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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Specific Issues in Antiretroviral Therapy for HIV-Infected Adolescents
(Last updated: March 5, 2015; last reviewed: March 5, 2015)
Panel's Recommendations Regarding Specific Issues in Antiretroviral Therapy for HIV-Infected Adolescents
Combination antiretroviral therapy regimens must be individually tailored to the adolescent (AIII).
Reproductive options including preconception care, contraception methods, and safer sex techniques for prevention of secondary HIV transmission to sexual partners should be discussed regularly (AI).
Adolescents who are considering a planned pregnancy should be receiving a maximally suppressive combination antiretroviral therapy regimen (AII).
Providers should be aware of potential interactions between combination antiretroviral therapy and hormonal contraceptives that could lower contraceptive efficacy (AII*).
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
Most children who acquired HIV infection through perinatal transmission in the United States are adolescents or young adults. They generally have had a long clinical course and extensive history of treatment with combination antiretroviral therapy (cART).1 Adolescents with non-perinatally acquired HIV infection generally follow a clinical course similar to that in adults; early intervention with cART should be considered for them.2
Dosing of Antiretroviral Therapy for HIV-Infected Adolescents
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
In addition, many antiretroviral (ARV) drugs (e.g., abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate [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. Data suggesting optimal doses for every ARV drug in adolescents are not available although 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.
Adolescent Contraception, Pregnancy, and Antiretroviral Therapy
The possibility of planned and unplanned pregnancy should also be considered when selecting a cART regimen for an adolescent female. The most vulnerable period in fetal organogenesis is the first trimester, often before pregnancy is recognized. Concerns about specific ARV drugs and birth defects should be promptly addressed to preclude any misinterpretation or lack of adherence by HIV-infected pregnant adolescents (for additional information please see the Perinatal Guidelines).5 Currently efavirenz is the only approved ARV drug that carries Food and Drug Administration Pregnancy Class D labeling, based on neural tube defects in primates. However, a recent updated meta-analysis found no increased risk of teratogenicity associated with first-trimester efavirenz exposure. This review contributed to the evidence base for the revised 2013 World Health Organization (WHO) guidelines on ARV therapy; WHO recommends including efavirenz as part of first-line therapy in adults regardless of gender, and indicates that it can be used throughout pregnancy, including during the first trimester. However, because of the low incidence of central nervous system anomalies in the overall population and relatively small number of exposures in the current literature, continued surveillance of birth outcomes is warranted.6 Although increasing data on the use of efavirenz in pregnancy are reassuring, many experts remain reluctant to consider use of efavirenz in adolescent females who are trying to conceive or who are not using effective birth control. Readers should consult the 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 for guidance in selection of ARV drugs during pregnancy.
Whether interactions with cART would compromise the contraceptive effectiveness of progestin-only injectable contraceptives (such as depot medroxyprogesterone 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.11,12 At this time, concerns about loss of bone mineral density (BMD) with long-term use of DMPA with or without cART (specifically tenofovir)13 should not preclude use of DMPA as an effective contraceptive, unless there is clinical evidence of bone fragility. However, more active monitoring of BMD in young women on DMPA may need to be considered.13 Minimal information exists about drug interactions with use of newer methods of hormonal contraception (e.g., the patch and vaginal ring).14 HIV-infected women can use all available contraceptive methods, including the transdermal patch and vaginal ring.4 Adolescents who want to become pregnant should be referred for preconception counseling and care, including discussion of special considerations for use of cART during pregnancy (see the Perinatal Guidelines).5
