Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Specific Issues in Antiretroviral Therapy for HIV-Infected Adolescents
(Last updated:11/1/2012; last reviewed:11/1/2012)
- Antiretroviral therapy (ART) regimens must be individually tailored to the adolescent (AIII).
- Appropriate dosing of ART for adolescents is complex, not always predictable, and dependent upon multiple factors, including body mass and composition and pubertal development (AII).
- Effective and appropriate methods should be selected to reduce the likelihood of unintended pregnancy and to prevent secondary transmission of HIV to sexual partners (AI).
- Providers should be aware of potential interactions between ART and hormonal contraceptives, which could lower contraceptive efficacy (AII*).
- Alternative regimens that do not include efavirenz should be strongly considered in adolescent females who are trying to conceive or who are not using effective and consistent contraception because of the potential for teratogenicity with first-trimester efavirenz exposure, assuming these alternative regimens are acceptable to the provider and will not compromise the woman’s health (BIII).
- Adolescent girls who require treatment with efavirenz should undergo pregnancy testing before initiation of treatment and receive counseling about potential fetal risk and desirability of avoiding pregnancy while receiving efavirenz-containing regimens (AIII).
- Pediatric and adolescent care providers should prepare adolescents for the transition into adult care settings (AIII).
|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
An increasing number of HIV-infected children who acquired HIV infection through perinatal transmission are now surviving into adolescence. They generally have had a long clinical course and extensive antiretroviral therapy (ART) treatment history.1 Adolescents with non-perinatally acquired HIV infection generally follow a clinical course similar to that in adults. Because non-perinatally infected adolescents are usually at the initial stages of their HIV disease, they are potential candidates for early intervention and treatment.2
Dosing of Antiretroviral Therapy for HIV-Infected Adolesents
Puberty is a time of somatic growth and sexual maturation, with females developing more body fat and males more muscle mass. These physiologic changes may affect drug pharmacokinetics (PK), which is especially important for drugs with a narrow therapeutic index that are used in combination with protein-bound medicines or hepatic enzyme inducers or inhibitors.3 Dosages of medications for HIV infection and opportunistic infections are prescribed according to Tanner staging of puberty4 rather than strictly on the basis of age.2 Using the Tanner method, adolescents in early puberty (i.e., Tanner stages I and II) are administered doses using pediatric schedules, whereas those in late puberty (i.e., Tanner stage V) are administered doses using adult schedules. However, Tanner stage and age are not necessarily directly predictive of drug PK, and dosing of antiretroviral (ARV) drugs during Tanner stages III and IV may be more challenging. Puberty may be delayed in children who were infected with HIV perinatally,5 adding to discrepancies between Tanner stage-based and age-based dosing, although delayed onset of puberty appears to be uncommon in those in whom potent combination ART was initiated at an early age.6
Many ARV drugs (e.g., abacavir, emtricitabine, lamivudine, tenofovir, and some protease inhibitors [PIs]) are administered to children at higher weight- or surface area-based doses than would be predicted by direct extrapolation of adult doses. This is based upon reported PK data indicating more rapid drug clearance in children. Continued use of these pediatric weight- or surface area-based doses as a child grows during adolescence can result in medication doses that are higher than the usual adult doses. Data suggesting optimal doses for every ARV drug in adolescents are not available. Appendix A: Pediatric Antiretroviral Drug Information includes a discussion of data relevant to adolescents for individual drugs and notes the age listed on the drug label for adult dosing, when available.
Adolescent Contraception, Pregnancy, and Antiretroviral Therapy
HIV-infected adolescents may be sexually active regardless of how they acquired the virus. Reproductive plans including preconception care, contraception methods, and safer sex techniques for prevention of secondary HIV transmission should be discussed with them regularly (see U.S. Medical Eligibility Criteria for Contraceptive Use).7 For additional information please see Health and Human Services (HHS) Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States (Preconception Care and Reproductive Options for HIV-Concordant and Serodiscordant Couples section).8
The possibility of an unplanned pregnancy should also be considered when selecting an ART regimen for an adolescent female. The most vulnerable period in fetal organogenesis is early in gestation, often before pregnancy is recognized. In addition, concerns about specific ARV drugs and birth defects should be addressed immediately to preclude misinterpretations or lack of adherence by adolescents with unexpressed plans for pregnancy.9 For additional information please see HHS Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States (Special Considerations Regarding the Use of Antiretroviral Drugs by HIV-Infected Pregnant Women and their Infants: Teratogenicity section).8 Alternative regimens that do not include efavirenz should be strongly considered in adolescent females who are trying to conceive or who are not using effective and consistent contraception because of the potential for teratogenicity with first-trimester efavirenz exposure, assuming these alternative regimens are acceptable to the provider and will not compromise the woman’s health.
