Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Last Updated: April 16, 2019; Last Reviewed: April 16, 2019
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
|Note: Bictegravir is only available in a fixed-dose combination tablet.
Fixed-Dose Combination Tablet:
|Dosing Recommendations||Selected Adverse Events|
|[Biktarvy] Bictegravir plus Emtricitabine plus TAF
Child and Adolescent (Aged <18 Years) Dose:
- Metabolism: Bictegravir is a substrate of cytochrome P450 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A1. Tenofovir alafenamide (TAF) is a substrate of P-glycoprotein and UGT1A1. Coadministration of Biktarvy and rifampin is contraindicated.1,2
- Renal effects: Bictegravir is an inhibitor of organic cation transporter 2 and multidrug and toxin extrusion protein 1, so it decreases tubular secretion of creatinine. This increases serum creatinine and reduces estimated glomerular filtration rate with no change in glomerular function. Drugs that decrease renal function could reduce clearance of emtricitabine.
- Absorption: Administering bictegravir concurrently with antacids lowers the plasma concentrations of bictegravir. This is due to formation of complexes in the gastrointestinal tract, and not because of changes in gastric pH. Chelation by high concentrations of divalent cations, such as iron, decreases absorption of integrase strand transfer inhibitors (INSTIs), including elvitegravir and bictegravir. For this reason, Biktarvy should be administered at least 4 hours before or after antacids and iron, calcium, aluminum, and/or magnesium-containing supplements or multivitamins, if Biktarvy is given on an empty stomach. Biktarvy and supplements containing calcium or iron can be taken together with food.
- More common: Diarrhea, nausea, headache. In two clinical trials, total bilirubin increased by up to 2.5 times the upper limit of normal in 12% of patients who received Biktarvy. In general, however, bilirubin increases were quite mild and did not lead to drug discontinuations in these trials.2 Bictegravir may cause an increase in creatine kinase concentration.
- Less common (more severe): Severe immune reconstitution inflammatory syndrome may be more common with INSTIs than with other antiretroviral (ARV) agents.
The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation. Bictegravir, dolutegravir, and cabotegravir, the “second-generation” INSTIs, have higher barriers to resistance than the first-generation INSTIs raltegravir and elvitegravir3,4 and may have more activity against non-B subtypes of HIV.5
Bictegravir is not approved for use in children or adolescents. Bictegravir was approved by the Food and Drug Administration in 2018 for use in adults who have no ARV treatment history. It is also approved to replace the current ARV regimen in patients who have been virologically suppressed (HIV RNA <50 copies/mL) on a stable ARV regimen for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of the fixed-dose combination product Biktarvy, which contains 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of TAF.2
Efficacy in Clinical Trials
In a short-term Phase 1 study, bictegravir monotherapy at doses of 50 mg or 100 mg was well tolerated. Three out of eight participants in both of these dosing groups achieved HIV RNA <50 copies/mL within 11 days during this study.6 The efficacy (viral load suppression [VLS] to HIV RNA <50 copies/mL) and safety (incidence of study drug discontinuation [SDD] or death) of Biktarvy were similar to the efficacy and safety of comparator regimens in two Phase 3 randomized trials in treatment-naive adults. VLS occurred in 89% of participants who received coformulated