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.

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.

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.

Tenofovir-Induced Renal Dysfunction Among HIV-Infected Patients: A Systematic Review.

Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug widely used as part of antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV-1) infection. Negative effects of tenofovir include impaired kidney function, especially with long-term use. In studies conducted among HIV-positive individuals, we found evidence of extensive kidney damage associated with TDF use. Despite the therapeutic importance of this consequence, its continued use in ART regimens was not contraindicated. The therapeutic and long-term effects of TDF are a major concern. However, in countries or settings where resources are limited and renal function monitoring cannot be ensured, screening methods to detect ART-related renal failure are still supported by data. Therefore, it is safe to re-evaluate the use of TDF-based ART. However, adherence to guidelines may be hampered by insufficient laboratory testing in low- and middle-income countries. More research is also needed among people under 18 years of age and pregnant and breastfeeding mothers.

Biktarvy for the treatment of HIV infection: Progress and prospects.

Bictegravir (BIC), a second-generation integrase strand-transfer inhibitor (INSTI) with high resilience to INSTI-resistance mutations, is integrated as a key component of Biktarvy® - a fixed-dose once-daily triple-drug regimen of bictegravir (BIC), emtricitabine (FTC) plus tenofovir alafenamide (TAF). Based on the accumulated evidence from HIV clinical trials and real-world studies, the clinical effectiveness of BIC + FTC + TAF has been proven non-inferior to other fixed-dose once-daily combinations such as dolutegravir + FTC + TAF and dolutegravir + abacavir + lamivudine. Biktarvy also shows limited drug-drug interactions and a high barrier to drug resistance. According to recent HIV guidelines, BIC + FTC + TAF is recommended as initial and long-term therapy for the treatment of HIV infection. For the pre-exposure prophylaxis, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) remains advisable, but BIC may be possibly added to TDF or TAF. In the development of a long-acting once-monthly regimen, the novel nano-formulation of BIC + FTC + TAF could be possibly developed in the future.

Cost-effectiveness of tenofovir prophylaxis during pregnancy for the elimination of mother-to-child transmission of the hepatitis B virus: real-world analysis from Thailand.

OBJECTIVE: Despite implementing hepatitis B immunoglobulin (HBIG) and vaccination, data suggest it would not be sufficient to reach the elimination targets. Tenofovir disoproxil fumarate (TDF) has been added to the Thai national standards of care for prevention of transmission of the hepatitis B virus during birth. To optimise national strategies in Thailand, we assessed TDF's effectiveness for prevention of mother-to-child transmission and conducted cost-effectiveness analyses of different TDF-based strategies. RESEARCH DESIGN AND METHODS: We retrospectively reviewed medical records of mother and infant pairs whose mothers were positive for hepatitis B e-antigen (HBeAg) and received TDF to prevent maternal transmission of viral hepatitis B during 2018-2020. Based on the available data on transmission rate, we also applied a decision tree to estimate the cost-effectiveness of different TDF-based strategies to eligible mothers. These included: (1) HBIG for all hepatitis B virus (HBV) exposed infants; (2) HBIG for only infants of HBeAg-positive mothers ('HBIG for e-positive') and (3) without HBIG to infants ('HBIG-free'). The incremental cost-effectiveness ratio between the different strategies and baseline intervention without TDF was calculated. The one-way sensitivity analysis was used to adjust prevalence of HBeAg-positive mothers, cost of HBIG, cost of TDF and transmission rate. RESULTS: Of 223 infants enrolled, 212 (95.0%) received HBIG, while 11 (5.0%) did not. None of the infants had chronic HBV infection. The most cost-saving intervention was 'HBIG-free' followed by 'HBIG for e-positive'. The one-way sensitivity demonstrated that the results were reasonably robust to changes. The cost-saving was greater with a higher hepatitis B virus surface antigen (HBsAg) prevalence. The HBIG-free strategy remained best at 0%-1.4% transmission rates, meeting the additional target for eliminations. CONCLUSION: The study is the first cost-effectiveness analyses to provide evidence supporting an HBIG-free strategy in an antiviral era. This approach should be considered to prevent mother-to-child transmission in resource-constrained settings, particularly in countries with a high HBsAg prevalence.

