Improvement of hepatic fibrosis after tenofovir disoproxil fumarate switching to tenofovir alafenamide for three years.

BACKGROUND: Both tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are the first-line treatments for chronic hepatitis B (CHB). We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase (ALT) improvement, but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis. AIM: To assess the benefits of TDF switching to TAF for 3 years on ALT, aspartate aminotransferase (AST), and hepatic fibrosis improvement in patients with CHB. METHODS: A single center retrospective study on 53 patients with CHB who were initially treated with TDF, then switched to TAF to determine dynamic patterns of ALT, AST, AST to platelet ratio index (APRI), fibrosis-4 (FIB-4) scores, and shear wave elastography (SWE) reading improvement at switching week 144, and the associated factors. RESULTS: The mean age was 55 (28-80); 45.3%, males; 15.1%, clinical cirrhosis; mean baseline ALT, 24.8; AST, 25.7 U/L; APRI, 0.37; and FIB-4, 1.66. After 144 weeks TDF switching to TAF, mean ALT and AST were reduced to 19.7 and 21, respectively. From baseline to switching week 144, the rates of ALT and AST < 35 (male)/25 (female) and < 30 (male)/19 (female) were persistently increased; hepatic fibrosis was also improved by APRI < 0.5, from 79.2% to 96.2%; FIB-4 < 1.45, from 52.8% to 58.5%, respectively; mean APRI was reduced to 0.27; FIB-4, to 1.38; and mean SWE reading, from 7.05 to 6.30 kPa after a mean of 109 weeks switching. The renal function was stable and the frequency of patients with glomerular filtration rate > 60 mL/min was increased from 86.5% at baseline to 88.2% at switching week 144. CONCLUSION: Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement, but also hepatic fibrosis improvement by APRI, FIB-4 scores, as well as SWE reading, the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.

Factors driving decisions in the use of HIV pre-exposure prophylaxis: a real-world study in the United States.

Background: Uptake of pre-exposure prophylaxis (PrEP) in the United States (US) remains below target, despite reported high efficacy in prevention of HIV infection and being considered as a strategy for ending new HIV transmissions. Here, we sought to investigate drivers for PrEP use and barriers to increased uptake using real-world data. Methods: Data were drawn from the Adelphi PrEP Disease Specific Programme™, a cross-sectional survey of PrEP users and PrEP non-users at risk for HIV and their physicians in the US between August 2021 and March 2022. Physicians reported demographic data, clinical characteristics, and motivations for prescribing PrEP. PrEP users and non-users reported reasons for or against PrEP use, respectively. Bivariate analyses were performed to compare characteris tics of users and non-users. Results: In total, 61 physicians reported data on 480 PrEP users and 121 non-users. Mean ± standard deviation of age of users and non-users was 35.3 ± 10.8 and 32.5 ± 10.8 years, respectively. Majority were male and men who have sex with men. Overall, 90.0% of users were taking PrEP daily and reported fear of contracting HIV (79.0%) and having at-risk behaviors as the main drivers of PrEP usage. About half of non-users (49.0%) were reported by physicians as choosing not to start PrEP due to not wanting long-term medication. PrEP stigma was a concern for both users (50.0%) and non-users (65.0%). More than half felt that remembering to take PrEP (57.0%) and the required level of monitoring (63.0%) were burdensome. Conclusions: Almost half of people at risk for HIV were not taking PrEP due to not wanting long-term daily medication and about half of current PrEP users were not completely adherent. The most common reason for suboptimal adherence was forgetting to take medication. This study highlighted drivers for PrEP uptake from physician, PrEP user, and non-user perspectives as well as the attributes needed in PrEP products to aid increased PrEP uptake.

Comparative evaluation of adverse drug reactions for tenofovir alafenamide and tenofovir disoproxil fumarate using the FAERS Database: a disproportionality analysis.

