Tenofovir Alafenamide Research Articles

In vitro and patient studies with platelets to explore off-target cardiovascular effects of integrase inhibitors.

People with HIV currently face a tenfold higher risk of developing cardiovascular disease (CVD) than those without HIV. Studies have shown various off-target effects of antiretroviral treatment (ART) on the cardiovascular system, but little is known about the effects of currently used integrase strand transfer inhibitors (INSTIs) on platelets. Platelet activation is associated with increased CVD, thrombus formation, and release of proinflammatory mediators, so exploring platelet effects from currently prescribed ART may contribute to the understanding of CVD etiopathogenesis in people with HIV. We aimed to identify potential effects of INSTIs on platelet aggregation and activation markers from individuals without HIV after in vitro treatment with clinically relevant drug concentrations. We used bictegravir (BIC) and dolutegravir (DTG) individually or in the therapeutic drug combinations BIC/emtricitabine (FTC)/tenofovir alafenamide fumarate (TAF) or DTG/lamivudine (3TC). Additionally, we conducted a pilot study to compare platelet activity profiles from people with HIV on BIC/FTC/TAF and DTG/3TC. Changes to in vitro platelet aggregation responses upon exposure to different INSTIs were observed both upon individual drug application and when using therapeutic combinations. However, these effects were not reflected in flow-cytometric evaluation of platelet degranulation. A pilot study in eight people with HIV and eight without HIV revealed no significant effects but established protocols for future patient studies. There is currently no consistent evidence of an effect of INSTIs on platelet activation. Further study is warranted, focusing on models with more pathophysiological relevance, including extensive studies in people with HIV.

Changes to inflammatory markers during 5 years of viral suppression and during viral blips in people with HIV initiating different integrase inhibitor based regimens

BackgroundHeightened levels of inflammatory markers are linked to increased morbidity/mortality in people with HIV (PWH) and often remain elevated after virologic suppression by antiretroviral therapy (ART). As new combinations of ART become available, an evaluation of their effects on immune activation and inflammation is warranted. Additionally, it remains unknown whether transient increases in viral load (“blips”) during ART are associated with increases in inflammation.MethodsWe utilized cryopreserved samples from treatment-naïve PWH enrolled in two Phase 3 clinical trials investigating the efficacy and safety of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) or dolutegravir, abacavir, and lamivudine (DTG/ABC/3TC) or DTG + F/TAF over a 5-year window (GS-US-380-1489/1490). At week 144, participants were offered the option to switch to open label B/F/TAF for an additional 96 weeks. We measured levels of interleukin-6 (IL-6), C-reactive protein (hsCRP), D-dimer, soluble CD14 (sCD14), and tumor necrosis factor-α receptor 1 (TNFR1) from available baseline, week 24, 48, 144, and 240 samples (B/F/TAF, N=123; DTG/ABC/3TC, N=62; DTG+F/TAF, N=58). Additional samples from PWH who experienced a viral blip (n=44, defined as a single HIV-1 RNA >50c/mL) were also analyzed and paired with the most recent available suppressed sample before the blip. Longitudinal biomarker changes were assessed using a constrained mixed effects linear regression model adjusting for covariates.ResultsBaseline demographics and selected laboratory characteristics were similar across groups. Levels of D-dimer, sCD14, and TNFR1 decreased significantly from baseline in all treatment arms, with no significant differences between arms at any timepoint. Biomarker levels also remained stable following ART-switch at week 144. No significant changes in hsCRP or IL-6 were observed versus baseline in any arm at any timepoint. A significant association was observed between sCD14 and increasing viral load (p=0.022) in viral blips; D-dimer also increased with blips in the B/F/TAF arm.ConclusionsViral suppression was associated with reductions in most inflammatory markers in PWH, with no significant differences among the three ART regimens during the 144-week randomized period. These decreases were sustained after the open label switch to B/F/TAF. Viral blips were associated with increases in monocyte activation (sCD14). Further analysis is needed to confirm these findings and determine the potential impact on clinical outcomes.

Fanconi Syndrome Due to Tenofovir Disoproxil Fumarate in a Patient with Chronic Hepatitis B Induced Cirrhosis: A Case Report

We present a 63-year-old woman with chronic hepatitis B. The patient has a history of cirrhosis due to chronic hepatitis B and is under treatment with Tenofovir disoproxil fumarate. The patient presented to our center with nausea, vomiting, and severe metabolic acidosis. After initial evaluation, along with the typical course of events and the exclusion of differential diagnoses of normal anion gap metabolic acidosis, we determined that the cause of illness was related to Tenofovir disoproxil fumarate. All our practical and laboratory data supported a diagnosis of proximal tubular acidosis. After discontinuing the drug for two weeks and providing supportive management, metabolic acidosis and electrolyte imbalance improved. The other isoform of Tenofovir (Tenofovir alafenamide) was initiated for the patient, and after two months of follow- up, there were no signs of acidosis or electrolyte imbalance

