Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
What Drugs to Start: Initial Combination Therapy for Antiretroviral Treatment-Naive Children
(Last updated:11/1/2012; last reviewed:11/1/2012)
- Combination therapy consisting of a dual-nucleoside/nucleotide reverse transcriptase inhibitor backbone with either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor is recommended for initial treatment of HIV-infected children (AI).
- The goal of therapy in treatment-naive children is to reduce plasma HIV RNA levels to below the limits of quantitation using the most sensitive assays and to preserve or normalize immune status (AI).
- Antiretroviral (ARV) drugs initiated for chemoprophylaxis of maternal-child transmission of HIV should be discontinued in infants who are confirmed to be HIV-infected (AI).
- ARV drug-resistance testing is recommended before initiation of therapy in all treatment-naive infants, children, and adolescents (AII infants; AIII children and adolescents).
|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 and adolescents but not studies limited to postpubertal adolescents
More than 20 antiretroviral (ARV) drugs are Food and Drug Administration-approved for use in HIV-infected adults and adolescents and 19 have an approved pediatric treatment indication.1 The majority of the agents approved for use in pediatric patients are available as a liquid, powder, chewable tablet, or small capsule or tablet suitable for pediatric use. ARV drugs fall into several major drug classes: nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors (including fusion inhibitors and CCR5 antagonists), and integrase inhibitors. Information on drug formulation, pediatric dosing, and toxicity for the individual drugs and detailed information on drug interactions can be found in Appendix A: Pediatric Antiretroviral Drug Information. Over time, new drugs and drug combinations that demonstrate sustainable viral load suppression and acceptable toxicity and dosing profiles will likely become available, which will increase treatment options for children.
Combination antiretroviral therapy (cART) with at least three drugs from at least two drug classes is recommended for initial treatment of HIV-infected infants, children, and adolescents because it provides the best opportunity to preserve immune function and delay disease progression.2-5 The goal of cART is to maximally suppress viral replication, preferably to below the limits of quantification, for as long as possible while preserving and/or restoring immune function and minimizing drug toxicity. Combination therapy slows disease progression and improves survival, results in a greater and more sustained virologic and immunologic response, and delays development of viral mutations that confer resistance to the drugs being used.4-6
If an infant is confirmed to be HIV-infected while receiving chemoprophylaxis to prevent mother-to-child transmission (PMTCT) of HIV, prophylactic ARV drugs should be discontinued promptly and treatment initiated with a combination regimen of at least three drugs. Zidovudine can be included as a component of the treatment regimen if zidovudine drug resistance is not detected.
Treatment-naive infants and children with perinatal HIV infection can have drug-resistant virus either because it was transmitted perinatally or during breastfeeding or because resistance developed while they were receiving ARV prophylaxis. Thus, ARV drug-resistance testing is recommended before initiation of therapy in all treatment-naive infants and children. In infants receiving prophylactic ARV drugs for PMTCT, ARV drug resistance testing can be performed at the same time as confirmatory HIV testing or when prophylactic ARV drugs are discontinued. In a study in New York State, genotypic drug resistance was identified in 12% of 91 HIV-infected infants born from 1998 to 1999 and in 19% of 42 infants born from 2000 to 2001.7,8 Detection of resistance in the infants was not significantly associated with a history of maternal and infant ARV prophylaxis. Similarly, following initiation of treatment, mutations associated with drug resistance were detected in 24% of 21 infants at a median age of 9.7 weeks. Most of the mutations were not associated with maternal/infant prophylaxis regimens and resistant virus was persistently archived in the resting CD4 cell reservoir in all the infants. In a study in Africa, infants, regardless of whether they were exposed to nevirapine as part of PMTCT, had higher rates of virologic failure on nevirapine-based regimens compared with lopinavir/ritonavir-based regimens.9-11 In a Spanish cohort of children, resistance mutations were detected in 13% of treatment-naive children.12 In the United States and Europe, drug-resistant virus has been identified in 6% to 16% of ARV-naive adults and 18% of adolescents with recently acquired HIV infection.13-17 For ARV-naive children beyond infancy, limited available data do not demonstrate that resistance testing before initiation of therapy correlates with greater success of initial ART.18 Nevertheless, because the prevalence of resistance in HIV-infected children is sufficiently high and on the basis of expert opinion, the Panel recommends ARV drug-resistance testing with a genotypic assay before initiation of therapy in all treatment-naive infants and children and use of resistance testing results to select the initial drug combination.19 (See Antiretroviral Drug-Resistance Testing.) Resistance testing in HIV-infected adolescents and adults is also recommended at entry into care.