BACKGROUND: Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are widely used nucleoside reverse transcriptase inhibitors (NRTIs), necessitating a thorough understanding of their safety profiles to ensure optimal patient care and treatment adherence. METHODS: We employed statistical methods including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS) to compare and evaluate the safety profiles of these NRTIs. RESULTS: TAF was significantly associated with weight increase (ROR: 6.43; 95% CI: 5.93-6.96) and specific psychiatric disorders. TDF showed a notable signal for renal disorders and product-related issues, including product dose omission (ROR: 3.53; 95% CI: 3.22-3.87). Additionally, the study highlighted differences in safety signals related to pregnancy outcomes, with TAF having a higher ROR for maternal exposure (ROR: 7.83; 95% CI: 7.06-8.69) and TDF for fetal exposure (ROR: 4.51; 95% CI: 3.93-5.18), underscoring the need for cautious use in pregnant women. The comparative analysis also identified signals for osteonecrosis (ROR: 108.81; 95% CI: 106.25-111.43) and bone loss (ROR: 714; 95% CI: 685.49-743.68) for TAF and TDF, respectively, highlighting the importance of bone health considerations in treatment plans. CONCLUSION: These findings underscore the importance of personalized antiviral therapy and patient safety.

Effect of Two Forms of Tenofovir on Duodenal Enterocytes - a Hypothesis for Different Effect of TDF and TAF on Body Weight and Plasma Lipids.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) compared to tenofovir alafenamide (TAF) leads to lower body weight and plasma lipids by an unknown mechanism. We hypothesize that TDF, when absorbed, may damage enterocytes of the proximal duodenum, leading to reduced absorption of nutrients. METHODS: People living with HIV, without significant gastrointestinal symptoms, receiving TDF (n=12) or TAF (n=12) containing regimen underwent esophagogastroduodenoscopies with duodenal biopsies. Plasma/serum concentrations of nutrients absorbed from proximal duodenum and serum intestinal fatty-acid-binding protein (I-FABP), a marker of enterocyte damage, were measured. COX/SDH histochemical staining and electron microscopy (EM) were conducted to evaluate mitochondria. RESULTS: Five patients in TDF (celiac disease (excluded from further analyses), helicobacter gastritis, and three esophagitis) and two in TAF group (two esophagitis) had a pathological finding in esophagogastroduodenoscopy. Villi were flatter (337 (59) vs. 397 (42) µm, p=0.016), crypts non-significantly deeper (200 (46) vs. 176 (27) µm, p=0.2), and villus to crypt ratio lower (1.5 (0.42) vs. 2.5 (0.51), p=0.009) in TDF vs. TAF group. I-FABP concentration was higher in TDF vs. TAF group (3.0 (1.07) vs. 1.8 (0.53) ng/ml, p=0.003). TDF group had numerically but not statistically significantly lower concentrations of folate, vitamins A, B1, D, and E. COX/SDH staining showed signs of mitochondrial damage in 10 participants in TDF and 11 in TAF group. EM studies showed similar mitochondrial damage in both groups. CONCLUSIONS: Duodenal villous alterations may explain TDF-associated decrease in body weight and plasma lipids. Larger studies are needed to evaluate concentrations of nutrients absorbed from duodenum among TDF users.

Tenofovir-Associated Kidney Dysfunction and Bone Fracture: A Case Report and Literature Review.

Tenofovir is an integral part of antiretroviral therapy used to treat HIV. Long-term use of tenofovir has been associated with decreased glomerular filtration rate, leading to chronic kidney disease, as well as acidosis, electrolyte imbalances, and tubular dysfunction. Tenofovir can also disrupt bone health by decreasing renal phosphate absorption, contributing to osteomalacia. This leads to disruption in mineral metabolism, elevated parathyroid hormone levels, and ultimately, low bone mineral density. Replacing tenofovir with alternative antiretroviral therapy can improve kidney function if done early in the course of the disease. Here, we discuss a case of a 65-year-old woman with HIV who presented with advanced renal failure and hypophosphatemia-induced bone fracture attributed to long-term use of tenofovir. We conclude monitoring kidney function and considering alternative antiretroviral therapy is important to prevent and manage these side effects in patients on long-term tenofovir therapy.

