Tenofovir Disoproxil Fumarate Group Research Articles

Tenofovir and Entecavir Have Similar Renal Adverse Events on Hepatocellular Carcinoma Patients Treated with Transarterial Chemoembolization

Background/Aims: Tenofovir disoproxil fumarate (TDF) is potentially nephrotoxic in chronic hepatitis B patients. Hepatocellular carcinoma (HCC) patients treated using transarterial chemoembolization (TACE) are at an increased risk of renal injury. The aim of this study was to determine whether TDF is associated with more renal adverse events than entecavir (ETV) in HCC patients treated with TACE. Methods: In this retrospective single-center study, we selected 53 HCC patients who were treated with TDF from January 2012 to July 2013 and had their first TACE procedure in the same period. These patients were matched by age and sex to patients treated with ETV. Results: There were no significant differences in baseline characteristics, including HCC factors, and nephrotoxic drug use, between the two groups. The median follow-up period was 17.0 and 20.0 months for the TDF and ETV groups, respectively. There was no difference during the follow-up period between the TDF and ETV groups in the increase in creatinine over 0.5 mg/dL (17.0% and 17.0%, P=1.00, respectively) and the decrease in eGFR over 25% (43.4% and 41.5%, P=0.84, respectively). Multivariate analysis revealed that Child-Pugh class over B (hazard ratio [HR], 7.30; 95% confidence interval [CI] 2.79-19.10; P<0.01) was associated with increase in creatinine, and Child-Pugh class over B (HR, 82.74; 95% CI 12.31-555.83; P<0.01) and Barcelona-Clinic Liver Cancer stage over B (HR, 14.93; 95% CI 1.60-139.51; P=0.02) were associated with decrease in eGFR. Conclusions: TDF has comparable safety to that of ETV for HCC patients undergoing TACE. (J Liver Cancer 2019;19:128-135)

Probiotics protect against tenofovir‐induced mandibular bone loss in mice by rescuing mandible‐derived mesenchymal stem cell proliferation and osteogenic differentiation

Tenofovir disoproxil fumarate (TDF), a primary antiretroviral agent used to treat AIDS, triggers systematic bone loss. However, the effect of TDF on osteopenia or osteoporosis in the jaw remains unclear. TDF-induced bone loss in the jaw, if any, likely involves mandible-derived mesenchymal stem cells (MMSCs), which play a key role in jawbone metabolism. Probiotics prevent long bone loss, and could prove efficacious in treating TDF-induced mandibular bone loss. To determine whether TDF triggers mandibular bone loss, elucidate the underlying mechanisms, and study the effect of Lactobacillus rhamnosus GG (LGG) on TDF-induced bone loss in the jaw. Tenofovir disoproxil fumarate was administered orally daily and LGG semiweekly from eight weeks to the end of the study (LGG group) to male C57BL6/J mice. The mice were sacrificed, and body weight (BW) and serum Ca and P were measured. Mandibular histomorphometry was evaluated by micro-CT. MMSCs and LGG culture supernatants were isolated, and MMSC proliferation and ALP production when treated with different concentrations of LGG supernatant and/or TDF were measured. Relative abundance of osteogenic markers was assessed by qPCR. Orally administered LGG protected against bone mass loss and deterioration of bone microarchitecture and increased serum P levels. The BW of the TDF group was highest among the study groups. TDF partially impaired osteogenesis and proliferation of MMSCs. LGG culture supernatant rescued MMSC osteogenesis and proliferation, and osteogenic gene expression. Lactobacillus rhamnosus GG protected against tenofovir-induced mandibular bone loss in mice by rescuing MMSC proliferation and osteogenesis.

Efficacy and safety of telbivudine and tenofovir disoproxil fumarate in preventing hepatitis B vertical transmission: A real-life practice.

