Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection

Squires, Kathleen; Pozniak, Anton; Pierone, Gerald; Steinhart, Corklin R.; Berger, Daniel; Bellos, Nicholaos C.; Becker, Stephen; Wulfsohn, Michael; Miller, Michael D.; Toole, John J.; Coakley, Dion F.; Cheng, Andrew

doi:10.7326/0003-4819-139-5_part_1-200309020-00006

Cited by 188 publications

(132 citation statements)

References 26 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…Studies demonstrating its safety and efficacy among both treatment-naive and treatment-experienced, HIV-infected adults led to its approval as part of combination antiretroviral therapy for HIV-infected adults in 2001. [4][5][6] We performed a phase I trial of a 6-day course of tenofovir DF monotherapy, followed by an individualized combination regimen that included tenofovir DF, for treatment-experienced, HIV-infected children. The toxicity and immunologic, virologic, and clinical effects of tenofovir DF as a salvage agent are reported here.…”

Section: H Ighly Active Antiretroviral Therapy (Haart)mentioning

confidence: 99%

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

et al. 2005

View full text Add to dashboard Cite

ABSTRACT. Objectives. Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children.Methods. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3-16.2 years) who had progressive disease with >2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks.Results. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3-5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log 10 copies per mL (range: 4.1-5.9 log 10 copies per mL) to 4.21 log 10 copies per mL at week 48 (n ‫؍‬ 15), with 6 subjects having <400 copies per mL, including 4 with <50 copies per mL. The overall median increases in CD4 ؉ T cell counts were 58 cells per mm 3 (range: ؊64 to 589 cells per mm 3 ) at week 24 and 0 cells per mm 3 (range: ؊274 to 768 cells per mm 3 ) at week 48. The CD4 ؉ cell responses among the virologic responders were high and sustained.The major toxicity attributed to tenofovir DF was a >6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log 10 copies per mL decreases in HIV plasma RNA levels.Conclusions. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatmentexperienced, HIV-infected children.

show abstract

Section: H Ighly Active Antiretroviral Therapy (Haart)mentioning

confidence: 99%

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

et al. 2005

View full text Add to dashboard Cite

show abstract

“…As a consequence of its tolerability, convenient dosing and efficacy, this nucleoside reverse transcriptase inhibitor (NRTI) has been widely used as a component of cART regimens. There are contradictory data on tenofovir-related damage: from documented damage in early reports [24][25][26][27] to a marked lack of renal toxicity in randomized placebo-controlled trials [28][29][30][31]; moreover, toxicity was found to be increased when tenofovir was given with ritonavir-boosted protease inhibitors (PI/r) compared with tenofovir given with nonnucleoside reverse transcriptase inhibitors (NNRTIs) or cART that did not include tenofovir [32]. A mechanism involving an interaction between tenofovir and PIs/r resulting in an increased risk of renal damage has been suggested [33].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure*

et al. 2010

View full text Add to dashboard Cite

The prevalence and factors associated with an increased risk of renal dysfunction in HIV-infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings. MethodsPatients in the ICONA Foundation cohort with at least two creatinine values available while still ART-naïve were enrolled in the study. A logistic regression analysis was performed to identify predictors of an estimated glomerular filtration rate (eGFR)o90 mL/min/1.73 m 2 at baseline. The incidence and predictors of a 420% reduction in eGFR from pre-combination ART (cART) levels (or a decrease from ! 90 to o90 mL/min/1.73 m 2 ) were evaluated by Poisson regression. ResultsA total of 1505 patients were included in the study; 363 (24%) had eGFRo90 mL/min/1.73 m 2 at baseline. Older patients [odds ratio (OR) 1.58 per 10 years older; Po0.00001], female patients (OR 2.41 vs. male patients; Po0.00001), those who had diabetes and/or hypertension (OR 2.36 vs. neither; Po0.03) and patients with higher baseline CD4 count (OR 1.06 per 100 cells/mL higher; Po0.03) showed a greater risk of eGFRo90 mL/min/1.73 m 2 . Ninety-six patients experienced an eGFR decrease of 420% from pre-cART levels (6.8 per 100 person-years). Older age [relative risk (RR) 1.41 per 10 years older; P 5 0.005], female gender (RR 2.25 vs. male; P 5 0.003) and current exposure to didanosine (ddI), tenofovir and protease inhibitors were the major determinants. ConclusionsWe observed a relatively high rate of mild renal dysfunction in the absence of ART. In addition to traditional risk factors such as older age and diabetes/hypertension, female gender and current use of ddI, tenofovir and protease inhibitors were associated with a greater risk of decreased renal function as measured by eGFR.Keywords: antiretroviral exposure, estimated glomerular filtration rate (eGFR), renal impairment [7][8][9][10][11], there are a number of other factors potentially influencing the onset of renal disorders through different mechanisms, whose prevalence may be different in an HIV-positive population compared with the general population. Indeed, patients' longer survival following the introduction of cART may be considered as an additional risk for renal dysfunction, as long-term toxic events associated with the prolonged used of ART have been observed (e.g. metabolic alterations, diabetes, hypertension and cardiovascular events) [12][13][14]. It has been hypothesized that antiretroviral medications may have a direct effect in increasing the risk of renal dysfunction, and a variety of cART-related effects, including proteinuria, renal tubular damage, interstitial nephritis and overall declines in glomerular filtration rates, have been noted [15][16][17][18][19][20][21][22][23].The potential role of tenofovir in renal toxicity is a current clinical research question. As a consequence of its tolerability, convenient dosing and efficacy, this nucleoside reverse transcriptase inhibitor (NRTI) has been widely used as a component of cART regimens. There are...

