Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Last Updated: March 1, 2016; Last Reviewed: March 1, 2016
Treatment of pediatric HIV infection has steadily improved since the introduction of potent combination antiretroviral (ARV) drug regimens that effectively suppress viral replication in most patients, resulting in a lower risk of virologic failure due to development of drug resistance. Antiretroviral therapy (ART) regimens including at least three drugs from at least two drug classes are recommended; such regimens have been associated with enhanced survival, reduction in opportunistic infections and other complications of HIV infection, improved growth and neurocognitive function, and improved quality of life in children.1,2 In the United States and the United Kingdom, significant declines in morbidity, mortality, and hospitalizations have been reported in HIV-infected children between 1994 and 2006, concomitant with increased use of highly active combination regimens.3-5 As a result, perinatally HIV-infected children are now living into the third and fourth decades of life, and likely beyond.
The increased survival of HIV-infected children is associated with challenges in selecting successive new ARV drug regimens. In addition, therapy is associated with short- and long-term toxicities, which can be recognized in childhood or adolescence6-9 (see Management of Medication Toxicity or Intolerance).
ARV drug-resistant virus can develop during ART when viral replication occurs in the presence of subtherapeutic ARV levels associated with poor adherence, poor absorption, a regimen that is not potent, or a combination of these factors. In addition, primary drug resistance may be seen in ARV-naive children who have become infected with a resistant virus.10-12 Thus, decisions about what drugs to choose in ARV-naive children (see What to Start) and how to best treat ARV-experienced children remain complex. Whenever possible, decisions regarding the management of pediatric HIV infection should be directed by or made in consultation with a specialist in pediatric and adolescent HIV infection. Treatment of ARV-naive children (when and what to start), when to change therapy, and treatment of ARV-experienced children will be discussed in separate sections of the guidelines.
In addition to trials demonstrating benefits of ART in symptomatic adults and those with lower CD4 T lymphocyte (CD4) cell counts,13 a randomized clinical trial has provided evidence of benefit with initiation of ART in asymptomatic adults with CD4 cell counts >500 cells/mm3.14 Similarly, improved outcomes have been shown with initiation of ART in asymptomatic infants between 6 and 12 weeks of age. Although there are fewer available data on the risks and benefits of immediate therapy in asymptomatic HIV-infected children than in adults, this Panel recommends ART for all HIV-infected children, with differing strengths of recommendation based on age and CD4 cell counts (see What to Start). Several factors need to be considered in making decisions about the urgency of initiating and changing ART in children, including:
- Severity of HIV disease and risk of disease progression, as determined by age, presence or history of HIV-related illnesses, degree of CD4 immunosuppression (see Revised Surveillance Case Definition for HIV Infection at http://www.cdc.gov/mmwr/pdf/rr/rr6303.pdf), and level of HIV plasma viremia;
- Availability of appropriate (and palatable) drug formulations and pharmacokinetic (PK) information on appropriate dosing in a child’s age/weight group;
- Potency, complexity (e.g., dosing frequency, food and fluid requirements), and potential short- and long-term adverse effects of the ART regimen;
- Effect of initial regimen choice on later therapeutic options;
- A child’s ART history;
- Presence of ARV drug-resistant virus;
- Presence of comorbidity, such as tuberculosis, hepatitis B or C virus infection, or chronic renal or liver disease, that could affect decisions about drug choice and the timing of initiation of therapy;
- Potential ARV drug interactions with other prescribed, over-the-counter, or complementary/alternative medications taken by a child; and
- The anticipated ability of the caregiver and child to adhere to the regimen.
The following recommendations provide general guidance for decisions related to treatment of HIV-infected children, and flexibility should be exercised according to a child’s individual circumstances. Guidelines for treatment of HIV-infected children are evolving as new data from clinical trials become available. Although prospective, randomized, controlled clinical trials offer the best evidence for formulation of guidelines, most ARV drugs are approved for use in pediatric patients based on efficacy data from clinical trials in adults, with supporting PK and safety data from Phase I/II trials in children. In addition, efficacy has been defined in most adult trials based on surrogate marker data, as opposed to clinical endpoints. For the development of these guidelines, the Panel reviewed relevant clinical trials published in peer-reviewed journals or in abstract form, with attention to data from pediatric populations when available.
Goals of Antiretroviral Treatment
Currently available ART has not been shown to eradicate HIV infection in perinatally infected infants, due to persistence of HIV in CD4 lymphocytes and other cells.15-17 This was demonstrated when an HIV-infected child treated with ART at 30 hours of age suffered viremic rebound after more than 2 years of undetectable HIV RNA levels while off ART.18,19 Some data suggest that the half-life of intracellular HIV proviral DNA is even longer in infected children than in adults (median 14 months vs. 5–10 months, respectively).20 Thus, based on currently available data, HIV causes a chronic infection likely requiring treatment for life once a child starts therapy. The goals of ART for HIV-infected children and adolescents include:
- Preventing and reducing HIV-related morbidity and mortality;
- Restoring and/or preserving immune function as reflected by CD4 cell measures;
- Maximally and durably suppressing viral replication;
- Preventing emergence of viral drug-resistance mutations;
- Minimizing drug-related toxicity;
- Maintaining normal physical growth and neurocognitive development;
- Improving quality of life;
- Reducing the risk of sexual transmission to discordant partners in adolescents who are sexually active; and
- Reducing the risk of perinatal transmission in adolescent females who become pregnant.
Strategies to achieve these goals require a complex balance of potentially competing considerations.
