Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Tenofovir disoproxil fumarate (TDF) is a substrate of the adenosine triphosphate–dependent transporters P-glycoprotein and breast cancer resistance protein. When TDF is coadministered with inhibitors of these transporters, an increase in TDF absorption may be observed, with the potential for enhanced TDF toxicity.¹
• Renal elimination: Drugs that decrease renal function or compete for active tubular secretion could reduce clearance of plasma tenofovir (TFV). Avoid frequent or long-term use of nonsteroidal anti-inflammatory drugs in patients who are taking TDF.
• Other nucleoside reverse transcriptase inhibitors: Didanosine (ddI) serum concentrations increase when this drug is coadministered with TDF, and this combination should not be used because of the increased risk of ddI toxicity.
• Protease inhibitors (PIs): Atazanavir (ATV) without ritonavir (RTV) should not be coadministered with TDF, because TDF decreases ATV plasma concentrations. The combination of ATV/r, darunavir (DRV)/r, and lopinavir/r increases plasma TFV concentrations and increases the risk of TDF-associated toxicity.^1,2
• Absorption: Administering elvitegravir (EVG) concurrently with antacids and supplements that contain iron, calcium, aluminum, and/or magnesium lowers plasma concentrations of EVG. Similarly, dolutegravir (DTG) should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or buffered medications.³ If using Stribild, see the Elvitegravir section of Appendix A: Pediatric Antiretroviral Drug Information for additional information.

Major Toxicities

• More common: Nausea, diarrhea, vomiting, flatulence
• Less common (more severe): TDF caused bone toxicity (osteomalacia and reduced bone mineral density [BMD]) in animals when given in high doses. Decreases in BMD have been reported in both adults and children taking TDF. Renal toxicity—including increased serum creatinine, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreased serum phosphate—has been observed. Patients at increased risk of renal glomerular or tubular dysfunction should be closely monitored. Cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported.

Resistance

The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

TDF has been approved by the U.S. Food and Drug Administration (FDA) for use in children aged ≥2 years and weighing ≥10 kg when used as a component of antiretroviral therapy (ART). TDF is available as a component of fixed-dose combination tablets (see Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents).

TDF has antiviral activity and efficacy against hepatitis B virus (HBV) and is approved by the FDA for HBV treatment in children aged ≥2 years and weighing ≥10 kg. For a comprehensive review of this topic, see the Hepatitis B Virus section in the Pediatric Opportunistic Infection Guidelines.

Efficacy in Clinical Trials in Adults Compared with Children and Adolescents

The standard adult dose that was approved by the FDA for adults and children aged ≥12 years and weighing ≥35 kg is TDF 300 mg once daily. For children aged 2 to 12 years, the FDA-approved dose is TDF 8 mg/kg per dose administered once daily, which closely approximates the dose of TDF 208 mg/m² per dose used in early studies in children.⁴

In adults, the recommended once-daily dose of TDF 300 mg is highly effective when used in combination with other antiretroviral (ARV) drugs.^5-12 The FDA approved Cimduo and Temixys (both of which contain lamivudine [3TC] 300 mg/TDF 300 mg) and Symfi (efavirenz [EFV] 600 mg/3TC 300 mg/TDF 300 mg) based on results of prior clinical trials.^6,13 FDA approval of Symfi Lo (EFV 400 mg/3TC 300 mg/TDF 300 mg) was based on a study that compared the use of EFV 400 mg with the use of EFV 600 mg, each administered with emtricitabine 200 mg and TDF 300 mg, in 630 ART-naive adults.¹⁴ See the Efavirenz section for a detailed discussion of this study. In a large randomized controlled trial comparing second-line ART regimens, continuing TDF was superior to switching to zidovudine, when given in combination with 3TC and either dolutegravir or DRV/r.^15-17

