Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans

Nonliver Comorbidities in Patients With Chronic Hepatitis B.

Background Tenofovir is one of the most widely used agents for human immunodeficiency virus (HIV) and hepatitis B virus (HBV) treatment, and pre-exposure prophylaxis (PrEP). Two forms of tenofovir are currently available: tenofovir disoproxil fumarate (TDF) and its prodrug, tenofovir alafenamide (TAF). TAF is associated with improved renal safety and non-inferior efficacy when compared to TDF. We aimed to comprehensively synthesize the evidence on renal outcomes of TDF and TAF regimens for treatment of HIV-1, HBV, or PrEP. Methods A systematic search of randomized controlled trials (RCTs) that compared TDF vs. TAF for the treatment of HIV-1, HBV, or PrEP and reported changes in estimated glomerular filtration rate (eGFR) or serum creatinine (SCr) from treatment initiation was conducted in PubMed, EMBASE, Web of Science, and the Cochrane Trial Registry. This search was performed on 12/6/2023 and supplemented a previous review by Gupta et al. (2019). Renal outcomes were pooled using mean differences with 95% confidence intervals (CIs). The heterogeneity was assessed using I2 test and explored via subgroup analyses of disease state and duration of follow-up. Results Out of 9,014 studies screened, 24 RCTs (total 21962 participants; 12756 in TAF; 9206 in TDF) reported eGFR outcomes and 21 RCTs (total 18454 participants; 10293 in TAF; 8161 in TDF) reported SCr outcomes. Compared to TDF, the use of TAF was associated with an improvement of 3.69 mL/min/1.73m2 (95% CI: 1.89 – 5.49) in eGFR from treatment initiation (I2 = 95.83%) (Figure 1). Subgroup analyses of disease state and study duration for eGFR are described in Table 1. The effect sizes were consistent across subgroups, low levels of heterogeneity were observed for analyses lasting > 48 weeks and for HBV. TAF was also associated with an improvement of SCr of 0.03 mg/dL (95% CI: 0.02 to 0.04) from treatment initiation compared to TDF (I2 = 82.47%) (Figure 2). Conclusion This synthesis of RCT results supports a comparative renal safety advantage of TAF over TDF when evaluated across a broad and diverse range of people including those diagnosed with HIV-1, HBV, HIV and HBV coinfection, and those receiving PrEP. Further exploration of sources of heterogeneity and the evaluation of observational study data are needed. Disclosures Kyu Yun Park, PharmD, Gilead Sciences, Inc.: Grant/Research Support Connor Willis, PharmD, ARUENA: Grant/Research Support|AstraZeneca: Grant/Research Support|Bayer: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|DexCom: Grant/Research Support|Gilead: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|Grail, Inc.: Grant/Research Support|Jazz: Grant/Research Support|Mainstay Medical: Grant/Research Support|Novartis: Grant/Research Support|PEAR Therapeutics: Grant/Research Support Rachel Rogers, Gilead Sciences, Inc.: Employee; Medical writing support provided by Aspire Scientific (Bollington, UK)|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Amy Weinberg, DNP, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Julia Green, MS, APRN, AGNP-C, ACRN, AAHIVE, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Aileen Chi, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Nathorn Chaiyakunapruk, PhD, Gilead Sciences, Inc.: Grant/Research Support

Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. We analyzed 834 patients with CHB previously treated with TDF for ≥12months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA<20IU/mL), biochemical (alanine aminotransferase [ALT]<35/25U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96weeks after switch. Viral suppression (P<0.001) and ALT normalization (P=0.003) rates increased significantly after switch, with a trend for increasing complete response (Ptrend = 0.004), while the eGFR trend (Ptrend >0.44) or mean eGFR (P>0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR<90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P=0.029) but not after TAF switch (P=0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1. Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study

Is there any need for new, long-acting nucleos(t)ide analogues for the treatment of hepatitis B infection?

We aimed to compare the effects of P-glycoprotein (ABCB1) on the intestinal uptake of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), and metabolites, tenofovir isoproxil monoester (TEM) and tenofovir (TFV), and to study the molecular mechanism of drug-drug interaction (DDI) between sofosbuvir (SOF) and TDF/TAF. Bidirectional transport experiments in Caco-2 cells and accumulation studies in precision-cut intestinal slices prepared from the ileal segment of rodent (rPCIS) and human (hPCIS) intestines were performed. TDF and TAF were extensively metabolised but TAF exhibited greater stability. ABCB1 significantly reduced the intestinal transepithelial transfer and uptake of the TFV(TDF) and TFV(TAF)-equivalents. However, TDF and TAF were absorbed more efficiently than TFV and TEM. SOF did not inhibit intestinal efflux of TDF and TAF or affect intestinal accumulation of TFV(TDF) and TFV(TAF)-equivalents but did significantly increase the proportion of absorbed TDF. TDF and TAF likely produce comparable concentrations of TFV-equivalents in the portal vein and the extent of permeation is reduced by the activity of ABCB1. DDI on ABCB1 can thus potentially affect TDF and TAF absorption. SOF does not inhibit ABCB1-mediated transport of TDF and TAF but does stabilise TDF, albeit without affecting the quantity of TFV(TDF)-equivalents crossing the intestinal barrier. Our data thus suggest that reported increases in the TFV plasma concentrations in patients treated with SOF and TDF result either from a DDI between SOF and TDF that does not involve ABCB1 or from a DDI involving another drug used in combination therapy.

