(Last updated: March 1, 2016; last reviewed: March 1, 2016)
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/adolescents, but not studies limited to post-pubertal adolescents
Most individuals in the United States who acquired HIV infection through perinatal transmission are now adolescents or young adults. Of the estimated 10,541 persons who acquired HIV infection through perinatal transmission in the United States, 2,574 are aged less than 13 years as of December 2012.1,2 Most have had a long clinical course with an extensive history of treatment with antiretroviral therapy (ART).3 Many older youth initially received non-suppressive mono- or dual therapy prior to the availability of combination regimens. Challenges in the treatment of perinatally infected adolescents include extensive drug resistance, complex regimens, and the long-term consequences of HIV and ART exposure.
Most post-pubertal HIV-infected children and adolescents in the United States acquired their infection by horizontal rather than perinatal transmission. They generally follow a clinical course similar to that of adults and the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents should be used for treatment recommendations.4
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 medications with a narrow therapeutic index that are used in combination with protein-bound medicines or hepatic enzyme inducers or inhibitors.5
In addition, many antiretroviral (ARV) drugs (e.g., abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate [TDF], and some protease inhibitors [PIs]) are administered to children at higher body weight- or body 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.
The choice of ART, specifically for TDF is based on sexual maturity rating (SMR, formerly Tanner staging) and not on age, related to concerns for associated toxicity. Therefore, adolescents in early puberty (i.e., SMR I-III) should be receiving pediatric dosing, whereas those in late puberty (i.e., SMR IV-V) should follow adult dosing guidelines. However, puberty may be delayed in children who were infected with HIV perinatally,6 and continued use of pediatric doses in puberty-delayed adolescents can result in medication doses that are higher per body weight than the usual adult doses. Therapeutic drug monitoring may help guide therapeutic decisions.
Timing and Selection of ARTRecommendations for initial therapy that are pertinent to adolescents whose SMR is between I and III, which include data and optimal dosing recommendations, are available in Appendix A: Pediatric Antiretroviral Drug Information and What to Start. Recommendations for initial therapy for adolescents and young adults whose SMR is between IV and V are available in the What to Start section of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. These recommendations also reflect results from two key randomized controlled trials in adults (START and TEMPRANO) which both demonstrated that the clinical benefits of ART are greater when ART is started early, with pre-treatment CD4 T lymphocyte (CD4) counts >500 cells/mm3, than when initiated at a lower CD4 cell count threshold.7,8
Adherence Concerns in Adolescents
HIV-infected adolescents are especially vulnerable to adherence problems resulting from their psychosocial and cognitive developmental trajectory. Comprehensive systems of care are required to serve both the medical and psychosocial needs of HIV-infected adolescents, who are frequently inexperienced with personally managing health care systems and may lack health insurance. Compared with adults, these youth have lower rates of viral suppression and higher rates of virologic rebound and loss to follow up.9,10 For a further discussion of interventions to promote adherence in adolescents, see the HIV-Infected Adolescents section of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and a review by Agwu and Fairlie.11
A particular challage is presented by youth who, despite interventions, remain unable to adhere to therapy. In these cases, alternative considerations to initiating or changing ARV therapy can include: reminders to the patient through cell phone alerts, a short-term deferral of treatment until adherence is improved or while adherence-related problems are aggressively addressed, an adherence testing and training period in which a placebo (e.g., vitamin pill) is administered, and the avoidance of any regimens with low genetic resistance barriers. Such decisions should be individualized and the patient’s clinical and laboratory status monitored carefully.
Sexually Transmitted Infections in Adolescents
Sexually transmitted infections (STIs), including human papilloma virus (HPV), should be addressed in all adolescents. In young men who have sex with men, screening for STIs may require sampling from several body sites, including the oropharynx, rectum, and urethra, since multiple sites of infection are common.12 For a more detailed discussion of STIs, see the most recent Centers for Disease Control and Prevention guidelines13 and the Adult and Pediatric Opportunistic Infection Guidelines on HPV among HIV-infected adolescents.14,15 All HIV-infected female adolescents who are sexually active should receive gynecologic care and all adolescents should be immunized with HPV vaccination.