Contraceptive-Antiretroviral Drug Interactions
Several PI and non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs alter metabolism of oral contraceptives, resulting in possible decreases in ethinyl estradiol or increases in estradiol or norethindrone levels (see the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents available at http://aidsinfo.nih.gov) (http://www.hiv-druginteractions.org/).10-12 These changes may decrease the effectiveness of the oral contraceptives or potentially increase the risk of estrogen- or progestin-related adverse effects. Some newer agents, such as integrase inhibitors (specifically raltegravir), appear to have no interaction with estrogen-based contraceptives.13 Providers should be aware of these drug interactions and consider alternative or additional contraceptive methods for patients receiving ART with such interactions. Whether interactions with ART would compromise the contraceptive effectiveness of progestogen-only injectable contraceptives (such as depot medoxyprogesterone acetate [DMPA]) is unknown because these methods produce higher blood hormone levels than other progestogen-only oral contraceptives and combined oral contraceptives. In one study, the efficacy of DMPA was not altered in women receiving concomitant nelfinavir-, efavirenz-, or nevirapine-based treatment, with no evidence of ovulation during concomitant administration for 3 months, no additional adverse effects, and no clinically significant changes in ARV drug levels.14,15 At this time, concerns about loss of bone mineral density (BMD) with long-term use of DMPA with or without ART (specifically tenofovir)16 should not preclude use of DMPA as an effective contraceptive. However, more active monitoring of BMD in young women on DMPA may need to be considered.16 Minimal information exists about drug interactions with use of newer hormonal contraceptive methods (e.g., the patch and vaginal ring).17 Intrauterine device (IUD) use while on ART is not restricted by current guidelines; however, IUD users with AIDS should be closely monitored for pelvic infection.7 Adolescents who want to become pregnant should be referred for preconception counseling and care, including discussion of special considerations with ART use during pregnancy (see HHS Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States available at http://aidsinfo.nih.gov). 8
HIV-Infected Pregnant Adolescents and Outcomes
Pregnancy should not preclude the use of optimal therapeutic regimens. However, because of considerations related to prevention of perinatal transmission and maternal and fetal safety, timing of initiation of treatment and selection of regimens may be different for pregnant women than for nonpregnant adults or adolescents. Details regarding choice of ART regimen in pregnant HIV-infected women, including adolescents, are provided in HHS Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States available at http://aidsinfo.nih.gov.8 Although information is limited about the pregnancies of adolescents who were HIV-infected perinatally, perinatal HIV transmission outcomes in this population appear similar to those in adult cohorts;18-21 however, there may be differences in pregnancy-related morbidities. Kenny et al22 reported pregnancy outcomes from the United Kingdom and Ireland in a group of 30 adolescents who were perinatally HIV-infected or who acquired HIV infection at a young age. Few of these pregnancies were planned and in many cases, the partner was unaware of the mother’s HIV status. Rates of elective termination, miscarriage, and prematurity were high. The rate of prematurity was twice that in the general adolescent population of Europe. Many of the women had an AIDS diagnosis before pregnancy, but only one infant was HIV-infected. Although the rate of perinatal transmission is reassuring, this study highlights some of the major challenges in caring for pregnant, perinatally HIV-infected youth.
