Complete Virological Response Research Articles

Effectiveness and Safety of Low Dose of Tenofovir Disoproxil Fumarate in Malagasy Patients with Chronic Hepatitis B.

Background Accessibility of full dose daily of tenofovir disoproxil fumarate (TDF) is limited in Madagascar with an estimated cost well above the purchasing power of Malagasy population. Objective The study is aimed at evaluating the efficacy and safety of low-dose tenofovir for the treatment of chronic hepatitis B (CHB). Methods This prospective cohort study from January 2018 to December 2020 was conducted in the Department of Hepato-Gastroenterology, University Hospital Joseph Raseta Befelatanana, Antananarivo, Madagascar. The patients enrolled in the study received low dose of TDF 900 mg/week (300 mg daily, three days per week). Results A total of 45 patients (male/female: 31/14) were included. The mean age was 45.1 ± 11.5 years. Fifteen patients were nucleos(t)ide (NA)-naïve, and 30 patients had prior NA therapy (NA-experienced). Thirty patients were HBeAg positive. A complete virological response (CVR) was achieved in 36/45 patients (80%) at 3 months, 41/45 (91.1%) at 6 months, and 43/45 (95.6%) at 12 months. High viral load at baseline was negative predictive factor of CVR at 3 months (HR: 0.14; 95% CI: 0.022–0.92; p: 0.041). There was no significant difference in response between HBeAg-positive and HBeAg-negative patients, NA-naïve and NA-experienced patients, and cirrhotic and noncirrhotic patients. Low dose of tenofovir was well tolerated. Ten patients (22.22%) had mild side effects. Mild renal failure was observed in 3 patients (6.7%) during follow-up. Conclusion Low dose of tenofovir is effective, safe, and well tolerated in a Malagasy population sample. These results still require verification in a large population.

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

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. 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). 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. 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.

A possible mechanism for low-level viremia occurrence in nucleos(t)ide analog-treated chronic hepatitis B patients

The first-line nucleos(t)ide analogs (NAs) based antiviral drugs can effectively inhibit HBV replication and slow down the progression of chronic hepatitis B. However, about 20% of patients receiving standard NAs antiviral therapy will still develop low-level viremia (LLV). Therefore, understanding the occurrence mechanism of LLV will help to optimize antiviral treatment regimens and improve the prognosis of patients with chronic hepatitis B. This article systematically summarizes the possible mechanisms of LLV occurrence, and the important factor of NAs failure. Taking into account the unique limitations of NAs competitive inhibition of virus replication, weakening host's immune response is not enough to directly eliminate infected hepatocytes. This makes it difficult to achieve a complete virological response in some patients with the active compensatory proliferation of residual infected hepatocytes and the accompanying effective removal or dilution of covalent, closed, circular DNA (cccDNA) pools. Therefore, it is speculated that activating host immunity can eliminate infected liver cells and may be more conducive to address LLV.

Very low-level viremia: new clinical attention-requiring problem during the course of anti-hepatitis B virus treatment

Clinical studies have validated low-level viremia is associated with a variety of adverse outcomes in patients with chronic hepatitis B during the course of receiving nucleos(t)ide analogue antiviral therapy. With the advancement of PCR technology, the high sensitivity PCR detection of HBV DNA can reach the lower limit of detection of < 5-10 IU/mL. The standard criterion for judging among patients who have achieved complete virological response is HBV DNA levels < 20 IU/ml. The use of highly sensitive PCR tests can detect very low-level viremia (HBV DNA < 20 IU/ml, but > 5-10 IU/mL) in some patients. However, there are currently fewer relevant studies, and more research data needs to be accumulated to answer this clinical question of whether long-term very low-level viremia affects the clinical outcome of patients with chronic hepatitis B.

Low-level viremia-induced liver fibrosis and hepatocellular carcinoma in chronic hepatitis B

Low-level viremia after antiviral therapy has gradually attracted attention due to its relation to liver fibrosis progression, hepatocellular carcinoma occurrence and long-term survival rate reduction in patients with chronic hepatitis B. In addition, it should be used as a risk factor for intervention during antiviral therapy in order to achieve complete virological response and improve the long-term prognosis of patients.

