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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Children Receiving Antiretroviral Therapy

Modifying Antiretroviral Regimens in Children with Sustained Virologic Suppression on Antiretroviral Therapy

(Last updated: March 5, 2015; last reviewed: March 5, 2015)


Panel's Recommendations

  • For children who have sustained virologic suppression on their current regimen, changing to a new antiretroviral regimen can be considered in order to facilitate adherence, decrease drug-associated toxicities, or improve safety (BII).
  • It is critical to consider past episodes of antiretroviral treatment failure, tolerability, and all prior drug resistance testing results to avoid choosing new ARV drugs for which archived drug resistance would limit activity.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials in children with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion

Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents

Initial ARV regimens are chosen based on safety, pharmacokinetic and efficacy data for drugs available in formulations suitable for the age of the child at initiation of cART. New ARV options may become available as children grow and learn to swallow pills and as new drugs, drug formulations, and data become available. For children who have sustained virologic suppression (e.g., 6–12 months) on their current regimen, changing to a new ARV regimen may be considered in order to permit use of pills instead of liquids, reduce pill burden, allow use of once-daily medications, reduce risk of adverse effects, and align their regimens with widely used, efficacious adult regimens.

Several studies have addressed switching ARV regimen components in children with sustained virologic suppression. Based on the NEVEREST study, young children (aged <3 years) with virologic suppression who switch from lopinavir/ritonavir to nevirapine can maintain virologic suppression as well as those who continue lopinavir/ritonavir, provided there is good adherence and no baseline resistance to nevirapine.1,2 In the NEVEREST 3 study, young children with history of exposure to nevirapine and with virologic suppression on lopinavir/ritonavir maintained virologic suppression when switched from lopinavir/ritonavir to efavirenz.3 By extrapolation, replacement of lopinavir/ritonavir with an equally potent protease inhibitor (PI) (e.g., darunavir, atazanavir), raltegravir, or another integrase inhibitor (INSTI) would likely be effective, but this has not been directly studied. Several small studies have demonstrated sustained virologic suppression and reassuring safety outcomes when drugs that have greater long-term toxicity risk are replaced with drugs that are thought to have less toxicity risk (e.g., replacing stavudine with tenofovir disoproxil fumarate, zidovudine, or abacavir; replacing PIs with non-nucleoside reverse transcriptase inhibitors), including improved lipid profiles, in small cohorts of children.4-8 Small studies have shown that children with virologic suppression on certain twice-daily regimens (i.e., abacavir, nevirapine) maintain virologic suppression if changed from twice daily to once daily (see Abacavir and Nevirapine drug sections) but show mixed results when switching lopinavir/ritonavir dosing from twice daily to once daily; therefore, once-daily lopinavir/ritonavir is not recommended.9-11

Table 14 displays examples of changes in ARV regimen components that are made for reasons of simplification, convenience, and safety profile in children who have sustained virologic suppression on their current regimen. When considering such a change, it is important to ensure that a child does not have virologic treatment failure. It is also critical to consider past episodes of ARV treatment failure, tolerability, and all prior drug resistance testing results in order to avoid choosing new ARV drugs for which archived drug resistance would limit activity. The evidence supporting many of these ARV changes is indirect, extrapolated from data about drug performance in initial therapy or follow-on therapy after treatment failure. When such changes are made, careful monitoring is important to ensure that virologic suppression is maintained.

Table 14: Examples of Changes in Antiretroviral Regimen Components that Are Made for Reasons of Simplification, Convenience, and Safety Profile in Children Who Have Sustained Virologic Suppression on Their Current Regimensa

