The treatment and prognosis of pediatric HIV infection have changed dramatically since the start of the epidemic in the 1980s. The Department of Health and Human Services (DHHS) Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children has developed guidelines for use of antiretroviral agents in pediatric HIV infection. These guidelines are updated regularly to ensure that recommendations are based on the most recent evidence. Similarly, specialists in pediatric HIV infection periodically update guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected and HIV-exposed, uninfected children. Guidance for HIV-infected children who have reached adolescence or for adolescents newly diagnosed with HIV is provided within the DHHS Adult and Adolescent Antiretroviral Guidelines. This chapter emphasizes the predominantly outpatient care-based approach to the use of antiretroviral therapy (ART).

Antiretroviral Therapy

The terms highly active ART (HAART) and combination ART (cART) were used early in the HIV epidemic to distinguish the potent, multidrug ARTs that are the current standard of care from single-drug and other less potent drug regimens. In this chapter, ART is used for multidrug regimens in current use.

Therapeutic Agents

As of 2021, >20 antiretroviral drugs (ARVs) are available for use in adults and adolescents with HIV infection, most of which have an approved pediatric treatment indication and are available as a pediatric formulation ( Table 113.1 ). The therapeutic efficacy of these agents results from interruption of viral replication via several mechanisms ( Fig. 113.1 ).

TABLE 113.1
Antiretroviral Drug Formulations and Pediatric Approval Status (as of July 2020)
Name (Abbreviation) Formulations Pediatric Approval
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Abacavir (ABC) Solution, tablet ≥3 months (US guidelines advise use ≥1 month)
Emtricitabine (FTC) Solution, capsule All ages
Lamivudine (3TC) Solution, tablet ≥3 months (US guidelines advise use from birth plus ≥32 weeks gestational age)
Tenofovir disoproxil fumarate (TDF) Powder (for mixing with food), tablet ≥2 years
Zidovudine (ZDV) Syrup, capsule, tablet All ages, including premature infants
TDF/FTC Tablet ≥17 kg (weight-based dosing for 17–35 kg)
Tenofovir alafenamide (TAF)/FTC Tablet ≥25 kg with INSTI or NNRTI, ≥35 kg with boosted PI
ABC/3TC Tablet ≥25 kg
NRTIs seldom or no longer used: Didanosine (ddI), Stavudine (d4T)
Non-Nucleoside Reverse Transcriptase Inhibitors
Doravirine (DOR) Tablet No
Efavirenz (EFV) Capsule, tablet ≥3 months plus ≥3.5 kg (US guidelines advise against use 3 months to <3 years)
Etravirine (ETR) Dispersible tablet ≥2 years plus ≥ 10 kg
Nevirapine (NVP) Suspension, tablet (immediate-release and extended release) ≥15 days (US guidelines advise investigational dosing for <14 days)
Rilpivirine (RPV) Tablet ≥12 years plus ≥35 kg
Protease Inhibitors
Atazanavir (ATV) Powder, capsule >3 months plus ≥5 kg
Darunavir (DRV) Suspension, tablet ≥3 years plus >10 kg
Lopinavir/ritonavir (LPV/r) Solution, tablet (also pellets and granules, outside the US) ≥14 days of age plus postmenstrual age of 42 weeks
PIs seldom or no longer used: Fosamprenavir (FPV), Indinavir (IDV), Nelfinavir (NFV), Saquinavir (SQV), Tipranavir (TPV)
Entry Inhibitors
Enfuvirtide (T-20) Injection ≥6 years
Maraviroc (MVC) Solution, tablet ≥2 years plus ≥10 kg
Integrase Strand Transfer Inhibitors
Dolutegravir (DTG) Tablet, tablet for oral suspension (PD formulation) >4 weeks plus >3 kg. (Formulation and dose adjustments are required.)
Elvitegravir (EVG) Only available co-formulated with TDF/FTC or TAF/FTC See as co-formulated below
Raltegravir (RAL) Tablets, granules From birth plus weight ≥2 kg
Bictegravir (BIC) Only available co-formulated with TAF/FTC See as co-formulated below
Pharmacologic Enhancers
Ritonavir (RTV) Solution, capsule, tablet >14 days of age for lopinavir (ritonavir a )
Cobicistat (COBI) Tablet ≥40 kg for darunavir; ≥35 kg for atazanavir
Once-Daily Single-Tablet Regimens
Bictegravir-Tenofovir AF-Emtricitabine ≥25 kg
Elvitegravir-Cobicistat-Tenofovir AF-Emtricitabine ≥25 kg
Elvitegravir-Cobicistat-Tenofovir DF-Emtricitabine ≥35 kg
Dolutegravir-Abacavir-Lamivudine ≥ 40 kg (US guidelines advise use ≥25 kg)
Dolutegravir-Rilpivirine No
Doravirine-Tenofovir DF-Lamivudine No
Efavirenz-Tenofovir DF-Emtricitabine ≥ 40 kg
Rilpivirine-Tenofovir AF-Emtricitabine ≥12 years plus ≥ 35 kg
Rilpivirine-Tenofovir DF-Emtricitabine ≥12 years plus ≥ 35 kg
Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine ≥40 kg
Dolutegravir-Lamivudine No