Degradants of Tenofovir Disoproxil Fumarate Under Forced Yet Mild Thermal Stress: Isolation, Comprehensive Structural Elucidation, and Mechanism.

In addition to understanding the mechanism of action for a specific drug candidate, information regarding degradation pathways/products under various stress conditions is essential to know about their short- and long-term effects on health and environment. In line with that, tenofovir disoproxil fumarate (TDF, a co-crystal form of the prodrug tenofovir with fumaric acid), particularly used as an antiretroviral drug for treatment of HIV and hepatitis-B among others, is subjected to primarily thermal and other ICH-prescribed forced degradation conditions and their various degradation products are identified. Upon thermal degradation at 60°C for 8 h, five different degradants (namely DP-1 to DP-5) are isolated, and their structures are unambiguously confirmed using advanced analytical and spectroscopic techniques including ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), high-resolution mass spectrometry (HRMS), state-of-the-art 1- and 2-dimensional nuclear magnetic resonance (1D and 2D NMR), and Fourier-transform infrared spectroscopic (FT-IR) techniques. Among fully characterized five degradants, two new degradants (DP-2 and DP-4) are identified which can potentially impact the stability of TDF via different pathways. Plausible mechanisms leading to all five thermal degradation products are also proposed including the generation of carcinogenic formaldehyde for some cases. The present systematic structural study especially combining MS and advanced NMR investigations unequivocally confirms the structures of the degradants and opens opportunities for connecting the various degradation pathways especially for the TDF-related pharmaceutical candidates.

Pharmacokinetic Feasibility of Stability-Enhanced Solid-State (SESS) Tenofovir Disoproxil Free Base Crystal.

Tenofovir (TEV) is a nucleotide reverse transcriptase inhibitor used against human immunodeficiency virus (HIV) reverse transcriptase. To improve the poor bioavailability of TEV, TEV disoproxil (TD), an ester prodrug of TEV, was developed, and TD fumarate (TDF; Viread®) has been marketed due to the hydrolysis of TD in moisture. Recently, a stability-enhanced solid-state TD free base crystal (SESS-TD crystal) was developed with improved solubility (192% of TEV) under gastrointestinal pH condition and stability under accelerated conditions (40 °C, RH 75%) for 30 days. However, its pharmacokinetic property has not been evaluated yet. Therefore, this study aimed to evaluate the pharmacokinetic feasibility of SESS-TD crystal and to determine whether the pharmacokinetic profile of TEV remained unchanged when administering SESS-TD crystal stored for 12 months. In our results, the F and systemic exposure (i.e., AUC and Cmax) of TEV in the SESS-TD crystal and TDF groups were increased compared to those in the TEV group. The pharmacokinetic profiles of TEV between the SESS-TD and TDF groups were comparable. Moreover, the pharmacokinetic profiles of TEV remained unchanged even after the administration of the SESS-TD crystal and TDF stored for 12 months. Based on the improved F after the SESS-TD crystal administration and the stable condition of the SESS-TD crystal after 12 months, SESS-TD crystal may have enough pharmacokinetic feasibility to replace TDF.

Blood immune cells from people with HIV on antiviral regimens that contain tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) have differential metabolic signatures.

BACKGROUND: Mitochondria regulate immune and organ function. It is unknown whether higher intracellular drug levels observed in peripheral blood mononuclear cells (PBMCs) treated with tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) may alter mitochondrial function and energy production in immune cells in HIV(+) patients. METHODS: Cellular bioenergetics were determined in PBMCs from HIV-1(-) participants exposed to TAF versus TDF in vitro, at a comparable concentration to a clinically relevant plasma exposure. A decrease in cellular oxygen consumption rate (OCR) at baseline (basal-OCR) and under cellular stress (max-OCR) may suggest mitochondrial dysfunction. We also assessed the in vivo impact of TAF vs TDF on OCR in PBMCs from 26 people with HIV (PWH) interchanged from TDF-based to TAF-based antiretroviral therapy (ART) over a 9-month period in the setting of an open label clinical trial. The Wilcoxon and Mann Whitney tests were used for comparison of continuous variables. RESULTS: PBMCs from HIV-1(-) participants exposed in vitro to a concentration of 0.12-3.3 µM for TAF and TDF at 2 and 24 h, reduced basal and maximal OCR compared to vehicle control. Switch studies of antivirals (TAF vs TDF) within the same PWH showed that TAF-based ART was associated with reduced OCR compared to TDF-based ART in PBMCs. We observed that TAF-treated PBMCs selectively relied more on glucose/pyruvate supply rather than fatty acid to fuel their mitochondria. CONCLUSIONS: Compared to TDF, TAF may alter bioenergetics in immune cells from PWH in vitro and in vivo. The clinical significance in terms of the differential impact caused by TAF versus TDF on mitochondrial function and energy production in immune cells, a regulator of immune function, requires further studied in HIV, preexposure prophylaxis and hepatitis B.