BackgroundPeople of color are underrepresented in clinical trials. TAF has shown improved renal and bone safety vs. TDF. We pooled 7 studies to evaluate efficacy/safety of TAF vs. TDF for ART initiation/switch in Hispanic/Latinx and Black participants.MethodsData from Hispanic/Latinx and Black adults who initiated/switched to TAF or TDF in 7 randomized trials (2 treatment-naïve, 5 suppressed switch) were analyzed. TAF-based regimens (elvitegravir/cobicistat/emtricitabine [FTC]/TAF, rilpivirine/FTC/TAF, FTC/TAF, or bictegravir/FTC/TAF) were compared with TDF-based regimens. Virologic suppression (VS; HIV-1 RNA < 50 c/mL, FDA snapshot) and % change in bone mineral density (BMD) and renal tubular biomarkers urine β-2-microglobulin (B2M):creatinine (Cr) ratio and retinol binding protein (RBP):Cr ratio are reported at W96.ResultsThe pooled population (N = 5,825) included 1138 Hispanic/Latinx and 1324 Black participants. Treatment-naïve participants (n = 1,733) were 15% female, 25% Black, 19% Hispanic/Latino, with median age 34 years, HIV-1 RNA 4.6 log10 c/mL, CD4 405 cells/mm3. Switch participants (n = 4,092) were 13% female, 22% Black, 20% Hispanic/Latino, median age 45 years, CD4 653 cells/mm3. There was no difference in VS rate with TAF vs. TDF in any group. VS rate (TAF vs. TDF) in naïve participants: 88% vs. 84% (Hispanic/Latinx); 78 vs. 79% (Black); 87% vs. 85% (overall). VS (TAF vs. TDF) was well maintained in switch participants: 91% both arms (Hispanic/Latinx); 86% vs. 87% (Black); 90% vs. 88% (overall). TAF and TDF were well tolerated with few discontinuations due to adverse events (0.6–2%) in all groups. At W96 there was less impact on renal biomarkers in all groups initiating TAF (P < 0.001; table), and decreases in BMD were smaller (P < 0.005; table) vs. TDF. All groups switching from TDF to TAF experienced decreases in tubular proteinuria and improvements in BMD (both P < 0.001; table) at W96.ConclusionHispanic/Latinx and Black participants who initiated/switched to TAF had significantly improved bone and renal parameters vs. TDF, with similar VS rates at W96. Efficacy and biomarkers were similar to the overall study population. These data in >2,400 Hispanic/Latinx and Black PLH demonstrate noninferior efficacy and safety advantages with TAF vs. TDF.DisclosuresAll authors: No reported disclosures.

Medication adherence can be challenging for persons with difficulty swallowing tablets. We investigated the bioequivalence of a dissolved tablet when compared with that of a whole tablet of the fixed-dose combination elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir (TFV) alafenamide fumarate (TAF). A within-subject fixed-order two-period open-label study was conducted in 12 HIV-negative research participants after obtaining informed consent. Participants took a single dose each of the whole tablet and dissolved tablet under direct observation, separated by a 14-day washout period. The dissolved tablet was prepared by adding one whole EVG/COBI/FTC/TAF tablet to 120 mL tap water and stirring. Both dosage types were taken with a standardized meal. Plasma samples were obtained for 72 h postdose. Plasma EVG, FTC, TAF, and TFV were analyzed with liquid chromatographic-tandem mass spectrometric methods. Peak plasma concentration (Cmax) and the area under the concentration-time curve extrapolated to infinity (AUC0-∞) were estimated using WinNonlin software (v.8.3). The primary outcome was bioequivalence consistent with FDA guidance using the 90% confidence interval or the geometric mean ratio. Of 12 participants, 7 were black (58%) and 5 were white (42%), 4 were women (33%), 8 were men (67%), and the mean age was 43.6 years (23-54). There were no complaints about taste with the dissolved tablet. Bioequivalence was established only for FTC. EVG Cmax and AUC0-∞ were higher by 18% and 12%, respectively, when taking the dissolved compared with the whole tablet. TAF AUC0-∞ and Cmax were both 8% lower, whereas TFV Cmax and AUC0-∞ were 8% and 5% lower, respectively, when taken after dissolution. EVG/COBI/FTC/TAF dissolved rapidly in water and had no unpleasant taste. Increases in EVG and decreases in TAF and TFV concentrations were observed when taking dissolved EVG/COBI/FTC/TAF. These changes were judged to be clinically insignificant. Dissolving EVG/COBI/FTC/TAF in water may be suitable for those with pill swallowing challenges. The trial was registered on (//clinicaltrials.gov NCT03717129).