Pregnant women with chronic hepatitis B virus infection at the assessment of tenofovir disoproxil fumarate prescription: Baseline characteristics of a prospective cohort study in Vietnam.

Objectives: We aimed to determine epidemiological characteristics and serologic markers among chronically hepatitis B virus (HBV)-infected pregnant women during the assessment of tenofovir disoproxil fumarate (TDF) prescription in Vietnam. Methods: We consecutively recruited 375 pregnant women with chronic HBV (cHBV) infection at week 25±2 of pregnancy, at which time they were assessed for TDF use as pre-prophylaxis and/or pre-treatment at the Hospital for Tropical Diseases in southern Vietnam during December 2019-April 2021. Demographic characteristics, serological biomarkers, and prenatal liver ultrasounds were obtained through interviews and reviews of medical records. Results: The median age of pregnant women was 29 years (interquartile range: 26-32). More than half of pregnant women (208/375; 55.5%) started TDF for prevention of mother-to-child transmission of HBV and/or treatment of chronic hepatitis B (CHB). Among the pregnant women initiating TDF, 96.1% (198/206) tested positive for hepatitis B e antigen, and 21.6% (45/208) had quantitative hepatitis B surface antigen (qHBsAg) ≤104 IU/mL. A relatively strong correlation between qHBsAg and HBV deoxyribonucleic acid (DNA) (r = 0.81; 95% CI: 0.76-0.85) was observed in pregnant women starting TDF. Conclusions: Our results demonstrate the high need for TDF prescription for prevention and/or treatment purposes in pregnant women with cHBV infection. Pregnant women with qHBsAg levels ≤104 IU/mL may prioritize HBV DNA testing over qHBsAg to decide on TDF prescription.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patient with chronic hepatitis B.

BACKGROUND AND AIM: Our study evaluated the outcomes of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with chronic hepatitis B (CHB). We assessed viral and biochemical responses as well as changes in the estimated glomerular filtration rate (eGFR) and bone mineral density (BMD). METHODS: This retrospective multicenter study included CHB patients who achieved virologic response (VR) (HBV DNA < 20 IU/mL) while on TDF and were subsequently switched to TAF between April 2018 and October 2021. RESULTS: This study included 309 patients with a median age of 59 years, and 42.1% were male. The mean duration of TDF and TAF administration were 54.0 and 37.5 months, respectively. All patients maintained VR after switching to TAF. Alanine aminotransferase (ALT) normalization rate significantly increased 6 months after switching (74.8%-83.5%; P = 0.008). Adjusted eGFR significantly improved at 6 months (+5.55 ± 10.52 mL/min/1.73 m2; P < 0.001) and 12 months (+6.02 ± 10.70 mL/min/1.73 m2; P < 0.001) after switching. In the subgroup of patients with renal impairment (eGFR < 60 mL/min/1.73 m2), significant improvement in renal function was observed at 6 months (+0.6 ± 10.5 mL/min/1.73 m2; P < 0.001) and 12 months (+1.0 ± 10.7 mL/min/1.73 m2; P < 0.001) after switching to TAF. In patients with osteoporosis (n = 182), switching to TAF resulted in significant improvement in spine and hip BMD at 12 months, with increases of 9.7% (95% CI: 7.0-12.5) and 9.4% (95% CI: 7.0-11.8), respectively. CONCLUSION: In this real-world study, switching to TAF was effective and safe in patients, with notable improvements in ALT levels, renal function, and BMD.

Five-year Treatment with Tenofovir Alafenamide Achieves High Rates of Viral Suppression, Alanine Aminotransferase Normalization, and Favorable Bone and Renal Safety in Chinese Chronic Hepatitis B Patients.

