gs-7340 and Renal-Insufficiency

Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear.. We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes.. We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios).. Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy.. These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Alanine; Anti-HIV Agents; Child; Female; Humans; Incidence; Male; Middle Aged; Renal Insufficiency; Tenofovir; Young Adult

Tenofovir disoproxil fumarate (TDF), an ester prodrug of tenofovir (TFV), is one of the recommended drugs for chronic hepatitis B (CHB) patients. However, reduced kidney function and loss of bone mineral density have been reported in some CHB patients treated with TDF. Consequent to these safety issues, tenofovir alafenamide (TAF) [Vemlidy®], a phosphonate prodrug of TFV, was developed for the treatment of CHB patients. Areas covered: The favourable pharmacological profile of TAF allows a marked reduction in dosage (25 mg/day) thus reducing systemic exposure to tenofovir and improving the bone and renal safety, keeping however the same virological efficacy, compared to TDF 300 mg/day. In two ongoing 96-week phase III trials in mainly treatment-naive HBeAg-positive or -negative patients, TAF showed similar viral suppression but was associated with significantly higher alanine aminotransferase normalization rates and more favourable renal and bone safety compared to TDF. In a 48-week TAF switch study enrolling patients treated with TDF for 96 weeks, glomerular, tubular and bone safety parameters rapidly improved while virological suppression was maintained. Expert commentary: Waiting long-term large scale clinical practice studies aimed to confirm these advantages, TAF represents an helpful treatment option for both naïve and TDF-exposed CHB patients.

Topics: Adenine; Alanine; Antiviral Agents; Bone Density; Dose-Response Relationship, Drug; Hepatitis B, Chronic; Humans; Prodrugs; Renal Insufficiency; Tenofovir

Tenofovir alafenamide (TAF) has recently been approved for chronic hepatitis B (CHB). It is more stable than tenofovir disoproxil fumarate (TDF) in the plasma and can provide similar efficacy with lower circulating concentration in patients with hepatitis B virus (HBV) infection. Areas covered: This synopsis will review the current anti-HBV standard practice and the changing epidemiology of CHB, specifically the controversies surrounding the renal and bone safety associated with TDF use in the context of an aging CHB population. We will review data from phase 3 registration trials, which demonstrated TAF was not inferior to TDF in antiviral efficacy for both HBeAg-positive and HBeAg-negative patients, while associated with less reduction in the estimated glomerular filtration rate and bone mineral density. Expert commentary: Current data supports the use of TAF as one of the first-line antiviral agents for general CHB patients without hepatic decompensation. However, more real-world data with long-term observation are needed to better define the role of TAF among other oral regimens. Additional studies are also needed to evaluate the efficacy and safety of TAF in special populations such as those with impaired hepatic function, existing impaired renal and/or bone function, and in pregnant women.

Topics: Adenine; Age Factors; Alanine; Antiviral Agents; Bone Density; Clinical Decision-Making; Female; Glomerular Filtration Rate; Hepatitis B, Chronic; Humans; Kidney; Male; Osteoporosis; Patient Safety; Pregnancy; Renal Insufficiency; Risk Factors; Tenofovir; Treatment Outcome