Safety and Effectiveness of Tenofovir Alafenamide in Usual Clinical Practice Confirms Results of Clinical Trials: TARGET-HBV.

BACKGROUND: Nucleos(t)ide analogues, with a proven record of safety and efficacy, have been the therapy of choice for over a decade for the treatment of chronic hepatitis B. The approval of tenofovir alafenamide (TAF) in 2016 provided an additional treatment option. AIMS: The aim of this study was to evaluate the characteristics and clinical outcomes of patients treated with TAF in usual clinical practice. METHODS: Retrospective data from electronic health records was obtained from those enrolled in TARGET-HBV, a longitudinal observational cohort study of patients with chronic hepatitis B managed according to local practice standards at community and academic medical centers throughout the U.S. RESULTS: Of 500 patients enrolled, most were male (66%) and of Asian race (66%) with median age of 55 years. Cirrhosis was evident in 15%. Most patients (82%) had switched to TAF after treatment with other antivirals. The perceived safety profile of TAF was cited as the primary reason for changing therapy (32%). TAF was well tolerated and only 4 patients discontinued therapy due to adverse event during a median duration of TAF dosing of 74 weeks. Among those with paired laboratory data 12-18 months after switching to TAF, biochemical response and HBV DNA suppression was maintained. Most patients had normal renal function which was essentially unchanged throughout follow-up. CONCLUSIONS: TAF is frequently utilized in routine clinical practice due to the perception of its improved safety profile. The current study supports the growing body of evidence regarding the safety and effectiveness of TAF. Trial Registration ClinicalTrials.gov identifier: NCT03692897, https://clinicaltrials.gov/ct2/show/NCT03692897 .

Changes in trabecular bone score and bone mineral density in Chinese HIV-Infected individuals after one year of antiretroviral therapy.

OBJECTIVE: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) have been associated with reduced bone mineral density (BMD) in persons with HIV (PWH). BMD provides information only about bone mineral quantity. Trabecular bone score (TBS) is a noninvasive tool that estimates bone microarchitecture. The aim of this study is to measure BMD and TBS of Chinese PWH after one-year ART. METHODS: We designed a retrospective study of adult Chinese PWH. Patients with a dual-energy X-ray absorptiometry (DXA) scan prior to ART initiation, and again 48 weeks later were included. Information regarding demographic and clinical history, HIV treatment history, BMD and TBS were collected. We analyzed differences in BMD and TBS over 48 weeks and associations between key risk factors and changes in BMD and TBS. RESULTS: Our study included 233 â€‹PWH (mean age â€‹= â€‹36.6 â€‹± â€‹11.1 years). Before ART initiation, 19.3% of PWH had normal BMD but abnormal TBS. Both BMD and TBS decreased after one-year ART. TDF and LPV/r-containing regimens were associated with greater declines in BMD at different site. Traditional risk factors such as old age, low BMI and female sex were associated with lower baseline TBS. Greater change in TBS over one year was associated with lower BMI and lower baseline CD4+ cell count, but unlike BMD measures, it was not correlated with treatment with TDF and LPV/r in our study population. CONCLUSIONS: We present the first longitudinal analysis of change in TBS over 48 weeks compared with BMD among Asian PWH receiving ART. Before ART initiation, approximately 20% of PWH with impaired bone microarchitecture would not have been identified if DXA were used alone to assess for bone damage. Both BMD and TBS decreased after one-year ART. Change in TBS was not associated with different antiretroviral agents. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The trabecular microarchitecture measured indirectly by TBS may provide clinicians additional information about bone damage in PWH.

