Review of Tenofovir Use in HIV-Infected Children
Tenofovir disoproxil fumarate (TDF) is approved by the Food and Drug Administration for use in children ages 2 years and older and is recommended by the World Health Organization for use as a preferred first-line nucleotide reverse transcriptase inhibitor in adults and adolescents ages 10 years and older. The simplicity of once daily dosing, few metabolic side effects and efficacy against hepatitis B virus make TDF suitable for use in a large scale program. Unlike thymidine analoge nucleoside reverse transcriptase inhibitors (NRTIs); tenofovir does not induce multi-NRTI resistance mutations, so more NRTI options are available for future second-line-regimens. Fixed-dose combinations of TDF with other ARVs as a single tablet regimen are now widely available for adults and adolescents, but none are available for young children. Current information on TDF including the pharmacokinetics, safety and tolerability in children and adolescents was reviewed. A dosing regimen according to body-weight-band has been established for pediatric use. Safety concerns of TDF mainly relate to its effects on renal function and bone mineral density. Regular monitoring of renal function in high-risk patients, including those on other nephrotoxic drugs, may be warranted to detect adverse renal effects. Long-term-data on renal and bone outcomes among HIV-infected children is needed. Lessons learned from clinical studies will help clinicians balance the risks and benefits of TDF and design appropriate antiretroviral regimens for children in different circumstances.
The success of antiretroviral therapy (ART) has dramatically changed the prognosis and natural history of pediatric HIV infection. A significant decline in morbidity and mortality has led to an increasing number of children entering their adolescent years. Current treatment strategies aim at improving quality of life for HIV-infected children and adolescents so that they can enter adult life as healthy as possible. Ongoing efforts have been made to develop novel antiretroviral agents with greater potency, higher tolerability and better safety profiles for the young population who need life-long therapy.
Tenofovir disoproxil fumarate (TDF) is an orally bioavailable ester prodrug of tenofovir (TFV). It is a nucleotide reverse-transcriptase inhibitor which has demonstrated inhibitory activity against HIV and also hepatitis B virus (HBV). Its active metabolite, intracellular TFV diphosphate (TFV-DP), is a competitive inhibitor of HIV-1 reverse-transcriptase enzyme and terminates the growing DNA chain. TDF has a long serum half-life of 17 hours which allows for convenient once-daily dosing. The intracellular half-life of TFV-DP ranges from 70 to 150 hours regardless of concomitant ART used. In the fasting state, 25% of the drug is absorbed, with bioavailability increasing to 40% when administered with a high-fat-meal. TFV is mainly eliminated unchanged by the kidneys; thus, dose adjustment is required in patients with significant renal impairment. TFV is not a substrate, inducer or inhibitor of the cytochrome p450 enzyme system. It appears less likely to cause mitochondrial toxicity when compared to nucleoside reverse-transcriptase inhibitors (NRTIs). This property may explain why TDF has less of an effect on lipid profiles and lower risk of lipodystrophy compared to many NRTIs.
In HIV-infected adults, TDF is a recommended first-line drug, replacing the thymidine analoge NRTIs stavudine and zidovudine. There are several fixed-dose combinations (FDC) that contain TDF: TDF/emtricitabine/efavirenz (Atripla), TDF/emtricitabine/rilpivirine (Complera) and TDF/emtricitabine/elvitegravir/cobicistat (Stribild). Other TDF-containing FDC's are still in clinical trials including TDF/lamivudine/efavirenz (Matrix Laboratories Ltd, Hyderabad, India; www.clinicaltrials.gov identifier: NCT01160120). The once-daily co-formulated agents with simple dosing requirements can help improve adherence. This could make the difference between success and failure of ART, especially for adolescents. However, currently, there is no TDF-containing FDC available for preadolescent children.
Abstract and Introduction
Abstract
Tenofovir disoproxil fumarate (TDF) is approved by the Food and Drug Administration for use in children ages 2 years and older and is recommended by the World Health Organization for use as a preferred first-line nucleotide reverse transcriptase inhibitor in adults and adolescents ages 10 years and older. The simplicity of once daily dosing, few metabolic side effects and efficacy against hepatitis B virus make TDF suitable for use in a large scale program. Unlike thymidine analoge nucleoside reverse transcriptase inhibitors (NRTIs); tenofovir does not induce multi-NRTI resistance mutations, so more NRTI options are available for future second-line-regimens. Fixed-dose combinations of TDF with other ARVs as a single tablet regimen are now widely available for adults and adolescents, but none are available for young children. Current information on TDF including the pharmacokinetics, safety and tolerability in children and adolescents was reviewed. A dosing regimen according to body-weight-band has been established for pediatric use. Safety concerns of TDF mainly relate to its effects on renal function and bone mineral density. Regular monitoring of renal function in high-risk patients, including those on other nephrotoxic drugs, may be warranted to detect adverse renal effects. Long-term-data on renal and bone outcomes among HIV-infected children is needed. Lessons learned from clinical studies will help clinicians balance the risks and benefits of TDF and design appropriate antiretroviral regimens for children in different circumstances.
Introduction
The success of antiretroviral therapy (ART) has dramatically changed the prognosis and natural history of pediatric HIV infection. A significant decline in morbidity and mortality has led to an increasing number of children entering their adolescent years. Current treatment strategies aim at improving quality of life for HIV-infected children and adolescents so that they can enter adult life as healthy as possible. Ongoing efforts have been made to develop novel antiretroviral agents with greater potency, higher tolerability and better safety profiles for the young population who need life-long therapy.
Tenofovir disoproxil fumarate (TDF) is an orally bioavailable ester prodrug of tenofovir (TFV). It is a nucleotide reverse-transcriptase inhibitor which has demonstrated inhibitory activity against HIV and also hepatitis B virus (HBV). Its active metabolite, intracellular TFV diphosphate (TFV-DP), is a competitive inhibitor of HIV-1 reverse-transcriptase enzyme and terminates the growing DNA chain. TDF has a long serum half-life of 17 hours which allows for convenient once-daily dosing. The intracellular half-life of TFV-DP ranges from 70 to 150 hours regardless of concomitant ART used. In the fasting state, 25% of the drug is absorbed, with bioavailability increasing to 40% when administered with a high-fat-meal. TFV is mainly eliminated unchanged by the kidneys; thus, dose adjustment is required in patients with significant renal impairment. TFV is not a substrate, inducer or inhibitor of the cytochrome p450 enzyme system. It appears less likely to cause mitochondrial toxicity when compared to nucleoside reverse-transcriptase inhibitors (NRTIs). This property may explain why TDF has less of an effect on lipid profiles and lower risk of lipodystrophy compared to many NRTIs.
In HIV-infected adults, TDF is a recommended first-line drug, replacing the thymidine analoge NRTIs stavudine and zidovudine. There are several fixed-dose combinations (FDC) that contain TDF: TDF/emtricitabine/efavirenz (Atripla), TDF/emtricitabine/rilpivirine (Complera) and TDF/emtricitabine/elvitegravir/cobicistat (Stribild). Other TDF-containing FDC's are still in clinical trials including TDF/lamivudine/efavirenz (Matrix Laboratories Ltd, Hyderabad, India; www.clinicaltrials.gov identifier: NCT01160120). The once-daily co-formulated agents with simple dosing requirements can help improve adherence. This could make the difference between success and failure of ART, especially for adolescents. However, currently, there is no TDF-containing FDC available for preadolescent children.
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