Real-World Single-Center Comparison of the Safety and Efficacy of Entecavir, Tenofovir Disoproxil Fumarate, and Tenofovir Alafenamide in Patients with Chronic Hepatitis B

Introduction: Chronic hepatitis B (CHB) is a major cause of chronic liver diseases and tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and entecavir (ETV) are recommended as primary treatments. This study aimed to evaluate the efficacy and safety of ETV, TDF, and TAF in a real-world clinical setting. Methods: In this retrospective cohort study, a total of 363 CHB patients who were treated with ETV (n = 163), TDF (n = 154), or TAF (n = 46) from July 2007 to September 2019 were enrolled. Results: Median patient age was 51 years and 66.4% of patients were male. Median duration of treatment with ETV, TDF, or TAF was 49.0 months (interquartile range, 27.0–74.0 months). In terms of safety, cholesterol was mildly increased in the ETV and TAF groups and significantly lowered in the TDF group than baseline (p < 0.001). There was no significant difference in liver cirrhosis-related complications among the 3 groups at 48 weeks (p = 0.235). Hepatitis B e antigen seroconversion, complete virological response, and alanine aminotransferase normalization at 48 weeks as measures of treatment efficacy were not significantly different among the 3 groups (p = 0.142, 0.538, and 0.520, respectively). There was also no significant difference in cumulative incidence rate of hepatocellular carcinoma (HCC) between the ETV and TDF groups (p = 0.894). Conclusions: ETV, TDF, and TAF were safe antiviral agents and showed similar antiviral effect for CHB at 48 weeks. Cirrhosis-related complications and annual HCC incidence rates did not differ significantly between the ETV and TDF groups over the 48 week follow-up period.

Efficacy and safety of tenofovir alafenamide fumarate in nucleoside analogue treatment-naïve patients with chronic hepatitis B

Tenofovir alafenamide fumarate (TAF) is a first-line drug for the antiviral treatment of patients with chronic hepatitis B (CHB) in China. In the present study, the efficacy and renal safety of TAF were evaluated in treatment-naive patients with CHB. Patients with CHB who had not been previously treated with nucleoside analogues (NAs) were recruited before TAF treatment was initiated. Changes in the levels of hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) were analyzed at 24 and 48 weeks using immunoassays. In addition, liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were analyzed using transient elastography, while alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels, calcium (Ca) and inorganic phosphorus (IP) levels were measured using biochemistry assay. In addition, the estimated glomerular filtration rate (eGFR) was calculated. After 48 weeks, the ALT normalization rate was 95.24% (40/42), the complete virological response (HBV DNA <20 IU/ml) rate was 69.05% (29/42) and the HBeAg seroconversion rate was 8.57% (3/35). The levels of HBV DNA and HBsAg were significantly decreased from the baseline at 5.49±1.95 to 1.26±0.66 log10 IU/ml and from 3.59±0.81 to 3.32±0.55 log10 IU/ml after 48 weeks of treatment, respectively. Compared with that in the baseline measurements, LSM at 48 weeks was significantly decreased from 13.00±8.15 to 8.66±4.45 kPa. No significant differences were observed in the TG, TC, LDL-C, CAP, eGFR, Ca and IP measurements. According to the baseline ALT levels, patients were divided into group A [ALT ≤1 x upper limit of normal (ULN); ULN=50 U/l; n=21], group B (1 x ULN < ALT <2 x ULN; n=22) and group C (ALT ≥2 x ULN; n=18). A significant decrease in HBsAg levels was observed in group B (3.63±0.68 vs. 3.53±0.63 log10 IU/ml) and group C (4.15±0.57 vs. 3.66±0.48 log10 IU/ml) at 24 weeks compared with the baseline. In conclusion, TAF was found to be effective and safe in NA treatment-naive patients with CHB. Moreover, the higher the ALT levels, the more prominent the curative effect from TAF treatment. Therefore, NA treatment-naive CHB patients could benefit from TAF treatment in real world.

Effectiveness of Tenofovir Alafenamide in Chronic Hepatitis B Patients with Normal Alanine Aminotransferase and Positive Hepatitis B Virus DNA.