Treatment with tenofovir disoproxil fumarate has been associated with renal toxicity or reductions in bone mineral density, or both, in some patients with chronic hepatitis B virus (HBV) infection. Tenofovir alafenamide is a tenofovir prodrug with high intrahepatic concentrations of active drug and reduced systemic tenofovir exposures compared with tenofovir disoproxil fumarate. In patients with chronic HBV, tenofovir alafenamide has shown efficacy non-inferior to that of tenofovir disoproxil fumarate with improved renal and bone safety. With this non-inferiority study, we aimed to evaluate the efficacy and safety of tenofovir alafenamide in patients with HBV infection switching from tenofovir disoproxil fumarate who are virally suppressed.. Patients with chronic HBV infection who had been receiving tenofovir disoproxil fumarate for 48 weeks or more and who had HBV DNA less than the lower limit of quantification (LLOQ) for at least 12 weeks were recruited to this randomised, multicentre, double-blind, phase 3 non-inferiority study. Patients were randomly assigned in a 1:1 ratio to receive tenofovir alafenamide 25 mg once a day or to continue tenofovir disoproxil fumarate 300 mg once a day. The primary efficacy endpoint was loss of virological control, defined as the proportion of patients who received at least one dose of study drug who had HBV DNA of at least 20 IU/mL at week 48 by the modified US Food and Drug Administration (FDA) snapshot algorithm. Key safety endpoints were changes in hip and spine bone mineral density, estimated creatinine clearance by Cockcroft-Gault, and markers of bone turnover and renal tubular function. The study was powered for non-inferiority in efficacy of tenofovir alafenamide versus tenofovir disoproxil fumarate with a 4% margin. Investigators and patients were unaware of treatment allocation and on-treatment results. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02979613.. Participants in this study were enrolled between Dec 29, 2016, and Oct 20, 2017. 541 patients were screened and 490 patients were randomly assigned to switch to tenofovir alafenamide or to stay on tenofovir disoproxil fumarate. Two patients assigned to receive tenofovir alafenamide did not receive treatment; thus the full analysis set for efficacy and safety analyses consisted of 243 patients in the tenofovir alafenamide group and 245 in the tenofovir disoproxil fumarate group. At week 48, one patient from each treatment group (both <1%) had HBV DNA of at least 20 IU/mL (difference in proportion 0·0%, 95% CI -1·9 to 2·0), thereby showing non-inferior efficacy of tenofovir alafenamide to tenofovir disoproxil fumarate. Patients who received tenofovir alafenamide had significantly increased bone mineral density at hip (mean change 0·66% [SD 2·08] vs -0·51% [SD 1·91]; difference in least square means 1·17% [95% CI 0·80 to 1·54; p<0·0001]) and at spine (mean change 1·74% [3·46] vs -0·11% [3·13]; difference in least square means 1·85% [1·24 to 2·46; p<0·0001]), creatinine clearance by Cockcroft-Gault relative to tenofovir disoproxil fumarate (median change 0·94 mL/min [IQR -4·47 to 6·24] vs -2·74 mL/min [-7·89 to 1·88]; p <0·0001), and improved markers of bone turnover and tubular function at week 48. The most common treatment-emergent adverse events were upper respiratory tract infection (18 [7%] of 243 patients in the tenofovir alafenamide group and 16 [7%] of 245 patients in the tenofovir disoproxil fumarate group) and nasopharyngitis (13 [5%] of 243 patients in the tenofovir alafenamide group and 12 [5%] of 245 patients in the tenofovir disoproxil fumarate group). The incidence of grade 3 and above adverse events and serious adverse events was low and similar between groups. No viral resistance was observed in patients who qualified for viral sequencing.. These findings suggest that tenofovir alafenamide can be substituted for tenofovir disoproxil fumarate in patients with HBV infection for improved safety without a loss of efficacy.. Gilead Sciences.

Topics: Adenine; Alanine; Antiviral Agents; Bone Density; Creatinine; DNA, Viral; Double-Blind Method; Drug Substitution; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nasopharyngitis; Renal Insufficiency; Respiratory Tract Infections; Sustained Virologic Response; Tenofovir

Data are lacking regarding overdose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF).. We present the first report of suicidal attempt with E/C/F/TAF in a Human Immunodeficiency Virus-infected subject.. A reversible acute renal failure with no proximal tubulopathy and neuropsychiatric issues are discussed. E/C/F/TAF withdrawal resulted in favourable renal and neuropsychiatric outcomes. The suicide attempt seemed unrelated to the integrase strand transfer inhibitor, being evenly explained within the context of stressful personal conflicts.. A suicidal attempt with an E/C/F/TAF overdose in an HIV-infected patient, resulted in a favourable outcome from a renal and neuropsychiatric standpoint.

Topics: Adenine; Alanine; Anti-HIV Agents; Cobicistat; Drug Combinations; Drug Overdose; Emtricitabine; HIV Infections; Humans; Male; Middle Aged; Quinolones; Renal Insufficiency; Suicide, Attempted; Tenofovir