Antiretroviral Therapy (ART) in Adolescents and Young Adults With HIV Infection

The number of cases of human immunodeficiency virus (HIV) infection among young adolescents had been increasing over the years. Since adolescents and young adults often acquire HIV through sexual activity, they are excellent candidates for intervention and prevention programs that have been implemented. However, they are the least likley age group to know their diagnois and be retained in care. The Centers for Disease Control and Prevention (CDC) data spanning 2015-2019 demonstrate a 15% decrease in HIV infections in the 13-24 year old age group. CDC estimates that 21% of the approximately 36,801 people newly diagnosed with HIV infection in 2019 were aged 13-24 years. ^[1]  Early intervention, including prevention strategies, counseling, and HIV testing, plays a key role in treating adolescents and young adults. ^[2]

In contrast, perinatal HIV infection is relatively rare in the United States, and most perinatally infected youth are now older and aging out of pediatric care, setting the stage for an increased need for transitional care. Many of these young adults are very treatment-experienced and can harbor significant HIV resistance mutations and comorbidities associated with past treatment. Mental health issues have been reported in up to 70% of perinatally infected youth, potentially complicating treatment and adherence. ^[3]

For postpubertal adolescents (Sexual Maturity Rating [SMR] 4 or 5), antiretroviral treatment guidelines for adults may be used; postpubertal youth who were perinatally infected may also use the adult antiretroviral treatment guidelines. ^[3] Special consideration may be needed in perinatally infected patients, as they are often more treatment-experienced and may have developed a significant burden of antiretroviral resistance. Newly diagnosed patients should begin a preferred regimen, when possible. Further information can be found at HIV Treatment Regimens CDC Guidelines, Adult/Adolescent.

Puberty has a direct effect on how a drug is metabolized and on the drugs' pharmacokinetic properties; therefore, dosage of medications for HIV infection should be based on the SMR (also known as Tanner staging) of puberty and not just on age alone. ^{[4, 5]}

Adolescents in early puberty (ie, SMR stages 3 and less) should be on pediatric dosing schedules found in the pediatric treatment guidelines, ^[6] whereas those in late puberty (ie, SMR stages 4 and 5) should follow adult dosing schedules. ^[3]

Adolescents who are undergoing their growth-spurt period (ie, Tanner stage 3 in females and Tanner stage 4 in males) should follow the adult dosing guidelines. They may require more frequent visits to manage dosing changes during this time.

Puberty may be delayed in children who were perinatally infected with HIV, adding to discrepancies between Tanner stage-based dosing and age-based dosing. ^[7]

Dosing of antiretroviral medications for adolescents can be unpredictable and is dependent on multiple factors, including body mass and composition and chronologic age. ^[3]

The possibility of pregnancy should be discussed with all adolescent females. Patients should be counseled on options to prevent pregnancy, as well as the potential for drug interactions with hormonal contraceptives. Guidelines for Use of Antiretroviral Agents in HIV Infected Adults and Adolescents Table 24a-f. provide further information on drug interactions. ^[3] In general, oral contraceptives have significant interactions with protease inhibitors, efavirenz, and elvitegravir. Long-acting injectable contraception is compatible with protease inhibitors and NNRTIs, but data are limited with integrase inhibitors. Further information can be found under Gynecologic Care of Women With HIV.

In women who are planning pregnancy or are likely to become pregnant, antiretrovirals should be chosen to minimize risks to the developing fetus while still providing maximal virologic control for the patient. Recent guidelines have relaxed prohibitions on the use of dolutegravir after a full analysis of the date from teh Tsepamo trial. ^[3] Further information can be found at HIV in Pregnancy.

Adolescents are at risk of transmitted drug resistance, and baseline genotype data should guide antiretroviral selection. ^[8]

The definition of "adolescent" may differ depending on the regimen; for regimens with specific definitions of "adolescent," the definition is provided in parentheses following the regimen.