Background and Aims: After 3-years (144 week) of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies, tenofovir alafenamide (TAF) showed similar efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety. In this study, we aimed to report the 5-year results from 2 years into the open-label TAF treatment phase. Methods: All participants completing the 144-week double-blind treatment were eligible to receive open-label TAF 25 mg once daily up to week 384. Serial analysis of viral suppression (hepatitis B virus DNA <29 IU/mL), alanine aminotransferase normalization, serological responses, and safety outcomes at year 5 (week 240) was performed. Results: The open-label phase included 93% (311/334) of the enrolled participants, which included 212 who switched from double-blind TAF to open-label TAF (TAF-TAF) and 99 who switched from double-blind TDF to open-label TAF (TDF-TAF). Baseline characteristics were comparable. Week 240 viral suppression rates were similar between groups [93.4% vs. 93.9%; difference: -1.5%, (95% CI: -6.4 to -3.5), p=0.857]. Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group. The frequencies of adverse events and laboratory abnormalities were low and similar between groups. Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5 (week 240, -2.85 mL/min vs. -3.29 mL/min, p=0.910). The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF. Conclusions: The 5-year TAF treatment efficacy was high and similar to that of 3-year TDF followed by 2-year TAF in Chinese chronic hepatitis B patients. Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

Weight, anthropometric and metabolic changes after discontinuing antiretroviral therapy containing tenofovir alafenamide (TAF) in people with HIV.

BACKGROUND: Antiretroviral therapy (ART)-related weight gain is of particular concern in people with HIV (PWH). While weight gain was observed among PWH receiving tenofovir alafenamide (TAF), little is known about the potential reversibility after TAF discontinuation. We evaluated weight and metabolic changes 12 months after TAF discontinuation in the Swiss HIV Cohort Study. METHODS: We included participants who received at least six months of TAF-containing ART between January 2016 and March 2023. Using multivariable mixed-effect models, changes in weight and lipid levels were compared between individuals who continued TAF and those who switched to one of the following TAF-free regimens: TDF-based ART, dolutegravir/lamivudine (DTG/3TC), or long-acting cabotegravir/rilpivirine (CAB/RPV). RESULTS: Of 6555 participants (median age 54 years, 24.3% female, 13% Black), 5485 (83.7%) continued and 1070 (16.3%) stopped TAF. Overall, discontinuing TAF was associated with an adjusted mean weight change of -0.54 kg (95% CI -0.98 to -0.11) after 12 months. In stratified analyses, switching from TAF to TDF led to an adjusted mean weight decrease of -1.84 kg (CI -2.72 to -0.97), and to a decrease in mean total cholesterol (-0.44 mmol/L) and triglycerides (-0.38 mmol/L) after 12 months. Switching from TAF-based ART to DTG/3TC (-0.17 kg, CI -0.82 to 0.48) or long-acting CAB/RPV (-0.64 kg, CI -2.16 to 0.89) did not lead to reductions in weight. CONCLUSIONS: Replacing TAF with TDF in PWH led to a decrease in body weight and an improved lipid profile within one year. Weight changes were not observed among individuals who switched to DTG/3TC or long-acting CAB/RPV.

Evaluation of the Efficacy and Safety of Tenofovir Disoproxil Fumarate in Intercepting Mother-to-Child Transmission of Hepatitis B Virus.

Vertical transmission of hepatitis B virus (HBV), especially in Asia, is a key target in the global elimination of HBV. This study assessed the effects of tenofovir disoproxil fumarate (TDF) in pregnant women for mother-to-infant transmission of HBV. A total of 122 pregnant women at our hospital met the inclusion criteria for high HBV DNA viral loads. They were randomly divided into TDF-treatment (n=70) and placebo (n=52) groups. Maternal liver function and serum HBV DNA load were tested before and after treatment. Clinical and laboratory data of infants were assayed at delivery and 7-months post-partum visit and compared between the two groups. There was no difference in clinical characteristics of participants between the two groups. There were no significant differences in liver function markers, including alanine aminotransferase, total bilirubin, blood creatinine, and blood urea nitrogen levels before and after TDF treatment. The serum HBV DNA viral load of the TDF-treated group became significantly lower than those of the control group and their own pre-medication levels. Infants showed no significant difference in body growth, including weight, height, head size, and five-min Apgar score. At 7 months after birth, 94.29% of infants in the TDF group and 86.54% of control-group infants had protective HBsAb levels ≥ 10 mIU/ml (p>0.05). The HBV infection rate of infants in the TDF-treated group was lower than that in the non-treated group. In high-HBV-DNA-load pregnant women, TDF administered from 28 weeks gestational age to delivery was associated with a lower risk of mother-to-infant transmission of HBV.