Comparison of lipid profile alterations in chronic hepatitis b patients receiving tenofovir alafenamide or tenofovir disoproxil fumarate

This study aimed to compare the serum lipid profiles between tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) in the long-term treatment of chronic hepatitis B (CHB). We analyzed data from treatment-naïve CHB patients administered with TDF or TAF, collected from electronic medical records between May 2017 and September 2022. Serum lipid indices, including total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL), and their ratios (TC/HDL, LDL/HDL), were assessed at baseline, and at 48 and 96 weeks. Propensity score matching (PSM) adjusted for baseline differences between groups. From 2344 patients initially screened, 418 were included for the 48-week analysis (265 on TDF, 153 on TAF) and 292 for the 96-week analysis (238 on TDF, 54 on TAF). At 48 weeks, comparing the serum lipid indicators between the pre- and post-treatment, TDF significantly reduced TC and TC/HDL, whereas TAF induced widespread dyslipidemia, characterized by elevated levels of TC, TG, LDL, LDL/HDL, and TC/HDL, and reduced HDL (P < 0.05). After PSM grouping, TAF remained significantly associated with higher TC, TG, LDL, LDL/HDL, and TC/HDL compared to TDF (P < 0.05). Over 48 weeks, TAF treatment was associated with significant increases in TC, TG, and LDL, whereas TDF treatment led to decreases (P < 0.05). TC/HDL and LDL/HDL increased in both groups, but more significant in TAF (P < 0.05). At 96 weeks, the TAF group continued to exhibit significantly higher levels of TC, LDL, and LDL/HDL compared to the TDF group (P < 0.05). Notably, LDL levels were 115.65 ± 28.07 mg/dL in TAF versus 96.07 ± 23.97 mg/dL in TDF. The increase in TC/HDL ratio in the TAF group was higher than in the TDF group, though not statistically significant. Furthermore, TAF treatment was associated with significant increases in LDL (18.58 ± 24.35 mg/dL) and LDL/HDL ratio (0.41 ± 0.95) over 96 weeks, while TDF treatment showed reductions in TC (-8.13 ± 30.86 mg/dL). Between 48 and 96 weeks, most lipid changes in the TDF group were not statistically significant, except for increases in LDL and LDL/HDL. In the TAF group, an increasing trend of LDL and TC/HDL was noted, although LDL showed a slight turnover after 48 weeks. This real-world study provides new evidence that TAF can induce dyslipidemia, while TDF exhibits a lipid-lowering effect in CHB. Patients at high risk for hepatic steatosis and cardiovascular diseases should consider these effects when choosing between TAF and TDF.

Ligand-Enabled Cu-Catalyzed Stereoselective Synthesis of P-Stereogenic ProTides.

Nucleoside analogues have seen significant advancements in treating viral infections and cancer through ProTide technology, leading to a series of FDA-approved drugs such as sofosbuvir, tenofovir alafenamide, and remdesivir. The stereochemical configuration at the phosphorus center of ProTides significantly influences their pharmacological properties, necessitating efficient stereoselective synthesis. Traditional methods using chiral auxiliaries or nonracemic phosphorylating agents are labor-intensive and inefficient, while recent organocatalytic approaches, despite their promise, still face limitations. Herein, we present a novel approach employing chiral metal complexes for the stereoselective assembly of P-stereogenic ProTides via asymmetric P-O bond formation. This approach leverages a chiral metal catalyst to activate the electrophilic phosphorylating reagent, facilitating a base-promoted nucleophilic replacement pathway. Our protocol, featuring mild reaction conditions and broad applicability, enables the highly stereoselective synthesis of previously inaccessible (S,RP) and (R,SP)-ProTide derivatives. The practical utility of this method is demonstrated through the preparation of pharmaceutically relevant ProTide targets and mechanistic studies were conducted to elucidate the reaction pathway, offering significant advancements for drug development and pharmaceutical research.

Lower Incidence of Hepatocellular Carcinoma with Tenofovir Alafenamide in Chronic Hepatitis B: Evidence from a Large-Scale Cohort

