gs-7340 and Kidney-Diseases

The antiviral agent tenofovir is highly effective for the treatment of HIV and hepatitis B virus infections, and the older prodrug tenofovir disoproxil fumarate (TDF) is also a component of daily preexposure prophylaxis (PrEP) to reduce the risk of HIV infection in high-risk populations. Although TDF is well tolerated, the potential for kidney and bone toxicity has important implications for public health given the large number of individuals exposed to TDF worldwide. This review summarizes the recent literature on kidney and bone health in individuals treated with TDF and the newer prodrug tenofovir alafenamide (TAF).. Risk factors for TDF toxicity appear to be similar in patients treated for HIV or hepatitis B virus and in HIV-uninfected PrEP users, although drug-drug interactions are a more important concern in HIV-positive individuals. The risk of toxicity appears to be lower with TAF, but further studies are needed to confirm the safety of long-term use and to evaluate the efficacy of TAF-based PrEP.. Nephrologists should be aware of the potential kidney and bone toxicity of TDF, as well as unique situations in which the newer prodrug TAF may contribute to kidney injury.

Topics: Adenine; Alanine; Antiviral Agents; Bone Density; Drug Interactions; Glomerular Filtration Rate; Hepatitis B; HIV Infections; Humans; Kidney Diseases; Pre-Exposure Prophylaxis; Prodrugs; Tenofovir

The aim of the study was to assess the effect of tenofovir alafenamide (TAF) on kidney and bone biomarkers in patients who developed proximal renal tubulopathy (PRT) while receiving tenofovir disoproxil fumarate (TDF).. Individuals with a history of TDF-associated PRT and currently suppressed HIV infection on a tenofovir-sparing regimen were randomized 1:1 to continue current antiretroviral therapy or initiate emtricitabine (F)/TAF with discontinuation of nucleoside reverse transcriptase inhibitors (NRTIs) as appropriate. Renal and bone biomarkers were analysed at baseline, week 4 and week 12. The primary outcome was the mean difference between study arms in urine retinol-binding protein:creatinine ratio (RBPCR) change from baseline to week 12. Data were analysed using linear regression, with robust standard errors (primary outcome), and repeated measures mixed effects models (secondary outcomes). The trial was registered under European Union Drug Regulating Authorities Clinical Trials Database 2016-003345-29.. We randomized 31 individuals [mean age 52.4 (standard deviation 0.3) years; 97% male; 90% white); all completed the study. At 12 weeks, there was no difference in change in RBPCR (β 19.6; 95% confidence interval -35.3, 74.5; P = 0.47), and no difference in change in estimated glomerular filtration rate (eGFR) (based on creatinine or cystatin C), albuminuria, proteinuria, renal phosphate or urea handling, (fasting) urine osmolality, parathyroid hormone and bone turnover markers in the control versus the F/TAF exposed groups. No cases of PRT were observed.. In people with a history of proximal renal tubulopathy while on TDF, 12-week exposure to TAF did not adversely affect renal tubular function. These data support continued evaluation of the long-term safety of TAF in this group of patients.

Topics: Adenine; Alanine; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Emtricitabine; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Diseases; Kidney Tubules, Proximal; Linear Models; Male; Middle Aged; Retinol-Binding Proteins; Tenofovir; Treatment Outcome; United Kingdom

Proximal renal tubulopathy (PRT) is an infrequent complication of tenofovir disoproxil fumarate (TDF). It remains to be established whether tenofovir alafenamide (TAF) can be safely administered to individuals who experienced PRT on TDF.. Individuals with a history of TDF-associated PRT and current estimated glomerular filtration rate (eGFR) over 30 mL/min/1.73 m2 initiated TAF and were followed for 96 weeks. The primary outcome of interest was recurrent PRT. Secondary outcomes were changes in kidney biomarkers, bone biomarkers, and bone mineral density (BMD). Data were analyzed using multilevel mixed-effects linear regression models. The trial was registered under EudraCT 2016-003345-29.. All 31 participants [median age 55 (inter-quartile range 51, 60) years, 97% men, 87% White ethnicity] remained on TAF at week 96, and none developed glycosuria or recurrent PRT. Participants experienced small declines in eGFR-creatinine [-1.9 (95% confidence interval: -3.5 to -0.3) mL/min/1.73 m2/yr; P = 0.024], but not in eGFR-cystatin C [-0.9 (-2.1 to 0.4) mL/min/1.73 m2/yr; P = 0.16]. Ten (32%) and 5 (16%) participants experienced rapid (>5 mL/min/1.73 m2/yr) decline in eGFR-creatinine and eGFR-cystatin C. No significant change in other kidney biomarkers, bone turnover, or BMD was observed (P > 0.2).. In individuals with a history of PRT on TDF, 96 weeks of TAF was not associated with recurrent PRT or adverse effects on renal tubular function, bone turnover, or BMD. These data suggest that TAF is a treatment option for this vulnerable population.