Mother-to-child transmission (MTCT) is a major obstacle in the elimination of hepatitis B virus (HBV) infection. Telbivudine (LdT) and tenofovir disoproxil fumarate (TDF) are the two most common antiviral medicines for preventing MTCT. However, the efficacy and safety of LdT and TDF in preventing HBV vertical transmission during the second to third trimester have not been compared rigorously. Therefore, we carried out a prospective multicentre cohort study of chronic hepatitis B in mothers with HBV DNA>106 IU/mL, receiving LdT or TDF during the second to third trimester. Among the 893 mothers enrolled, 857 (LdT/TDF/untreated group (NTx)=396/325/136) completed consecutive follow-up with 854 infants (LdT/TDF/NTx=395/323/136). LdT and TDF treatment resulted in a similar decrease of HBV DNA in mothers at delivery. Multivariate analysis indicated that only HBsAg titre at the baseline correlated with viral DNA decrease (P=0.015). With intention-to-treat analysis, MTCT rates in the LdT, TDF and NTx group were 4.41%, 2.42% and 22.08%, respectively. An increasing vertical transmission rate was found to be closely associated with higher HBsAg titre,5.32% and 17.65% infection rate was estimated in infants born to mothers with HBsAg>4 and >5 log10 IU/mL, respectively. No serious side effects were reported in either mothers or infants. LdT and TDF treatments were well tolerated and showed comparable efficacy in reducing MTCT. Higher risk of MTCT was shown in pregnant women with HBsAg>4 log10 IU/mL.

A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea

It is currently unclear which antiviral agent, entecavir (ETV) or tenofovir disoproxil fumarate (TDF), is superior for improving prognosis in patients with chronic hepatitis B (CHB). Here, we assessed the ability of these 2 antivirals to prevent liver-disease progression in treatment-naïve patients with CHB. From 2012 to 2014, treatment-naïve patients with CHB who received ETV or TDF as a first-line antiviral agent were recruited from 4 academic teaching hospitals. Patients with decompensated cirrhosis or hepatocellular carcinoma (HCC) at enrollment were excluded. Cumulative probabilities of HCC and death or orthotopic liver transplant (OLT) were assessed. In total, 2,897 patients (1,484 and 1,413 in the ETV and TDF groups, respectively) were recruited. The annual HCC incidence was not statistically different between the ETV and TDF groups (1.92 vs. 1.69 per 100 person-years [PY], respectively; adjusted hazard ratio [HR] 0.975 [p = 0.852] by multivariate analysis). Propensity score (PS)-matched and inverse probability of treatment weighting (ITPW) analyses yielded similar patterns of results (HR 1.021 [p = 0.884] and 0.998 [p = 0.988], respectively). The annual incidence of death or OLT was not statistically different between the ETV and TDF groups (0.52 vs. 0.53 per 100 PY, respectively; adjusted HR 1.202 [p = 0.451]). PS-matched and ITPW analyses yielded similar patterns of results (HR 1.248 [p = 0.385] and 1.239 [p = 0.360], respectively). These findings were consistently reproduced in patients with compensated cirrhosis (all p >0.05). The overall prognosis in terms of HCC and death or OLT was not statistically different between the ETV and TDF groups. Further studies are needed to validate our results. It is currently unclear which antiviral agent, entecavir or tenofovir disoproxil fumarate, is superior for improving prognosis in patients with chronic hepatitis B virus infection. In this analysis we found that there was no difference in terms of overall prognosis, including risk of hepatocellular carcinoma, death, or the need for a liver transplant, in patients receiving either antiviral.

HBV flare associated with immunosuppressive treatments: it is still dangerous in the third-generation antivirals era.

