Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
(Last updated:2/12/2014; last reviewed:2/12/2014)
Antiretroviral (ARV) treatment of pediatric HIV infection has steadily improved with the introduction of potent combination drug regimens that effectively suppress viral replication in most patients, resulting in a lower risk of failure due to development of drug resistance. Currently, combination antiretroviral treatment (cART) 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.1-5 In the United States and the United Kingdom, significant declines (81%–93%) in mortality have been reported in HIV-infected children between 1994 and 2006, concomitant with increased use of highly active combination regimens;6-8 significant declines in HIV-related morbidity and hospitalizations in children have been observed in the United States and Europe over the same time period.4,7 As a result, some perinatally HIV-infected children are now living into the third and fourth decades of life, and potentially, 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 adolescence9-12 (see Management of Medication Toxicity or Intolerance).
ARV drug-resistant virus can develop during cART because of poor adherence, a regimen that is not potent, or a combination of these factors which results in incomplete viral suppression. In addition, primary drug resistance may be seen in ARV-naive children who have become infected with a resistant virus.13-15 Thus, decisions about when to start therapy (see When to Initiate), 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.
Several factors need to be considered in making decisions about initiating and changing cART in children, including:
- Severity of HIV disease and risk of disease progression, as determined by age, presence or history of HIV-related or AIDS-defining illnesses (see Centers for Disease Control and Prevention (CDC) pediatric clinical staging system for HIV http://www.cdc.gov/mmwr/preview/mmwrhtml/00032890.htm),16 degree of CD4 T lymphocyte (CD4) immunosuppression, 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 group;
- Potency, complexity (e.g., dosing frequency, food and fluid requirements), and potential short- and long-term adverse effects of the cART regimen;
- Effect of initial regimen choice on later therapeutic options;
- A child’s cART 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 drug choice;
- Potential ARV drug interactions with other prescribed, over-the-counter, or complementary/alternative medications taken by a child; and
- The 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
Although there is a single case report of “functional cure” in an HIV-infected child treated with a cART regimen initiated at age 30 hours,17 current cART does not eradicate HIV infection in the majority of perinatally infected infants because of the long half-life of latently infected CD4 cells.18-20 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).21 Thus, based on currently available data, HIV causes a chronic infection likely requiring treatment for life once a child starts therapy. The goals of cART for HIV-infected children and adolescents include:
- Reducing HIV-related mortality and morbidity;
- 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 complex balancing of sometimes competing considerations.
Use and Selection of cART
The treatment of choice for HIV-infected children is a regimen containing at least three drugs from at least two classes of ARV drugs. The Panel has recommended several preferred and alternative regimens (see What to Start). The most appropriate regimen for an individual child depends on multiple factors as noted above. A regimen that is characterized as an alternative choice may be a preferred regimen for some patients.
Drug Sequencing and Preservation of Future Treatment Option
The choice of ARV treatment 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.
As 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 enhances 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 the decision to initiate therapy is made. Participation by the caregiver and child in the decision-making process is crucial. Potential problems should be identified and resolved before starting therapy, 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 before making changes to the cART regimen.
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Table 4. 1994 Revised HIV Pediatric (Age <13 Years) Classification System: Clinical Categories*
|Category N: Not Symptomatic
|Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category A.