Background: Replacing tenofovir disoproxil fumarate (TDF) with tenofovir alafenamide (TAF) is associated with improvements in renal tubular markers in HIV infected individuals, but the impact on estimated glomerular filtration rate (eGFR) remains unclear. Methods: We included all participants from the Swiss HIV Cohort Study who either switched from a TDF to a TAF-containing antiretroviral regimen or continued TDF. We estimated changes in eGFR and urine protein-tocreatinine ratio over time using multivariable mixed effect models. Findings: Of 3'520 individuals, (26·6% women, median age 50 years), 1'664 (47·3%) had an eGFR below 90 mL/min, 194 (5·5%) had an eGFR below 60 mL/min, and 285 (8%) had marked proteinuria defined as a urine protein-to-creatinine ratio ≥50 mg/mmol prior to switch. In patients with a normal renal function at baseline, eGFR decreased physiologically at 18 months irrespective of the use of TDF or TAF (-1·7 ml/min). In those with renal dysfunction at baseline, switching to TAF was associated with an increase in eGFR: 1·5 mL/min (95% CI 0·5 to 2·5) in individuals with a baseline eGFR of 60-89 mL/min, and 4·1 mL/min (95% CI 1·6 to 6·6) in those with a baseline eGFR <60 mL/min. In contrast, eGFR decreased by 5·8 mL/min (95% CI 2·3 to 9·3) with continuous use of TDF in those with a baseline eGFR <60 mL/min. Urine protein-to-creatinine ratio decreased by 6·1 mg/mmol (95% CI 4·3 to 7·8) at 18 months after replacing TDF by TAF. Interpretation: Switching from TDF to TAF leads to improvements in eGFR and urine protein-to-creatinine ratio in patients with renal dysfunction. Funding Statement: This work was funded by the framework of the SHCS, supported by the Swiss National Science Foundation [SNF grant number 177499, SHCS project number 842]. GW was supported by a Professorship from the Swiss National Science Foundation [PP00P3_176944]. Declaration of Interests: BS reports support to his institution for travel grants from Gilead. BL has received travel grants, grants or honoraria from Gilead and ViiV. AC reports no conflict of interest. MC’s institution has received a research grant from ViiV and Gilead and offered expert testimony for Abbvie, MSD, Gilead and Sandoz. HFG has received unrestricted research grants from Gilead Sciences (HIV cure grant) and Roche; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, ViiV and Merck, Sandoz and Mepha. HK reports supports for travel grants from MSD and Gilead. MS reports no conflict of interest. EB reports support to his home institution for advisory boards and/or travel grants from MSD, Gilead Sciences, ViiV, Pfizer, Abbvie and Sandoz. PS reports no conflict of interest. CAF reports no conflict of interest. HF reports unrestricted educational grant supports to his home institution by Gilead Sciences, ViiV, Abbvie, Bristol-Myers Squibb and MSD outside the submitted work. AR reports support to his institution for advisory boards and/or travel grants from Janssen-Cilag, MSD, Gilead Sciences, Abbvie, and Bristol-Myers Squibb, and an unrestricted research grant from Gilead Sciences. All remuneration went to his home institution and not to AR personally, and all remuneration was provided outside the submitted work. GW reports support to his home institution for advisory boards and/or travel grants from MSD, Gilead Sciences and Abbvie, and an unrestricted research grant from Gilead Sciences. Ethics Approval Statement: Local ethical committees of all cohort centers approved this cohort study and all patients provided a written informed consent.