Delayed Irreversible Fanconi Syndrome Associated With Vertebral Fracture After Tenofovir Discontinuation.

The use of tenofovir disoproxil fumarate (TDF) as an antiretroviral agent has been reported to adversely affect both renal tubules and bone health, leading to pathological fractures. While such an effect is largely reversible, substituting TDF with tenofovir alafenamide (TAF) might result in lower rates of adverse events with the preservation of tenofovir effectiveness. We report a case of a 40-year-old lady with HIV infection who had a vertebral fragility fracture secondary to TDF-associated Fanconi syndrome. The syndrome developed four years after TDF cessation and switching to TAF. Other etiologies for decreased bone mass were excluded, and the diagnosis of Fanconi syndrome was established based on her bone mineral density (BMD) and urine parameters. She was treated conservatively with active vitamin D, calcium, and progesterone/estrogen combination, but her phosphate wasting persisted despite switching to TAF; this likely represents a delayed irreversible effect of TDF on the patient's bone remodeling. This case report highlights the chronic sequelae of TDF therapy and the importance of monitoring for and early detection of renal tubulopathy and osteoporotic fractures in this patient population.

HBsAg kinetics after 7 years of therapy with tenofovir disoproxil fumarate in a cohort of naïve patients affected by chronic hepatitis B with different genotypes.

The role of different genotypes in nucleos(t)ide analogs (NAs) treatment is still debated. Previous studies conducted on special populations evidenced that the E genotype had the lower virological and serological response. This descriptive study aims to recognize the hepatitis B "s" antigen (HBsAg) decline during tenofovir disoproxil fumarate (TDF) treatment in a cohort of patient affected by chronic hepatitis B (CHB). We retrospectively included all patients with CHB treated with TDF between April 2007 and March 2012 with a duration of treatment of 7 years. Kinetics of HBsAg was determined as serological response in this cohort. We include 110 subjects; virological response was observed in all subjects with genotypes A, B, and D; in 17 patients with C genotype (94.4%) and 24 with E genotype (96%). HBeAg loss was observed in 2 patients with genotype A (50%), 3 with B (100%), 0 with C (0%), 1 with D (20%), and 1 with E genotype (25%). In multivariate analysis we observed as predictive factors of HBsAg decline the baseline level of HBsAg (OR = 1.467; 95%CI: 1.221-5.113; p = 0.017) and viral genotypes (OR = 11.218; 95%CI: 5.441-41.138; p < 0.001). This study confirmed higher HBsAg decline after 7 years of treatment in A and B genotypes, and lower in C, E, and D genotypes. However, no evidence is enough to choose a single NAs, but in special populations, as well as in genotype E, the use of TDF should be preferred to entecavir.

HIV-1 Incidence, Adherence, and Drug Resistance in Individuals Taking Daily Emtricitabine/Tenofovir Disoproxil Fumarate for HIV-1 Pre-Exposure Prophylaxis: Pooled Analysis From 72 Global Studies.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings. METHODS: HIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentration in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies. RESULTS: Among 17,274 participants, there were 101 cases with new HIV-1 diagnosis (0.77 per 100 person-years; 95% CI 0.63-0.94). In 78 cases with resistance data, 18 (23%) had M184I or V, one (1.3%) had K65R, and three (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of <2, 2-3, 4-6, and ≥7 doses/week, respectively, and the corresponding incidence was 3.9 (95% CI 2.9-5.3), 0.24 (0.060-0.95), 0.27 (0.12-0.60), and 0.054 (0.008-0.38) per 100 person-years. Adherence was low in younger participants, Hispanic/Latinx and Black participants, cisgender women, and transgender women. Bone and renal adverse event incidence rates were 0.69 and 11.8 per 100 person-years, respectively, consistent with previous reports. CONCLUSIONS: Leveraging the largest pooled analysis of global PrEP studies to date, we demonstrate that F/TDF is safe and highly effective, even with less than daily dosing, in diverse clinical settings, geographies, populations, and routes of HIV-1 exposure.