Background and AimsWith an increasing understanding of hepatitis B, the antiviral indications have been broadening gradually. To evaluate the effectiveness of tenofovir alafenamide (TAF) in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and detectable hepatitis B virus (HBV) DNA, those who are ineligible for broader antiviral criteria from the Chinese CHB prevention guide (2019).MethodsA total of 117 patients were recruited and their data were collected from paper or electronic medical records. HBV DNA and liver function were measured at baseline and throughout the 24-week follow-up. The effectiveness endpoint was complete virological response. The safety endpoint was the first occurrence of any clinical adverse event during the treatment.ResultsAmong the 117 patients, 45 had normal ALT as well as detectable HBV DNA and they were not recommended for antiviral therapy according to Chinese Guidelines (2019). After TAF antiviral therapy, the rates of patients who achieved HBV DNA <20 IU/mL at 4, 12 and 24 weeks were 77.1%, 96.7% and 96.8% respectively. Among them, the undetectable rates of HBV DNA in patients with low baseline viral load at 4, 12 and 24 weeks were 92.3%, 100% and 100%, while the rates of those with high baseline viral load were 68.2%, 94.1% and 94.4%. Compared with 71.4%, 94.4% and 94.7% in the high baseline group, the undetectable rates of HBV DNA at 4, 12 and 24 weeks in the low baseline liver stiffness group were 85.7%, 100% and 100%. There was no statistical significance among the above groups.ConclusionsCHB patients who had normal ALT and detectable HBV DNA and did not meet “CHB prevention guide (2019)”, could achieve complete virological response in 24 weeks after antiviral treatment by TAF.

First experience of off-label use GLE/PIB+SOF in treating a patient with relapse of RNA HCV 1b viremia and RAS R117H in the NS3 region after NS3/4A PI + NS5AI + NS5BI failure of 3D-therapy PTV/R/OBV+DSV in Russia (case report)

For the first time in Russia, a description of a case of full application in clinical practice of a completely interferon-free mode of the 3D-mode GLE/PIB + SOF for the treatment of recurrence of HCV 1b RNA viremia after a primary course of interferonfree therapy in the PTV/r/OBV + DSV mode, which included inhibitors of NS3/4A PI, NS5Ai and NS5Bi, in a patient with combined HCV syndrome is presented. The target result of the repeated course of interferon-free therapy — SVR12 — was achieved despite the presence of significant RAS R117H in the NS3 region of the HCV genome and multiple RASs in the NS3 and NS5A regions, the nature of resistance of which to the corresponding inhibitors of GLE and PIB was unknown. Along with a complete virological response, the treatment also achieved a complete immunological response, which lasted for 12 weeks after the end of the repeated course of interferon-free therapy.

Tenofovir Disoproxil Fumarate Is Superior to Entecavir in Reducing Hepatitis B Surface Antigen for Chronic Hepatitis B in China: 2-Year Comprehensive Comparative Result of a Matched Comparative Study.

Aim: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are equally recommended as the first-line antiviral treatments for chronic hepatitis B (CHB) at present. We aimed to compare the long-term efficacy and safety between ETV and TDF therapy in CHB patients who had not received nucleoside analog treatment.Method: In this single-center retrospective study, 414 patients who received ETV (290 patients) or TDF (124 patients) therapy at our center from January 2017 to May 2019 were included. To reduce the imbalance of baseline variables, propensity score matching (PSM) was employed to yield 124 pairs of patients at a ratio of 1:1 based on the treatment regimen.Result: After PSM, the cumulative rate of patients who achieved complete virological response (CVR) was not different by drug therapy at each inspection time (1, 3, 6, 12, 18, and 24 months). Subgroup analysis on HBeAg status and level of HBV DNA demonstrated that evolution of proportion of achieving CVR was not significantly different between groups. Despite the insignificant incidence of HBsAg seroclearance in either group, patients in TDF group achieved higher on-treatment HBsAg decline at each inspection time (1, 3, 6, 9, 12, 18, and 24 months), 0.39, 0.51, 0.61, 0.64, 0.68, 0.76, and 0.91 log IU/mL, respectively; while the corresponding reduction were 0.27, 0.37, 0.40, 0.45, 0.48, 0.55, and 0.66 log IU/mL in ETV group (p < 0.05). In subgroup analysis, we found that the significant difference still existed in patients with high baseline HBsAg level (>3 log IU/mL). Additionally, the proportion of patients who achieved on-treatment HBsAg decline >1 log IU/mL in TDF and ETV group was 33.3 and 17.1% (p < 0.01) at the 12th month, 44.4 and 29.5% (p = 0.03) at the 24th month, respectively. Mean increase in serum creatinine from baseline was 0.10 and 0.08 mg/dL in TDF and ETV group (p = 0.11), with no patient experienced acute kidney injury.Conclusions: TDF has higher potency in reducing HBsAg than ETV in this study. Considering the effect still existed in patients with high HBsAg level (>3 log IU/mL), TDF might be a superior therapeutic regimen combining with its relatively safety.