In children, the published efficacy data for TDF-containing ARV combinations are mixed, but potency equal to that in adults has been seen in pediatric patients aged 3 to 18 years with susceptible virus. In children aged 2 years to <12 years, TDF 8 mg/kg per dose once daily was noninferior to twice-daily zidovudine-containing ART or stavudine-containing ART over 48 weeks of randomized treatment.^18,19 Virologic success is lower in treatment-experienced patients with extensive multiclass drug resistance.^20-22 In an analysis of genotypic resistance testing performed on 650 unique patients at a single laboratory in the Republic of South Africa, predicted intermediate or high-level resistance to TDF was lower for children experiencing virologic failure while on abacavir (ABC)-containing (8.5%) and zidovudine-containing (9.4%) regimens than those experiencing virologic failure while on a TDF-containing regimen (24.6%). Clinical data are lacking in children on the efficacy of switching from a failing regimen containing these NRTIs to a regimen containing TDF.²³

Pharmacokinetics

Relationship of Drug Exposure to Virologic Response

Virologic suppression is most closely related to intracellular tenofovir diphosphate (TFV-DP) concentrations and, for TDF, intracellular TFV-DP is linked to plasma TFV concentration.²⁴ A modeling study suggests that children and adolescents who are treated with TDF may have higher intracellular TFV-DP concentrations than adults,²⁵ even though plasma TFV concentrations are lower in children and adolescents, because weight-adjusted renal clearance of TFV is higher in children than in adults.^4,26,27

Formulations

Special Considerations

The taste-masked granules that make up the TDF oral powder give the vehicle (e.g., applesauce, yogurt) a gritty consistency. Once mixed with a vehicle, TDF should be administered promptly because its taste becomes bitter when it is allowed to sit for too long.

Toxicity

Bone Toxicity

TDF administration is associated with decreased BMD in both adults^28,29 and children.^19,30-32 When treated with TDF, younger children with sexual maturity ratings (SMRs) of 1 and 2 may be at a higher risk of decreased BMD than children with more advanced pubertal development (i.e., SMRs ≥3).²⁶ Discontinuation of TDF results in partial or complete recovery of BMD.^30,33

In the study that led to FDA approval of TDF in adolescents aged ≥12 years and weighing ≥35 kg, 6 of 33 participants (18%) in the TDF arm experienced a >4% decline in absolute lumbar spine BMD in 48 weeks, whereas only 1 of 33 participants (3%) in the placebo arm experienced this decline.²⁰

TDF administration disrupts vitamin D metabolism,^34,35 and the decrease in BMD associated with TDF initiation was attenuated in adults with coadministration of high doses of vitamin D3 (4,000 International Units [IU] daily) and calcium carbonate (1,000 mg daily) for the first 48 weeks of TDF treatment.³⁶ During chronic TDF administration, youth with HIV who received vitamin D3 supplements (50,000 IU once monthly) had decreased serum parathyroid hormone levels and increased lumbar spine BMD compared with study participants who were not treated with high doses of vitamin D3.^34,37 The serum 25‑hydroxy vitamin D concentration was 37 ng/mL in the group with improved BMD. Similar improvements in BMD were seen in youth with HIV who were treated with an ARV regimen that included TDF and who received vitamin D3 2,000 IU or 4,000 IU daily.³⁸ Measurement of plasma vitamin D concentration is recommended for patients who are being treated with an ARV regimen that includes TDF, and vitamin D supplementation is recommended for those with vitamin D deficiency (see Table 17j. Osteopenia and Osteoporosis).

High concentrations of the TDF metabolite plasma TFV have been associated with TDF-related endocrine disruption and low BMD.³⁹ Plasma TFV concentrations are higher when TDF is coadministered with boosted PIs.¹ Tenofovir alafenamide (TAF), which is associated with lower plasma TFV concentrations than TDF, has less effect on parathyroid hormone levels⁴⁰ and causes less decline in BMD than TDF. See the Tenofovir Alafenamide section for more information. Consider switching from TDF to TAF or avoiding coadministration of TDF with boosted PIs in patients for whom loss of BMD is a concern.