Background & AimsThe newer tenofovir alafenamide (TAF) lacks extensive research regarding its impact on hepatocellular carcinoma (HCC). This study aims to evaluate and compare the effects of TAF, tenofovir disoproxil fumarate (TDF), and entecavir (ETV) on HCC incidence using nationwide claim data. MethodsA total of 75,816 treatment-naïve chronic hepatitis B patients were included and divided into TAF (n=25,680), TDF (n=26,954), and ETV (n=23,182) groups after exclusions. Propensity score matching (1:1:1) resulted in 17,537 patients per group, and HCC incidence rates were compared. ResultsBefore matching, the incidence of HCC was significantly lower in the TAF group compared to the TDF and ETV groups (11.47 vs. 15.04 and 14.24 per 1,000 person-years). The incidence rate ratio for TDF was 1.31 (1.19-1.44) and for ETV was 1.24 (1.12-1.37). Before matching, the TAF group had a significantly lower HCC compared to TDF and ETV in both cirrhotic and non-cirrhotic patients. After matching, the TAF group had a lower HCC incidence compared to TDF (12.38 vs. 15.39, incidence rate ratio 1.24, p<0.001) but not ETV (incidence rate ratio 1.08, p=0.219). In cirrhotic patients, TAF had lower HCC incidence than TDF and ETV (30.25 vs. 39.56 and 38.51). In non-cirrhotic patients, TAF had lower HCC incidence than TDF (incidence rate ratio 1.19, p=0.030) but not ETV (incidence rate ratio 0.85, p=0.066). Cox regression analysis showed TAF had a significantly lower HCC incidence compared to TDF (hazard ratio 1.335, p<0.001) and ETV (hazard ratio 1.162, p=0.011), after adjusting for age, gender, and cirrhosis status. ConclusionsThe TAF group consistently demonstrated a lower incidence of HCC compared to the TDF and ETV groups, especially in patients with cirrhosis. IMPACT and IMPLICATIONSThe scientific justification for this work lies in its potential to fill the knowledge gap regarding the comparative efficacy of Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF), and Entecavir (ETV) in reducing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients. The study's findings are particularly crucial for healthcare providers and policymakers, as they highlight the significantly lower incidence of HCC associated with TAF, especially in patients with cirrhosis. These results suggest that TAF could be a preferable antiviral therapy option to mitigate HCC risk, thus influencing clinical decision-making and healthcare guidelines. Practically, these findings can guide physicians in prescribing more effective treatments, assist researchers in designing further studies to explore the mechanisms behind TAF's effectiveness, and inform policymakers in crafting healthcare policies that optimize patient outcomes while considering potential limitations such as the observational nature of the study and residual confounding factors.

Tenofovir alafenamide compared to tenofovir disoproxil fumarate, induces dysglycemia, and dyslipidemia in Wistar rats.

To determine the metabolic effects of tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) in vivo . Male Wistar rats ( Rattus novergicus , 250-300 g body weight) were divided into three groups ( n = 8) and orally treated daily with 1.0 ml distilled water (group 1), TAF (0.42 mg/kg) (group 2), or TDF (5.0 mg/kg) (group 3), respectively, for 56 days. Glucose tolerance tests were done before the animals were sacrificed by halothane overdose, and blood was collected by cardiac puncture for the analysis of plasma lipids, electrolytes, and insulin. The kidney and pancreatic tissues were excised and homogenized to measure oxidative stress. Compartmentation of TAF and TDF was determined in NRK-52 and peripheral blood mononuclear cells (PBMCs). There were no significant differences in weight gain among controls, TAF- or TDF-treated rats. TAF-treated rats had significantly increased fasting blood glucose (FBG), fasting plasma insulin (FPI), insulin resistance, impaired glucose tolerance, and dyslipidemia compared to control or TDF-treated rats, respectively. There was increased lipid peroxidation in the pancreas of TAF-treated compared to TDF-treated or control animals, respectively. TDF- treated rats presented with symptoms of Fanconi syndrome compared to TAF-treated or control animals, respectively. Kidney homogenates from TDF-treated animals had significantly reduced antioxidant enzyme activity compared to TAF-treated animals or controls, respectively. Intracellular concentrations of TAF were significantly higher than TDF in both NRK-52E cells and PBMC, respectively. TAF treatment is weight-neutral and causes dysglycemia, and dyslipidemia but not Fanconi syndrome compared to TDF.

P23 A case of visceral leishmaniasis presenting as seropositive erosive rheumatoid arthritis in an immunocompromised patient