bictegravir/emtricitabine/TAF (BIC/FTC/TAF) 50 mg/200 mg/25 mg (N = 320) and in 93% of participants who received a regimen of dolutegravir 50 mg plus emtricitabine 200 mg plus TAF 25 mg (N = 325). SDD occurred in 1% of participants in both groups. In a separate trial, VLS occurred in 92% of participants who received BIC/FTC/TAF (N = 314) and in 93% of participants who received coformulated abacavir/dolutegravir/lamivudine (ABC/DTG/3TC) 600 mg/50 mg/300 mg (N = 315). SDD was not reported for any of the participants who received BIC/FTC/TAF, though SDD did occur in 1% of participants who received ABC/DTG/3TC.2,7 Studies that randomized virologically suppressed patients on stable ARV regimens to either continue their current regimens or switch to coformulated BIC/FTC/TAF have shown that BIC/FTC/TAF has similar safety and efficacy to existing regimens. VLS occurred in 94% of participants who were randomized to switch to BIC/FTC/TAF (N = 282) and in 95% of participants who continued taking ABC/DTG/3TC (N = 281). SDD was reported in 2% of participants and 1% of participants, respectively. Ninety-two percent of participants who were randomized to switch to BIC/FTC/TAF (N = 290) achieved VLS, while 89% of participants who continued receiving atazanavir-based or darunavir-based combination ARV regimens (N = 287) achieved VLS. SDD occurred in 1% of participants in both of these groups.2
Pharmacokinetic studies of the adult formulation of Biktarvy, which contains 50 mg of bictegravir, have been performed in adults, adolescents aged 12 years to <18 years who weigh ≥35 kg, and children aged 6 years to <12 years who weigh ≥25 kg. These studies show a higher bictegravir Cmax in the younger cohorts than in the older cohorts, perhaps because the administered dose is higher on a mg/kg basis (see Table A). The lower Ctrough and higher Cmax in the younger age/lower body weight cohorts suggests more rapid clearance in children and adolescents than adults. Even though the mean serum trough concentrations in the child and adolescent cohorts are similar, there is a higher variability among the serum trough concentrations of the child cohort than among those of the adolescent or adult cohorts. This leads to a lower geometric mean ratio when Cmin is compared to adult values, and the lower 90% confidence interval (CI) for the child cohort suggests that some patients have quite rapid clearance. This raises the concern that some of the patients in the youngest age/lowest body weight cohort may experience suboptimal troughs (see Table B).
Aged 6 Years to <12 Years and Weighing ≥25 kg8
Aged 12 Years to <18 Years and Weighing ≥35 kg9
|Dose for the lowest weight in the cohort (mg/kg)||2||1.43||1.25a|
|121,000 (36)||109,668 (31)||102,000 (26.9)|
|11,000 (28)||8,087 (30)||6,150 (22.9)|
|2,370 (79)||2,327 (49)||2,610 (35)|
|aThis dose was calculated using 40 kg as the lowest weight for adults.
Key to Acronyms: AAUCtau = area under the concentration time curve over the dosing interval; Cmax = maximum serum concentration; Ctau = trough serum concentration at the end of the dosing interval; PK = pharmacokinetic
|Cohort Characteristics||Dose (mg)||Dose for Lowest Weight in Cohort (mg/kg)||GMR% (90% CI) Compared to Adult Valuesa|
|Aged 6 Years to <12 Years and Weighing ≥25 kg8||50||2||116 (104–130)||177 (162–194)||78.3 (63.4–96.7)|
|Aged 12 Years to <18 Years and Weighing ≥35 kg9||50||1.43||107 (97–118)||130 (119–143)||86 (74–100)|
|a In this table, child and adolescent PK values are compared to the PK values of adults who received bictegravir 50 mg. The dose for the lowest weight in the adult cohort was 1.25 mg/kg; this was calculated using 40 kg as the lowest weight for adults.
