Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Last Updated: September 8, 2016; Last Reviewed: September 8, 2016
|Dolutegravir (DTG, Tivicay)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
|Tablets: 10 mg, 25 mg, and 50 mg
Fixed-Dose Combination Tablet:
|Dosing Recommendations||Selected Adverse Events|
Note: When ordering dolutegravir 10 mg or 25 mg tablets have the pharmacy call their drug wholesaler and tell the drug wholesaler to order directly from the GSK distribution center. The GSK distribution center will ship the formulation directly to the pharmacy.
[Triumeq] Abacavir plus Dolutegravir plus Lamivudine:
Adolescent (Weighing ≥40 kg) and Adult Dose:
Drug Interactions(see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)
- Metabolism: Dolutegravir is a UGT1A1 and CYP3A substrate and may require dosage adjustments when administered with UGT1A1 or CYP3A-modulating medications. Because etravirine significantly reduces plasma concentrations of dolutegravir, dolutegravir should not be administered with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir, which counteracts this effect on dolutegravir concentrations. Dolutegravir should not be administered with nevirapine because of insufficient data.
- Before dolutegravir is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions.
- More common: Insomnia and headache
- Less common (more severe): Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, neuropsychiatric symptoms.
The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10), and the Stanford University HIV Drug Resistance database offers a discussion of integrase strand transfer inhibitor (INSTI) mutations (http://hivdb.stanford.edu/DR/). The efficacy of 50 mg dolutegravir twice daily is reduced in patients with INSTI-resistance Q148 substitution plus two or more additional INSTI-resistance mutations: T66A, L74I/M, E138A/K/T, G140SA/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.
Dolutegravir is Food and Drug Administration (FDA)-approved in combination with other antiretroviral drugs for children, weighing at least 30 kg, and who are treatment-naive or treatment-experienced but INSTI-naive.1
Efficacy and Pharmacokinetics
IMPAACT P1093 is an ongoing open-label trial of HIV-infected children with the plan to enroll down to age 4 weeks. FDA approval of dolutegravir down to age 12 years/40 kg was based on data from 23 treatment-experienced, INSTI-naive adolescents.2 Intensive pharmacokinetic (PK) evaluations were performed on the first 10 participants (9 weighing ≥40 kg and receiving 50 mg, 1 weighing 37 kg and receiving 35 mg) and revealed exposures comparable to those seen in adults receiving 50 mg once daily. Nine of 10 participants achieved HIV RNA concentration <400 copies/mL at week 4 (optimal background therapy was added 5 to 10 days after dolutegravir was started). An additional 13 participants were then enrolled for evaluation of long-term outcomes. At 48 weeks, 61% had achieved HIV RNA concentration <50 copies/mL. No safety or tolerability concerns were identified. By week 144, 39% and 30% had achieved HIV RNA concentrations <400 and <50 copies/mL, respectively.3 All who experienced virologic failure were nonadherent. In addition, children aged ≥6 to <12 years are undergoing PK and longer-term follow up in P1093, with those weighing ≥30 to <40 kg receiving the 35 mg dose and those weighing ≥40 kg using the 50 mg dose. To date, data from 11 participants have demonstrated a favorable safety profile, adequate PK, and virologic efficacy through 24 weeks.2,4 This has led to FDA approval of the lower strength tablets for HIV-infected children as young as 6 years and with body weight as low as 30 kg. An oral pediatric granule formulation is also being studied. Doses for smaller children are under investigation in P1093.
|Population of Study||Weight (kg)||Dose (mg/day)||Tablets||Tablet Size (mg)||Dosing Frequency||Dose for Lowest Weight in Weight Band (mg/kg)||Trough Plasma Concentrationa mcg/mL|
|Adults with Prior INSTI Treatment||>40||100||2||50||Twice daily||2.5||2.12 (47)b|
|Adults without Prior INSTI Treatment||≥40||50||1||50||Once daily||1.25||1.11 (46)|
|Children without Prior INSTI Treatment (N = 14)||≥40||50||1||50||Once daily||1.25||0.99 (66)|
|Children without Prior INSTI Treatment (N = 3)||30 to <40||35||2||10 plus 25||Once daily||1.17||1.33 (93)|
|a Source: Dolutegravir [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204790Orig1s008lbl.pdf
b Geometric mean (percent coefficient of variation)
Note: Recommendations for 100 mg/day are for adults in special circumstances using 50 mg twice daily (see product label or text above).
- Dolutegravir [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204790Orig1s008lbl.pdf. Accessed August 29, 2016.
- Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV-1 infected adolescents: 48-week results from IMPAACT P1093. Pediatr Infect Dis J. 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/26244832.
- Viani R, Alvero C, Fenton T, et al. Long-term safety and efficacy of dolutegravir in HIV treatment-experienced adolescents. Presented at: Infectious Disease Week. 2015. San Diego, CA.
- Viani R, Carmelita A, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV+ children. Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.