Comparisons of pregnancy incidence and outcomes between perinatally infected and non-perinatally infected youth are few and may offer special insight into the effects of prolonged HIV infection on pregnancy-related sequelae. Agwu et al23 retrospectively evaluated pregnancies at four clinics. Non-perinatally infected youth were more likely to have one or more pregnancies despite similar age at first pregnancy between groups. They also appeared to have more premature births and spontaneous abortions, but that is tempered by the fact that the perinatally infected youth were more likely to have an elective termination. The perinatal transmission rate for the entire cohort was 1.5%. Similar results were found in several other studies.24,25 However, in a single-center review of perinatal versus non-perinatal birth outcomes, infants born to women with perinatal HIV infection were more likely to be small for gestational age, indicating the potential for future adverse health outcomes.26
Transition of Adolescents into Adult HIV Care Settings
Facilitating a smooth transition of adolescents with chronic health conditions from their pediatric/adolescent medical home to adult care can be difficult and is especially challenging for HIV-infected adolescents. Transition is described as "a multifaceted, active process that attends to the medical, psychosocial, and educational or vocational needs of adolescents as they move from the child-focused to the adult-focused health-care system."27 Care models for children and adolescents with perinatally acquired HIV tend to be family-centered, consisting of a multidisciplinary team that often includes pediatric or adolescent physicians, nurses, social workers, and mental health professionals. These providers generally have long-standing relationships with patients and their families, and care is rendered in discreet, more intimate settings. Although expert care is also provided under the adult HIV care medical model, an adolescent may be unfamiliar with the more individual-centered, busier clinics typical of adult medical providers and uncomfortable with providers with whom he or she often does not have a long-standing relationship. Providing an adolescent and an adult medical care provider with support and guidance regarding expectations for each partner in the patient-provider relationship may be helpful. In this situation, it may also be helpful for a pediatric and an adult provider to share joint care of a patient for a period of time. Providers should also have a candid discussion with a transitioning adolescent to understand what qualities the adolescent considers most important in a provider (such as confidentiality, small clinic size, after-school appointments). Some general guidelines about transitional plans and who might benefit most from them are available.28-32 Pediatric and adolescent providers should have a formal plan to transition adolescents to adult care.
Outcomes are variable in young adult patients transitioned to adult care. Definitions of “successful transition” have ranged from the ability to maintain a certain level of follow-up in the new clinic, to laboratory measures of stability, to comparisons of younger and older adult patients.33-35 Factors that should be taken into consideration during transition include social determinants such as developmental status, behavioural/mental health issues, housing, family support, employment, recent discharge from foster care, peer pressure, illicit drug use, and incarceration. Currently there is no definitive model of transition to adult care, but in one study, adherence to medical visits just prior to the transition was predictive of successful transfer.33 Psychiatric co-morbidities and their effective management also predict adherence to medical care and therapy.36,37 With more perinatally infected children surviving into adulthood, transitioning these patients to adult care settings remains challenging.
- Van Dyke RB, Patel K, Siberry GK, et al. Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr. Jun 1 2011;57(2):165-173. Available at http://www.ncbi.nlm.nih.gov/pubmed/21407086.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed on August 17, 2012.
- Rogers A. Pharmacokinetics and pharmacodynamics in adolescents. January 20-21, 1994. Proceedings. J Adolesc Health. Dec 1994;15(8):605-678. Available at http://www.ncbi.nlm.nih.gov/pubmed/7696278.
- Schneider MB. Physical examination. In: Friedman SB, Fisher MM, Schoenberg SK, Alderman EM, eds. Comprehensive adolescent health care. 2nd ed. St. Louis, MO: Mosby-Year Book, Inc. 1998:69-80.
- Buchacz K, Rogol AD, Lindsey JC, et al. Delayed onset of pubertal development in children and adolescents with perinatally acquired HIV infection. J Acquir Immune Defic Syndr. May 1 2003;33(1):56-65. Available at http://www.ncbi.nlm.nih.gov/pubmed/12792356.
- del Bianco GP, Heresi G, Frederick T, et al. for the LEGACY Consortium. Onset of puberty and Sexual Maturation in Perinatally HIV-infected Children and Adolescents in the United States in the HAART era. Abstract 575. Abstract presented at 48th Annual IDSA Meeting, Vancouver, October 21-24, 2010. Available at: https://idsa.confex.com/idsa/2010/webprogram/Paper2859.html.