Key to Acronyms: AUCtau = area under the concentration time curve over the dosing interval; CI = confidence interval; Cmax = maximum serum concentration; Ctau = trough serum concentration at the end of the dosing interval; GMR = geometric mean ratio; PK = pharmacokinetic
Use of Biktarvy in Adolescents Aged 12 Years to <18 Years
The adult dose formulation of Biktarvy (BIC/FTC/TAF 50 mg/200 mg/25 mg) was administered to adolescents aged 12 years to <18 years who weighed ≥35 kg and who had had viral loads of <50 copies/mL for ≥6 months on their previous ARV regimens. The drug was well tolerated, and it was associated with a fall in estimated glomerular filtration rate (eGFR) that was similar to the one seen in adult studies. This decrease in eGFR was related to changes in tubular secretion of creatinine and was not a true change in glomerular function. While the area under the curve (AUC) and Cmax for bictegravir were similar in adolescents and adults, the mean bictegravir trough in adolescents aged 12 years to <18 years was 2,327 ng/mL (with a CV of 49%); in adults, the mean bictegravir trough was 2,610 ng/mL (CV 35%). The geometric mean ratio of the adolescent/adult trough concentration was 86% (90% CI, 74–100). All 24 participants in the study maintained viral loads <50 copies/mL at Week 24.9
Use of Biktarvy in Children Aged 6 Years to <12 Years
BIC/FTC/TAF 50 mg/200 mg/25 mg was administered to children aged 6 years to <12 years who weighed ≥25 kg and who had had viral loads <50 copies/mL for ≥6 months on their current ARV regimens. Despite a high AUC and Cmax, the drug combination was well tolerated, with a fall in eGFR similar to that seen in adult studies, which is related to changes in tubular secretion of creatinine and not a true change in glomerular function. There is higher variability among the serum trough concentrations of the child cohort than among those of the adolescent or adult cohorts, and a lower geometric mean ratio when Cmin is compared to adult values (Table B), although population pharmacokinetic modeling suggests a Cmin comparable to adult values.10 All 50 participants in the study had viral loads <50 copies/mL at Week 12, and the 26 participants with data up to Week 24 likewise all had viral loads <50 copies/mL.8
The two studies described above were combined and carried to 48 weeks, at which time 74 of 75 participants had viral load <50 copies/mL.10
- Custodio JM, West SK, Collins S, et al. Pharmacokinetics of bictegravir administered twice daily in combination with rifampin. Presented at: Conference on Retroviruses and Opportunistic Infections. 2018. Boston, MA. Available at: http://www.croiconference.org/sessions/pharmacokinetics-bictegravir-administered-twice-daily-combination-rifampin.
- Bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf.
- Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60(12):7086-7097. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27645238.
- Hassounah SA, Alikhani A, Oliveira M, et al. Antiviral activity of bictegravir and cabotegravir against integrase inhibitor-resistant SIVmac239 and HIV-1. Antimicrob Agents Chemother. 2017;61(12). Available at: https://www.ncbi.nlm.nih.gov/pubmed/28923862.
- Neogi U, Singh K, Aralaguppe SG, et al. Ex-vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV type 1 non-B subtypes. AIDS. 2018;32(4):469-476. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29239896.
- Gallant JE, Thompson M, DeJesus E, et al. Antiviral activity, safety, and pharmacokinetics of bictegravir as 10-day monotherapy in HIV-1-infected adults. J Acquir Immune Defic Syndr. 2017;75(1):61-66. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28196003.
- Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063-2072. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28867497.
- Cotton M, Liberty A, Rodriguez CA, et al. Pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) single-tablet regimen in HIV-1-infected children (6 to < 12 years) Presented at: International AIDS Conference. 2018. Amsterdam, Netherlands. Available at: http://www.natap.org/2018/IAC/IAC_39.htm.
- Gaur A, Rodriguez C, McGrath EJ, et al. Bictegravir/FTC/TAF single-tablet regimen in adolescents: week 24 results. Presented at: Conference on Retroviruses and Opportunistic Infections. 2018. Boston, MA. Available at: http://www.croiconference.org/sessions/bictegravirftctaf-single-tablet-regimen-adolescents-week-24-results.
- Gaur A, Cotton M, Rodriguez C, et al. Bictegravir/FTC/TAF single-tablet regimen in adolescents & children: week 48 results. Presented at: Conference on Retroviruses and Opportunistic Infections. 2019. Seattle, WA. Available at: http://www.croiwebcasts.org/p/2019croi/46.