There are limited data about the mortality and morbidity of patients with HBV flare related to immunosuppressive treatments (IST) in the third-generation antivirals era. Herein, we performed a multi-centric study in patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) and evaluated their clinical course. The study group included patients who were referred to gastroenterology or infectious disease specialists at eight different hospitals in Turkey. HBV flare was defined as at least a threefold elevation in alanine aminotransferase (ALT) levels above the upper limit of normal range. The demographic data, IST protocol, virological markers, liver tests, international normalized ratio (INR), HBV DNA, reactivation risk profile according to AGA guideline, MELD and MELD-Na scores were retrospectively evaluated. The primary aim of the study was to determine the liver-related mortality, including transplantation, at 12 weeks and factors predicting it. Secondary aims were to compare ETV and TDF with respect to mortality and time to ALT, bilirubin normalization and HBV DNA undetectability. The study group included 40 patients (29 males, mean age: 57 ±12 years). Twenty-five patients (62.5%) had a high risk of reactivation. Twenty-six patients received TDF and 14 patients received ETV treatment. Eight (20%) patients developed acute liver failure and one patient (2.5%) underwent living donor liver transplantation. Seven patients died due to liver-related complications, revealing a mortality rate of 17.5%. In multivariate analysis, total bilirubin levels at the onset, ALT levels and delta-MELD score at the first week were the independent risk factors for liver related mortality (HR: 1.222, 1.003, 1.253 and 95% CI: 1.096, 1.362; 1.001, 1.004 and 1.065, 1.470, respectively). There was no significant difference between the TDF and ETV groups with respect to time to normalize ALT and bilirubin levels, HBV DNA undetectability and mortality rates (16% and 21.4%, respectively). HBV flare associated with IST has a high mortality in the third-generation antivirals era. High total bilirubin at the onset and high ALT and delta-MELD score at the first week predict poor prognosis.

Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial

Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25-30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per μL, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 μg of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659. Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1·84, 95% CI 0·86-3·91, p=0·12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D. The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.

Comparison of the effect of tenofovir disoproxil fumarate and entecavir in the treatment of chronic hepatitis B with positive E antigen

Objective To compare the efficacy and safety of tenofovir disoproxil fumarate(TDF) and entecavir(ETV) in the treatment of chronic hepatitis B(CHB) with positive hepatitis B E antigen(HBeAg). Methods A total of 104 cases with newly diagnosed HBeAg positive CHB were selected and randomly divided into TDF group and ETV group, with 52 cases in each group.The TDF group was given 300mg/d TDF, and the ETV group was given 0.5mg/d ETV.All the patients were continuously treated for 12 months.The serum HBV DNA, HBeAg and ALT levels before and after treatment were compared between the two groups. Results Before treatment, there were no statistically significant differences in serum HBV DNA, HBeAg and ALT levels between the two groups (t=0.12, 1.51, 1.62, all P>0.05). The serum HBV DNA, HBeAg and ALT levels in the two groups were decreased after treatment, and the decrease of serum HBV DNA level in the TDF group was more significant than that in the ETV group, the difference was statistically significant(t=3.54, P 0.05). The total effective rate of the TDF group was 92.31%(48/52), which was significantly higher than 76.92%(40/52) in the ETV group (χ2=4.73, P 0.05). Conclusion TDF has better clinical effect in treating newly diagnosed HBeAg positive CHB than ETV due to TDF can inhibit HBV DNA replication significantly, but the safety of TDF and ETV is similar. Key words: Hepatitis B, chronic; Hepatitis B e antigens; Alanine transaminase; Deoxyribonucleases; Tenofovir; Entecavir; Drug therapy; Controlled Clinical trial

Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir.

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line long-term monotherapy for treatment of chronic hepatitis B (CHB) infection. High virological relapse rates are found after cessation of either ETV or TDF in CHB patients. To compare hepatitis B virus (HBV) relapse rates in CHB patients without cirrhosis who discontinued ETV or TDF. A retrospective-prospective study was conducted in 342 CHB patients (108 hepatitis B e antigen (HBeAg)-positive and 234 HBeAg-negative) who received ETV and 165 (46 HBeAg-positive, 119 HBeAg-negative) who received TDF were recruited. All patients had post-treatment follow-up for at least 6months. All fulfilled the stopping criteria of the Asia-Pacific Association for the Study of the Liver of 2012. Patients who discontinued TDF had significantly higher rates and earlier times of virological and clinical relapse than those who discontinued ETV. This was also seen in propensity score (PS)-matched HBeAg-positive and HBeAg-negative patients. Multivariate analysis showed that being in the TDF group was an independent factor for virological and clinical relapse in all patients and PS-matched HBeAg-positive and HBeAg-negative patients. The rate of off-therapy HBsAg loss was comparable between the ETV and TDF groups after 2-3years follow-up. Clinical relapse tended to be more severe in the TDF group compared with the ETV group. HBV relapse occurs sooner and is more severe after cessation of TDF than after cessation of ETV.