- Food and Drug Administration. Approved antiretroviral drugs for pediatric treatment of HIV infection. Accessed on June 20, 2012. http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118951.htm.
- Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: A randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA. Jan 26 2000;283(4):492-498. Available at http://www.ncbi.nlm.nih.gov/pubmed/10659875.
- Chiappini E, Galli L, Gabiano C, Tovo PA, de Martino M, Italian Register for HIVIiC. Early triple therapy vs. mono or dual therapy for children with perinatal HIV infection. JAMA. Feb 8 2006;295(6):626-628. Available at http://www.ncbi.nlm.nih.gov/pubmed/16467231.
- de Martino M, Tovo PA, Balducci M, et al. Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. Italian Register for HIV Infection in Children and the Italian National AIDS Registry. JAMA. Jul 12 2000;284(2):190-197. Available at http://www.ncbi.nlm.nih.gov/pubmed/10889592.
- Gortmaker SL, Hughes M, Cervia J, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med. Nov 22 2001;345(21):1522-1528. Available at http://www.ncbi.nlm.nih.gov/pubmed/11794218.
- Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. Nov 20 2008;359(21):2233-2244. Available at http://www.ncbi.nlm.nih.gov/pubmed/19020325.
- Karchava M, Pulver W, Smith L, et al. Prevalence of drug-resistance mutations and non-subtype B strains among HIV-infected infants from New York State. J Acquir Immune Defic Syndr. Aug 15 2006;42(5):614-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/16868498.
- Parker MM, Wade N, Lloyd RM Jr., et al. Prevalence of genotypic drug resistance among a cohort of HIV-infected newborns. J Acquir Immune Defic Syndr. Mar 1 2003;32(3):292-297. Available at http://www.ncbi.nlm.nih.gov/pubmed/12626889.
- Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med. Oct 14 2010;363(16):1510-1520. Available at http://www.ncbi.nlm.nih.gov/pubmed/20942667.
- Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. Jun 21 2012;366(25):2380-2389. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716976.
- Persaud D, Palumbo P, Ziemniak C, et al. Early archiving and predominance of nonnucleoside reverse transcriptase inhibitor-resistant HIV-1 among recently infected infants born in the United States. J Infect Dis. May 15 2007;195(10):1402-1410. Available at http://www.ncbi.nlm.nih.gov/pubmed/17436219.
- de Mulder M, Yebra G, Martin L, et al. Drug resistance prevalence and HIV-1 variant characterization in the naive and pretreated HIV-1-infected paediatric population in Madrid, Spain. J Antimicrob Chemother. Oct 2011;66(10):2362-2371. Available at http://www.ncbi.nlm.nih.gov/pubmed/21810838.
- Cane P, Chrystie I, Dunn D, et al. Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study. BMJ. Dec 10 2005;331(7529):1368. Available at http://www.ncbi.nlm.nih.gov/pubmed/16299012.
- Novak RM, Chen L, MacArthur RD, et al. Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis. Feb 1 2005;40(3):468-474. Available at http://www.ncbi.nlm.nih.gov/pubmed/15668873.
- Viani RM, Peralta L, Aldrovandi G, et al. Prevalence of primary HIV-1 drug resistance among recently infected adolescents: a multicenter adolescent medicine trials network for HIV/AIDS interventions study. J Infect Dis. Dec 1 2006;194(11):1505-1509. Available at http://www.ncbi.nlm.nih.gov/pubmed/17083034.
- Weinstock HS, Zaidi I, Heneine W, et al. The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-infected persons in 10 US cities. J Infect Dis. Jun 15 2004;189(12):2174-2180. Available at http://www.ncbi.nlm.nih.gov/pubmed/15181563.
- Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis. Sep 15 2005;192(6):958-966. Available at http://www.ncbi.nlm.nih.gov/pubmed/16107947.
- Fiscus SA, Kovacs A, Petch LA, et al. Baseline resistance to nucleoside reverse transcriptase inhibitors fails to predict virologic response to combination therapy in children (PACTG 338). AIDS Res Ther. 2007;4:2. Available at http://www.ncbi.nlm.nih.gov/pubmed/17280617.
- Hecht FM, Grant RM. Resistance testing in drug-naive HIV-infected patients: is it time? Clin Infect Dis. Nov 1 2005;41(9):1324-1325. Available at http://www.ncbi.nlm.nih.gov/pubmed/16206109.