Daclatasvir plus asunaprevir in treatment-na?ve patients with hepatitis C virus genotype 1b infection

AIM To assess daclatasvir plus asunaprevir(d UAL) in treatment-na?ve patients from China's Mainland, Russia and South Korea with hepatitis C virus(HCV) genotype 1 b infection. METHODS Patients were randomly assigned(3:1) to receive 24 wk of treatment with d UAL(daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period(immediate treatment arm) or following 12 wk of matching placebo(placebodeferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12(SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin(70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in d UAL-treated patients compared with placebo patients during the first 12 wk(doubleblind phase), and during 24 wk of d UAL in both arms combined.RESULTS In total, 207 patients were randomly assigned to immediate(n = 155) or placebo-deferred(n = 52) treatment. Most patients were Asian(86%), female(59%) and aged < 65 years(90%). Among them, 13% had cirrhosis, 32% had IL28 B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/m L. Among patients in the immediate treatment arm, SVR12 was achieved by 92%(95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate(70%). SVR12 was largely unaffected by cirrhosis(89%), age ≥ 65 years(92%), male sex(90%), baseline HCV RNA ≥ 6 million(89%) or IL28 B non-CC genotypes(96%), although SVR12 was higher among patients without(96%) than among those with(53%) baseline NS5 A resistanceassociated polymorphisms(at L31 or Y93 H). during the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving d UAL. during 24 wk of d UAL therapy(combined arms), the most common adverse events(≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities(alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued d UAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths.CONCLUSION d UAL was well-tolerated during this phase 3 study, and SVR12 with d UAL treatment(92%) exceeded thehistorical SVR rate for peg-interferon plus ribavirin of 70%.

Spectrum-effect relationship between HPLC fingerprints and bioactive components of Radix Hedysari on increasing the peak bone mass of rat

The traditional Chinese medicine of Radix Hedysari plays an important role in invigorating gas for ascending, benefiting blood for promoting production of fluid, and promoting circulation for removing obstruction in collaterals, which is consistent with the principle of treatment for osteoporosis. This study is designed to investigate the bioactive components on increasing peak bone mass (PBM) by exploring the spectrum-effect relationship between chromatography fingerprints and effect. Multiple indicators are selected to evaluate the pharmacological activity. In fingerprints, 21 common peaks are obtained, five of which are identified. Furthermore, gray relational analysis (GRA) is a quantitative method of gray system theory and is used to describe the correlation degree of common peaks and pharmacological activities with relational value. 21 components are then divided into three different regions, of which ononin and calycosin play an extremely significant role in increasing PBM. In addition, factor analysis and hierarchical cluster analysis (HCA) are used to screen the optimal producing area for Radix Hedysari. This provides a comprehensive and efficient method to improve the quality evaluation of Radix Hedysari, confirming the bioactive components for PBM-enhancement and further develop its medicinal value.

Antiviral treatment for chronic hepatitis B: Safety, effectiveness, and prognosis

The goal of chronic hepatitis B (CHB) therapy is to improve the patient prognosis through the sustained inhibition of viral replication. However, due to the uncertainty and potentially unlimited duration of the treatment course, nucleus(t)ide analogue (NA) resistance and safety, financial costs and patient compliance, different endpoints of antiviral treatment have been proposed in CHB prevention and treatment guidelines. Different treatment endpoints are closely associated with the safety of drug withdrawal and improvements in prognosis. Antiviral treatment suppresses HBV DNA replication, drug withdrawal leads to relapse, and long-term treatment causes drug safety and resistance issues. Although hepatitis B e antigen seroconversion based on HBV DNA inhibition is considered as “a satisfactory endpoint”, drug withdrawal still leads to high relapse rates. Hepatitis B surface antigen (HBsAg) clearance is the “ideal endpoint” in terms of the safety of drug withdrawal and improvements in prognosis. However, the HBsAg clearance rate is low using the conventional single drug treatment and fixed course regimens. Recently, the application of an “optimized antiviral treatment strategy” has improved the HBsAg clearance rate, and make an “ideal endpoint” possible. This article reviews the different antiviral treatment endpoints in terms of the safety of drug withdrawal, improvements in prognosis and relevant advances.