Adolescent Contraception, Pregnancy, and Antiretroviral Therapy
The possibility of planned and unplanned pregnancy should also be considered when selecting a ART 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 (for additional information please see the Perinatal Guidelines).17 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.
Contraceptive-Antiretroviral Drug Interactions
HIV-infected women can use all available contraceptive methods, including the transdermal patch and vaginal ring.
Several PI and non-nucleoside reverse transcriptase inhibitor drugs alter metabolism of oral contraceptives, which may reduce the efficacy of oral contraceptive agents or increase the risk of estrogen- or progestin-related adverse effects (see the Adult and Adolescent Antiretroviral Guidelines and http://www.hiv-druginteractions.org).18-20 Integrase inhibitors (specifically raltegravir) appear to have no interaction with estrogen-based contraceptives.21 For more information about potential interactions between ARVs and hormonal contraceptives please see Table 3 in 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.
Concerns about loss of bone mineral density (BMD) with long-term use of depot medroxyprogesterone acetate (DMPA) with or without ART (specifically TDF) should not preclude use of DMPA as an effective contraceptive, unless there is clinical evidence of bone fragility. However, monitoring of BMD in young women on DMPA should be considered.6
HIV-Infected Pregnant Adolescents and OutcomesAdolescents who want to become pregnant should be referred for preconception counseling and care, including discussion of special considerations for use of ART during pregnancy (see 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).17 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 or women planning to become pregnant than for non-pregnant women. Details regarding choice of ART regimen in pregnant HIV-infected women, including adolescents, are provided in the Perinatal Guidelines.17 Pregnancies are currently being reported as perinatally infected girls enter adolescence and young adulthood.22,23 Some studies suggest higher rates of adverse pregnancy outcome, such as small for gestational age infants, among pregnant women with perinatal compared to horizontal infection, and unplanned pregnancy appears frequent.23-25 However, the rate of perinatal transmission among perinatally infected pregnant women who are receiving ART appears similar to that among women on ART who were infected by horizontal transmission.26-30
Transition of Adolescents into Adult HIV Care Settings
Facilitating a seamless transition of HIV-infected adolescents from their pediatric/adolescent medical home to adult care is important but challenging. Pediatric and adolescent providers and their multidisciplinary teams should have a formal written plan in place to transition adolescents to adult care. While transition generally occurs when individuals are in their late teens or early 20s, the transition process should be initiated early in the second decade of life. Transition is “a multifaceted, active process that attends to the medical, psychosocial, cognitive and educational, or vocational needs of adolescents as they move from the child-focused to the adult-focused health-care system.”31 Care models for children and adolescents with perinatal 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 do not have a long-standing relationship. Providing adolescents and their new adult medical care providers with support and guidance regarding expectations for each partner in the patient-provider relationship may be beneficial. In this situation, it may be helpful for a pediatric and an adult provider to share joint care of a patient for a period of time.
The adolescent provider should have a candid discussion with the transitioning adolescent to understand what qualities the adolescent considers most important in choosing an adult care setting (e.g., confidentiality, small clinic size, after-school appointments). Additional factors that should be considered 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.32-35 Currently there is no definitive model of transition to adult HIV care and only limited reports about outcomes following transition. A report from the United Kingdom suggests an increased risk of mortality after transition.34 In the United States, 19.8% (or 91/647) of participants followed in HIV Research Network sites were lost to follow-up after transitioning to adult clinics at age 21 years.36
Some general guidelines are available about transitional plans and who might benefit most from them.37-44 To maximize the likelihood of success, providers should prepare adolescents for transition long before it occurs. Attention to the following key areas could improve retention in care and minimize the risk of interruptions to ART: