Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: A nested case-control study

ArticleinAIDS (London, England) 24(4):525-34 · February 2010with14 Reads
DOI: 10.1097/QAD.0b013e3283333680 · Source: PubMed
Abstract
To investigate the association between tenofovir disoproxil fumarate (TDF) use and renal abnormality in a large cohort of HIV-1-infected children on antiretroviral therapy (ART). Nested case-control study. Patients were from the Collaborative HIV Paediatric Study, a cohort of approximately 95% of HIV-1-infected children in the UK/Ireland. Serum (but not urine) biochemistry results for 2002-2008 were obtained for 456 ART-exposed children (2-18 years) seen at seven hospitals. Cases had either confirmed hypophosphataemia DAIDS grade at least 2 or estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m; three controls per case were matched by hospital. Conditional logistic regression identified risk factors for renal abnormality. Twenty of 456 (4.4%) had hypophosphataemia, and one had eGFR less than 60 ml/min per 1.73 m. Ten of 20 (50%) cases versus 11 of 60 (18%) controls had taken TDF-containing ART for a median [interquartile range (IQR)] of 18 [17-20] months, as part of second-line or salvage therapy. The hypophosphataemia incidence rate was 4.3/100 person-years in the TDF group versus 0.9/100 person-years in those not exposed to TDF. In multivariable analysis, only TDF exposure in the previous 6 months was associated with hypophosphataemia [odds ratio (OR) = 4.81, 95% confidence interval (CI) 1.45-16.0, P = 0.01]. In six of 10 children with hypophosphataemia and at least four subsequent phosphate measurements, phosphate values returned to normal when TDF was stopped; in four with three measures or less, values rose but remained subnormal. Hypophosphataemia was uncommon (4%), but was associated with prolonged TDF use, and was generally reversible following TDF withdrawal. Findings highlight the importance of continuing to monitor longer-term renal function, in particular tubular function, especially in those taking TDF. Further studies assessing urine biochemistry measures which more accurately indicate renal tubular damage are required.

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    • "Accurate dosing is an important issue; historically, this was a challenge as TFV was previously only available as a once-daily adult dose of 300 mg, but a children's formulation has now been made available by the manufacturer. Several studies have examined the effect of TFV on kidney function in HIV-infected children (summarized inTable 1)7273747576777879 . The outcomes of these studies were variable , with some reporting evidence of renal impairment (including decrease in eGFR, hypophosphatemia, and PT dysfunction) and others not. "
    [Show abstract] [Hide abstract] ABSTRACT: Tenofovir (TFV) is a widely used and effective treatment for HIV infection. Numerous studies have shown that TFV exposure is associated with small but significant declines in estimated glomerular filtration rate (eGFR). However, TFV toxicity is targeted mainly at the proximal tubule (PT), and in severe cases can cause the renal Fanconi syndrome or acute kidney injury. Severe toxicity occurs in a minority of patients, but milder PT dysfunction is more common; the long-term significance of this on kidney and bone health is uncertain. Recent work suggests that changes in eGFR on TFV therapy might be explained by inhibition of PT creatinine secretion rather than actual alterations in glomerular function. Risk factors for nephrotoxicity include pre-existing kidney disease, increased age, and low body mass. Mitochondria in the PT are the targets of TFV toxicity, but the exact mechanisms remain unclear. Substantial improvement of renal function occurs in many patients with TFV toxicity upon stopping therapy, but function does not always return to baseline. In recent years, TFV usage has been extended to new clinical spheres, including pediatrics, resource-poor settings and treatment of Hepatitis B infection; theoretical reasons exist as to why some of these patients might be at higher or lower risk of TFV toxicity. Finally, strategies have been proposed to prevent TFV toxicity or enhance recovery.
    Article · Aug 2012
    • "Furthermore we assessed renal impairment without analyzing urine tests and other more sensitive indicators such as β-2 microglobulinuria that may have shown some milder renal abnormalities. Moreover, we didn't assess the association of TDF and PI with lower bone mineral density as reported by other studies [13,17,33], and the clinical significance of kidney abnormalities observed remains not fully known. Further studies with more sensitive urine markers, bone density assays, and longer follow-up are warranted. "
    [Show abstract] [Hide abstract] ABSTRACT: Kidney disease is an important complication in HIV infected people, and this may be related to infection or antiretroviral therapy (ART). Our aim is to assess renal function in HIV infected paediatric patients, who may be particularly affected and are likely to take ART for longer than adults, and investigate the long term role of Tenofovir Disoproxil Fumarate (TDF) alone or co-administered with Ritonavir-boosted Protease Inhibitors (PI). Serum creatinine, phosphate and potassium levels, with estimated Glomerular Filtration Rate (eGFR), had been prospectively evaluated for 2 years in a cohort of HIV infected children and adolescents (age 9-18) on ART, and data analyzed according to the exposure to TDF or simultaneous TDF and PI. Forty-nine patients were studied (57% female, mean age 14). Sixty-three percent were treated with ART containing TDF (Group A), and 37% without TDF (Group B); 47% with concomitant use of TDF and PI (Group C) and 53% without this combination (Group D). The groups didn't differ for age, gender or ethnicity. The median creatinine increased in the entire cohort and in all the groups analyzed; eGFR decreased from 143.6 mL/min/1.73 m2 at baseline to 128.9 after 2 years (p = 0.006) in the entire cohort. Three patients presented a mild eGFR reduction, all were on TDF+PI. Phosphatemia decreased significantly in the entire cohort (p = 0.0003) and in TDF+PI group (p = 0.0128) after 2 years. Five patients (10%) developed hypophosphatemia (Division of Acquired Immune Deficiency AE grade 1 or 2), and four of them were on TDF+PI. Renal function decrease and hypophosphatemia occur over time in HIV infected children and adolescents on ART. The association with co-administration of TDF and PI appears weak, and further studies are warranted.
    Full-text · Article · Jan 2012
    • "Moreover, serum phosphate alterations were significantly related to both TPR changes and time on TDF treatment. In the study by Judd et al. [8], a difference was seen in the incidence of hypophosphatemia (DAIDS grade 2) between patients on TDF and those who had never received this drug. Along this same line, Izzedine et al. suggested that hypophosphatemia (as well as glucosuria in the absence of hyperglycemia) would be a good marker of tubular toxicity due to TDF [15]. "
    [Show abstract] [Hide abstract] ABSTRACT: to describe the impact of tenofovir disoproxil fumarate (TDF) use on renal function in HIV-infected pediatric patients. it is a prospective, multicenter study. The setting consisted of five third-level pediatric hospitals in Spain. The study was conducted on patients aged 18 years and younger who had received TDF for at least 6 months. The intervention was based on the study of renal function parameters by urine and serum analyses. The main outcome measures were renal function results following at least 6 months of TDF therapy. forty patients were included (32 were white and 26 were diagnosed with AIDS). Median (range) duration of TDF treatment was 77 months (16-143). There were no significant changes in the estimated creatinine clearance. Urine osmolality was abnormal in eight of 37 patients, a decrease in tubular phosphate absorption was documented in 28 of 38 patients, and 33 of 37 patients had proteinuria. A statistically significant decrease in serum phosphate and potassium concentrations was observed during treatment (P = 0.005 and P = 0.003, respectively), as well as a significant relationship between final phosphate concentration and tubular phosphate absorption (P = 0.010). A negative correlation was found between phosphate concentration and time on TDF. TDF use showed a significant association with renal tubular dysfunction in HIV-infected pediatric patients. Periodic assessment of tubular function may be advisable in the follow-up of this population.
    Full-text · Article · Nov 2010
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