Hepatitis B virus (HBV) viral load, liver and renal function in adults treated with tenofovir disoproxil fumarate (TDF) vs. untreated: a retrospective longitudinal UK cohort study.

BACKGROUND: Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. METHODS: We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. RESULTS: We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. CONCLUSIONS: Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.

Tenofovir Alafenamide Rescues Renal Tubules in Patients with Chronic Hepatitis B.

Nucles(t)ide analogs (NAs) are effective for chronic hepatitis B (CHB). NAs suppress hepatic decompensation and hepatocarcinogenesis, leading to a dramatic improvement of the natural course of patients with CHB. However, renal dysfunction is becoming an important issue for the management of CHB. Renal dysfunction develops in patients with the long-term treatment of NAs including adefovir dipivoxil and tenofovir disoproxil fumarate. Recently, several studies have reported that the newly approved tenofovir alafenamide (TAF) has a safe profile for the kidney due to greater plasma stability. In this mini-review, we discuss the effectiveness of switching to TAF for NAs-related renal tubular dysfunction in patients with CHB.

Tenofovir and emtricitabine concentrations in hair are comparable between individuals on tenofovir disoproxil fumarate versus tenofovir alafenamide-based ART.

Tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) is the backbone for both human immunodeficiency virus (HIV) treatment and pre-exposure prophylaxis (PrEP) worldwide. Tenofovir alafenamide (TAF) with FTC is increasingly used in HIV treatment and was recently approved for PrEP among men-who-have-sex-with-men. TDF and TAF are both metabolized into tenofovir (TFV). Antiretrovirals in plasma are taken up into hair over time, with hair levels providing a long-term measure of adherence. Here, we report a simple, robust, highly sensitive, and validated high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS)-based analytical method for analyzing TFV and FTC from individuals on either TDF/FTC or TAF/FTC in small hair samples. TFV/FTC are extracted from ~5 mg hair and separated on a column using a gradient elution. The lower quantification limits are 0.00200 (TFV) and 0.0200 (FTC) ng/mg hair; the assay is linear up to 0.400 (TFV) and 4.00 (FTC) ng/mg hair. The intra-day and inter-day coefficients of variance (CVs) are 5.39-12.6% and 6.40-13.5% for TFV and 0.571-2.45% and 2.45-5.16% for FTC. TFV concentrations from participants on TDF/FTC-based regimens with undetectable plasma HIV RNA were 0.0525 ± 0.0295 ng/mg, whereas those from individuals on TAF/FTC-based regimens were 0.0426 ± 0.0246 ng/mg. Despite the dose of TFV in TDF being 10 times that of TAF, hair concentrations of TFV were not significantly different for those on TDF versus TAF regimens. Pharmacological enhancers (ritonavir and cobicistat) did not boost TFV concentrations in hair. In summary, we developed and validated a sensitive analytical method to analyze TFV and FTC in hair and found that hair concentrations of TFV were essentially equivalent among those on TDF and TAF.

Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes.

Tenofovir disoproxil fumarate (TDF) has been regarded as the most potent drug for treating patients with chronic hepatitis B (CHB). However recently, viral mutations associated with tenofovir have been reported. Here, we found a CHB patient with suboptimal response after more than 4 years of TDF treatment. Clonal analysis of hepatitis B virus (HBV) isolated from sequential sera of this patient identified the seven previously reported TDF-resistant mutations (CYELMVI). Interestingly, a threonine to alanine mutation at the 301 amino acid position of the reverse-transcriptase (RT) domain, (rtT301A), was commonly accompanied with CYELMVI at a high rate (72.7%). Since the rtT301A mutation has not been reported yet, we investigated the role of this naturally occurring mutation on the viral replication and susceptibility to tenofovir in various liver cells (hepatoma cells as well as primary human hepatocytes). A cell-based phenotypic assay revealed that the rtT301A mutation dramatically impaired the replication ability with meaningful reduction in sensitivity to tenofovir in hepatoma cell lines. However, attenuated viral replication by the rtT301A mutation was significantly restored in primary human hepatocytes (PHHs). Our findings suggest that the replication capability and drug sensitivity of HBV is different between hepatoma cell lines and PHHs. Therefore, our study emphasizes that validation studies should be performed not only in the liver cancer cell lines but also in the PHHs to understand the exact viral fitness under antiviral pressure in patients.