Abacavir (ABC)

Patients must be tested for HLA-B*5701 prior to initiation. Patients who are positive are at the highest risk of abacavir hypersensitivity. ^[3]

• ABC 300 mg PO BID or 600 mg PO once daily (adolescent, ≥16 years); liquid formulation available at 20 mg/mL with the same recommended dose
• Trizivir: Combination formulation including ABC 300 mg/lamivudine (3TC) 150 mg/zidovudine (ZDV) 300 mg; give 1 tablet PO BID (adolescent, ≥40 kg); not a first-line therapy
• Epzicom: Combination formulation including ABC 600 mg/3TC 300 mg; give 1 tablet PO once daily (adolescent, >16 years)

Emtricitabine (FTC)

• Oral solution: 240 mg (24 mL) PO once daily; capsules: 200 mg PO once daily (adolescent, ≥18 years)
• Truvada: Combination formulation including FTC 200 mg/tenofovir (TDF) 300 mg; 1 tablet PO once daily (adult dose; not recommended for patients < 18 years)

Lamivudine (3TC)

• If ≥50 kg, give 150 mg PO BID or 300 mg PO once daily; if < 50 kg, give 4 mg/kg (up to 150 mg) BID (adolescent, ≥16 years)
• Combivir: Combination formulation including 3TC 150 mg/ZDV 300 mg; give 1 tablet PO BID (adolescent, ≥30 kg)
• Trizivir: Combination formulation including ABC 300 mg/3TC 150 mg/ZDV 300 mg; give 1 tablet PO BID (adolescent, ≥ 40 kg)
• Epzicom: Combination formulation including ABC 600 mg/3TC 300 mg; give 1 tablet PO once daily (adolescent, ≥40 kg)
• Cimduo: Combination formulation including 3TC 300 mg/TDF 300 mg; 1 tablet PO once daily (adolescent, ≥35 kg)

Tenofovir DF (TDF)

• 300 mg PO once daily (adolescent, ≥12 years and ≥35 kg)
• Truvada: Combination formulation including FTC 200 mg/TDF 300 mg; 1 tablet PO once daily (≥35 kg)
• Although TDF is approved for age >2 years, data pointing to decreased bone mineral density have led to the recommendation to reserve use until later adolescence (Tanner stage 4 or 5) ^[7]
• Pediatric dosing of Truvada (≥17 kg) is as follows:

  • 17 to < 22 kg: One 100 mg/150 mg tablet PO daily
  • 22 to < 28 kg: One 133 mg/200 mg tablet PO daily
  • 28 to < 35 kg: One 167 mg/250 mg tablet PO daily
  • ≥35 kg: One 200 mg/300 mg tablet PO daily
• Cimduo: Combination formulation including 3TC 300 mg/TDF 300 mg; 1 tablet PO once daily (adolescent, ≥35 kg)

Tenofovir AF (TAF)

• 25 mg PO once daily
• Pediatric patients ≥12 years and ≥35 kg: Indicated in combination with other antiretroviral agents
• Adolescents and children who weigh 25-35 kg: In combination with other antiretroviral agents other than protease inhibitors requiring a CYP3A inhibitor
• Descovy: Combination formulation including FTC 200 mg/TAF 25 mg;1 tablet PO once daily

Zidovudine (ZDV)

• 200 mg PO TID or 300 mg PO BID (adolescent, ≥18 years); oral solution 10 mg/mL
• Combivir: Combination formulation including 3TC 150 mg/ZDV 300 mg; give 1 tablet PO BID (adolescent, ≥30 kg)
• Trizivir: Combination formulation including ABC 300 mg/3TC 150 mg/ZDV 300 mg; give 1 tablet PO BID (adolescent, ≥40 kg)

Other combinations

• Stribild: elvitegravir/cobicistat/emtricitabine/tenofovir TD approved for adults and adolescents aged 12 years or older who weigh at least 35 kg. Combination formulation including EVG 150 mg/Cobi 150 mg/emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg; take once daily with food
• Genvoya: Similar to Stribild with the exception that it contains 10 mg of tenofovir alafenamide (AF). It is approved for adults and adolescents aged 12 years or older who weigh at least 35 kg.
• Biktarvy: Bictegravir (BIC), FTC, and tenofovir alafenamide (TAF) approved for adults and adolescents who weigh ≥25 kg. Combination formulation including BIC 50 mg/ FTC 200 mg/TAF 25mg; take once daily with food ^[9]
• Symtuza: Darunavir/cobicistat/FTC/TAF approved for adults and adolescents who weigh ≥40 kg. The complete regimen includes darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir AF 10 mg and may be taken with meals. ^[10]

The definition of "adolescent" may differ depending on the regimen; for regimens with specific definitions of "adolescent," the definition is provided in parentheses following the regimen.