Abstract Introduction Visceral leishmaniasis (VL) is a potentially fatal parasitic infection occurring primarily in the tropics, subtropics, and southern Europe. A strong humoral response can be observed in VL due to polyclonal activation of B-lymphocytes, and it can also result in the production of rheumatoid factor (RF), anti-CCP and anti-nuclear antibodies. We present this case here of visceral leishmaniasis presenting as seropositive RA on the background of HIV and hepatitis B infection. Case description We present a case of a 46-year-old Caucasian male with a two-year history of skin nodules, symmetrical arthralgia and weight loss. He was diagnosed with HIV a decade ago which was well controlled with bictegravir, emtricitabine and tenofovir alafenamide. He received pulmonary tuberculosis (TB) treatment in 2012 and had chronic e-antigen-positive hepatitis B. He previously resided in Ukraine and travelled frequently to Crimea and the Middle East. There was no history of Raynaud’s, chest pain, shortness of breath, sicca symptoms, mouth ulcers, genital ulcers, hair loss or photosensitivity. On examination, he was cachectic with generalised lymphadenopathy and multiple subcutaneous (1-2cm, firm, mildly tender, non-ulcerating) forearm nodules. There was synovitis on two joints but no tenosynovitis or joint deformity. Initial investigations revealed pancytopenia, hyperuricemia, proteinuria, positive RF (&amp;gt;200 IU/ml) and anti-CCP, positive ANA and anti-Ro antibody and erosion of proximal phalanx of the big toe bilaterally. His CD4 count was 166 (33%) with undetectable HIV viral load. Imaging showed lymphadenopathy and splenomegaly (17.5cm). A diagnosis of rheumatoid arthritis with possible connective tissue disease overlap was made and he was initiated on hydroxychloroquine. Because of systemic symptoms and atypical skin nodules, further investigation was undertaken including lymph node, bone marrow and skin biopsies, all of which confirmed a diagnosis of leishmaniasis. Blood PCR was positive for L. donovani complex, and serological analysis showed direct agglutination test and k39 Ag positivity. Treatment was initiated by the infectious diseases team initially with amphotericin B 40 mg/kg monotherapy, later on further amphotericin B 30 mg/kg and miltefisone. He responded well as evidenced by reduced splenomegaly, resolution of skin nodules and improvement in cytopenia. His joint symptoms also improved except for the recurrence of ankle pain for which he received intra-articular steroids. Discussion It has been widely reported in literature that leishmaniasis can trigger autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis. There have also been multiple studies confirming the presence of rheumatoid factor, anti-CCP and ANA in patients with leishmaniasis without any presence of symptomatic autoimmune disease. The mechanisms involved in the pathophysiology of autoantibody productions are not yet fully understood. There is some evidence that these are related to activation of polyclonal B cells due to a decreased regulatory T cell activity. Another possible mechanism would be production of autoantigen in response to cross reaction between the parasite and the hoarse tissue antigens. There have been multiple case reports of leishmaniasis in patients with rheumatoid arthritis who were taking anti-TNF biologics. This represents the reactivation of leishmaniasis due to immunosuppression. There has been a long-known link between HIV infection and leishmaniasis. Our patient was a known case of HIV. Interestingly, not only did he have significantly positive rheumatoid factor, anti-CCP, ANA and anti-Ro antibodies, but he also had active synovitis on his joints and even erosions were seen on the X-ray. He fulfilled the criteria for rheumatoid arthritis. Our case was unique in the sense that this is a case of visceral leishmaniasis in an HIV patient who presented with rheumatoid arthritis. Skin nodules in this patient were appearing similar to rheumatoid nodules. Later on, the biopsy confirmed that these were due to leishmaniasis. It is also a challenge to manage RA in patients with HIV especially when have already an opportunistic infection like leishmaniasis. A high prevalence of hyperuricemia in HIV infection has been reported in multiple studies. Our case did have raised urate but his disease was not consistent with gout clinically. Key learning points • This is a rare case showing seropositive erosive RA coexisting with VL in an HIV patient, underscoring the link between autoimmune diseases and chronic infections. Chronic infections are always considered an important differential in inflammatory arthritis or connective tissue disease especially when they present with systemic features of fever, weight loss and organomegaly. • Although this disease is considered rare in the Western hemisphere, in the diverse, multiethnic and immigrant UK population this should be considered an important differential diagnosis. Another key element in clenching these diagnoses is detailed travel history. Multidisciplinary approach is key in managing such difficult cases. Our case was managed jointly by the rheumatology, dermatology and infectious disease teams, and the national leishmaniasis multidisciplinary team from University College London Hospitals. • It is important to do a holistic assessment for these patients and get help from other specialities especially in such challenging cases.

Effectiveness, safety, and patient-reported outcomes of emtricitabine/tenofovir alafenamide-based regimens for the treatment of HIV-1 infection: Final 24-month results from the prospective German TAFNES cohort study.

Tenofovir alafenamide (TAF) was introduced in the European Union in 2015 as a novel prodrug of tenofovir showing similar efficacy in clinical trials and a more favorable safety profile than tenofovir disoproxil fumarate (TDF). The German TAFNES cohort study (2016-2019) was conducted to generate real-world evidence. Treatment-naïve (TN) and treatment-experienced (TE) people with HIV (PWH) receiving elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF), rilpivirine/F/TAF (R/F/TAF) or F/TAF + 3rd agent were included. Month (M) 24 outcomes included virologic effectiveness (HIV RNA <50 copies/mL), treatment persistence, adverse drug reactions (ADRs) and patient-reported outcomes, using the HIV Symptom Index (HIV-SI), 36-Item Short Form Health Survey (SF-36) and HIV Treatment Satisfaction (HIVTSQ) questionnaires. The study included 767 PWH (92% men, median age 46 years; 301 TN, 466 TE; E/C/F/TAF [n = 318], R/F/TAF [n = 192], F/TAF + 3rd agent [n = 257]). Among TN, 35% had late HIV diagnosis (CD4 < 350/μL and/or AIDS). Of TE, 95% were on suppressive antiretroviral therapy (ART) before switching. D:A:D (Data Collection on Adverse Effects of Anti-HIV Drugs) 5-year risks for chronic kidney disease were high for about 1 in 10 TN and 4 in 10 TE. Overall treatment persistence at M24 was 81% (E/C/F/TAF: 88%; R/F/TAF: 86%; F/TAF + 3rd agent: 70%, with ART simplification of multiple-tablet regimens in 13%). M24 viral suppression (missing = excluded) was 96% (479/501). Discontinuations due to virologic failure or ADRs were rare, 2% (12/767) and 4% (30/767), respectively. HIV-SI and SF-36 summary scores improved in TN; HIVTSQ change scores showed an improvement in treatment satisfaction in TE. Real-world data confirmed a favorable safety profile and high virologic effectiveness with high treatment satisfaction on F/TAF-based ART.