Monitoring Potential Bone Toxicity

The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) does not recommend routine dual-energy X-ray absorptiometry (DXA) monitoring for children or adolescents who are being treated with TDF (see Table 17j. Osteopenia and Osteoporosis).

TDF has been shown to be effective, and it can be administered once daily; however, the use of TDF has been associated with a risk of BMD loss. Because childhood and early adolescence are important periods of rapid bone accrual, and because children with perinatally acquired HIV are at risk for low peak bone mass,^41,42 the Panel favors the use of abacavir or TAF over TDF in children with SMRs 1 to 3.

Renal Toxicity

New-onset renal impairment and worsening renal impairment have been reported in adults⁴³ and children^44,45 receiving TDF. In one study, renal toxicity led to discontinuation of TDF in 6 of 159 (3.7%) children with HIV who were treated with TDF.²² Although TDF is clearly associated with a decline in glomerular filtration rate, the effect is generally small, and severe glomerular toxicity is rare.^43,44 Irreversible renal failure is quite rare, but cases have been reported.⁴⁶

The main target of TDF nephrotoxicity is the renal proximal tubule.⁴⁴ Case reports highlight the infrequent but most severe manifestations of renal Fanconi syndrome, hypophosphatemia, hypocalcemia, diabetes insipidus, myalgias, bone pain, and fractures.^47,48

Subclinical renal tubular damage is more common than clinically apparent renal tubular injury. Increased urinary beta-2 microglobulin was identified in 12 of 44 children (27%) who were treated with TDF and in 2 of 48 children (4%) who were not treated with TDF.⁴⁹ The risks of TDF-associated proteinuria and chronic kidney disease increase with the duration of treatment.^50,51 Of 89 participants aged 2 to 12 years who received TDF in Gilead Study 352 (where participants had a median drug exposure of 104 weeks), four participants were discontinued from the study for renal tubular dysfunction, with the discontinuations occurring between 84 and 156 weeks on TDF therapy.¹⁸ In adults, renal dysfunction is more common when TDF is used in patients with older age or a pre-existing renal disease⁵²; in children, renal dysfunction may be more common when TDF is used with boosted PIs than with non-nucleoside reverse transcriptase inhibitors.⁵³

Plasma TFV is the TDF metabolite most closely associated with both glomerular^39,54 and proximal tubular⁵⁵ toxicity. As previously noted, plasma TFV concentrations are higher when TDF is coadministered with boosted PIs.¹ TAF, which generates lower plasma TFV concentrations than TDF, is associated with a lower risk of renal toxicity than TDF⁵⁶ (see Tenofovir Alafenamide).

Monitoring Potential Renal Toxicity

Because TDF has the potential to decrease creatinine clearance and cause renal tubular dysfunction, the Panel recommends measuring serum creatinine and using a urine dipstick to check protein and glucose concentration before initiating TDF. It is unclear how often creatinine and renal tubular function (urine protein and glucose) should be monitored in asymptomatic patients. Many Panel members monitor creatinine with other blood tests every 3 to 4 months and perform urinalysis every 6 to 12 months. Serum phosphate should be measured if clinically indicated; renal phosphate loss can occur in the presence of normal creatinine and in the absence of proteinuria. Because nephrotoxicity increases with the duration of TDF treatment, monitoring should be continued during long-term therapy with the drug.

Because renal glomerular damage primarily increases the concentration of albumin in urine, and proximal renal tubular damage increases the concentration of low-molecular-weight proteins like beta-2 microglobulin in urine, dipstick urinalysis (which primarily measures urine albumin) may be a relatively insensitive marker for TDF-associated tubular damage. Measuring urine albumin and urine protein and calculating the ratio of urine albumin to urine protein can be helpful in identifying the non-albumin proteinuria that is seen in TDF-associated nephrotoxicity.^57,58 Although these more complex and expensive tests may be used in research settings, in clinical practice, using a renal dipstick to identify normoglycemic glycosuria and proteinuria is the easiest way to detect renal damage.

References

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