Efavirenz (EFV)

• 600 mg PO once daily (adolescent, ≥40 kg) ^[11]
• Atripla: Combination formulation including EFV 600 mg/emtricitabine (FTC) 200 mg/ tenofovir disoproxil fumarate (TDF) 300 mg; 1 tablet PO once daily (drug combination should not be used in pediatric patients, < 40 kg, in whom the EFV dose would be excessive)
• Symfi Lo: Combination formulation including EFV 600 mg/3TC 300 mg/TDF 300 mg; 1 tablet PO once daily (adolescent, ≥35 kg)

Etravirine (ETR)

• General adult dosing: 200 mg (one 200-mg tablet or two 100-mg tablets) PO BID following a meal

Rilpivirine (RPV)

• Indicated in combination with other antiretroviral agents for treatment of HIV-1 infection in treatment-naïve adolescents aged 12-17 years with HIV-1 RNA ≤100,000 copies/mL (approved by FDA for adolescents in August 2015)
• 25 mg PO once daily; take with food
• Complera: Combination formulation including RPV 25 mg/emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg; take once daily with food
• Odefsey: Combination formulation including RPV 25 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide fumarate (TAF) 25 mg; take once daily with food
• Juluca: Combination formulation including RPV 25 mg/DTG 50mg; take once daily with food

The definition of "adolescent" may differ depending on the regimen; for regimens with specific definitions of "adolescent," the definition is provided in parentheses following the regimen.

Atazanavir (ATV)

• Age 16-21 years: For antiretroviral-naive patients, give ATV 300 mg PO plus ritonavir (RTV) 100 mg PO with food or ATV 400 mg PO once daily with food ^[12]
• Antiretroviral-experienced patients: ATV 300 mg PO plus RTV 100 mg PO, both once daily with food
• Dosing recommendations during coadministration with other antiretrovirals: ATV in combination with EFV in therapy-naive patients only (adult dose): ATV 400 mg plus RTV 100 mg PO plus EFV 600 mg PO, all once daily but at separate times (ATV + RTV with food, EFV without food)
• ATV in combination with TDF (adult dose): ATV 300 mg PO plus RTV 100 mg PO plus TDF 300m g PO, all once daily with food
• Only RTV-boosted ATV should be used in combination with TDF, because TDF decreases ATV exposure

Darunavir (DRV)

• Treatment naive: Adolescent (≥18 years)/adult dose: DRV 800 mg PO plus RTV 100 mg PO, both once daily with food
• Treatment experienced: Adolescent (≥18 years)/adult dose: DRV 600 mg PO plus RTV 100 mg PO, both twice daily with food

Lopinavir/ritonavir (LPV/RTV)

• LPV 400 mg/RTV 100 mg per dose BID (adolescent, ≥40 kg)
• Pediatric dose (>6 mo - 18 years): For individuals receiving concomitant nelfinavir (NFV), NVP, EFV, or FPV (these drugs induce LPV metabolism and reduce LPV plasma levels), increased LPV/RTV dosing is required with concomitant administration of these drugs and/or in treatment-experienced patients in whom reduced susceptibility to LPV is suspected (such as those with prior treatment with other protease inhibitors)
• Once-daily dosing is not recommended in adolescents

Ritonavir (RTV)

• RTV as a pharmacokinetic enhancer: Major use of RTV is as a pharmacokinetic enhancer of other protease inhibitors; dose of RTV recommended varies with the different protease inhibitors

Enfuvirtide (ENF)

• 90 mg (1 mL) injected SC BID into the upper arm, anterior thigh, or abdomen (adolescent defined as >16 years):

Maraviroc (MVC)

Indicated in combination with other antiretrovirals for the treatment of only CCR5-tropic HIV-1 infection in patients aged ≥2 years who weigh at least 10 kg

It is imperative to test all patients for CCR5 tropism using a highly sensitive tropism assay before initiating the drug

Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on maraviroc

Dosing for patients older than 16 years

• When given with potent CYP3A inhibitors (with or without CYP3A inducers), including protease inhibitors (except TPV/RTV): 150 mg PO BID
• When given with nucleoside reverse transcriptase inhibitors, ENF, TPV/RTV, NVP, raltegravir (RAL), and drugs that are not potent CYP3A inhibitors or inducers: 300 mg PO BID
• When given with potent CYP3A inducers, including EFV and ETR (without a strong CYP3A inhibitor): 600 mg PO BID
• Additional dose adjustment required with renal impairment