- Centers for Disease C, Prevention. U S. Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR Recomm Rep. Jun 18 2010;59(RR-4):1-86. Available at http://www.ncbi.nlm.nih.gov/pubmed/20559203.
- Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed on August 17, 2012.
- Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: An updated systematic review and meta-analysis. AIDS. Nov 28 2011;25(18):2301-2304. Available at http://www.ncbi.nlm.nih.gov/pubmed/21918421.
- El-Ibiary SY, Cocohoba JM. Effects of HIV antiretrovirals on the pharmacokinetics of hormonal contraceptives. Eur J Contracept Reprod Health Care. Jun 2008;13(2):123-132. Available at http://www.ncbi.nlm.nih.gov/pubmed/18465473.
- Sevinsky H, Eley T, Persson A, et al. The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women. Antivir Ther. 2011;16(2):149-156. Available at http://www.ncbi.nlm.nih.gov/pubmed/21447863.
- Zhang J, Chung E, Yones C, et al. The effect of atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women. Antivir Ther. 2011;16(2):157-164. Available at http://www.ncbi.nlm.nih.gov/pubmed/21447864.
- Anderson MS, Hanley WD, Moreau AR, et al. Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women. Br J Clin Pharmacol. Apr 2011;71(4):616-620. Available at http://www.ncbi.nlm.nih.gov/pubmed/21395656.
- Watts DH, Park JG, Cohn SE, et al. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. Feb 2008;77(2):84-90. Available at http://www.ncbi.nlm.nih.gov/pubmed/18226670.
- Cohn SE, Park JG, Watts DH, et al. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther. Feb 2007;81(2):222-227. Available at http://www.ncbi.nlm.nih.gov/pubmed/17192768.
- Beksinska ME, Smit JA, Ramkissoon A. Progestogen-only injectable hormonal contraceptive use should be considered in analysis of studies addressing the loss of bone mineral density in HIV-positive women. J Acquir Immune Defic Syndr. Aug 2010;54(4):e5. Available at http://www.ncbi.nlm.nih.gov/pubmed/20611032.
- Vogler MA, Patterson K, Kamemoto L, et al. Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188. J Acquir Immune Defic Syndr. Dec 2010;55(4):473-482. Available at http://www.ncbi.nlm.nih.gov/pubmed/20842042.
- Cruz ML, Cardoso CA, Joao EC, et al. Pregnancy in HIV vertically infected adolescents and young women: a new generation of HIV-exposed infants. AIDS. Nov 13 2010;24(17):2727-2731. Available at http://www.ncbi.nlm.nih.gov/pubmed/20827164.
- Elgalib A, Hegazi A, Samarawickrama A, et al. Pregnancy in HIV-infected teenagers in London. HIV Med. Aug 29 2010. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20807252.
- Meloni A, Tuveri M, Floridia M, et al. Pregnancy care in two adolescents perinatally infected with HIV. AIDS Care. Jun 2009;21(6):796-798. Available at http://www.ncbi.nlm.nih.gov/pubmed/19806493.
- Williams SF, Keane-Tarchichi MH, Bettica L, Dieudonne A, Bardeguez AD. Pregnancy outcomes in young women with perinatally acquired human immunodeficiency virus-1. Am J Obstet Gynecol. Feb 2009;200(2):149 e141-145. Available at http://www.ncbi.nlm.nih.gov/pubmed/18973871.
- Kenny J, Williams B, Prime K, Tookey P, Foster C. Pregnancy outcomes in adolescents in the UK and Ireland growing up with HIV. HIV Med. May 2012;13(5):304-308. Available at http://www.ncbi.nlm.nih.gov/pubmed/22136754.
- Agwu AL, Jang SS, Korthuis PT, Araneta MR, Gebo KA. Pregnancy incidence and outcomes in vertically and behaviorally HIV-infected youth. JAMA. Feb 2 2011;305(5):468-470. Available at http://www.ncbi.nlm.nih.gov/pubmed/21285423.
- Koenig LJ, Pals SL, Chandwani S, et al. Sexual transmission risk behavior of adolescents With HIV acquired perinatally or through risky behaviors. J Acquir Immune Defic Syndr. Nov 2010;55(3):380-390. Available at http://www.ncbi.nlm.nih.gov/pubmed/20802343.