Efficacy and Safety of Besifovir Dipivoxil Maleate Compared With Tenofovir Disoproxil Fumarate in Treatment of Chronic Hepatitis B Virus Infection

Besifovir dipivoxil maleate (BSV) has activity against hepatitis B virus (HBV). We performed a phase 3 study to compare the antiviral efficacy and safety of BSV vs tenofovir disoproxil fumarate (TDF) in patients with chronic HBV infection in Korea. We conducted a double-blind, non-inferiority trial of 197 patients with chronic HBV infection at 22 sites in South Korea, from November 2013 through February 2016. Patients were randomly assigned to groups given BSV (150 mg, n= 99) or TDF (300 mg, n= 98) for 48 weeks. We evaluated virologic responses to therapy (HBV DNA <69 IU/mL or 400 copies/ml), bone mineral density (BMD), and renal outcomes for safety analysis. The main efficacy endpoint was the proportion of patients with a virologic response at week 48. After 48 weeks, TDF was switched to BSV (150 mg) for an additional 48 weeks. After 48 weeks of treatment, 80.9% of patients given BSV and 84.9% of patients given TDF met the efficacy endpoint, indicating the non-inferiority of BSV to TDF. At week 96, 87.2% of patients in the BSV-BSV and 85.7% of patients in the TDF-BSV had a virologic response. At week 48, changes in hip and spine BMD differed significantly between the BSV and TDF groups, whereas the estimated glomerular filtration rate in the TDF group was significantly lower than that in the BSV group. However, at 96 weeks, there were no significant differences in BMD and estimated glomerular filtration rate between the BSV-BSV and TDF-BSV groups. BSV has antiviral efficacy comparable to that of TDF after 48 weeks of treatment, with durable effects for 96 weeks. BSV has a better safety profile than TDF, in terms of bone and renal outcomes. ClinicalTrials.gov no: NCT01937806.

Risk of renal events during tenofovir disoproxil fumarate and entecavir antiviral prophylaxis in HBsAg-positive cancer patients undergoing chemotherapy.

The risk of renal events in HBsAg-positive cancer patients receiving tenofovir disoproxil fumarate (TDF) or entecavir (ETV) antiviral prophylaxis during chemotherapy has not been evaluated. This study aimed to evaluate the renal safety of TDF and ETV during chemotherapy. Consecutive, 219 HBsAg-positive cancer patients treated with TDF (n=106) or ETV (n=113) for antiviral prophylaxis during chemotherapy with baseline serum creatinine (SCr) <1.2mg/dL were retrospectively enrolled. Serial SCr levels and estimated glomerular filtration rate (eGFR) were monitored. The incidence of acute kidney injury (AKI) during antiviral prophylaxis was 33% and 38.9% in TDF and ETV groups, respectively (P=0.441), while the incidence of sustained kidney injury was 11.3% and 11.5%, respectively (P=1.000). By multivariate analysis, diuretics use (hazard ratio (HR)=2.011, P=0.042) and serum albumin levels (HR=0.441, P=0.001) were independent predictors of AKI; serum albumin levels (HR=0.252, P=0.002) was the only factor associated with sustained kidney injury; age (HR=2.752, P<0.001), baseline SCr levels (HR=3.386, P<0.001), and serum albumin levels (HR=0.437, P=0.001) were factors associated with a new eGFR <60mL/min. 34.9% of patients in TDF group and 35.4% in ETV group had deteriorated chronic kidney disease (CKD) stage at the end of follow-up, respectively. There were no significant differences in the risk of renal events or CKD stage migration between TDF and ETV groups. Renal events may develop in about one-third of HBsAg-positive cancer patients undergoing chemotherapy. The risk of renal function impairment was comparable between patients treated with TDF and ETV antiviral prophylaxis.