Use and Selection of Antiretroviral Therapy
Drug Sequencing and Preservation of Future Treatment Option
The choice of ART regimens should include consideration of future treatment options, such as the presence of or potential for drug resistance. Multiple changes in ARV drug regimens can rapidly exhaust treatment options and should be avoided. Appropriate sequencing of drugs for use in initial and second-line therapy can preserve future treatment options and is another strategy to maximize long-term benefit from therapy. Current recommendations for initial therapy are to use two classes of drugs (see What to Start), thereby sparing three classes of drugs for later use.
Maximizing AdherenceAs discussed in Adherence to Antiretroviral Therapy in HIV-Infected Children and Adolescents, poor adherence to prescribed regimens can lead to subtherapeutic levels of ARV medications, which increases the risk of development of drug resistance and likelihood of virologic failure. Issues related to adherence to therapy should be fully assessed, discussed, and addressed with a child’s caregiver and the child (when age appropriate) before therapy is initiated. Potential problems should be identified and resolved before starting therapy, generally even if this delays initiation of therapy. In addition, frequent follow-up is important to assess virologic response to therapy, drug intolerance, viral resistance, and adherence. Finally, in patients who experience virologic failure, it is critical to fully assess adherence and possible viral resistance before making changes to the ART regimen.
- Lindsey JC, Malee KM, Brouwers P, Hughes MD, Team PCS. Neurodevelopmental functioning in HIV-infected infants and young children before and after the introduction of protease inhibitor-based highly active antiretroviral therapy. Pediatrics. 2007;119(3):e681-693. Available at http://www.ncbi.nlm.nih.gov/pubmed/17296781.
- Guillen S, Garcia San Miguel L, Resino S, et al. Opportunistic infections and organ-specific diseases in HIV-1-infected children: a cohort study (1990-2006). HIV Med. 2010;11(4):245-252. Available at http://www.ncbi.nlm.nih.gov/pubmed/20050937.
- Brady MT, Oleske JM, Williams PL, et al. Declines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era. J Acquir Immune Defic Syndr. 2010;53(1):86-94. Available at http://www.ncbi.nlm.nih.gov/pubmed/20035164.
- Judd A, Doerholt K, Tookey PA, et al. Morbidity, mortality, and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996-2006: planning for teenage and adult care. Clin Infect Dis. 2007;45(7):918-924. Available at http://www.ncbi.nlm.nih.gov/pubmed/17806062.
- Kapogiannis BG, Soe MM, Nesheim SR, et al. Mortality trends in the US Perinatal AIDS Collaborative Transmission Study (1986-2004). Clin Infect Dis. 2011;53(10):1024-1034. Available at http://www.ncbi.nlm.nih.gov/pubmed/22002982.
- Van Dyke RB, Wang L, Williams PL, Pediatric ACTGCT. Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis. 2008;198(11):1599-1608. Available at http://www.ncbi.nlm.nih.gov/pubmed/19000014.
- Foster C, Lyall H. HIV and mitochondrial toxicity in children. J Antimicrob Chemother. 2008;61(1):8-12. Available at http://www.ncbi.nlm.nih.gov/pubmed/17999978.
- Kim RJ, Rutstein RM. Impact of antiretroviral therapy on growth, body composition and metabolism in pediatric HIV patients. Paediatr Drugs. 2010;12(3):187-199. Available at http://www.ncbi.nlm.nih.gov/pubmed/20481647.
- Heidari S, Mofenson LM, Hobbs CV, Cotton MF, Marlink R, Katabira E. Unresolved antiretroviral treatment management issues in HIV-infected children. J Acquir Immune Defic Syndr. 2012;59(2):161-169. Available at http://www.ncbi.nlm.nih.gov/pubmed/22138766.
- Delaugerre C, Chaix ML, Blanche S, et al. Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome. Retrovirology. 2009;6:85. Available at http://www.ncbi.nlm.nih.gov/pubmed/19765313.
- 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. 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. 2011;66(10):2362-2371. Available at http://www.ncbi.nlm.nih.gov/pubmed/21810838.
- Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010;363(3):257-265. Available at http://www.ncbi.nlm.nih.gov/pubmed/20647201.
- Insight Start Study Group. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795-807. Available at http://www.ncbi.nlm.nih.gov/pubmed/26192873.
- Persaud D, Siberry GK, Ahonkhai A, et al. Continued production of drug-sensitive human immunodeficiency virus type 1 in children on combination antiretroviral therapy who have undetectable viral loads. J Virol. 2004;78(2):968-979. Available at http://www.ncbi.nlm.nih.gov/pubmed/14694128.
- Chun TW, Justement JS, Murray D, et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS. 2010;24(18):2803-2808. Available at http://www.ncbi.nlm.nih.gov/pubmed/20962613.
- Dahl V, Josefsson L, Palmer S. HIV reservoirs, latency, and reactivation: prospects for eradication. Antiviral Res. 2010;85(1):286-294. Available at http://www.ncbi.nlm.nih.gov/pubmed/19808057.
- Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013;369(19):1828-1835. Available at http://www.ncbi.nlm.nih.gov/pubmed/24152233.
- Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med. 2015;372(8):786-788. Available at http://www.ncbi.nlm.nih.gov/pubmed/25693029.
- Saitoh A, Hsia K, Fenton T, et al. Persistence of human immunodeficiency virus (HIV) type 1 DNA in peripheral blood despite prolonged suppression of plasma HIV-1 RNA in children. J Infect Dis. 2002;185(10):1409-1416. Available at http://www.ncbi.nlm.nih.gov/pubmed/11992275.