a RTV is approved for but is no longer used as an antiretroviral agent in children as young as 4 weeks. As a pharmacokinetic enhancer in co-formulated LPV/r, it is approved for those ≥14 days of age.

FIGURE 113.1, HIV life cycle and location of action of various antiretroviral medications. cDNA, complementary DNA; mRNA, messenger RNA.

Nucleoside and Nucleotide Analog Reverse Transcriptase Inhibitors

The nucleoside-analog reverse transcriptase inhibitors (NRTIs) were the first class of ARVs available for the treatment of HIV infection. NRTIs inhibit the HIV reverse transcriptase enzyme, which is responsible for the reverse transcription of viral RNA into DNA. The nucleotide-analog reverse transcriptase inhibitor (NtRTI) tenofovir competitively inhibits viral reverse transcriptase, but because it already possesses a phosphate molecule, it bypasses the initial phosphorylation step that is required for activation of NRTIs.

NRTIs/NtRTIs (N[t]RTIs) are the backbone of ART. In general, two of these agents are used with a protease inhibitor (PI), non-nucleoside analog reverse transcriptase inhibitor (NNRTI), or integrase strand transfer inhibitor (INSTI) as first-line therapy. Fixed-dose combinations of N(t)RTIs are available to simplify dosing. With subsequent regimens, one or more of the N(t)RTIs used in an earlier regimen are often used again to take advantage of a favorable resistance profile.

Unusual but serious toxicities that can occur with the use of N(t)RTIs include lactic acidosis, hepatic steatosis, cardiomyopathy, and rapidly ascending muscular weakness. However, these toxicities are more commonly seen with the use of the older, less frequently used NRTIs (didanosine (ddI), stavudine (d4T), zidovudine (ZDV)), rather than the more commonly used lamivudine (3TC), abacavir (ABC), and tenofovir. Tenofovir appears to cause fewer mitochondrial toxicities, but concerns about its deleterious effects on bone and kidneys limit its use in children; studies in adults suggest that tenofovir alafenamide (TAF), a different oral form of tenofovir, can achieve therapeutic activity with less risk of bone and kidney toxicity than the original oral form, tenofovir disoproxil fumarate (TDF). TAF is US Food and Drug Administration (FDA)-approved for children >25 kg and is available in fixed-dose combinations.