ARV Drug(s) Current Age Body Size Attained Potential ARV Regimen Change Commentb
NRTIs
ABC Twice Daily ≥1 year Any ABC once daily See Abacavir in Appendix A: Pediatric Antiretroviral Drug Information for full discussion.
ZDV or ddI (or d4Tc)
≥1 year N/A ABC Once-daily dosing (see Abacavir in Appendix A: Pediatric Antiretroviral Drug Information). Less long-term mitochondrial toxicity.
Adolescence
Pubertal maturity (i.e., Tanner IV or V) TDF
ABC
Once-daily dosing. Less long-term mitochondrial toxicity. Co-formulation with other ARVs can further reduce pill burden.
PIs
LPV/r
Twice Daily1
≥1 year ≥3 kg RAL or ATV/r Better palatability. Less adverse lipid effect. Lower pill burden. Once-daily dosing (ATV/r).
≥3 years N/A ATV/r
EFV
DRV/r
RAL
Once-daily dosing (EFV and ATV/r). Better palatability. Less adverse lipid effect. See Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information regarding concerns about dosing for children <3 years.
≥12 years
≥40 kg DRV/r
ATV/r
DTG
Once-daily dosing possible. Lower pill burden.
Other
Any Multi-Pill and/or Twice-Daily Regimen Adolescence Pubertal maturity (i.e., Tanner IV or V) Co-formulated:
  • TDF/FTC/EFV
  • TDF/FTC/EVG/COBI
  • TDF/FTC/RPV
  • ABC/3TC/DTG
Once-daily dosing. Single pill. Alignment with adult regimens.
a This list is not exhaustive in that it does not necessarily list all potential options, but instead, shows examples of what kinds of changes can be made.
b Comments relevant to the potential ARV change listed. Does not include all relevant information. Please refer to individual drug tables for full information.
c Because of concerns about long-term adverse effects, d4T may be replaced with a safer drug even before sustained virologic suppression is achieved (see Stavudine in Appendix A: Pediatric Antiretroviral Drug Information).
Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ATV/r = atazanavir/ritonavir; COBI = cobicistat; d4T = stavudine; ddI = didanosine; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FTC = emtricitabine; LPV/r = lopinavir/ritonavir; RAL = raltegravir; RPV = rilpivirine; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

References

  1. Coovadia A, Abrams EJ, Stehlau R, et al. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial. JAMA. 2010;304(10):1082-1090. Available at http://www.ncbi.nlm.nih.gov/pubmed/20823434.
  2. Kuhn L, Coovadia A, Strehlau R, et al. Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial. Lancet Infect Dis. 2012;12(7):521-530. Available at http://www.ncbi.nlm.nih.gov/pubmed/22424722.
  3. Coovadia A, Abrams E, Strehlau R, et al. NEVEREST Study Team. Virologic Efficacy of Efavirenz Maintenance Therapy in Nevirapine Prophylaxis-Exposed Children. Abstract #73. Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
  4. Vigano A, Aldrovandi GM, Giacomet V, et al. Improvement in dyslipidaemia after switching stavudine to tenofovir and replacing protease inhibitors with efavirenz in HIV-infected children. Antivir Ther. 2005;10(8):917-924. Available at http://www.ncbi.nlm.nih.gov/pubmed/16430197.
  5. Fabiano V, Giacomet V, Vigano A, et al. Long-term body composition and metabolic changes in HIV-infected children switched from stavudine to tenofovir and from protease inhibitors to efavirenz. Eur J Pediatr. 2013;172(8):1089-1096. Available at http://www.ncbi.nlm.nih.gov/pubmed/23636286.
  6. Rosso R, Nasi M, Di Biagio A, et al. Effects of the change from Stavudine to tenofovir in human immunodeficiency virus-infected children treated with highly active antiretroviral therapy: studies on mitochondrial toxicity and thymic function. Pediatr Infect Dis J. 2008;27(1):17-21. Available at http://www.ncbi.nlm.nih.gov/pubmed/18162932.
  7. Aurpibul L, Puthanakit T, Sirisanthana T, Sirisanthana V. Haematological changes after switching from stavudine to zidovudine in HIV-infected children receiving highly active antiretroviral therapy. HIV Med. 2008;9(5):317-321. Available at http://www.ncbi.nlm.nih.gov/pubmed/18331562.
  8. Gonzalez-Tome MI, Amador JT, Pena MJ, Gomez ML, Conejo PR, Fontelos PM. Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children. BMC Infect Dis. 2008;8:144. Available at http://www.ncbi.nlm.nih.gov/pubmed/18945352.
  9. Foissac F, Blanche S, Dollfus C, et al. Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents. Br J Clin Pharmacol. 2011;72(6):940-947. Available at http://www.ncbi.nlm.nih.gov/pubmed/21649692.
  10. Chokephaibulkit K, Prasitsuebsai W, Wittawatmongkol O, et al. Pharmacokinetics of darunavir/ritonavir in Asian HIV-1-infected children aged >/=7 years. Antivir Ther. 2012;17(7):1263-1269. Available at http://www.ncbi.nlm.nih.gov/pubmed/22954687.
  11. Lyall H. Final results of Koncert: A randomized noninferiority trial of QD vs BD LPV/r dosing in children. Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.

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