Comparison of the efficacy and safety of TAF, TDF, and LdT to prevent the transmission of hepatitis B in pregnant women: A retrospective study.

OBJECTIVE: To compare the efficacy and safety of telbivudine (LdT), tenofovir alafenamide fumarate (TAF), and tenofovir disoproxil fumarate (TDF) for preventing hepatitis B transmission in immune-tolerant pregnant women with HBV infection. METHODS: We conducted a retrospective cohort study involving women who had hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥ 2 × 105 IU/mL and initiated LdT, TDF, or TAF to prevent mother-to-child transmission (MTCT). The primary endpoint was the safety of mothers and infants. The secondary endpoints were maternal HBV DNA reduction at delivery and MTCT rate. RESULTS: A total of 96 patients were enrolled in the study (LdT group, n = 36; TDF group, n = 35; TAF group, n = 25). All infants received hepatitis B virus immunoprophylaxis. The MTCT rate was 0%([0 of 25] vs. [0 of 35] vs. [0 of 36], p > .05). No severe liver function damage occurred in any of the mothers. Babies delivered in all groups had prenatal ultrasound screening abnormalities, but abnormality rates were not statistically significant between groups. CONCLUSION: The application of TDF, TAF, or LdT to immune-tolerant HBV-infected pregnant women in middle-late pregnancy can successfully interrupt MTCT of the HBV virus. However, for all three groups of pregnant women who delivered babies with abnormal prenatal ultrasound screening, an expanded sample size may be needed for further observation.

Renal function and lipid metabolism in Japanese HIV-1-positive individuals 288 weeks after switching from tenofovir disoproxil fumarate to tenofovir alafenamide fumarate: a single-center, retrospective cohort study.

BACKGROUND: Continued use of tenofovir disoproxil fumarate (TDF), an antiretroviral drug, causes renal function decline and tubular damage in individuals with HIV. While tenofovir alafenamide fumarate (TAF) may have less damaging effects, it causes weight gain and abnormal lipid metabolism. METHODS: This single-center, retrospective cohort study used medical records from the National Hospital Organization Sendai Medical Center to investigate renal function of Japanese HIV-1-positive individuals who switched from TDF to antiretroviral therapy including TAF by 2017. The endpoints were: estimated glomerular filtration rate (eGFR), urinary ß2 microglobulin (Uß2MG), weight, and lipid metabolism parameters at 288 weeks after switching. Possible correlation between eGFR and Uß2MG and factors affecting eGFR decline were examined. RESULTS: Sixty patients switched from TDF to TAF and continued therapy for 288 weeks. eGFR showed a significant decline after 144 weeks, although it was controlled from the time of change until 96 weeks. In the renal impairment group, the decline was suppressed until week 288. Uß2MG continued to decrease significantly after 48 weeks. However, the suggested correlation between eGFR and Uß2MG disappeared when patients switched from TDF to TAF. Weight and lipid metabolic parameters increased significantly at 48 weeks and were maintained. Factors associated with decreased eGFR were: history of acquired immune deficiency syndrome (AIDS) and Uß2MG. However, considering the odds ratio, the switch from TDF to TAF suppressed the eGFR decline in the group with a history of AIDS, and Uß2MG had no effect on the eGFR decline. CONCLUSIONS: Switching from TDF to TAF for the long term slows eGFR decline, decreases Uß2MG levels, and reduces worsening of renal function. Weight gain and abnormal lipid metabolism may occur in the short term but are controllable.