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 women. Details regarding choice of cART regimen in pregnant HIV-infected women, including adolescents, are provided in the Perinatal Guidelines.5 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;15-18 however, there may be differences in pregnancy-related morbidities. Kenny et al19 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 al20 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.21,22 However, in a single-center review of perinatal versus non-perinatal birth outcomes, infants born to women who were perinatally infected with HIV were more likely to be small for gestational age.23 Recently Badell and colleagues noted that 20 perinatally infected pregnant women were significantly more likely to be younger, have a detectable viral load, and have HIV-genotypic resistance compared to 80 non-perinatally infected pregnant women. The median gestational age at delivery and rates of obstetrical and neonatal complications were similar between the groups. There was one case of perinatal transmission in an infant born to a perinatally infected mother versus two transmission events in offspring of the mothers who were not perinatally infected.24
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 those who are HIV-infected. 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.”25 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 they, in many cases, do 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 an adult care setting (e.g., confidentiality, small clinic size, after-school appointments). Pediatric and adolescent providers should have a formal plan in place to transition adolescents to adult care. Some general guidelines about transitional plans and who might benefit most from them are available.26-32
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 Factors that should be taken into consideration during transition include social determinants such as developmental status, behavioral/mental health issues, housing, family support, employment, recent discharge from foster care, peer pressure, illicit drug use, and incarceration. Psychiatric comorbidities and their effective management predict adherence to medical care and therapy.34-36 Currently there is no definitive model of transition to adult HIV care and only limited reports about outcomes following transition. One such article from the United Kingdom suggests a higher mortality risk after transition.36
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. 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. 2014. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed on December 25, 2014.
Rogers A. Pharmacokinetics and pharmacodynamics in adolescents. January 20-21, 1994. Proceedings. J Adolesc Health. 1994;15(8):605-678. Available at http://www.ncbi.nlm.nih.gov/pubmed/7696278.
Centers for Disease Control and Prevention. U S. medical eligibility criteria for contraceptive use, 2010. MMWR Recomm Rep. 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. 2014. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed on November 25, 2014.
Ford N, Mofenson L, Shubber Z, et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS. 2014;28 Suppl 2:S123-131. Available at http://www.ncbi.nlm.nih.gov/pubmed/24849471.
El-Ibiary SY, Cocohoba JM. Effects of HIV antiretrovirals on the pharmacokinetics of hormonal contraceptives. Eur J Contracept Reprod Health Care. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 2012;26(7):855-859. Available at http://www.ncbi.nlm.nih.gov/pubmed/22313958.
Badell ML, Kachikis A, Haddad LB, Nguyen ML, Lindsay M. Comparison of pregnancies between perinatally and sexually HIV-infected women: an observational study at an urban hospital. Infect Dis Obstet Gynecol. 2013;2013:301763. Available at http://www.ncbi.nlm.nih.gov/pubmed/24106419.
Reiss JG, Gibson RW, Walker LR. Health care transition: youth, family, and provider perspectives. Pediatrics. 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. 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. 2011;22(4):283-294. Available at http://www.ncbi.nlm.nih.gov/pubmed/20541443.
Transitioning HIV-Infected Adolescents into Adult Care. New York State Department of Health AIDS Institute. Available at http://www.hivguidelines.org/clinical-guidelines/adolescents/transitioning-hiv-infected-adolescents-into-adult-care/. Accessed December 26, 2014.
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. 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. 2011;128(4):762-771. Available at http://www.ncbi.nlm.nih.gov/pubmed/21930548.
Committee On Pediatric Aids. Transitioning HIV-infected youth into adult health care. Pediatrics. 2013;132(1):192-197. Available at http://www.ncbi.nlm.nih.gov/pubmed/23796739.
Transitioning of Care and Other Services for Adolescents Living with HIV in Sub-Saharan Africa. USAID. Available at http://www.aidstar-one.com/focus_areas/care_and_support/resources/technical_briefs/alhiv_transitions#tab_1. Accessed December 1, 2014.
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. 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. 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. 2011;25(8):493-501. Available at http://www.ncbi.nlm.nih.gov/pubmed/21745118.
Fish R, Judd A, Jungmann E, O'Leary C, Foster C, Network HIVYP. Mortality in perinatally HIV-infected young people in England following transition to adult care: an HIV Young Persons Network (HYPNet) audit. HIV Med. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/24112550.