Topics: Adenine; Adult; Alanine; Anti-HIV Agents; Creatinine; Cystatin C; Female; HIV Infections; Humans; Kidney Diseases; Kidney Tubules, Proximal; Male; Middle Aged; Tenofovir

Whereas tenofovir disoproxil fumarate (TDF) can lead to renal adverse events, tenofovir alafenamide (TAF) has a more favorable renal safety profile. However, the impact of replacing TDF with TAF on renal function and liver parameters among HIV/hepatitis B virus (HBV)-coinfected individuals with renal dysfunction remains unclear.. We included all participants from the Swiss HIV Cohort Study with an HIV/HBV coinfection who switched from TDF to TAF and had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m and a suppressed HIV viral load (<200 cp/mL). We assessed changes in eGFR, urine protein-to-creatinine ratio, and alanine aminotransferase (ALT) after 1 year using mixed-effect models with interrupted time series.. Among 106 participants (15.1% women, median age 53 years), eGFR was 60-89 mL/min/1.73 m in 84 (79.2%) and <60 mL/min/1.73 m in 22 (20.8%) individuals at the time of switch. One year after the switch from TDF to TAF, individuals with an eGFR between 60 and 89 mL/min/1.73 m experienced increases in eGFR of 3.2 mL/min/1.73 m (95% confidence interval [CI] 1.2 to 5.2), whereas those with an eGFR <60 mL/min/1.73 m experienced improvements of 6.2 mL/min/1.73 m (95% CI 2.4 to 10.0). Urine protein-to-creatinine ratio decreased overall (-6.3 mg/mmol, 95% CI -10.0 to -2.7), and ALT levels declined in patients with elevated baseline levels (-11.8 IU/L, 95% CI -17.3 to -6.4) 1 year after replacing TDF with TAF.. Switching from TDF to TAF among HIV/HBV-coinfected individuals with renal impairment led to improvements in eGFR, a decline in proteinuria, and to ALT normalization in those with elevated ALT levels.

Topics: Adenine; Aged; Alanine; Anti-HIV Agents; Female; Glomerular Filtration Rate; Hepatitis B; Hepatitis B virus; HIV Infections; Humans; Interrupted Time Series Analysis; Kidney Diseases; Kidney Function Tests; Liver; Male; Middle Aged; Prospective Studies; Tenofovir; Viral Load

Tenofovir alafenamide (TAF) is a novel prodrug that reduces tenofovir plasma levels by 90% compared to tenofovir disoproxil fumarate (TDF), resulting in decreased bone mineral density (BMD) loss and renal toxicity. We aimed to study changes in BMD and markers of renal function of chronic hepatitis B (CHB) patients previously treated with TDF who were switched to TAF in as early as 12 weeks. This was a prospective single-arm open-label study of 75 CHB patients treated with TDF 300 mg daily who were switched to TAF 25 mg daily and followed for 24 weeks. All patients had been treated with TDF for at least 12 months and had HBV DNA <21 IU/mL at the time of switch. BMD and markers of renal function were taken on the day of switch and repeated after 12 and 24 weeks of TAF treatment. Hip and spine bone mineral density significantly increased from baseline to week 12 (+12.9% and +2.4%, respectively, P < 0.01). There were significant decreases in urinary beta-2-microglobulin to creatinine and retinol-binding protein to creatinine ratios by week 12 (P < 0.01 for both). Mean estimated glomerular filtration rate (GFR) did not change. Tubular reabsorption of phosphate was decreased at week 24 (P < 0.05). In conclusion, CHB patients previously treated with TDF experienced significant improvement in bone density and some markers of renal tubular function and as early as 12 weeks after switching to TAF. Bone density changes associated with TDF may not be entirely related to renal handling of phosphate.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Alanine; Bone Density; Drug Substitution; Female; Glomerular Filtration Rate; Hepatitis B, Chronic; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Pelvic Bones; Phosphorous Acids; Prospective Studies; Spine; Tenofovir; Treatment Outcome; Young Adult

HIV eradication is not feasible and lifelong treatment is warranted to manage HIV infection. In this scenario, the advent of single-tablet, once-daily, fixed-dose co-formulations is important for reducing pill burden and maximize long-term drug adherence. Cobicistat-boosted darunavir along with emtricitabine and tenofovir alafenamide co-formulation (DRV/c/FTC/TAF or the trade name Symtuza®) is the first marketed protease inhibitor-based fixed-dose combination regimen for the treatment of HIV infection. It was approved in late 2017 by the European Medical Agency both for naïve patients and treatment-experienced patients with viral suppression. Areas covered: PubMed, ClinicalTrials.gov and presentations at scientific meetings were searched with the terms 'darunavir/cobicistat' and 'tenofovir alafenamide and emtricitabine' for clinical trials either conducted to date or ongoing as well as a review of abstracts from major HIV/AIDS and infectious diseases conferences from 2015 to up to date. Expert opinion: DRV/c/FTC/TAF is a novel unique antiretroviral drug co-formulation that exhibits a convenient dosing, satisfactory safety profile, and high antiviral efficacy, even in patients harboring viruses with resistance to antivirals other than darunavir in the short-midterm. It represents the first fixed-dose combination therapy including a protease inhibitor given as one single pill once daily for drug-naïve patients and as second-line antiretroviral therapy.

Topics: Adenine; Alanine; Anti-HIV Agents; Clinical Trials as Topic; Cobicistat; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; HIV Infections; Humans; Kidney Diseases; Tablets; Tenofovir

Topics: Adenine; Alanine; Antiviral Agents; Drug Substitution; Female; HIV Infections; Humans; Kidney Diseases; Middle Aged; Proteinuria; Tenofovir

Tenofovir alafenamide (TAF) is novel prodrug of Tenofovir, a nucleotide reverse transcriptase inhibitor. TAF is less nephrotoxic than its predecessor prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir causes mitochondrial dysfunction and tubular injury when there is elevated accumulation in proximal tubule cells. TAF's unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage. TAF has not been associated with the histologic markers of tenofovir-associated nephrotoxicity that are seen with TDF, such as dysmorphic mitochondria in proximal tubule cells. Here, we report a patient with dysmorphic mitochondria on kidney biopsy after initiating therapy with TAF.. This case suggests that at risk individuals may experience tubular mitochondrial injury from lower concentrations of tenofovir with TAF.

Topics: Adenine; Alanine; Anti-HIV Agents; HIV Infections; Humans; Kidney Diseases; Male; Middle Aged; Mitochondria; Prodrugs; Tenofovir