Dosing for children

Recommended dosage differs based on concomitant medications owing to drug interactions; examples are listed below (ie, not an exhaustive list)

Noninteracting concomitant medications

< 30 kg: Not recommended

≥30 kg: 300 mg PO BID

Noninteracting drugs include tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide

Also, all other medications that are not potent CYP3A inhibitors or inducers

Potent CYP3A inhibitors (with or without a potent CYP3A inducer)

10 kg to < 20 kg: 50 mg PO BID

20 kg to < 30 kg: 75 mg (tablet) or 80 mg (oral solution) PO BID

30 kg to < 40 kg: 100 mg PO BID

≥40 kg: 150 mg PO BID

Potent CYP3A inhibitors include protease inhibitors (except tipranavir/ritonavir), delavirdine, elvitegravir/ritonavir, ketoconazole, itraconazole, clarithromycin, and other potent CYP3A inhibitors (eg, nefazodone, telithromycin)

Potent CYP3A inducers (without a potent CYP3A inhibitor)

Maraviroc is NOT recommended for children taking potent CYP3A inducers

Potent CYP3A inducers include efavirenz, rifampin, etravirine, carbamazepine, phenobarbital, and phenytoin

Raltegravir (RAL)

• Isentress 400-mg tab: 400 mg PO BID (adults and children who weigh ≥25 kg)
• Isentress HD 600-mg tab: 1200 mg PO once daily (adults and adolescents who weigh ≥40 kg) ^[13]

Dolutegravir (DTG)

• 50 mg PO once daily (adolescents ≥12 y)
• Not recommended in women who may become pregnant because of a possibility of teratogenicity
• Pediatric dosing is as follows:

  • < 30 kg: Safety and efficacy not established
  • ≥30 kg to < 40 kg: 35 mg PO daily (ie, one 25-mg tablet and one 10-mg tablet)
  • ≥40 kg: 50 mg PO daily
• Triumeq: Combination formulation including DTG 50 mg/lamivudine (3TC) 300 mg/abacavir (ABC) 600 mg; take once daily with or without food; must check HLA B5701
• Dovato: Combination formulation including DTG 50 mg/lamivudine (3TC) 300 mg
• Juluca: Combination formulation including RPV 25 mg/DTG 50mg; take with food

Elvitegravir (EVG)

• Vitekta: 85 mg or 150 mg used in combination with an HIV protease inhibitor (ie, atazanavir, lopinavir, darunavir, fosamprenavir, or tipranavir) and coadministered with ritonavir plus other antiretroviral drug(s) as indicated for the treatment of HIV-1 infection in antiretroviral treatment–experienced adults; limited data (off-label) available for adolescents aged 12-17 y
• Stribild: Elvitegravir is a component of the FDA-approved “quad” pill, elvitegravir/cobicistat/emtricitabine/tenofovir TD (Stribild) approved for adults and adolescents aged 12 y or older who weigh at least 35 kg. Combination formulation including EVG 150 mg/Cobi 150 mg/emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg; take once daily with food
• Genvoya: Identical to elvitegravir with the exception that it contains 10 mg of tenofovir alafenamide (AF). It is approved for adults and adolescents aged 12 y or older who weigh at least 35 kg.

Bictegravir (BIC)

• Biktarvy: Combination formulation including BIC 50 mg/emtricitabine (FTC) 200 mg/tenofovir AF (TAF) 25 mg; take once daily with or without food

Cobicistat (Tybost) is a CYP3A inhibitor. As a single agent, it is indicated to increase systemic exposure of atazanavir or darunavir (once-daily dosing regimen) in combination with other antiretroviral agents. These indications are weight-dependent in adolescents (ie, use with atazanavir in adolescents weighing at least 35 kg or with darunavir in those weighing at least 40 kg).

Cobicistat may be used for treatment-naïve or treatment-experienced patients (without darunavir resistance–associated substitutions). The dosage is 150 mg PO once daily plus atazanavir 300 mg PO once daily or darunavir 800 mg PO once daily.

It is also a component of elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild), elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya), darunavir/cobicistat (Prezcobix), and atazanavir/cobicistat (Evotaz).

Use in patients aged 12 years or older has been approved for the combination products elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild, Genvoya).