Zidovudine-Based Treatments Inhibit the Glycosylation of ADAM17 and Reduce CD163 Shedding From Monocytes

sCD163, a biomarker of monocyte-macrophage activation, has been identified as a predictor of all-cause mortality in treated HIV-infected individuals. Nevertheless, little is known about whether different antiretroviral drugs differentially regulate sCD163 levels and monocyte activation. A total of 123 patients receiving zidovudine (ZDV)-based (n = 55) or tenofovir disoproxil fumarate (TDF)-based (n = 68) antiretroviral regimens were enrolled, and their viral loads, CD4 counts, as well as plasma sCD163 and sCD14 levels were quantified. Twenty-eight (14 in each group) patients donated additional blood samples for flow cytometry and gene expression analyses using purified monocytes. THP-1 cultures were also used to investigate the effect of ZDV on ADAM17, which is responsible for CD163 shedding. As compared to the TDF-treated group, the ZDV-treated group had lower plasma sCD163 levels and higher CD163 expression on CD14++CD16 monocytes. Five metabolic-inflammatory genes exhibited significantly different expression levels between purified monocytes of the ZDV and TDF groups (IL-6, 2.90-fold lower in ZDV group, P < 0.001; iNOS, 1.81-fold higher; CX3CR1, 1.72-fold lower; MIP-1β, 1.10-fold lower; and PPARγ-1, 1.36-fold higher, P < 0.05). Moreover, we show that ZDV treatment increases the surface expression of CD163 in cultured THP-1 cells, accompanied by the inhibition of glycosylation and surface expression of ADAM17. Compared with TDF treatment, ZDV treatment causes lower plasma sCD163 levels, probably by inhibiting the glycosylation of ADAM17 and CD163 shedding. Our results show that ZDV functions as an ADAM17 inhibitor in vivo and extend our understanding of its immune-modulatory effects and adverse effects.

Risk of Nephrotoxicity in Patients With Drug-Resistant Tuberculosis Treated With Kanamycin/Capreomycin With or Without Concomitant Use of Tenofovir-Containing Antiretroviral Therapy.

The intersection of HIV and drug-resistant (DR) tuberculosis (TB) presents the challenge of managing convergent drug toxicities. We conducted a retrospective study of adult patients with DR-TB treated with a kanamycin/capreomycin-based (KM) regimen, with or without concomitant antiretroviral therapy (ART). We estimated the incidence of nephrotoxicity (defined as an increase in serum creatinine greater than 26.5 µmol, or an increase in serum creatinine to 1.5 times the baseline value, or a decline in glomerular filtration rate to less than 60 mL/min/1.73 m), and evaluated the association between reported drug use and nephrotoxicity using Kaplan-Meier plots. A total of 215 patients with DR-TB were treated with a kanamycin/capreomycin-based regimen, with or without concomitant ART. The incidence rate of nephrotoxicity was 3.6 [95% confidence interval (CI): 1.4 to 7.3], 6.9 (95% CI: 5.2 to 9.0), and 12 (95% CI: 3.3 to 30.9) cases per 100 person-months of follow-up in the KM only group (n = 42), the KM + TDF (tenofovir disoproxil fumarate) group (n = 163), and the KM + Other ART group (n = 10), respectively. Using the KM only group as a reference, the hazard ratio was 2.06 (95% CI: 0.92 to 4.63) in the KM + TDF group, and 4.09 (95% CI: 1.17 to 14.25) in the KM + Other ART group. Advancing age was an independent predictor of nephrotoxicity (adjusted hazard ratio 1.29, 95% CI: 1.14 to 1.46). Our findings provide evidence of a significant risk of nephrotoxicity during treatment with a kanamycin/capreomycin-based DR-TB regimen, with or without concurrent treatment with ART. This study lends further support to calls for the substitution of TDF during the intensive phase of DR-TB treatment and for close monitoring of renal function during DR-TB treatment, especially in settings where the use of kanamycin/capreomycin is unavoidable.