Effects of antiviral agents and HBV genotypes on intrahepaticcovalently closed circular DNA in HBeAg-positive chronichepatitis B patients

AIM： To evaluate the effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA （ccc DNA） in HBeAg-positive chronic hepatitis B patients.METHODS： Seventy-one patients received lamivudine （n = 35）, or sequential therapy with lamivudine- interferon alpha 2b （IFN-α 2b, n = 24） for 48 wk, or IFN-α 2b （n = 12） for 24 wk. All subjects were followed up for 24 wk. Intrahepatic ccc DNA was measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP.RESULTS： Sequential lamivudine- INF-α therapy, lamivudine and INF-α monotherapy reduced ccc DNA of 1.7 log, 1.4 log and 0.8 log, respectively （P 〈 0.05）. Seventeen out of the 71 patieots developed HBeAg seroconversion, the reduction of ccc DNA in the HBeAg seroconversion patients was more significant than that in the HBeAg positive patients （3.0 log vs 1.6 log, P = 0.0407）. Twenty-four weeks after antiviral therapy withdrawal, 16 patients had a sustained virological response, the baseline intrahepatic ccc DNA in the patients with a sustained virological response was significantly lower than that in the patients with virological rebound （4.6 log vs 5.4 log, P = 0.0472）. HBV genotype C accounted for 85.9% （n = 61）, and genotype B for 14.1% （n = 10）, respectively, in the 71 patients. There was no significant difference in the change of ccc DNA level between HBV genotypes C and B （2.1 log vs 1.9 log）.CONCLUSION： Forty-eight week sequential lamivudine- INF-α therapy and lamivudine monotherapy reduce ccc DNA more significantly than 24-wk INF-α monotherapy. Low baseline intrahepatic ccc DNA level may predict the long-term efficacy of antiviral treatment. HBV genotypes C and B have no obvious influence on ccc DNA load.

Intrahepatic HBV DNA as a predictor of antivirus treatment efficacy in HBeAg-positive chronic hepatitis B patients

AIM： To evaluate the effect of antiviral agents on intrahepatic HBV DNA in HBeAg-positive chronic hepatitis B patients. METHODS： Seventy-one patients received treatment with lamivudine, interferon alpha （IFN-α2b） or sequential therapy with lamivudine-IFN-α2b for 48 wk. All subjects were followed up for 24 wk. Serum and intrahepatic HBV DNA were measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS： At the end of treatment, the intrahepatic HBV DNA level in 71 patients decreased from a mean of （6.1 ± 1.0） Iog10 to （4.9± 1.4） Iog10. Further, a larger decrease was seen in the intrahepatic HBV DNA level in patients with HBeAg seroconversion. Intrahepatic HBV DNA level （before and after treatment） was not significantly affected by the patients＇ HBV genotype, or by the probability of virological flare after treatment. CONCLUSION： Intrahepatic HBV DNA can be effectively lowered by antiviral agents and is a significant marker for monitoring antivirus treatment. Low intrahepatic HBV DNA level may achieve better efficacy of antivirus treatment.

Tenofovir disoproxil fumarate in Chinese chronic hepatitis B patients:Results of a multicenter,double-blind,double-dummy,clinical trial at 96 weeks

BACKGROUND Tenofovir disoproxil fumarate(TDF)is a prodrug of a nucleotide analogue.As an antiviral drug,TDF has been proposed in the first-line treatment of chronic hepatitis B(CHB).Qingzhong,a brand name of TDF,commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd.,and Viread,another brand name of TDF,commercialized by GlaxoSmithKline,have both been approved by the State Food and Drug Administration,China.AIM To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients.METHODS This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857.A total of 330 Chinese CHB patients,among which 232 were hepatitis B e antigen(HBeAg)-positive,were included in this 5-year-long,multicenter,double-blinded,double-dummy,randomized-controlled,noninferiority phase III trial.The participants were initially randomized into two groups:Group A(n=161),in which the participants received 300 mg Qingzhong once a day for 48 wk;and Group B,in which the participants received 300 mg Viread once a day for 48 wk.Starting from week 49,all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week.In this study,the primary endpoint was the decrease in plasma level of hepatitis B virus(HBV)DNA at the 96th week,while the secondary endpoints were suppression of HBV replication,alanine aminotransferase(ALT)normalization,HBeAg loss,and HBeAg seroconversion rates.RESULTS For the participants with HBeAg-positive CHB,the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B(5.77 vs 5.73 log10 IU/mL,P>0.05)at the 96th week.In addition,similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA,HBeAg loss,and HBeAg seroconversion(71.05%vs 77.97%,31.00%vs 27.27%,and 20.22%vs 15.79%,respectively,in Group A vs Group B;P>0.05).For the participants with HBeAg-negative CHB,the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B(4.46 vs 4.70 log10 IU/mL,P>0.05)at the 96th week.In addition,similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA(87.23%vs 94.12%in Group A vs Group B,respectively;P>0.05).Finally,similar percentages of CHB patients(HBeAg-positive or HBeAg-negative)in the two groups exhibited normalization of ALT(80.14%vs 84.57%in Group A vs Group B,respectively;P>0.05),and similar incidences of adverse events were observed(106 vs 104 in Group A vs Group B,respectively;P>0.05).CONCLUSION Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C