MDSC-targeted liposomal all-trans retinoic acid suppresses mMdscs and improves immunotherapy in HBV infection.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are evolving as a prominent determinant in cancer occurrence and development and are functionally found to suppress T cells in cancer. Not much research is done regarding its involvement in viral infections. This research was designed to investigate the role of MDSCs in hepatitis B virus (HBV) infection and how targeting these cells with our novel all-trans retinoic acid encapsulated liposomal formulation could improve immunotherapy in C57BL/6 mice. METHODS: Ten micrograms (10 µg) of plasmid adeno-associated virus (pAAV/HBV 1.2, genotype A) was injected hydrodynamically via the tail vein of C57BL/6 mice. An all-trans retinoic acid encapsulated liposomal formulation (L-ATRA) with sustained release properties was used in combination with tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor (nRTI) to treat the HBV infection. The L-ATRA formulation was given at a dose of 5 mg/kg intravenously (IV) twice a week. The TDF was given orally at 30 mg/kg daily. RESULTS: Our results revealed that L-ATRA suppresses MDSCs in HBV infected mice and enhanced T-cell proliferation in vitro. In vivo studies showed higher and improved immunotherapeutic effect in mice that received L-ATRA and TDF concurrently in comparison with the groups that received monotherapy. Lower HBV DNA copies, lower concentrations of HBsAg and HBeAg, lower levels of ALT and AST and less liver damage were seen in the mice that received the combination therapy of L-ATRA + TDF. CONCLUSIONS: In effect, targeting MDSCs with the combination of L-ATRA and TDF effectively reduced mMDSC and improved immunotherapy in the HBV infected mice. Targeting MDSCs could provide a breakthrough in the fight against hepatitis B virus infection.

Cost-effectiveness of switching from tenofovir disoproxil fumarate to tenofovir alafenamide versus entecavir for chronic hepatitis B patients in Greece.

Aim: This study assessed the clinical impact and cost-effectiveness of switching from tenofovir disoproxil fumarate (TDF) to either tenofovir alafenamide (TAF) or entecavir (ETV) in a Greek chronic hepatitis B (CHB) population. Patients & methods: A Markov model from the perspective of a third-party payer in Greece quantified the health and economic benefits of switching from TDF to either TAF or ETV over a lifetime horizon. Results: Over a lifetime, patients who switch from TDF to TAF versus patients who switch from TDF to ETV had an overall lower incidence of compensated cirrhosis (0.4% lower), decompensated cirrhosis (0.04% lower) and hepatocellular carcinoma (0.25% lower). Chronic kidney disease and end-stage renal disease were also lower in patients who switch to TAF; major osteoporotic fractures were similar for both groups. While total costs were higher for switching from TDF to TAF versus TDF to ETV due to the higher cost of TAF, switching from TDF to TAF versus ETV was cost effective with an incremental cost-effectiveness ratio of €17,113 per quality-adjusted life year. Conclusion: Switching from TDF to TAF in patients living with CHB is a cost effective strategy to reduce adverse liver disease outcomes, while improving bone- and renal-related safety outcomes.

Preventing viral relapse with prophylactic tenofovir in hepatitis B carriers receiving chemotherapy: a phase IV randomized study in Taiwan.

BACKGROUND AND AIMS: This study aimed to compare the efficacy of shorter vs. longer tenofovir disoproxil fumarate (TDF) prophylaxis in preventing hepatitis B virus (HBV) relapse in cancer patients with chronic hepatitis B (CHB) undergoing chemotherapy. METHODS: This phase IV, prospective randomized trial enrolled cancer patients with CHB from 2014 to 2019 in Taiwan. Included patients were randomized to receive either 24- (Arm A) or 48-week (Arm B) post-chemotherapy TDF and compared for cumulative incidence of virological and clinical relapse. Logistic regressions were conducted to determine the factors associated with HBV relapse. RESULTS: One hundred patients were randomized, and 41 patients in Arm A and 46 in Arm B completed the TDF treatment. No significant difference was found in cumulative incidence of virological relapse (Arm A: 94.4%, Arm B: 93.1%, p = 0.110) or clinical relapse among patients with baseline HBV DNA > 2000 IU/mL (Arm A: 38.9%, Arm B: 26.7%, p = 0.420) between the two arms. High baseline HBV DNA ≥ 10,000 IU/mL (OR = 51.22) and HBsAg ≥ 1000 IU/mL (OR = 8.64) were independently associated with an increased virological relapse. Alanine aminotransferase (ALT), serum phosphorus, vitamin D, and estimated glomerular filtration rate (eGFR) remained stable throughout the study. CONCLUSIONS: The 24-week preventative TDF has comparable efficacy to the 48-week treatment in virologic and clinical relapse. High baseline HBsAg or HBV DNA is associated with a higher risk of HBV relapse. These findings imply a 24-week duration of TDF treatment with a close monitor for patients with a high baseline viral load. Hepatitis B virus infection is a prominent cause of liver cancer and chronic liver disease and affected millions of people worldwide. When HBV-infected people are exposed to immunosuppressive medication or chemotherapy for cancer, the chance of HBV reactivation rises considerably. This trial showed 24-week tenofovir disoproxil fumarate (TDF) may be sufficient for preventing HBV relapse in cancer patients receiving chemotherapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02081469.