RETRACTION: Improved Bone Safety of Tenofovir Alafenamide Compared to Tenofovir Disoproxil Fumarate Over 2 Years in Patients with Chronic HBV Infection

Long-term use of tenofovir disoproxil fumarate (TDF) reduces bone mineral density (BMD). Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has shown non-inferior efficacy to TDF in patients with chronic hepatitis B virus (HBV) infection, with improved bone effects at 48 weeks. We performed a randomized trial to evaluate the bone safety of TAF compared with TDF over 2 years, assessing baseline risk factors for bone loss, were evaluated after 2 years of treatment. In a double-blind study, hepatitis B e antigen (HBeAg)-positive patients (n= 873) and HBeAg-negative patients (n= 425) were randomly assigned (2:1) to groups given TAF (25 mg; n= 866) or TDF (300 mg; n= 432) once daily. We assessed bone safety, including hip and spine BMD, using dual-energy X-ray absorptiometry and measured changes in serum markers of bone turnover over 96 weeks. At baseline, treatment groups were well matched. At week 96, patients receiving TAF had significantly smaller decreases in hip BMD (mean reduction of 0.33%) than patients receiving TDF (mean reduction of 2.51%) (P < .001) and spine BMD (reduction of 0.75% in patients receiving patients receiving TAF vs reduction of 2.57% in patients receiving TDF) (P < .001). For hip BMD, the magnitude of difference in bone loss between the TAF and TDF groups increased at week 96 compared to week 48 (P < .001). The TAF group had minimal changes in markers of bone turnover by 12 weeks of treatment, but the TDF group had significant changes, compared to baseline. Risk factors for bone loss had fewer effects in patients receiving TAF than TDF at week96. In double-blind randomized trials, we found that after 2 years of treatment, patients receiving TAF had continued improvements in bone safety compared with patients receiving TDF. Clinicaltrial.gov ID NCT01940471 and NCT01940341.

Research in brief

Tenofovir disoproxil fumarate (TDF) did not significantly reduce mother-to-child transmission of hepatitis B virus (HBV) in a recent phase 3 trial conducted in Thailand. Gonzague Jourdain and colleagues randomly assigned pregnant women who were hepatitis B e antigen (HBeAg)-positive and who had with an alanine aminotransferase concentration of 60 IU/L or less to receive TDF (n=168) or placebo (n=163) from 28 weeks of gestation to 2 months post-partum. Infants received hepatitis B immunoglobulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. A total of 294 infants (147 in each group) were followed through 6 months. In the TDF group, none of the 147 infants were infected (0%, 95% CI 0–2) versus three of 147 in the placebo group (2%, 0–6) at 6 months (p=0·12). There was no significant difference in adverse events between groups, and the researchers determined that there was no significant benefit in adding TDF to current strategies. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trialNGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population. Full-Text PDF

Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B

BackgroundPregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants’ receiving hepatitis B immune globulin.MethodsIn this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)–positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)–positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group).ResultsFrom January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log10 IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29).ConclusionsIn a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822.)

Tenofovir plus hepatitis B immunoglobulin treatment resulted in a rapid HBV DNA load decline in high-risk pregnant women who missed the optimal time window of antiviral prophylaxis.

Tenofovir disoproxil fumarate (TDF) administration in the third trimester for pregnant women with high HBV DNA load has been accepted as a wise practice to prevent mother-to-infant transmission (MTIT). However, for those women who missed the optimal time window of antiviral prophylaxis, this treatment is lacking in the current clinical guidelines. Forty-eight pregnant women who did not receive antiviral prophylaxis before 28 weeks of gestation were screened and were administrated with TDF plus hepatitis B immunoglobulin (HBIG; TDF+HBIG group) or TDF alone (TDF group). HBV DNA inhibition and the safety profile were compared between two groups. A decline of HBV DNA load was observed in both groups after a short period of treatment, and no infant had MTIT. However, compared with the TDF group, the speed of HBV DNA load decline was more rapid (P=0.002) and a much more striking HBV DNA load decline in the first 4 weeks of treatment was exhibited in the TDF+HBIG group (P=0.001). The percentages of mothers with HBV DNA <4 log10 IU/ml and 3 log10 IU/ml at delivery were both much higher in the TDF+HBIG group than the TDF group (P=0.034 and 0.024, respectively). TDF and HBIG were found to be well-tolerated with no safety concerns in the mothers and their infants. TDF plus HBIG treatment resulted in a rapid HBV DNA load decline in high-risk women who missed the optimal time window of antiviral prophylaxis in pregnancy, which potentially protected infants from HBV infection.