Efficacy and Safety of Tenofovir Amibufenamide and Tenofovir Alafenamide for First-Time HBV-Related Decompensated Cirrhosis.

Clinical studies of tenofovir amibufenamide (TMF) and tenofovir alafenamide (TAF) treatment in patients with HBV-related decompensated cirrhosis (HBV-DC) are limited. This study evaluated the efficacy and safety of TMF versus TAF in naive-treated patients with first-time HBV-DC. Based on the antiviral drug used, patients were categorised into the TMF group and the TAF group. Virological and serological responses, hepatic and renal functions and blood lipid changes in both groups were evaluated during 48 weeks of treatment. A total of 98 patients were enrolled, 45 in the TMF group and 53 in the TAF group. At 48 weeks of treatment, the proportions of patients who achieved complete virological response (CVR) were 85.7% and 90.7%, respectively (p = 0.791). Improvement of at least 2 points in Child-Turcotte-Pugh scores was observed in 64.3% versus 79.1% (p = 0.169) of the patients. There were no significant changes in serum creatinine, estimated glomerular filtration rate or total cholesterol from baseline to week 48 between the two groups. Cystatin C remained stable in the TMF group but increased over time in the TAF group (p < 0.001). Low-density lipoprotein cholesterol remained stable in the TMF group but increased significantly in the TAF group at week 48 (p = 0.015). These results suggest that both TMF and TAF can rapidly suppress HBV replication, improve hepatic function and have no negative effects on renal function among patients with HBV-DC. Regarding lipid metabolism, both showed a better safety, while regular monitoring of blood lipid levels is recommended.

Effect of Tenofovir Alafenamide Fumarate on the outcomes of hospitalized COVID-19 patients: a prospective, block-balanced, open-label, randomized controlled trial

BackgroundThe global effort to cure COVID-19 is still ongoing. Thus, a prospective, block-balanced, open-label, randomized controlled trial was conducted to evaluate how Tenofovir Alafenamide Fumarate affects hospitalized COVID-19 patients’ outcomes.MethodsThe intervention and control groups of 60 hospitalized COVID-19 patients were randomly allocated. Along with normal medication, the intervention group received 25 mg of tenofovir orally daily for seven days. The control group got normal therapy, including remdesivir and corticosteroids. ICU hospitalization duration, laboratory data, fever, dyspnea, arterial blood oxygen saturation with and without an oxygen face mask, mechanical ventilation, and mortality were the outcomes.ResultsSixty of 236 eligible patients between September 2020 and February 2021 were enrolled. The intervention group had a mean age (±SD) of 61.33 (±13.09) years and the control group 60.03 (±18.03). Sixteen (53.3%) intervention patients and 15 (50.0%) control patients were males. The intervention group had fewer mechanical ventilation and ICU days. Tenofovir Alafenamide Fumarate did not improve fever, dyspnea, oxygen saturation with or without a face mask or nasal cannula, or laboratory data including WBC, ESR, CRP, AST, ALT, AlkP, total and direct bilirubin, in COVID-19 patients.ConclusionAccording to this pilot trial, Tenofovir Alafenamide Fumarate, along with conventional treatment, significantly reduced mechanical ventilation and ICU stay in COVID-19 patients. Further thorough research is necessary to verify this conclusion.

Birth outcomes following bictegravir exposure during pregnancy.