Non-Nucleoside Analog Reverse Transcriptase Inhibitors

The NNRTIs have specific activity against HIV-1 but not HIV-2 or other retroviruses. NNRTIs noncompetitively bind to and disrupt the catalytic site of reverse transcriptase. Because drug resistance to NNRTIs requires a single mutation that does not appear to affect viral fitness, resistance can develop rapidly after initiation of NNRTI in a non-suppressive regimen. Cross-resistance occurs readily between the NNRTIs efavirenz (EFV), nevirapine (NVP), and rilpivirine (RPV); cross-resistance is less common with etravirine (ETR) and doravirine (DOR). In adults, NNRTI-based ART regimens are at least as effective as PI-based regimens in achieving durable viral suppression; however, in children under age 3 years, the NNRTI NVP is inferior to the PI lopinavir (LPV)/ritonavir (RTV). , NNRTIs appear to be associated with less long-term toxicity than PIs.

NNRTIs are associated with several types of hepatic toxicity, including asymptomatic elevation in transaminases, clinical hepatitis, and hypersensitivity reactions with hepatitis. However, serious liver dysfunction appears to occur much less commonly in children receiving NVP than in adults.

Hypersensitivity reactions are reported more commonly with NNRTIs (especially NVP) than with other antiretroviral agents. Effects of EFV on the central nervous system (CNS) include confusion, hallucinations, and nightmares. Concern about an increased risk of neural tube defects with EFV led to avoidance of this drug in early pregnancy, but more recent evidence has been reassuring. The FDA continues to recommend against the use of EFV in women who may become pregnant and during early pregnancy, but the DHHS Guidelines and the World Health Organization (WHO) assessment is that EFV is a safe component of ART at any time in pregnancy. ETR has been approved for children 2 years or older; it is typically used in combination with PIs and other ARVs in children for whom other ART regimens have failed. RPV is approved for use in children >12 years and 35 kg. DOR, the newest NNRTI, is not currently approved for use in children, though studies in children 12 years and older are ongoing.

Protease Inhibitors

PIs inhibit the HIV protease enzyme, which is required to cleave viral polyprotein precursors and generate functional viral proteins. PIs have a potent antiretroviral effect, especially when used in combination with N(t)RTIs and/or NNRTIs. Because resistance to PIs requires multiple mutations, some of which reduce viral fitness, PI resistance usually develops slowly. However, compared with NNRTIs, PIs are associated with more long-term toxicity, such as fat redistribution, lipodystrophy syndrome, hyperlipidemia, diabetes mellitus, and hyperglycemia. In children, most PIs require coadministration with a pharmacologic enhancer, usually RTV, because cobicistat (COBI) is not yet approved for use in children. The pharmacologic enhancer inhibits cytochrome P450 (CYP) 3A4 enzymes and increases the concentrations of other PIs. RTV is no longer used in therapeutic doses for anti-HIV activity. The most commonly used PI in children is a coformulation of LPV and RTV known as LPV/r. Other PIs co-administered with a pharmacologic enhancer include atazanavir (ATV) and darunavir (DRV). Fosamprenavir (FPV) and tipranavir (TPV) are less frequently used. All PIs are metabolized by and/or inhibit enzymes in the CYP system; therefore, attention to potential drug–drug interactions is required.

Integrase Inhibitors

The drugs in this class—raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), and bictegravir (BIC)—inhibit the viral integrase, preventing the strand transfer step that is necessary for the integration of the viral genome into the host cell genome. RAL is approved for use from birth in infants who are full term and weigh at least 2 kg. EVG is available only in coformulation with other drugs in convenient single-pill, once-daily regimens but only for children weighing at least 25 kg. Both RAL and EVG have a relatively low barrier to resistance. Once-daily DTG has a high barrier to resistance and the 50 mg adult tablet can be used in children weighing at least 20 kg. The FDA approved a pediatric DTG formulation and dosing for children >4 weeks of age and 3 kg in 2020. The newest INSTI, BIC, has a barrier to resistance similar to that of DTG. It is approved for pediatric patients >25 kg and is available only as a co-formulated tablet.