|Category A: Mildly Symptomatic
Children with two or more of the following conditions but none of the conditions listed in Categories B and C:
- Lymphadenopathy (≥0.5 cm at more than 2 sites; bilateral = 1 site)
- Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
|Category B: Moderately Symptomatic
Children who have symptomatic conditions, other than those listed for Category A or Category C, that are attributed to HIV infection. Examples of conditions in Clinical Category B include, but are not limited to, the following:
- Anemia (<8 g/dL), neutropenia (<1,000 cells/mm3), or thrombocytopenia (<100,000 cells/mm3) persisting ≥30 days
- Bacterial meningitis, pneumonia, or sepsis (single episode)
- Candidiasis, oropharyngeal (i.e., thrush) persisting for >2 months in children aged >6 months
- Cytomegalovirus infection with onset before age 1 month
- Diarrhea, recurrent or chronic
- Herpes simplex virus (HSV) stomatitis, recurrent (i.e., more than 2 episodes within 1 year)
- HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month
- Herpes zoster (i.e., shingles) involving at least two distinct episodes or more than one dermatome
- Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
- Fever lasting >1 month
- Toxoplasmosis with onset before age 1 month
- Varicella, disseminated (i.e., complicated chickenpox)
|Category C: Severely Symptomatic
Children who have any condition listed in the 1987 surveillance case definition for AIDS (below), with the exception of LIP, which is a Category B condition:
- Serious bacterial infections, multiple or recurrent (i.e., any combination of at least 2 culture-confirmed infections within a 2-year period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections)
- Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
- Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes)
- Cryptococcosis, extrapulmonary
- Cryptosporidiosis or isosporiasis with diarrhea persisting >1 month
- Cytomegalovirus disease with onset of symptoms at age >1 month (at a site other than liver, spleen, or lymph nodes)
- Encephalopathy—at least one of the following progressive findings present for at least 2 months in the absence of a concurrent illness other than HIV infection that could explain the findings:
- Failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests
- Impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by computerized tomography or magnetic resonance imaging (serial imaging is required for children aged <2 years)
- Acquired symmetric motor deficit manifested by two or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance
- HSV infection causing a mucocutaneous ulcer that persists for >1 month or bronchitis, pneumonitis, or esophagitis for any duration affecting a child aged >1 month
- Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes)
- Kaposi sarcoma
- Lymphoma, primary, in brain
- Lymphoma, small, noncleaved cell (Burkitt), or immunoblastic or large cell lymphoma of B-cell or unknown immunologic phenotype
- Mycobacterium tuberculosis, disseminated or extrapulmonary
- Mycobacterium, other species or unidentified species, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
- Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
- Pneumocystis jirovecii pneumonia
- Progressive multifocal leukoencephalopathy
- Salmonella (nontyphoid) septicemia, recurrent
- Toxoplasmosis of the brain with onset at age >1 month
- Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings:
- Persistent weight loss >10% of baseline; or
- Downward crossing of at least two of the following percentile lines on the weight-for-age chart (such as 95th, 75th, 50th, 25th, 5th) in a child ≥1 year of age; or
- <5th percentile on weight-for-height chart on two consecutive measurements, ≥30 days apart plus
- Chronic diarrhea (that is, ≥2 loose stools per day for >30 days) or documented fever (for ≥30 days, intermittent or constant)
- 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. Mar 2007;119(3):e681-693. Available at http://www.ncbi.nlm.nih.gov/pubmed/17296781.
- Nachman SA, Lindsey JC, Moye J, et al. Growth of human immunodeficiency virus-infected children receiving highly active antiretroviral therapy. Pediatr Infect Dis J. Apr 2005;24(4):352-357. Available at http://www.ncbi.nlm.nih.gov/pubmed/15818296.
- Storm DS, Boland MG, Gortmaker SL, et al. Protease inhibitor combination therapy, severity of illness, and quality of life among children with perinatally acquired HIV-1 infection. Pediatrics. Feb 2005;115(2):e173-182. Available at http://www.ncbi.nlm.nih.gov/pubmed/15629958.
- Viani RM, Araneta MR, Deville JG, Spector SA. Decrease in hospitalization and mortality rates among children with perinatally acquired HIV type 1 infection receiving highly active antiretroviral therapy. Clin Infect Dis. Sep 1 2004;39(5):725-731. Available at http://www.ncbi.nlm.nih.gov/pubmed/15356789.
- 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. Apr 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. Jan 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. Oct 1 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. Nov 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. Dec 1 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. Jan 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. Jun 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. Feb 1 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. 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.
- Schneider E, Whitmore S, Glynn KM, et al. Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years--United States, 2008. MMWR Recomm Rep. Dec 5 2008;57(RR-10):1-12. Available at http://www.ncbi.nlm.nih.gov/pubmed/19052530.
- Persaud D, Gay H, Ziemniak C, et al. Absence of detectable viremia after treatment cessation in an infant. N Engl J Med 2013;369:1828-35. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24152233
- 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. Jan 2004;78(2):968-979. Available at http://www.ncbi.nlm.nih.gov/pubmed/14694128.
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- 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. May 15 2002;185(10):1409-1416. Available at http://www.ncbi.nlm.nih.gov/pubmed/11992275.