Real-world single-center experience with entecavir and tenofovir disoproxil fumarate in treatment-naïve and experienced patients with chronic hepatitis B.

Background/Aim:The goal of antiviral therapy for chronic hepatitis B (CHB) is to improve survival of the patients by achieving a complete virological response (CVR). This study aimed to evaluate long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in nucleos(t)ide analog (NA)-naïve and NA-experienced Korean patients with CHB and to determine the incidence of cirrhosis-related complications in these patients.Patients and Methods:We retrospectively reviewed medical records of all patients treated with ETV or TDF from July 2007 to January 2017. We examined CVR and analyzed the predictive factors influencing the rate of CVR and evaluated the incidences of cirrhosis-related complications.Results:The proportion of patients who achieved CVR was 94.2% in the ETV group and 91.1% in the TDF group (P = 0.358). Among patients who achieved CVR, the mean time to CVR was 13.5 ± 14.3 months in the ETV group and 11.5 ± 10.6 months in the TDF group (P = 0.169). Positive predictive factors for CVR included the current treatment with TDF, a low hepatitis B virus DNA level, negative hepatitis B e-antigen status, and high alanine aminotransferase level in baseline laboratory test. The annual incidence rate of HCC was 127 per 10,000 patient-years (1.27% per year) in ETV group, and 85 per 10,000 patient-years (0.85% per year) in TDF group (P = 0.526).Conclusion:Both ETV and TDF therapy resulted in a high CVR, and the annual incidence rates of HCC and other cirrhosis-related complications were not significantly different between the two treatment groups.

Clinical effect of entecavir versus tenofovir in treatment of HBeAg-positive chronic hepatitis B patients with a high viral load: a comparative analysis

Objective: To investigate the clinical effect and safety of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in the treatment of previously untreated HBeAg-positive chronic hepatitis B (CHB) patients with a high viral load. Methods: A retrospective analysis was performed for the clinical data of 152 HBeAg-positive CHB patients with a high viral load (HBV DNA≥10(6) IU/ml) who were firstly treated with ETV (ETV group) or TDF (TDF group), with 76 patients in each group. The serum levels of alanine aminotransferase (ALT), HBV DNA, HBeAg, anti-HBe, creatinine, and creatine kinase were measured at baseline, and the patients were followed up and evaluated at weeks 4, 12, 24, 36, 48, 60, 72, 84, and 96 of treatment. The Kaplan-Meier survival curves were used to analyze cumulative complete virologic response, HBeAg seroconversion, and ALT normalization rate. The Cox proportional hazards regression model was used to identify the influencing factors for virologic response. P < 0.05 was considered statistically significant. Results: There were no significant differences in ALT normalization rate between the ETV group and the TDF group at weeks 4, 12, 24, 48, 72, and 96 of treatment (18.1%/55.6%/83.3%/90.3%/93.1%/97.2% vs 16.0%/53.6%/75.4%/94.2%/100%/100%, P > 0.05). There were also no significant differences in virologic response rate between the ETV group and the TDF group at weeks 48 and 96 of treatment (89.5%/97.3% vs 93.4%/98.7%, P > 0.05). The multivariate analysis showed that the baseline parameters were not predictive factors for virologic response. At week 48 of treatment, the TDF group had a significantly higher HBeAg seroconversion rate than the ETV group (14.5% vs 3.9%, P = 0.048); at week 96 of treatment, there was no significant difference in HBeAg seroconversion rate between the two groups (15.8% vs 7.9%, P = 0.132). The Kaplan-Meier survival analysis showed that there were no significant differences between the two groups in cumulative ALT normalization rate, cumulative HBV DNA undetectable rate, and cumulative seroconversion rate. Only one patient in the ETV group experienced virologic breakthrough from weeks 60 to 72 of treatment, and there were no serious adverse reactions. Conclusion: TDF and ETV had similar clinical effects, HBeAg seroconversion rate, and safety in previously untreated HBeAg-positive CHB patients with a high viral load.