In May 2018, FDA warned that women taking DTG around conception might have a higher risk of potential neural tube defects in their infants based on a study in Botswana (where there is no fortification of food with folate). Additional results from that ongoing study have been less concerning, leading the US guidelines to recommend DTG as a preferred agent in pregnancy, irrespective of gestational age.

Cabotegravir is an investigational, long-acting antiretroviral administered intramuscularly. Studies in adolescents are ongoing.

Other Classes

Enfuvirtide (T-20), the only FDA-approved fusion inhibitor, which prevents viral entry, requires twice-daily subcutaneous injections. Maraviroc (MVC), an entry inhibitor, binds to and alters the structure of the CCR5 chemokine receptor, preventing it from being used by HIV as a coreceptor. Because some strains of HIV also can infect cells by using the CXC chemokine receptor type 4 (CXCR4) molecule as a coreceptor, MVC is ineffective in individuals who harbor CXCR4-tropic HIV or dual-tropic virus (i.e., able to bind to both CCR5 and CXCR4). These two drugs are seldom used in children.

Ibalizumab is a monoclonal antibody administered via infusion, which acts as a CD4-directed post-attachment inhibitor, blocking HIV from binding to the CCR5 and CXCR co-receptors. It is approved for use in treatment-experienced adults with multidrug-resistant HIV infection. There is no experience or trial in children.

Fostemsavir was approved by the FDA in 2020 for treatment-experienced adults with multidrug-resistant HIV infection. It is a gp120 attachment inhibitor, which interferes with virus attachment to the CD4 receptor. There is no experience or trial in children.

Initiation of Antiretroviral Therapy

Infants

The high mortality rate of HIV-infected infants <12 months of age and the relatively poor ability of the CD4 + lymphocyte count and other factors to predict which infants will have rapid disease progression have led to a longstanding recommendation in the US that ART should commence in all infected infants as soon as they are identified. The CHER trial provided clear evidence in resource-limited settings of the benefit of initiating ART in any infant <12 months of age regardless of CD4 + lymphocyte count. In that study, infected infants (6–12 weeks old) with >25% CD4 + lymphocytes were randomized to either initiation of ART or delay until certain defined criteria were met. The fourfold higher mortality rate in the delayed initiation arm led the WHO in 2010 to recommend ART for all infants. Because of the increased mortality and poor predictive capacity of CD4 + lymphocyte counts in those aged 1–2 years, the WHO also recommended therapy for all 1- to 2-year-old children, although direct clinical trial evidence was lacking.

Older Children and Adolescents

Initiation of ART in older children and adolescents was long based on clinical and immunologic staging. Based on evidence from large trials in adults demonstrating the clinical benefit of immediate ART initiation irrespective of CD4 + lymphocyte count and on availability of expanding safe, potent treatment options, ART is now recommended by DHHS and WHO guidelines for all people with HIV infection, including children of all ages. , , ,

Limited virologic testing capabilities in many countries hinder the timely diagnosis of perinatally infected children. Delayed recognition of children with HIV infection still occurs in the US, usually because of unrecognized perinatal HIV exposure. Older children with delayed diagnosis of perinatal HIV and adolescents with newly acquired HIV should start ART as soon as is feasible. Rapid initiation of ART may improve engagement in care, prevent clinical and immunologic decline, decrease time to viral suppression, and, in adolescents, reduce transmission by sexual activity or injection drug use.

Comorbid conditions, such as tuberculosis (TB), that require treatment with medications that can interact with the ARVs should be addressed before treatment begins. At the time of ART initiation, intensive counseling and support often are necessary to address other complicating factors in the lives of families affected by HIV. Families should be educated about the medications and the critical importance of adherence, and such counseling and support should continue at every visit. ART initiation in newly diagnosed adolescents should be accompanied by a discussion of the daily management of HIV, information on navigating the health system, as well as education on risk factor reduction and sexual health, including sexually transmitted infections (STIs).

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