Bictegravir is increasingly prescribed as a co-formulated tablet with tenofovir alafenamide and emtricitabine to pregnant persons with HIV (PWH) despite limited pregnancy and birth outcome data. We sought to provide birth outcome data following exposure to bictegravir during pregnancy. We conducted a descriptive analysis of infants born to pregnant PWH 18-45 years of age enrolled in at least one Pediatric HIV/AIDS Cohort Study (PHACS)-affiliated study who received bictegravir for ≥7 days during pregnancy and completed follow-up through delivery. The outcomes of interest were gestational age at birth, preterm birth (<37 weeks' gestation), gestational-age adjusted birth weight (BWZ) and length (BLZ) z-scores, small for gestational age (SGA, birthweight <10th percentile), congenital anomalies, neonatal deaths in the first 28 days of life, and infant HIV status. A total of 177 infants born to 170 unique PWH were exposed to bictegravir for ≥7 days during gestation; 55% were exposed to bictegravir from the time of conception. Median gestational age at birth was 38.1 weeks. The prevalence of preterm birth was 15.8% and SGA was 9.3%. Mean BWZ and BLZ were -0.48 and 0.03. No neonatal deaths or perinatal HIV transmissions were reported. Among 126 infants exposed to first-trimester bictegravir, 7 (5.6%) had major congenital anomalies with no specific pattern suggestive of a syndrome. These findings provide preliminary data without significant safety concerns for fetal bictegravir exposure in this United States cohort. Comparative data and continued surveillance of outcomes among infants exposed to bictegravir during gestation are warranted.

Neuropsychiatric adverse events in tenofovir disoproxil fumarate- and tenofovir alafenamide-based HIV therapy and prophylaxis: a systematic review and meta-analysis.

Tenofovir is integral to antiretroviral therapy (ART) and preexposure prophylaxis (PrEP) for HIV, but its neuropsychiatric adverse events (NPAEs) have not been systematically investigated. This systematic review aims to characterize common NPAEs during tenofovir-based ART and PrEP and to assess tenofovir's specific role in their emergence. Four literature databases and three trial registries were searched up to December 31, 2023, for randomized controlled trials reporting NPAEs in treatment-naïve adults receiving tenofovir-based ART or PrEP. Meta-analyses compared tenofovir (with/without emtricitabine) to placebo and tenofovir alafenamide- to tenofovir disoproxil fumarate-based regimens. Sixty-nine trials (62 on ART, 7 on PrEP) with 29 340 patients on tenofovir-based therapies revealed headache, dizziness, insomnia, and depression as common NPAEs, especially in HIV studies. Meta-analyses of tenofovir (with/without emtricitabine) versus placebo only indicated an increased risk of dizziness (OR 1.32; CI 1.09-1.59; P = 0.004). Comparisons between tenofovir alafenamide and disoproxil fumarate did not reveal significant differences in NPAE risks, although sensitivity analyses suggested a higher risk of headache with tenofovir alafenamide in HIV studies (OR 1.24; CI 1.01-1.52; P = 0.04). Common NPAEs in tenofovir-based HIV multi-drug regimens highlight the need to screen HIV patients for neuropsychiatric complications. The lack of effect of tenofovir compared to placebo for most analyzable NPAEs suggests that tenofovir itself is mostly safe regarding NPAEs. However, a possible increase in dizziness risk with tenofovir, and a potential rise in headache risk with tenofovir alafenamide- compared to tenofovir disoproxil fumarate-based regimens in HIV therapy, merit further investigation.

Expected 8-Week Prenatal vs 12-Week Perinatal Tenofovir Alafenamide Prophylaxis to Prevent Mother-to-Child Transmission of Hepatitis B Virus: A Multicenter, Prospective, Open-Label, Randomized Controlled Trial.

The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study. In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3-9.0 log 10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected 8 week) or to 4 weeks postpartum (expected 12 week) were randomly enrolled at a 1:1 ratio and followed until 6 months postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary end point was the safety of mothers and infants. The secondary end point was the HBV-MTCT rate of infants at the age of 7 months. Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in 2 groups completed the study. Overall, TAF was well tolerated, no one discontinued the therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%-1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%-1.6%). The infants' physical development at birth (n = 231) and at 7 months (n = 222) was normal. Furthermore, 97.0% (224/231, 95% CI 93.9%-98.5%) of women achieved HBV DNA <5.3 log 10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%-11.1%) and 0% (0/222, 95% CI 0%-1.7%) at the age of 7 months. Comparatively, 15.1% (18/119, 95% CI 9.8%-22.7%) vs 18.3% (22/120, 95% CI 12.4%-26.2%) of women in the 2 groups had mildly elevated alanine aminotransferase levels at 3 months and 6 months postpartum, respectively ( P = 0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%-3.1%] vs 0% [0/120, 0%-3.1%]). Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected 8-week prenatal duration is feasible. ClinicalTrials.gov , NCT04850950.

