Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Emtricitabine

Drug Interactions

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

• Other nucleoside reverse transcriptase inhibitors (NRTIs): Do not use emtricitabine (FTC) in combination with lamivudine (3TC), because these agents share similar resistance profiles and lack additive benefit. Do not use FTC with fixed-dose combination (FDC) medications that contain 3TC or FTC. See Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a Co-packaged Formulation, by Drug Class, and refer to other sections of the Drug Appendix for drug interaction information for each individual component of an FDC tablet.
• Renal elimination: FTC may compete with other compounds that undergo renal tubular secretion. Drugs that decrease renal function could decrease clearance of FTC.

Major Toxicities

• More common: Headache, insomnia, diarrhea, nausea, rash. Hyperpigmentation/skin discoloration, which may be more common in children than in adults.
• Less common (more severe): Neutropenia. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Exacerbations of hepatitis have occurred in patients with hepatitis B virus (HBV)/HIV coinfection who switched from regimens that included FTC to regimens that did not include FTC.

Resistance

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

Pediatric Use

Approval

FTC is approved by the U.S. Food and Drug Administration for once-daily administration in children, starting at birth. FTC often is used as part of a dual-NRTI backbone in antiretroviral (ARV) regimens for children and adolescents because of its once-daily dosing, minimal toxicity, and favorable pediatric pharmacokinetic (PK) data.

Efficacy and Pharmacokinetics

Comparative Clinical Trials

Studies that assess the efficacy and/or potency of nucleoside/nucleotide analogues have been more concerned with the dynamic components of the regimen—such as tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), or abacavir—than the more static components, such as FTC or 3TC. FTC and 3TC have been considered interchangeable, but data to support this conclusion are lacking. Investigators studying the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort compared the efficacy of TDF plus FTC with TDF plus 3TC when these drugs were administered with a ritonavir-boosted protease inhibitor (darunavir, atazanavir, or lopinavir) in antiretroviral therapy (ART)-naive patients.¹ The adjusted hazard ratio for the virologic failure of 3TC-containing regimens compared with FTC-containing regimens within 240 weeks of starting therapy was 1.15 (95% confidence interval, 0.58–2.27). No difference between these regimens was observed in the time to virologic suppression during the first 48 weeks of therapy or time to virologic failure after attaining suppression. A Swiss cohort study found a potential difference in efficacy between FTC and 3TC; however, the difference disappeared after adjusting for pill burden.² Current evidence suggests that FTC and 3TC have equivalent efficacy and toxicity in ARV-naive patients.

Efficacy

Following a dose-finding study (described in the Pharmacokinetics: Liquid Versus Capsule section below),³ a once-daily dose of FTC 6 mg/kg administered in combination with other ARV drugs was studied in 116 patients aged 3 months to 16 years.⁴ The study used a maximum dose of 240 mg of the FTC liquid formulation. PK results showed that the plasma exposures seen in these children and adolescents were similar to those seen in adults who received FTC 200 mg once daily. Follow-up data extending to Week 96 indicated that 89% of ART-naive children and 76% of ARV-experienced children maintained plasma HIV RNA <400 copies/mL (75% of ARV-naive children and 67% of ARV-experienced children had HIV RNA <50 copies/mL). Minimal toxicity was observed during this trial. Pediatric AIDS Clinical Trials Group (PACTG) P1021⁵ evaluated the use of FTC 6 mg/kg (with a maximum dose of FTC 200 mg per day of the liquid formulation) as part of a three-drug regimen dosed once daily to ARV-naive children aged 3 months to 21 years. In this trial, 85% of children achieved HIV RNA <400 copies/mL, and 72% of children maintained virologic suppression (HIV RNA <50 copies/mL) through 96 weeks of therapy. The median CD4 T lymphocyte count rose by 329 cells/mm³ at Week 96.

Pharmacokinetics: Liquid Versus Capsule

A single-dose PK study of the FTC oral solution and FTC capsules enrolled 25 children with HIV aged 2 years to 17 years.³ FTC was found to be well absorbed following oral administration, with a mean elimination half-life of 11 hours (range, 9.7–11.6 hours). Plasma concentrations in children who received the once-daily dose of FTC 6 mg/kg were approximately equivalent to those seen in adults who received the standard dose of FTC 200 mg. However, plasma concentrations of FTC after administration of the capsule formulation were approximately 20% higher than those observed after administration of the oral solution in this small cohort of children.

Pharmacokinetics in Infants

A study in South Africa evaluated the PKs of FTC in 20 infants aged <3 months with perinatal HIV exposure. The participants received a dose of FTC 3 mg/kg once daily for two 4-day courses, separated by an interval of ≥2 weeks.⁶ FTC exposure (area under the curve [AUC]) in neonates receiving FTC 3 mg/kg once daily was within the range of exposures seen in pediatric patients aged >3 months who received the recommended dose of FTC 6 mg/kg once daily and adults who received the recommended dose of FTC 200 mg once daily. During the first 3 months of life, FTC AUC decreased with increasing age, correlating with an increase in total body clearance of the drug. In a small group of neonates (n = 6) who received a single dose of FTC 3 mg/kg and whose mothers received a single dose of FTC 600 mg during delivery, the FTC AUC exceeded the AUC seen in adults and older children. However, FTC had a half-life of 9.2 hours in these neonates, which is similar to that observed in adults and older children.⁷ Extensive safety data are lacking for this age range.

Considerations for Use

The FTC oral solution has an advantage over the liquid formulation of 3TC because it can be given once daily at ARV initiation, whereas the liquid formulation of 3TC needs to be given twice daily at ARV initiation. When pill formulations of 3TC or FTC are used, they can be administered once daily.

Both FTC and 3TC have antiviral activity and efficacy against HBV. For a comprehensive review of this topic, see the Hepatitis B Virus section in the Pediatric Opportunistic Infection Guidelines.

References

1. Rokx C, Gras L, van de Vijver D, et al. Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment-naive HIV-1-infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. HIV Med. 2016;17(8):571-580 Available at: http://www.ncbi.nlm.nih.gov/pubmed/26842457.
2. Yang WL, Kouyos RD, Scherrer AU, et al. Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV cohort study. J Antimicrob Chemother. 2015;70(12):3323-3331. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26362944.
3. Wang LH, Wiznia AA, Rathore MH, et al. Pharmacokinetics and safety of single oral doses of emtricitabine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2004;48(1):183-191. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14693538.
4. Saez-Llorens X, Violari A, Ndiweni D, et al. Long-term safety and efficacy results of once-daily emtricitabine-based highly active antiretroviral therapy regimens in human immunodeficiency virus-infected pediatric subjects. Pediatrics. 2008;121(4):e827-835. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18332076.
5. McKinney RE, Jr., Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS clinical trials group protocol P1021. Pediatrics. 2007;120(2):e416-423. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17646352.
6. Blum M, Ndiweni D, Chittick Gea. Steady state pharmacokinetic evaluation of emtricitabine in neonates exposed to HIV in utero. Presented at: Conference on Retroviruses and Opportunistic Infections; 2006. Denver, CO. Available at.
7. Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob Agents Chemother. 2011;55(12):5914-5922. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21896911.