Switching from entecavir to tenofovir alafenamide for chronic hepatitis B patients with low-level viraemia.

About 20% of patients receiving nucleos(t)ide analogues treatment experienced low-level viraemia (LLV), which is associated with progression of liver fibrosis and high risk of hepatocellular carcinoma. We aimed to evaluate the effectiveness and safety of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in ETV-treated patients with LLV. In this prospective study, ETV-treated patients with LLV, presented to our hospital from December 2018 to October 2019, were enrolled. Switching to TAF or continuing ETV was given. The primary effectiveness endpoint was complete virological response (CVR) at 24weeks, and the safety endpoint was the first occurrence of any clinical adverse event during the treatment. Totally, 211 patients were recruited and propensity score matching (PSM) generated 75 patients in either TAF or ETV group. After PSM, baseline characteristics were balanced in two groups. After 24-week treatment, the CVR and ALT normalization in TAF group were 62.7% and 47.6%, which were higher than 9.3% and 10.5% in ETV group (OR 16.4, 95% CI 6.6-40.0, P<.001) respectively. Subgroup analysis showed that switching to TAF achieved favours CVR regardless of the status of sex, age, CHB family history, HBV DNA, HBeAg and cirrhosis, whereas alcohol consumption and diabetes mellitus might compromise the CVR of switching to TAF. Both therapies were well tolerated and had satisfying renal safety. For ETV-treated patients with LLV, switching to TAF is safe enough and superior compared with continuing ETV monotherapy regarding both virological and biochemical benefits.

Chronic Carriage of Hepatitis B Virus at the University Teaching Hospital Yalgado Ouedraogo: Therapeutic Aspects and Outcome in a Cohort of HBeAg+ Outpatients

Introduction: The HbsAg prevalence in Burkina Faso was 9.1%. We aimed at describing the therapeutic features and the clinical outcome for the patients taking antiretroviral treatment. Materials and Methods: We implemented a cross-sectional study from January 1st, 2004 to December 31st, 2015. Patients aged more than 15 years with positive hepatitis B surface antigen for over six months and positive hepatitis B e-antigen were included. Results: We analyzed the data of 148 participants for a sex ratio of 3; sixty-three patients including 49 men (77.8%) were on treatment. and 81.5% had inflammatory activity greater than one. Under tenofovir, the normalization of ALT was observed in 42 (84%) patients while HBV-DNA became undetectable in 24/33 patients. HBeAg negativation was observed in 16/25 (64%) patients after seven years of treatment. With lamivudine, 2/9 patients had a complete virologic response and six had a normalization of their ALT. Two and 9 patients lost HBeAg after 7 and 9 years of treatment, respectively. Overall 63% and 27% of the patients were in the high or low-adherence group, respectively. In the low-adherence group, all patients had normal or abnormal ALT, but detectable HBV DNA. Ten patients taking lamivudine developed resistance including primary resistance in three patients. No resistance has been observed with tenofovir. Conclusion: The management of the viral hepatitis B includes often a long follow up period without any medication. When antiviral is indicated, the adherence to the treatment is crucial to a long-term control of the virus. In our setting, the low purchase power of the patients may jeopardize their therapeutic future and there is a need to support this group of patients with free-of-charge medicines as it is provided for the HIV infected people.

Two-year Single-Center Real-Life Data of Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B Patients in Togo

