Long-term Exposure to Tenofovir and Renal Function in HIV
Long-term Exposure to Tenofovir and Renal Function in HIV
Objectives: To investigate the effect of long-term tenofovir disoproxil fumarate (TDF) use on renal function, especially in patients with low body weight who are vulnerable to TDF nephrotoxicity.
Design: A single-center, observational study in Tokyo, Japan.
Methods: We performed a 10 years cohort study of 792 HIV-1-infected patients. The effect of long-term TDF use on estimated glomerular filtration rate (eGFR) was investigated on treatment-naive patients who started TDF-containing antiretroviral therapy (n = 422) and those who started abacavir-containing antiretroviral therapy as control (n = 370). Three renal endpoints were examined by the logistic regression model: decrement in eGFR of higher than 10 ml/min per 1.73 m relative to the baseline, more than 25% decrement in eGFR, and eGFR lower than 60 ml/min per 1.73 m at least 3 months apart. The loss in eGFR was estimated using linear mixed models for repeated measures.
Results: The median weight at baseline was 63 kg. TDF use increased the risk of all three renal outcomes compared with the control group: higher than 10 ml/min per 1.73 m decrement in eGFR [adjusted odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.45–3.14, P < 0.001], more than 25% decrement (adjusted OR = 2.1, 95% CI 1.50–2.90, P < 0.001), and eGFR lower than 60 ml/min per 1.73 m at least 3 months apart (adjusted OR = 3.9, 95% CI 1.62–9.36, P = 0.002). The cumulative mean loss relative to the control after 1, 2, 3, 4, and 5 years of TDF exposure was −3.8, −3.6, −5.5, −6.6, and −10.3 ml/min per 1.73 m, respectively, indicating that the loss in eGFR increased over time (P < 0.001).
Conclusion: In this cohort of patients with low body weight, TDF exposure increased the risk of renal dysfunction. Furthermore, the loss in eGFR relative to the control increased continuously up to 5 years.
Tenofovir disoproxil fumarate (TDF) is one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV-1 infection in both resource-rich and resource-limited settings, and also for the treatment of hepatitis B infection. Furthermore, TDF, at a fixed dose with emtricitabine, has been approved in the United States for the prevention of sexual transmission of HIV-1 in uninfected adults as preexposure prophylaxis.
TDF is known to cause renal proximal tubular dysfunction and also reduces estimated glomerular filtration rate (eGFR) more than other NRTIs. To date, the extent of TDF-induced renal dysfunction is regarded as mild and tolerable, and one meta-analysis recommended that TDF use should not be restricted even when regular monitoring of renal function and serum phosphate levels is impractical. Furthermore, although evidence is limited, most of the TDF-induced loss in renal function is considered to occur during the first year of exposure.
However, a large proportion of studies that investigated TDF nephrotoxicity were based on an analysis of a relatively short observation period, typically a few years, and little information is available on the effect of long-term TDF use on the prognosis of renal function. This is important as HIV-1 infection requires lifelong antiretroviral therapy (ART). In this regard, although small body weight is a well established risk factor for TDF nephrotoxicity, the TDF-related renal dysfunction has hardly been evaluated in patients with small body weight, who are potentially at higher risk for larger drug exposure and, thus, more severe toxicity.
Based on the above background, the current study was designed to investigate the effects of long-term TDF use on renal function in HIV-1-infected patients with low body weight, using 10 years data from our observational cohort study.
Abstract and Introduction
Abstract
Objectives: To investigate the effect of long-term tenofovir disoproxil fumarate (TDF) use on renal function, especially in patients with low body weight who are vulnerable to TDF nephrotoxicity.
Design: A single-center, observational study in Tokyo, Japan.
Methods: We performed a 10 years cohort study of 792 HIV-1-infected patients. The effect of long-term TDF use on estimated glomerular filtration rate (eGFR) was investigated on treatment-naive patients who started TDF-containing antiretroviral therapy (n = 422) and those who started abacavir-containing antiretroviral therapy as control (n = 370). Three renal endpoints were examined by the logistic regression model: decrement in eGFR of higher than 10 ml/min per 1.73 m relative to the baseline, more than 25% decrement in eGFR, and eGFR lower than 60 ml/min per 1.73 m at least 3 months apart. The loss in eGFR was estimated using linear mixed models for repeated measures.
Results: The median weight at baseline was 63 kg. TDF use increased the risk of all three renal outcomes compared with the control group: higher than 10 ml/min per 1.73 m decrement in eGFR [adjusted odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.45–3.14, P < 0.001], more than 25% decrement (adjusted OR = 2.1, 95% CI 1.50–2.90, P < 0.001), and eGFR lower than 60 ml/min per 1.73 m at least 3 months apart (adjusted OR = 3.9, 95% CI 1.62–9.36, P = 0.002). The cumulative mean loss relative to the control after 1, 2, 3, 4, and 5 years of TDF exposure was −3.8, −3.6, −5.5, −6.6, and −10.3 ml/min per 1.73 m, respectively, indicating that the loss in eGFR increased over time (P < 0.001).
Conclusion: In this cohort of patients with low body weight, TDF exposure increased the risk of renal dysfunction. Furthermore, the loss in eGFR relative to the control increased continuously up to 5 years.
Introduction
Tenofovir disoproxil fumarate (TDF) is one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV-1 infection in both resource-rich and resource-limited settings, and also for the treatment of hepatitis B infection. Furthermore, TDF, at a fixed dose with emtricitabine, has been approved in the United States for the prevention of sexual transmission of HIV-1 in uninfected adults as preexposure prophylaxis.
TDF is known to cause renal proximal tubular dysfunction and also reduces estimated glomerular filtration rate (eGFR) more than other NRTIs. To date, the extent of TDF-induced renal dysfunction is regarded as mild and tolerable, and one meta-analysis recommended that TDF use should not be restricted even when regular monitoring of renal function and serum phosphate levels is impractical. Furthermore, although evidence is limited, most of the TDF-induced loss in renal function is considered to occur during the first year of exposure.
However, a large proportion of studies that investigated TDF nephrotoxicity were based on an analysis of a relatively short observation period, typically a few years, and little information is available on the effect of long-term TDF use on the prognosis of renal function. This is important as HIV-1 infection requires lifelong antiretroviral therapy (ART). In this regard, although small body weight is a well established risk factor for TDF nephrotoxicity, the TDF-related renal dysfunction has hardly been evaluated in patients with small body weight, who are potentially at higher risk for larger drug exposure and, thus, more severe toxicity.
Based on the above background, the current study was designed to investigate the effects of long-term TDF use on renal function in HIV-1-infected patients with low body weight, using 10 years data from our observational cohort study.
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