- Setse RW, Siberry GK, Gravitt PE, et al. Correlates of sexual activity and sexually transmitted infections among human immunodeficiency virus-infected youth in the LEGACY cohort, United States, 2006. Pediatr Infect Dis J. Nov 2011;30(11):967-973. Available at http://www.ncbi.nlm.nih.gov/pubmed/22001904.
- Jao J, Sigel KM, Chen KT, et al. Small for gestational age birth outcomes in pregnant women with perinatally acquired HIV. AIDS. Apr 24 2012;26(7):855-859. Available at http://www.ncbi.nlm.nih.gov/pubmed/22313958.
- Reiss JG, Gibson RW, Walker LR. Health care transition: youth, family, and provider perspectives. Pediatrics. Jan 2005;115(1):112-120. Available at http://www.ncbi.nlm.nih.gov/pubmed/15629990.
- Rosen DS, Blum RW, Britto M, Sawyer SM, Siegel DM, Society for Adolescent M. Transition to adult health care for adolescents and young adults with chronic conditions: position paper of the Society for Adolescent Medicine. J Adolesc Health. Oct 2003;33(4):309-311. Available at http://www.ncbi.nlm.nih.gov/pubmed/14519573.
- Gilliam PP, Ellen JM, Leonard L, Kinsman S, Jevitt CM, Straub DM. Transition of adolescents with HIV to adult care: characteristics and current practices of the adolescent trials network for HIV/AIDS interventions. J Assoc Nurses AIDS Care. Jul-Aug 2011;22(4):283-294. Available at http://www.ncbi.nlm.nih.gov/pubmed/20541443.
- New York State Department of Health AIDS Institute. Transitioning HIV-Infected Adolescents into Adult Care. 2011:1-83. Available at http://www.hivguidelines.org/clinical-guidelines/adolescents/transitioning-hiv-infected-adolescents-into-adult-care/.
- Andiman WA. Transition from pediatric to adult healthcare services for young adults with chronic illnesses: the special case of human immunodeficiency virus infection. J Pediatr. Nov 2011;159(5):714-719. Available at http://www.ncbi.nlm.nih.gov/pubmed/21868035.
- Dowshen N, D'Angelo L. Health care transition for youth living with HIV/AIDS. Pediatrics. Oct 2011;128(4):762-771. Available at http://www.ncbi.nlm.nih.gov/pubmed/21930548.
- Arazi-Caillaud SE, Mecikovsky D. Transition of HIV-Infected Adolescents to Adult HIV Care : 2 Years of Follow-up, Abstract CDB426. IAS; July 17-20, 2011, 2011; Rome, Italy. Available at: http://pag.ias2011.org/abstracts.aspx?aid=4426.
- Saavedra-Lozano J, Navarro M, al. e. Status of Vertically-Acquired HIV-Infected Children at the Time of Their Transfer to an Adult Clinic, Abstract 693. Conference on Retroviruses and Opportunistic Infections (CROI); 2011; Boston, MA. Available at: http://www.retroconference.org/2011/Abstracts/42269.htm
- Ryscavage P, Anderson EJ, Sutton SH, Reddy S, Taiwo B. Clinical outcomes of adolescents and young adults in adult HIV care. J Acquir Immune Defic Syndr. Oct 1 2011;58(2):193-197. Available at http://www.ncbi.nlm.nih.gov/pubmed/21826014.
- Mellins CA, Tassiopoulos K, Malee K, et al. Behavioral health risks in perinatally HIV-exposed youth: co-occurrence of sexual and drug use behavior, mental health problems, and nonadherence to antiretroviral treatment. AIDS Patient Care STDS. Jul 2011;25(7):413-422. Available at http://www.ncbi.nlm.nih.gov/pubmed/21992620.
- Kapetanovic S, Wiegand RE, Dominguez K, et al. Associations of medically documented psychiatric diagnoses and risky health behaviors in highly active antiretroviral therapy-experienced perinatally HIV-infected youth. AIDS Patient Care STDS. Aug 2011;25(8):493-501. Available at http://www.ncbi.nlm.nih.gov/pubmed/21745118.