Long-term trabecular bone score and bone mineral density changes in Chinese antiretroviral-treated HIV-infected individuals.

This is the first 5-year analysis among persons with HIV (PWH) that reports both trabecular bone score (TBS), which is a novel index that estimates bone microarchitecture, and bone mineral density (BMD) over time to evaluate the long-term impact of antiretroviral therapy (ART) on bone health. PURPOSE: HIV infection and antiretroviral therapy (ART) have been associated with decreased bone mineral density (BMD). This study aims to evaluate long-term changes in trabecular bone score (TBS), a novel index that estimates bone microarchitecture, and BMD among Chinese persons with HIV (PWH) treated with ART. METHODS: We conducted a retrospective chart review of adult PWH at a large tertiary care hospital in China. Patients who had a DXA scan prior to ART and at least one follow-up DXA after ART initiation were included. Subgroup analyses examined the TBS and BMD changes in patients who switch from a non-TDF-containing regimen to one containing TDF, as compared to those who did not switch. RESULTS: Four hundred fifty-nine PWH were included. Among 68 patients ≥ 50 years, 13 patients (19.1%) had a normal BMD but partially degraded or degraded TBS. The mean percent decrease in lumbar spine (LS) BMD nadired at 48 weeks after ART initiation and then gradually improved. Percent decrease in femoral neck (FN) and total hip (TH) BMD nadired at 96 weeks and remained stably low thereafter. After switch to a TDF-containing regimen, only percent change in TH BMD was significant (-3.2%, p = 0.006). In the regression analyses, switch to a TDF-containing regimen was not associated with long-term change in TBS or BMD. CONCLUSION: This is the first study among PWH to evaluate the long-term impact of ART on TBS and BMD. At baseline, approximately 20% of patients had a normal BMD but impaired bone microstructure based upon TBS. For patients with 5 years of exposure to ART, there is a stabilization of TBS and BMD after initial nadir in the first 144 weeks. However, FN BMD, TH BMD, and TBS remained low at 5 years relative to baseline.

Tenofovir disoproxil fumarate for prevention of mother-to-child transmission of hepatitis B virus: A systematic review and meta-analysis of randomised control trials.

Hepatitis B virus (HBV) infection caused by mother-to-child transmission (MTCT) continues to pose challenges to global health. This study aimed to assess the efficacy and safety of tenofovir disoproxil fumarate (TDF) for preventing HBV MTCT. PubMed and the Cochrane Central Register of Controlled Trials were searched through August 2020. Randomised controlled trials (RCTs) were selected that evaluated the efficacy and safety of TDF for preventing MTCT of HBV compared with the standard of care, placebo or other HBV therapies. The primary outcomes were HBV MTCT rate and maternal HBV DNA level. Secondary outcomes were infant and maternal safety outcomes. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines, and prospectively registered on PROSPERO (CRD42020186275). Of 240 citations, three RCTs that involved 651 participants were included. The pooled result showed that TDF can reduce the risk of HBV MTCT after 6 months postpartum by 80% (risk ratio [RR] 0.2, 95% confidence interval [CI 0.06-0.7], n = 584) with low heterogeneity (I2  = 0%). TDF demonstrated HBV DNA suppression at delivery, though there was heterogeneity among individual studies (RR 0.13, 95% CI [0.08-0.20] and (RR 0.36, 95% CI [0.27-0.49]). Maternal and infant safety outcomes were comparable among treated and untreated mothers and infants born to them. The quality of evidence varied from high to very low. There is evidence that TDF effectively interrupted MTCT of HBV and suppressed HBV DNA level. Available studies on safety are very limited and heterogeneous, emphasising the need for additional RCTs with complete safety indicators.

Tenofovir alafenamide (TAF) clinical pharmacology.