BACKGROUND Entecavir(ETV)is a potent and selective nucleotide analog with significant activity against hepatitis B virus(HBV).ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV(Baraclude)when used in Chinese patients with chronic hepatitis B(CHB)in phase III clinical trials(Clinical Trials.gov number,NCT-01926288)at weeks 48,96,and 144.AIM To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C.METHODS In this double-blind study,we randomly assigned patients to receive 0.5 mg/d ETV(Group A)or ETV maleate(Group B)(ratio,1:1),each with a placebo tablet for 48 wk.Then,all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49.The primary efficacy endpoint was the reduction in HBV DNA levels from baseline.Secondary endpoints included the proportion of patients with undetectable HBV DNA(<20 IU/m L),serologic response,serum alanine aminotransferase(ALT)normalization and development of resistance mutations.RESULTS Two hundred eighteen patients who were hepatitis B e antigen(HBe Ag)positive and 57 who were HBe Ag negative were analyzed and predominantly presented with genotype B(49.82%)or C(48.73%).For the HBe Ag-positive CHB patients,the mean HBV DNA level decrease(6.61 Log10 IU/m L vs 6.69 Log10 IU/m L,P>0.05),viral suppression with HBV DNA<20 IU/m L(83.33%vs 79.17%,P>0.05)and HBe Ag seroconversion(28.77%vs 20.00%,P>0.05)occurred similarly between Groups A and B at week 192.However,there was a significant difference in the proportion of patients with normal ALT levels(91.14%vs 78.38%,P<0.05).For the HBe Ag-negative CHB patients,no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline(6.05 Log10 IU/m L vs 6.03 Log10 IU/m L,P>0.05),percentages of patients who achieved undetectable HBV DNA(100%vs 100%,P>0.05)and rates of ALT normalization(95.65%vs 100.00%,P>0.05).Safety and adverse event profiles were similar between Groups A and B.Two HBe Ag-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV.CONCLUSION Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

Chinese Consensus on Diagnosis and Treatment of Hepatic Encephalopathy

Hepatic encephalopathy(HE)is a complex,neuropsychiatric abnormality that occurs as a consequence of metabolic disorders in patients with hepatic insufficiency.The pathogenesis is complex with a strong prognosticator of death.To standardize the clinical management of HE,relevant new data were reviewed and assessed by Chinese Committee of Experts on Hepatic Encephalopathy in China and was discussed and debated extensively.Then the consensus on the management of HE was developed.The final recommendations are based on the data available at the time of production of the document and may be updated with pertinent scientific developments at a later time.All the discussion was organized by the editorial board of Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition),Chinese Journal of Liver Diseases(Electronic Edition)and Infection International(Electronic Edition).The evidence gradings in the consensus are listed in Table1.

NRTIs’ effect on the sequence of mitochondrial DNA HV 2 in HIV infected patients

Potent combination antiretroviral therapy(cART)has significantly improved the life expectancy of people living with human immunodeficiency virus(HIV),but it has many side effects such as lipodystrophy(LD),hepatic steatosis,and lactic acidosis.Nucleoside reverse transcriptase inhibitors(NRTIs)could damage the mito-chondria by inhibiting the human DNA polymerase gamma,leading to mtDNA deletion.However,it remains uncertain whether NRTIs could induce the hypervariable region(HV)mutations of the D loop of mitochondria in Chinese HIV/AIDS patients,and whether that effect is different between individuals with and without LD.Hereby,30 Chinese AIDS patients who were receiving antiretroviral drugs were recruited,among which 16 had symptomatic LD and 14 did not.Blood samples were collected prior to and after 96 weeks of treatment.Total DNA was extracted from peripheral blood mononuclear cells(PBMCs).Fragments of 728 bp in length containing HV 2 were amplified by standard polymerase chain reaction(PCR).Direct DNA-sequencing analysis techni-ques were used to detect mitochondrial sequence variants between paired longitudinal samples.Alterations were compared with the revised Cambridge Reference Sequence(rCRS)to determine mutation or polymorphism.Results showed that two years after ART,totally seven cases exhibited sequence variations,five individuals showed 73 A!G revised variation(two with and three without LD),while two cases of LD were found to have other nucleotide alterations.There was no new alteration in individuals without LD.In conclusion,NRTIs could induce mutation of mtDNA HV 2,which might contribute to the development of LD.