Incidence and risk factors for tenofovir-associated nephrotoxicity among human immunodeficiency virus-infected patients in Korea.

Background/AimsLittle is known about tenofovir disoproxil fumarate (TDF)-induced nephrotoxicity in human immunodeficiency virus (HIV)-infected patients in Korea. The objective of this study was to evaluate the incidence and risk factors of TDF-associated nephrotoxicity among HIV-infected patients in Korea.MethodsA single-center retrospective cohort study was conducted on HIV-infected patients in Korea. We included patients who had started TDF or abacavir (ABC)-based antiretroviral therapy (ART) between October 2006 and December 2014. Estimated glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease-Epidemiology Collaboration equation. Renal dysfunction was defined as > 25% decrease of baseline eGFR. A propensity matched case-control study was conducted to compare renal dysfunction rates between the two groups. The risk factors of nephrotoxicity were analyzed by Cox regression analysis.ResultsA total of 210 HIV-infected patients were included in the study, of which, 108 were TDF-based ART group and 102 were ABC-based ART group. Renal dysfunction occurred in 16 patients (14.8%) in the TDF group and 11 (10.8%) in the ABC group. Incidence of renal dysfunction of TDF and ABC group was 9.66 per 100 person-years (PYs) and 5.14 per 100 PYs, respectively (p = 0.176). In propensity-score-matched analysis, renal dysfunction rates were TDF 13.3% versus ABC 13.3% (p > 0.999). In multivariable analysis, Centers for Disease Control and Prevention clinical category C was a significant risk factor for renal dysfunction.ConclusionsApproximately, 13% of HIV-infected patients treated with TDF had renal dysfunction. Advanced stage of HIV infection was a significant risk factor for renal dysfunction.

Comparison between tenofovir disoproxil fumarate and entecavir treatment in real‐world clinical practice

SummaryBackground and aimsEntecavir (ETV) and tenofovir disoproxil fumarate (TDF) are effective as two first‐line anti‐viral therapies for chronic hepatitis B (CHB); however, data are limited on directly comparing the safety and effectiveness of these two antivirals. Hence, we compared the efficacy and safety of TDF and ETV on treatment‐naïve patients with CHB.MethodsWe performed a hospital‐based, retrospective cohort study of 257 treatment‐naïve patients with CHB receiving TDF (n = 79) or ETV (n = 178). Virological and biochemical response as well as nephrotoxicity were assessed between TDF and ETV treatment groups.ResultsAt month 12, TDF group had faster on HBV DNA complete suppression than ETV group (p = 0.001). Multivariate analysis indicated that treatment with TDF was a significant predictor of HBV DNA suppression (HR = 1.33; 95% CI = 1.01 – 1.76; p = 0.045). In addition, HBeAg positivity (HR = 0.70; 95% CI = 0.52 – 0.96; p = 0.025) and higher baseline HBV DNA level (HR = 0.84; 95% CI = 0.76 – 0.92; p &lt; 0.001) were significant negative predictors for viral suppression. The ALT normalization rate between these two treatment groups were similar (p = 0.114). TDF group had more populations in ≧ 20% decrease of eGFR MDRD at month 24 than ETV group (31.5% vs. 17.2%, p = 0.044), but only the baseline eGFR was the independent factor by multivariate analysis (OR = 1.05; 95% CI = 1.03 – 1.07; p &lt; 0.001).ConclusionsTDF was significantly more effective in achieving complete viral suppression beyond month 12, and there was no significance in nephrotoxicity than ETV group.Copyright © 2017, The Gastroenterological Society of Taiwan, The Digestive Endoscopy Society of Taiwan and Taiwan Association for the Study of the Liver.