7172 Osteoporosis Associated with Antiretroviral Therapy - Case report

Abstract Disclosure: C.E. Guillen Lopez: None. L.A. Sanchez Ato: None. A. Patel: None. A. Molkina: None. T. Ayub: None. L. Robles: None. A. Arce Gastelum: None. Osteoporosis presents a substantial public health challenge, contributing significantly to morbidity and mortality through fractures. While postmenopausal osteoporosis is common, secondary osteoporosis affects a significant number of patients, including over 30% of postmenopausal and 50-80% of men. People living with HIV (PLWH) experience age-related medical comorbidities earlier and more extensively than those without HIV. The compromised bone health in PLWH is attributed to factors associated with the virus, antiretroviral therapy (ART) side effects, and health disparities such as inadequate nutrition, low body weight, hypogonadism, vitamin D deficiency, and increased recreational substance use. More recently, it has become apparent that vertebral fractures are more common in PLWH, with a prevalence of 11.1% and a 2.30-fold more significant risk than the general population. Low bone mass density (BMD) is twice as common in PLWH, increasing to 3 times as common in PLWH on ART. ART initiation leads to transient bone loss with nucleotide reverse transcriptase inhibitors such as tenofovir disoproxil fumarate (TDF) and protease inhibitors, causing higher BMD loss. In contrast, integrase and specific reverse-transcriptase inhibitors have minimal adverse effects on BMD. The newer formulation, tenofovir alafenamide (TAF), is believed to have a more favorable impact on bone health than TDF. The repercussions of diminished bone health, particularly osteoporotic fractures, have significant medical and economic implications. They are leading to early mortality, disability, and a loss of independence. The HIV Medicine Association (HIVMA) and Infectious Diseases Society of America (IDSA) recommend BMD screening for all HIV-infected patients at 50 years. 58-year-old male PLWH reveals a history of osteoporosis with multiple spinal (L1, L4-5, S1) and bilateral wrist fractures on TDF for 15 years. The patient has been treated with bisphosphonates. Alendronate was initially prescribed, but due to acid reflux side effects, zoledronic acid was a better option. Despite various ART regimens, Dolutegravir/Lamivudine was started four years ago without further fractures. Recent bone density assessments showed improvement in the lumbar spine, returning to a normal range with a T-score of 0.6. However, the left femoral neck remains at -2.5, and the right femoral neck is at -2.2, showing minimal change. To enhance BMD in PLWH on ART, transitioning to alternatives with lower bone loss associations and using bisphosphonates as tolerated are suggested. As the HIV-infected population ages, proactive screening for low BMD is vital to manage evolving health needs and prevent bone-related complications. A holistic approach includes evaluation for secondary etiologies of osteoporosis, medical treatment, and vitamin D and calcium supplementation. Presentation: 6/3/2024

12553 Severe Hyperglycemia After Initiation Of Bictegravir Antiretroviral Therapy With Resolution Upon Discontinuation

Abstract Disclosure: S. Hudson: None. J. Aurora: None. K. Grossman: None. L. Kogelman: None. A.G. Pittas: None. Background: Antiretroviral therapy (ART) containing bictegravir (BIC), a second-generation integrase strand transfer inhibitor (INSTI), is a first-line treatment for HIV. There are mixed reports of INSTIs causing adverse metabolic effects, such as weight gain and hyperglycemia. There are cases of BIC causing hyperglycemia and diabetic ketoacidosis (DKA) within weeks to months following initiation; however, this has not been reported in clinical trials (1). It is unclear whether discontinuing BIC resolves hyperglycemia. We report a case of a patient with prediabetes who developed severe hyperglycemia after switching to a BIC-containing ART. The discontinuation of BIC resulted in significant improvement in glycemia, leading to the de-escalation of diabetes pharmacotherapy. Clinical Case: A 36-year-old woman with obesity was diagnosed with HIV during pregnancy, which was complicated by gestational diabetes mellitus. After pregnancy, she had prediabetes. Her initial ART was darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Due to intolerable GI side effects, six years later, she was switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Laboratory tests four months before starting BIC/FTC/TAF were consistent with prediabetes (HbA1c 6.4%, non-fasting blood glucose of 118 mg/dL). After one month, she was started on metformin when her HbA1c increased to 9.1% with a non-fasting blood glucose of 332 mg/dL. Another month later, HbA1c increased to 12.8% with a non-fasting blood glucose of 685 mg/dL without DKA. She was hospitalized for diabetes management. There were no significant changes in weight, viral load, or CD4 count. A search for secondary causes of hyperglycemia (diabetogenic medications, hypercortisolism, and autoimmune diabetes) was not revealing. She was discharged on metformin and insulin glargine. Her HIV regimen was switched to FTC/TAF and doravirine due to suspicion of BIC-induced hyperglycemia. After five months, she developed symptoms of hypoglycemia, and her estimated HbA1c by continuous glucose monitoring was 6.3%. Insulin glargine was discontinued. While on metformin, HbA1c three months later was 6.3%. Two years later on metformin and linagliptin: HbA1c was 6.1% and beta-cell function did not reveal insulin deficiency or resistance (non-fasting blood glucose 96 mg/dL, insulin 13.5 uIU/mL [RR 2.6-24.9 mIU/mL], C-peptide 3.7 ng/mL [RR 1.1-4.4 ng/mL]). Conclusion: Patients with HIV and a history of obesity and/or dysglycemia who are switched to a BIC-containing ART regimen should be educated and monitored for acute hyperglycemia. This may be due to impaired beta-cell function and/or insulin resistance; however, further research is needed to understand the mechanism. An alternative ART regimen should be considered if hyperglycemia develops. Reference: 1. Nolan NS, et al. Open Forum Infect Dis. 2021;16;8(5): ofab077. Presentation: 6/3/2024