Tenofovir today exists in two pharmaceutical forms, such as Tenofovir disoproxil fumarate (TDF) and the newer Tenofovir alafenamide (TAF). The two different salts are required in order to promote intestinal absorption of the active molecule (TFV). Once absorbed the distribution of TFV into compartments is driven by the salt to which the drug is conjugated; in case of TDF, following absorption most of TFV is cleared from its link with the salt and the drug is widely distributed into different tissues, while in case of TAF the reverse is true as TFV remains mostly associated to its alafenamide salt and its distribution is restricted to cells with high carboxyesterase and catepsin A activity, such as hepatocytes and lymphocytes. This generates higher plasma levels of TFV in case of TDF while in the case of TFV much higher intracellular concentrations in target cells are achieved. The main reason for TAF development was to reduce the impact of the drug on proximal renal function and this was actually obtained by the much lower plasma concentration of TFV. Numerous clinical trials consistently demonstrated the significant lesser impact of TAF vs TDF on both renal function and structural bone integrity.

Characterization of Hepatitis B virus polymerase mutations A194T and CYEI and tenofovir disoproxil fumarate or tenofovir alafenamide resistance.

Both the A194T and a quadruple mutation CYEI (S106C, H126Y, D134E and L269I) in hepatitis B virus (HBV) polymerase reverse transcriptase domain (pol/RT) are suggested to be associated with treatment failure with tenofovir disoproxil fumarate (TDF). To further evaluate this assertion, the prevalence of these mutations at baseline as well as their development and/or loss during TDF and tenofovir alafenamide (TAF) treatment was analysed in 3886 patients enrolled in Gilead HBV clinical studies. In total, six out of 3886 (0.2%) patients carried the rtA194T mutation, while only 1 patient carried a triple CYE and 2 patients carried a quadruple CYEI mutation at baseline. All the patients harbouring rtA194T or CYE/CYEI at baseline achieved viral suppression by week 96 after TDF or TAF treatment. No patients developed an rtA194T mutation or > 1 substitution of CYEI, and the number of patients losing any substitutions of CYEI (n = 17) was similar to the number who developed a single substitution of CYEI (n = 32) during treatment. Phenotypic evaluation of the site-directed mutant (SDM) panel containing these mutations with or without other resistance mutations did not demonstrate a significant shift in TFV and TAF potency in vitro. No evidence of rtA194T and CYEI conferring resistance to TDF or TAF was observed based on the treatment responses to TDF or TAF in patients with mutations at baseline, the lack of selection of mutations after starting TDF or TAF treatment and no change in susceptibility to TFV or TAF in vitro.

Association of tenofovir disoproxil fumarate exposure with chronic kidney disease and osteoporotic fracture in US veterans with HIV.

BACKGROUND: Tenofovir disoproxil fumarate (TDF)-based regimens have been associated with impaired kidney function and loss of bone mineral density among patients living with HIV (PLWH). We assess the association between TDF exposure and the odds of chronic kidney disease (CKD) and osteoporotic fracture in HIV patients. METHODS: Demographics, administrative claims, and pharmacy dispensation were extracted from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Patients were categorized based on TDF utilization. Incidence rates for patients exposed and unexposed to TDF were calculated per 1000 patient-years (PYs). Logistic regression was used to calculate the odds of outcome after adjusting for baseline and clinical characteristics. RESULTS: The sample included 4,630 PLWH who were currently exposed to TDF and 1,181 who were never exposed to TDF for the CKD analyses. For fracture analyses, the sample included 6,883 PLWH who were currently exposed to TDF and 1,951 who were never exposed to TDF. In adjusted models, current TDF exposure was associated with increased odds of CKD compared to never having been exposed (OR: 1.48, 95% CI: 1.18-1.85). Odds of fracture were 2.32 times higher for patients who were currently on a TDF regimen (OR: 2.32, 95% CI: 1.58-3.42) compared to those who had never been exposed to TDF in adjusted models. CONCLUSIONS: In a large cohort of US veterans with HIV, current exposure to TDF was associated with a 48% higher odds of CKD and a greater than two-fold increase in the odds of osteoporotic fracture.