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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

  • 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

Background

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

HIV-infected adolescents may be sexually active and usually initiate activity during or after puberty. Reproductive health options 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).4 For additional information please see the Perinatal Guidelines section entitled—Reproductive Options for HIV-Concordant and Serodiscordant Couples.5

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. 

Contraceptive-Antiretroviral Drug Interactions

Several PI and non-nucleoside reverse transcriptase inhibitor drugs alter metabolism of oral contraceptives, resulting in possible decreases in ethinyl estradiol or increases in estradiol or norethindrone levels (see the Adult and Adolescent Antiretroviral Guidelines and http://www.hiv-druginteractions.org).7-9 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.10 Providers should be aware of these drug interactions and consider alternative or additional contraceptive methods for patients receiving cART. 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 located at http://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/152/overview.

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 

References

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