Objective: to evaluate the treatment efficacy of Tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB) in the Teaching hospital campus of Lome. Patients and method: retrospective cross-sectional study, conducted in the outpatient department of the Hepato-Gastro-Enterology department of the Teaching hospital campus of Lome from January 2018 and December 2020. Patients with HBsAg were included. Outpatient patients having achieved at least HBeAg, anti-HBe antibody, anti-HCV antibody, anti-HBc IgG; viral load hepatic assessment; retroviral serology. Some patients had achieved actitest-fibrotest. Patients with abdominal pain, clinical signs of portal hypertension or hepatocellular insufficiency had achieved alphafetoprotein, protidogram, and abdominal ultrasound. These explorations made it possible to classify patients into different virological profiles. Results: More than sixty-four percent of the patients were male. The patients were asymptomatic at 97.37%. HBeAg was positive in 15.19% of patients. The viral load was detectable in 80.43% of cases with a value of 52000000 IU / ml +/- 280000000UI / ml. Ninety-five point twenty-four patients had an inflammatory activity less than 2 and 52.38% a fibrosis greater than 2 on the Metavir grid. The APRI and Fib-4 scores found a strong predictive value for fibrosis in 16.22% and 11.01% of cases, respectively. HBeAg negative chronic hepatitis was the most common virologic profile (58%). Cirrhosis was the most common complication (9.97%). Tenofovir was the therapeutic molecule used. At 12 months of treatment, HBe seroconversion was noted in 100% of cases, an undetectable viral load in 50% of cases and normalization of the hepatic balance in 84% of cases. No side effects of the treatment were reported Conclusion: TDF treatment shows high rate of complete virologic response in CHB patients. TDF is tolerable and safe during the 96 weeks of treatment period. Monitoring of HBV DNA level and drug adherence is important for achieving complete suppression of HBV DNA, particularly in patients with high viral load.

Seronegative fibrosing cholestatic hepatitis С after liver retransplantation for unresectable neuroendocrine tumor liver metastases

We present an uncommon case of liver graft dysfunction caused by seronegative hepatitis C-related fibrosing cholestatic hepatitis after cadaver liver transplantation for unresectable liver metastases of neuroendocrine small intestine cancer followed by living relation donor liver fragment retransplantation for primary graft nonfunction. Early postoperative period was complicated by hepatic artery thrombosis, cerebral hemorrhage, acute cellular rejection, bilateral polysegmental pneumonia, bleeding into neck soft tissues, severe surgical site infection, and sepsis. Anticoagulant therapy, as well as the absence of Hepatitis C Virus antibodies made difficult early diagnostics of fibrosing cholestatic hepatitis. A present-day antiviral therapy produced a complete clinical and virological response. At control examination performed at 240 days after surgery, there were neither signs of cancer progression no graft dysfunction. Liver transplantation in that case was an example of radical and effective treatment method for unresectable liver metastases of neuroendocrine small intestine cancer. Timely diagnosis and proper treatment of fibrosing cholestatic hepatitis made it possible to save the liver graft and patient's life.

Partial Virological Response after 2 Years of Entecavir Therapy Increases the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Associated Cirrhosis.

Background/AimsThe clinical significance of partial virological response (PVR) in patients undergoing antiviral therapy is not well known. This study investigated whether PVR after 2 years of entecavir (ETV) therapy is associated with hepatocellular carcinoma (HCC) development in cirrhotic patients.MethodsA total of 472 naïve patients with hepatitis B virus (HBV)-associated cirrhosis who were treated with ETV for at least 2 years were retrospectively enrolled. Clinical characteristics, laboratory data, PVR, and noninvasive fibrosis markers (aspartate aminotransferase to platelet ratio and FIB-4 index) at 2 years after ETV commencement were analyzed for HCC risk.ResultsAfter excluding those who developed HCC within 2 years of ETV therapy, 359 patients (mean age, 51±10 years; male 64.3%) were examined. During a median follow-up of 82 months, 80 patients developed HCC. In the univariate analysis, older age (hazard ratio [HR], 1.056; p<0.001), PVR (HR, 2.536; p=0.002), higher aspartate aminotransferase (HR, 1.018; p=0.005), lower albumin level (HR, 0.463; p<0.001), lower platelet count (HR, 0.993; p=0.01), and higher FIB-4 index (HR, 1.141; p<0.001) at 2 years after ETV commencement were risk factors for HCC. In the multivariate analysis, older age (HR, 1.046; 95% confidence interval [CI], 1.022 to 1.072; p<0.001), PVR (HR, 2.358; 95% CI, 1.310 to 4.245; p=0.004), and higher FIB-4 index (HR, 1.103; 95% CI, 1.035 to 1.177; p=0.003) were independent risk factors.ConclusionsPVR and higher FIB-4 index after 2 years of ETV therapy were independent risk factors for HCC. Therefore, efforts to accomplish a complete virological response and reduce the FIB-4 index should be made. (Gut Liver 2021;15-439)

Safety and efficacy of Sofosbuvir and Velpatasvir in children with active hepatitis C virus infection undergoing haploidentical transplantation.

Direct Acting Antivirals (DAA) have changed the landscape of hepatitis C virus (HCV) infection with high cure rates across genotypes. However, the use of these agents in the setting of allogeneic hematopoietic cell transplantation (HCT) has been limited. In this context, we report the outcome of five children (5-12years) with relapsed and refractory leukemia and active HCV infection (genotype 1b), who underwent urgent haploidentical HCT and were treated with Sofosbuvir and Velpatasvir (Sof-Vel) from initiation of treatment to 24weeks post-HCT. All achieved complete virologic response (VR) at a median of 2weeks, with normalization of liver enzymes. There were no adverse events related to the use of Sof-Vel, with no major fluctuations in cyclosporine levels. Two of the patients developed chronic GVHD and one relapsed. Sof-Vel was continued in one of them along with sirolimus without affecting drug levels. With a median follow-up of 15months, four patients are disease free with sustained VR. Our study shows that combination of Sof-Vel might be effective in inducing rapid complete and sustained VR during HCT without any major untoward drug interaction.

Efficacy and cost-effectiveness of antiviral regimens for entecavir-resistant hepatitis B: A systematic review and network meta-analysis

BackgroundChronic hepatitis B (CHB) patients who had exposed to lamivudine (LAM) and telbivudine (LdT) had high risk of developing entecavir (ETV)-resistance after long-term treatment. We aimed to conduct a systematic review and a network meta-analysis on the efficacy and cost-effectiveness on antiviral regimens in CHB patients with ETV-resistance. Data sourcesWe searched PubMed, EMBASE and Web of Science for studies on nucleos(t)ide analogues (NAs) treatment [including tenofovir disoproxil fumarate (TDF)-based rescue therapies, adefovir (ADV)-based rescue therapies and double-dose ETV therapy] in CHB patients with ETV-resistance. The network meta-analysis was conducted for 1-year complete virological response (CVR) and biological response (BR) rates using GeMTC and ADDIS. A cost-effective analysis was conducted to select an economic and effective treatment regimen based on the 1-year CVR rate. ResultsA total of 6 studies were finally included in this analysis. The antiviral efficacy was estimated. On network meta-analysis, the 1-year CVR rate in ETV-TDF [odds ratio (OR) = 22.30; 95 % confidence interval (CI): 2.78-241.93], LAM-TDF (OR = 70.67; 95 % CI: 5.16-1307.45) and TDF (OR = 16.90; 95 % CI: 2.28-186.30) groups were significantly higher than that in the ETV double-dose group; the 1-year CVR rate in the LAM-TDF group (OR = 14.82; 95 % CI: 1.03-220.31) was significantly higher than that in the LAM/LdT-ADV group. The 1-year BR rate of ETV-TDF (OR = 28.68; 95 % CI: 1.70-1505.08) and TDF (OR = 21.79; 95 % CI: 1.43-1070.09) therapies were significantly higher than that of ETV double-dose therapy. TDF-based therapies had the highest possibility to achieve the CVR and BR at 1 year, in which LAM-TDF combined therapy was the most effective regimen. The ratio of cost/effectiveness for 1-year treatment was 8 526, 17 649, 20 651 Yuan in the TDF group, TDF-ETV group, and ETV-ADV group, respectively. ConclusionsTDF-based combined therapies such as ETV-TDF and LAM-TDF therapies were the first-line treatment if financial condition is allowed.

Impact of Hepatic Steatosis on the Antiviral Effects of PEG-IFNα-2a in Patients with Chronic Hepatitis B and the Associated Mechanism.

Objective To investigate the risk factors for hepatic steatosis in chronic hepatitis B (CHB), to determine its correlation with liver necroinflammation and fibrosis and response to peginterferon alpha-2a (PEG-IFNα-2a) antiviral therapy, and to explore the mechanisms underlying the poor antiviral effect of PEG-IFNα-2a in CHB patients with hepatic steatosis. Methods We analysed the impact of hepatic steatosis on the antiviral effect of PEG-IFNα-2a on CHB patients in a cohort of 226 patients who underwent pretherapeutic liver biopsy. To assess the complete response (CR), virological response (VR), and biochemical response (BR), the 226 patients were treated with PEG-IFNα-2a for 48 weeks and were followed-up for 24 weeks. The expressions of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in the liver tissue were detected in all patients to explore the possible mechanism of hepatic steatosis with regard to antiviral effects. Results The patients were divided into four groups based on the severity of hepatic steatosis: 119 with no steatosis, 76 with mild steatosis, 22 with moderate steatosis, and 9 with severe steatosis. In the hepatic steatosis groups, the proportions of male patients, patients aged >40 years, patients with hyperuricaemia, patients with a BMI > 23 kg/m2, and total cholesterol (TC), triglyceride (TG), glucose (GLU), and uric acid (UA) levels were significantly higher than those in the group without steatosis, whereas the alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were significantly lower than those in the group without steatosis. The multivariate analysis results indicated that a BMI > 23 kg/m2 was independently associated with CHB patients with hepatic steatosis; the levels of baseline AST and UA were independently associated with CHB patients with significant hepatic steatosis, and the baseline AST level was independently associated with significant liver fibrosis. After 48 weeks of treatment and 24 weeks of follow-up, the rates of CR, VR, and BR had gradually decreased, whereas the severity of hepatic steatosis had increased. Conclusion Hepatic steatosis can reduce the efficacy of PEG-IFNα-2a in the treatment of CHB patients, and its mechanism may be related to the different HBcAg expression patterns in liver tissue.

Optimal drug administration manner would rescue partial virological response in chronic hepatitis B patients with entecavir or tenofovir treatment.

Not all treatment-naïve patients receiving entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy can achieve complete virological response, and many factors may be related with the outcome of partial virological response. This study aimed to determine whether the manner of drug administration affects the antiviral efficacy of ETV/TDF monotherapy. All eligible patients were divided into complete or partial response cohorts based on their virological response following 24-week therapy. Factors related with partial response were evaluated. Patients with partial response were further grouped depending on whether they later adjusted the manner of drug administration, and the antiviral efficacy was compared between the two groups during prolonged treatment. A total of 518 patients were enrolled. Suboptimal drug administration (OR 77.511, P=.000), positive-HBeAg (OR 3.191, P=.000) and ETV treatment (OR 2.537, P=.001) were identified as independent risk factors for partial response. Among patients with partial response, 213 were in the adjusted group and 76 were in the unadjusted group. The percentages of patients with undetectable serum HBV DNA (78.9% vs 31.6%, P<.001) and with normal alanine aminotransferase (ALT) (88.7% vs 68.4%, P<.001) were both higher in the adjusted group than that in unadjusted group following a further 6-month therapy. In conclusion, the manner of drug administration is an important factor influencing the efficacy of ETV/TDF therapy, and optimal drug administration manner can help to increase antiviral efficacy and rescue patients with partial response.

Tenofovir disoproxil fumarate for patients with chronic hepatitis B who suboptimal response to non‐tenofovir disoproxil fumarate nucleos(t)ide analogs therapy

AbstractThe efficacy of tenofovir disoproxil fumarate (TDF) for previously nucleos(t)ide analogs (NA)‐treated patients in Taiwan is limited. In this retrospective study, our aim is to evaluate the efficacy of TDF in chronic hepatitis B (CHB) with suboptimal response (SR) to non‐TDF NA therapy. We retrospectively analyzed CHB patients with SR to non‐TDF NA treatment, in Show Chwan Memorial Hospital, Changhua, Taiwan, from September 2011 to December 2018. The primary endpoint was defined as achieving complete virological response (CVR) during TDF therapy. Twenty‐eight patients were included in this study. Sixteen (57.1%) patients achieved CVR at a median duration of 135 weeks of TDF therapy. Nine patients (32.1%) achieved CVR early at 24‐weeks treatment. One patient developed virological breakthrough during TDF treatment, which was due to poor drug adherence. The remainders had marked HBV DNA virological suppression (HBV DNA &lt; 1000 IU/mL) after TDF treatment. One patient had renal function deterioration after 144 weeks of TDF therapy. Three of 17 (17.6%) patients developed HBeAg seroconversion after TDF treatment. TDF monotherapy is a potent rescue therapy for CHB patients with SR to non‐TDF NA. Closely monitor renal function is necessary especially in patient with renal dysfunction initially.