Replacing tenofovir disoproxil fumarate (TDF) with tenofovir alafenamide (TAF) improves renal tubular markers in HIV-infected individuals but the impact on estimated glomerular filtration rate (eGFR) remains unclear. In all participants from the Swiss HIV Cohort Study who switched from TDF to TAF-containing antiretroviral regimen or continued TDF, we estimated changes in eGFR and urine protein-to-creatinine ratio (UPCR) after 18 months using mixed-effect models. Of 3520 participants (26.6% women, median age 50 years), 2404 (68.5%) switched to TAF. Overall, 1664 (47.3%) had an eGFR <90 mL/min and 1087 (30.9%) an UPCR ≥15 mg/mmol. In patients with baseline eGFR ≥90 mL/min, eGFR decreased with the use of TDF and TAF (-1.7 mL/min). Switching to TAF was associated with increases in eGFR of 1.5 mL/min (95% confidence interval [CI], .5-2.5) if the baseline eGFR was 60-89 mL/min, and 4.1 mL/min (95% CI, 1.6-6.6) if <60 mL/min. In contrast, eGFR decreased by 5.8 mL/min (95% CI, 2.3-9.3) with continued use of TDF in individuals with baseline eGFR <60 mL/min. UPCR decreased after replacing TDF by TAF, independent of baseline eGFR. Switching from TDF to TAF improves eGFR and proteinuria in patients with renal dysfunction.

We aimed to compare the one-year retreatment efficacy and renal safety of entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) after HBV relapse in patients who discontinued entecavir or TDF. This retrospective study included 289 chronic hepatitis B (CHB) patients without cirrhosis who received entecavir (n = 93), TDF (n = 103), or TAF (n = 86) retreatment for at least 12months after entecavir or TDF cessation. The rate of virological response (HBV DNA < 20IU/mL) at 12months of retreatment was 79/93 (84.9%) in the entecavir group, 92/103 (89.3%) in the TDF group, and 72/86 (83.7%) in the TAF group. The rate of ALT normalization (ALT ≤ 40 U/L) after 12months of retreatment was 76/93 (81.7%) in the entecavir group, 77/103 (74.7%) in the TDF group , and 73/86 (84.9%) in the TAF group. There was no significant difference in the rates of virological response (p = 0.495) and ALT normalization (p = 0.198) among the three groups. Multivariate analysis showed thatlower HBV DNA and HBsAg levels at baseline were independently associated with virological response at 12months of retreatment. The TDF group (37.8 ± 34.8 U/L) had higher ALT levels at 12months of retreatment than the TAF (27. ± 17.9 U/L, p = 0.015) and entecavir (28.3 ± 19.3 U/L, p = 0.022) groups. In patients with eGFR 60-90mL/min/1.73 m2, eGFR change between baseline and 12months of retreatment increased in the entecavir and TAF groups and decreased in the TDF group. TAF could be one of the retreatment options for retreatment of HBV relapse after entecavir or TDF cessation.

Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial

BackgroundNucleoside analogues are currently applied as a first-line treatment for chronic hepatitis B (CHB) patients. However, the long-term effects of this type of treatment on kidney and bone tissue need to be further investigated.MethodsWe conducted a search of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) for treatment of CHB patients through October 29, 2023. Side effects of the three drugs were compared. Standardized mean difference (SMD), 95% confidence interval (95%CI), and surface under the cumulative ranking curve (SUCRA) were reported for each outcome. Further subgroup analysis was conducted according to duration of administration.ResultsETV and TAF exhibited less effect on estimated glomerular filtration rate (eGFR) than TDF (SMD = -3.60 (95%CI: -1.94 ~ -5.26) and SMD = -4.27 (95%CI: -2.62 ~ -5.93)). ETV also exhibited less effect on creatinine rise than TAF and TDF (SMD = -0.55 (95%CI: -0.09 ~ -1.01) and SMD = -0.61 (95%CI: -0.15 ~ -1.06)). Moreover, the effect of TAF on bone mineral density (BMD) was less than that of TDF (SMD = -0.02 (95%CI: -0.01 ~ -0.02)). The probabilities of the three drugs changing relevant indicators exhibited similar patterns: eGFR (TDF (100.0%) > ETV (41.2%) > TAF (8.8%)), creatinine (TDF (94.7%) > TAF (54.7%) > ETV (0.6%)), BMD (TDF (79.7%) > ETV (50.6%) > TAF (19.6%)), and blood phosphorus (TDF (90.6%) > TAF (49.8%) > ETV (9.7%)). After 6 and 24 months of treatment, no statistically significant difference in renal function or bone tissue was observed between ETV and TDF. However, greater adverse effects on renal function were observed for TDF than ETV at 60 months compared to 12 months. TDF also exhibited greater adverse effects on bone tissue than ETV at 36 months than at 12 months.ConclusionsLong-term administration of TDF has resulted in stronger adverse effects than TAF and ETV in regard to both renal function and bone tissue in CHB patients. The effect of TAF on creatinine increase was greater than ETV. The difference in side effects between ETV and TDF was independent of treatment duration.

BackgroundIn 2 similarly designed double-blind (DB), randomized (2:1), Phase 3 studies (Study 108 in HBeAg-negative [N=425] and Study 110 in HBeAg-positive [N=873] patients), tenofovir alafenamide (TAF) demonstrated non-inferior efficacy with...

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.