show abstract

“…In particular, a dose-and timedependent development of a Fanconi-like syndrome has been reported [5,6]. In pivotal studies assessing the safety and efficacy of TDF, renal safety profiles were found to be similar in individuals receiving and in those not receiving TDF-containing highly active antiretroviral therapy (HAART) [2][3][4]. In addition, a recent large cohort has described no significant evidence of renal dysfunction with the use of TDF in clinical practice [7].…”

mentioning

confidence: 99%

Minor changes in calculated creatinine clearance and anion‐gap are associated with tenofovir disoproxil fumarate‐containing highly active antiretroviral therapy

et al. 2006

View full text Add to dashboard Cite

BackgroundTenofovir disoproxil fumarate (Tenofovir DF, TDF), the first nucleotide reverse transcriptase inhibitor approved for the treatment of HIV disease, has been associated with renal dysfunction in isolated cases. The aim of this study was to assess changes in renal parameters in individuals receiving TDFand non-TDF-containing highly active antiretroviral therapy (HAART). MethodsAll individuals on HAART attending our clinic were included in the analysis. Time-weighted changes in serum creatinine, calculated creatinine clearance (CCrCl) and anion-gap were assessed for individuals on TDF-and non-TDF HAART. ResultsOf 948 individuals on HAART, 290 (31%) and 618 (65%) were on TDF-and non-TDF HAART, with 40 (4%) having ceased TDF HAART. Baseline values for serum creatinine, CCrCl and anion-gap were similar for those on TDF-and non-TDF HAART. In a multivariate analysis, statistically significant differences were observed in time-weighted change from baseline in anion-gap and CCrCl between individuals on TDF-and non-TDF HAART [mean difference in change between groups: anion-gap 0.78 mmol/L (standard error, 0.19) and CCrCl À 6.80 (standard error 2.2); P 5 0.005 and P 5 0.032, respectively] after adjusting for baseline anion-gap and CCrCl, respectively. Two cases of TDF-associated renal failure were observed. ConclusionOvert renal failure with TDF HAART is rare. However, subtle but statistically significant changes in anion-gap and CCrCl were observed which were associated with TDF HAART. These parameters may be of use in monitoring individuals on HAART. Cidofovir and adefovir, compounds structurally related to TDF, have been associated with an increased risk of acute renal insufficiency. In particular, a dose-and timedependent development of a Fanconi-like syndrome has been reported [5,6]. In pivotal studies assessing the safety and efficacy of TDF, renal safety profiles were found to be similar in individuals receiving and in those not receiving TDF-containing highly active antiretroviral therapy (HAART) [2][3][4]. In addition, a recent large cohort has described no significant evidence of renal dysfunction with the use of TDF in clinical practice [7]. However, there are mounting numbers of anecdotal reports describing Fanconi's syndrome and renal insufficiency induced by TDF therapy [8][9][10][11][12][13][14][15][16][17][18]. Predisposing factors for the development of acute renal failure with the use of TDF remain obscure.Several groups reporting no significant evidence of renal dysfunction with the use of TDF have relied on serum creatinine as a marker of renal function [7]. A recent report utilizing glomerular filtration rate (GFR) calculated on the basis of a 24-h urine collection has observed a lower GFR associated with TDF treatment [19].The aim of this study was to investigate changes in anion-gap and calculated creatinine clearance (CCrCl) in a large cohort of HIV-1-infected individuals receiving TDFand non-TDF-containing HAART. Methods Study designAll individuals currently on HAART attending the Departmen...

show abstract

Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection

Abstract: In treatment-experienced patients with suboptimal viral suppression, tenofovir DF significantly reduced HIV-1 RNA level and had a safety profile similar to that of placebo.

Cited by 188 publications

References 26 publications

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure*

Minor changes in calculated creatinine clearance and anion‐gap are associated with tenofovir disoproxil fumarate‐containing highly active antiretroviral therapy

Contact Info

Product

Resources

About