Bictegravir alters glucose tolerance in vivo and causes hepatic mitochondrial dysfunction

Growing evidence associates antiretroviral therapies containing integrase strand transfer inhibitors or tenofovir alafenamide (TAF) with increased weight gain and metabolic diseases, but the underlying mechanisms remain unclear. This study evaluated the impact of lamivudine, dolutegravir (DTG), bictegravir (BIC), tenofovir disoproxil fumarate, and TAF on metabolic alterations, and explored glucose homeostasis and mitochondrial stress as potential mechanisms. These pathways were analyzed both in vivo (C57BL/6J mice treated with the abovementioned drugs or vehicle for 16 weeks) and in vitro (in Hep3B cells). Mice treated with BIC exhibited higher glucose levels and a slower decrease during a glucose tolerance test. Functional enrichment analyses of livers from antiretroviral-treated mice revealed that only BIC altered the cellular response to insulin and induced a gluconeogenic-favoring profile, with Fgf21 playing a significant role. In vitro, BIC significantly reduced hepatocyte glucose uptake in a concentration-dependent manner, both under basal conditions and post-insulin stimulation, while the other drugs produced no significant changes. Hep3B cells treated with clinically relevant concentrations of BIC exhibited significant alterations in the mRNA expression of enzymes related to glucose metabolism. Both DTG and BIC reduced mitochondrial dehydrogenase activity, but only BIC increased reactive oxygen species, mitochondrial membrane potential, and cellular granularity, thereby indicating mitochondrial stress. BIC promoted mitochondrial dysfunction, modified carbohydrate metabolism and glucose consumption in hepatocytes, and altered glucose tolerance and gluconeogenesis regulation in mice. These findings suggest that BIC contributes to insulin resistance and diabetes in people living with HIV, warranting clinical studies to clarify its association with carbohydrate metabolism disorders.

High plasma concentration of tenofovir alafenamide in people living with HIV with ABCB1 genetic variants

ObjectivesWe aimed to analyze the relationships between single nucleotide polymorphisms in the ATP-binding cassette transporter B1 (ABCB1) and G2 (ABCG2) genes and plasma concentrations of tenofovir alafenamide (TAF), tenofovir (TFV), and emtricitabine (FTC). MethodsWe recruited 10 people living with HIV receiving once-daily treatment with a single tablet containing TAF (25 mg), FTC (200 mg), and bictegravir (50 mg). Peripheral blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 12, and 24 h after administration. Plasma concentrations of TAF, TFV, and FTC were quantified using liquid chromatography-tandem mass spectrometry. Genotyping for allelic variants of ABCB1, including 1236 C>T (rs1128503), 2677 G>T/A (rs2032582), 3435 C>T (rs1045642), 4036 A>G (rs3842) and ABCG2 421 C>A (rs2231142), was performed using TaqMan Drug Metabolism Assays. ResultsNone of the genotypes for ABCB1 1236 C>T, 2677 G>T/A, 3435 C>T, and ABCG2 421 C>A exhibited correlations with plasma concentrations of TAF, TFV, and FTC. In contrast, individuals with the ABCB1 4036 AG genotype (188.7 ng/mL, n = 3) exhibited a significantly higher mean peak plasma concentration of TAF than those with the ABCB1 4036 AA genotype (67.7 ng/mL, n = 7) (p = 0.0167). However, these genotypes did not affect the elimination of terminal half-lives of TAF. ConclusionsThe allelic variant ABCB1 4036 A>G is associated with reduced protein expression and function of ABCB1. Individuals with this genetic variant exhibited significantly high peak plasma concentrations of TAF, potentially due to the reduced expression of efflux transporters in the intestines linked to this variant.

Proteinuria Outcomes of Tenofovir Alafenamide Fumarate (TAF) vs. Tenofovir Disoproxil Fumarate (TDF) Regimens for Treatment of HIV, HBV, and HIV PrEP: A Systematic Literature Review and Meta-Analysis

Proteinuria Outcomes of Tenofovir Alafenamide Fumarate (TAF) vs. Tenofovir Disoproxil Fumarate (TDF) Regimens for Treatment of HIV, HBV, and HIV PrEP: A Systematic Literature Review and Meta-Analysis

Evaluation of the Effect of Racial Differences on Longitudinal Trajectories of Kidney Function in People with HIV (PWH) on Tenofovir Alafenamide (TAF)-Based Antiretroviral Treatment (ART) Regimens

Evaluation of the Effect of Racial Differences on Longitudinal Trajectories of Kidney Function in People with HIV (PWH) on Tenofovir Alafenamide (TAF)-Based Antiretroviral Treatment (ART) Regimens