contribute to virologic failure in patients with persistent LLV.CXXC5 and SOX5 may serve as targets for the development of latency-reversing agents.

Chronic Hepatitis B Infection with Low Level Viremia Correlates with the Progression of the Liver Disease

Background and Aims:Currently,insufficient clinical data are available to address whether low-level viremia(LLV)observed during antiviral treatment will adversely affect the clinical outcome or whether treatment strategies should be altered if LLV occurs.This study compared the clinical out-comes of patients with a maintained virological response(MVR)and patients who experienced LLV and their treatment strategies.Methods:A retrospective cohort of 674 patients with chronic hepatitis B virus(HBV)infection who received antiviral treatment for more than 12 months was analyzed for the development of end-stage liver disease and treatment strategies during the follow-up period.End-stage liver disease included decompensated liver cirrhosis and hepatocellular carcinoma(HCC).Results:During a median 42-month follow-up,end-stage liver disease developed more frequently in patients who experienced LLV than in those who experienced MVR(7.73%and 15.85%vs.0.77%and 5.52%at 5 and 10 years,respectively;p=0.000).The trend was consistent after propensity score matching.In the high-risk group of four HCC risk models,LLV patients had a higher risk of HCC development(p<0.05).By Cox proportional hazard model analysis,LLV was an independent risk factor for end-stage liver disease and HCC(hazard ratio[HR]=6.280,confidence interval[CI]=2.081-18.951,p=0.001;HR=5.108,CI=1.392-18.737,respectively;p=0.014).Patients achieved a lower rate of end-stage liver disease by adjusting treatment compared to continuing the original treatment once LLV occurred(p<0.05).Conclusions:LLV is an independent risk factor for end-stage liver disease and HCC,and treatment adjustments can be considered.

德宏州ART后HIV低病毒血症毒株基因亚型和耐药分析

目的探究接受抗病毒治疗的HIV/AIDS低病毒血症患者耐药情况和影响因素,基因亚型与耐药位点突变情况。方法纳入病毒载量50-999copies/mL的HIV/AIDS患者,巢式PCR扩增HIV-1的pol基因后进行耐药检测,根据世界卫生组织耐药标准和斯坦福大学耐药数据库判定耐药、确定突变位点以及毒株对ART药物的敏感性,Logistic回归分析耐药影响因素。结果896例低病毒血症患者中65.6%(588例)pol基因扩增成功。总耐药率为24.7%(145/588),NNRITs耐药率最高,为21.3%(125/588),部分患者存在多重耐药。588例HIV/AIDS低病毒血症患者中HIV-1毒株BC重组亚型占25.2%(148人),B亚型占24.5%(144人),C亚型占23.5%(138人),CRF 01_AE亚型占14.3%(84人)。Logistic回归分析发现,耐药与HIV-1病毒亚型有关。B亚型耐药率最高,为43.1%(62/144),CRFs、C亚型、URFs耐药率分别为22.7%(32/141)、18.8%(26/138)、15.2%(25/165)。所有亚型中K103 N、M184V/I突变频率最高,分别产生了对EFV/NVP、3TC/FTC的高度耐药。结论德宏州接受ART的HIV/AIDS低病毒血症患者耐药较为常见,不同毒株基因亚型耐药率不同,出现了常见的几种耐药突变,并产生对NNRTIs和NRTIs的耐药。应及时监测该人群的耐药情况,为更换ART药物、改善预后提供依据。

Adverse Effect of Nonalcoholic Fatty Liver Disease on the Therapeutic Response in Patients with Chronic Hepatitis B

Background and Aims:The impact of nonalcoholic fatty liver disease(NAFLD)on the treatment outcome of chronic hepatitis B(CHB)is undefined and deserves an in-depth investigation.Methods:Histologically-proven CHB receiving first-line antiviral regimens as initial therapy was enrolled and grouped by the concurrence of NAFLD,and followed up at six monthly intervals.Therapeutic response related data were recorded and compared at multiple time points.Kaplan-Meier and Cox regression analyses were utilized to estimate the impact of NAFLD on complete virological response(CVR).Results:We enrolled 267 patients(CHB:164;CHB with NAFLD:103)with comparable follow-up durations.They were also comparable in baseline HBV DNA levels and HBeAg positivity.Patients with concomitant NAFLD showed less significant decline in HBV DNA,qHBsAg,pgRNA,and liver enzyme levels over time;moreover,their cumulative incidences of CVR were significantly lower and that of low-level viremia(LLV)were significantly higher at 6,12,18,24 months.First CVR of CHB was delayed with the presence NAFLD(11.0 vs.7.0 months,p<0.001)and further prolonged with higher grade of liver steatosis(Grade 2–3 vs.1:13.0 vs.9.0 months).On multivariate analysis,HBeAg positivity(HR:0.650,p=0.036),grade of steatosis(G2[HR:0.447,p=0.004];G3[HR:0.085,p=0.002])and HBV DNA(log10 IU/mL)(HR:0.687,p<0.001)were significantly associated with delayed CVR,whereas grade of necroinflammation(HR:1.758,p<0.001)accelerated the CVR.Conclusions:In CHB patients receiving initial antiviral therapy,NAFLD was associated with higher levels of HBV DNA,pgRNA,and liver enzymes,and higher incidence of LLV and delayed CVR.