Entecavir versus tenofovir for prevention of hepatitis B virus-associated hepatocellular carcinoma after curative resection: study protocol for a randomized, open-label trial.

BACKGROUND: Entecavir and tenofovir disoproxil fumarate (TDF) are standard first-line treatments to prevent viral reactivation and hepatocellular carcinoma (HCC) in individuals chronically infected with the hepatitis B virus (HBV), but the long-term efficacy of the two drugs remains controversial. Also unclear is whether the drugs are effective at preventing viral reactivation or HCC recurrence after hepatectomy to treat HBV-associated HCC. This trial will compare recurrence-free survival, overall survival, viral indicators and adverse events in the long term between patients with HBV-associated HCC who receive entecavir or TDF after curative resection. METHODS: This study is a randomized, open-label trial. A total of 240 participants will be randomized 1:1 into groups receiving TDF or entecavir monotherapy. The two groups will be compared in terms of recurrence-free and overall survival at 1, 3, and 5 years after surgery; adverse events; virological response; rate of alanine transaminase normalization; and seroreactivity at 24 and 48 weeks after surgery. DISCUSSION: This study will compare long-term survival between patients with HBV-associated HCC who receive TDF or entecavir monotherapy. Numerous outcomes related to prognosis will be analyzed and compared in this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02650271. Registered on January 7, 2016.

Co-emulsified Alginate-Eudragit Nanoparticles: Potential Carriers for Localized and Time-defined Release of Tenofovir in the Female Genital Tract.

This research aimed to explore the possibilities of Eudragit S100 (ES100) and sodium alginate as carriers for tenofovir disoproxil fumarate (TDF) in the female genital tract. Alginate and alginate-ES100 nanoparticles were prepared using the ionic gelation and emulsion/gelation complexation method, respectively. The nanocarriers were tested using morphological, physicochemical, in vitro drug release, and cytotoxicity analyses. In SEM and TEM images, the presence of spherical and uniformly distributed nanoparticles was revealed. The FTIR spectrum showed that alginate and calcium chloride interacted due to ionic bonds linking divalent calcium ions and the -COO- of alginate groups. Alginate and ES100 interacted via the ester C=O amide stretching. The results obtained from XRD and DSC, on the other hand, revealed a favorable interaction between sodium alginate and ES100 polymers, as evidenced by the crystallization peaks observed. Under experimental design analysis and optimization, overall size distribution profiles ranged from 134.9 to 228.0 nm, while zeta potential results showed stable nanoparticles (-17.8 to -38.4 MV). The optimal formulation exhibited a maximum cumulative in vitro release of 72% (pH 4.2) up to 96 h. The cytotoxicity tests revealed the safety of TDF-loaded nanoparticles on vaginal epithelial cells at concentrations of 0.025 mg/mL, 0.5 mg/mL, and 1 mg/mL for 72 h. These results indicated that alginate-ES100 nanoparticles have the potential to preserve and sustain the release of the TDF drug in the FGT. The future goal is to develop a low-dose non-toxic microbicide that can be administered long term in the vagina to cater to both pregnant and non-pregnant HIV patients.