Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Abacavir (ABC) neither inhibits nor is metabolized by hepatic cytochrome P450 enzymes. Therefore, it does not cause significant changes in the clearance of agents, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), that are metabolized through these pathways.
• ABC plasma concentrations can decrease when ABC is used concurrently with the ritonavir-boosted PIs atazanavir/ritonavir, lopinavir/ritonavir (LPV/r), and darunavir/ritonavir.^1-3 The mechanism and the clinical significance of the drug interactions with these PIs are unknown. Currently, no recommendations exist for dose adjustments when ABC is coadministered with one of these boosted PIs.
• In the pooled analysis of 230 African children with HIV with a median age of 2.1 years (range 0.1–12.8) and a median weight of 9.8 kg (range 2.5–30.0), the population pharmacokinetics (PK) of ABC showed that children on boosted PI LPV/r or NNRTI efavirenz (EFV) had similar ABC exposures, while concomitant tuberculosis treatment and use of super-boosting with LPV significantly reduced ABC concentrations.⁴
• Alcohol exposure (0.7 g per kg ethanol, which is equivalent to five alcoholic drinks) interferes with ABC metabolism; it affects the activity of alcohol dehydrogenase and glucuronyl transferase. This interference increased ABC area under the curve (AUC) plasma exposure by 41% in adult men with HIV who received ABC 600 mg daily.⁵
• ABC oral solution contains sorbitol, which decreased the exposure of lamivudine (3TC) oral solution in adults when the drugs were administered concurrently.⁶ The clinical significance of this interaction is unknown. 

Major Toxicities

• More common: Nausea, vomiting, fever, headache, diarrhea, rash, anorexia
• Less common (more severe): Serious and sometimes fatal hypersensitivity reactions (HSRs) have been observed in approximately 5% of adults and children (rate varies by race/ethnicity) receiving ABC. HSRs generally occur during the first 6 weeks of therapy, but they have also been reported after a single dose of ABC. The risk of an ABC HSR is associated with the presence of the HLA-B*5701 allele; the risk is greatly reduced by not using ABC in those who test positive for the HLA-B*5701 allele. The HSR to ABC is a multiorgan clinical syndrome usually characterized by rash, or signs or symptoms in two or more of the following groups:
• Fever
• Constitutional symptoms, including malaise, fatigue, or achiness
• Gastrointestinal signs and symptoms, including nausea, vomiting, diarrhea, or abdominal pain
• Respiratory signs and symptoms, including dyspnea, cough, or pharyngitis
• Laboratory and radiologic abnormalities, including elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, lymphopenia, and pulmonary infiltrates. Lactic acidosis and severe hepatomegaly with steatosis—including fatal cases—also have been reported. Pancreatitis with laboratory abnormalities can occur.

If an HSR is suspected, ABC should be stopped immediately and not restarted because hypotension and death may occur upon rechallenge.

• Rare: Increased levels of liver enzymes, elevated blood glucose levels, elevated triglycerides (see information on cardiovascular risk below). Pancreatitis, lactic acidosis, and severe hepatomegaly with steatosis—including fatal cases—have been reported.
• Rare: Drug reaction (or rash) with eosinophilia and systemic symptoms (DRESS) syndrome.

Resistance 

The International Antiviral Society–‍USA maintains a list of updated HIV drug resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

ABC is approved by the U.S. Food and Drug Administration (FDA) for use in children with HIV aged ≥3 months as part of the nucleoside reverse transcriptase inhibitor (NRTI) component of antiretroviral therapy (ART). The World Health Organization (WHO), however, provides dosing guidance for ABC as a component of the NRTI backbone for full-term neonates starting at birth and weighing ≥2 kg (see Annex 1: Dosages for ARV Drugs in the WHO Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery, and Monitoring). The WHO guidance for ABC dosing in neonates increases the choices of antiretroviral (ARV) agents for the management of newborns in special situations where stock outs of nevirapine or zidovudine (ZDV) may affect the ability to effectively provide postnatal prophylaxis or treatment of neonatal HIV. The WHO recommendation of ABC dosing for infants starting at 1 month of age is based on the inclusion of ABC as a preferred NRTI component of the first- and second-line ARV regimens for children in the WHO Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery, and Monitoring. This recommendation also takes into account the availability of the President’s Emergency Plan for AIDS Relief (PEPFAR) tentatively approved pediatric generic ABC formulations—including coformulations that include 3TC—and the cost of ARV drugs in resource-limited settings.

Efficacy

Both the once-daily and twice-daily doses of ABC have demonstrated durable antiviral efficacy in pediatric clinical trials that is comparable to the efficacy observed for other NRTIs in children.^7-11 In an observational study of nine cohorts from the International Epidemiology Databases to Evaluate AIDS (IeDEA) Southern Africa collaboration, 6- and 12-month viral suppression (<400 copies/mL) rates were evaluated among infants who initiated ART at age <3 months, and were compared with infants aged <28 and ≥28 days and weighing <3 and ≥3 kg at the time of ART initiation. Viral suppression at 12 months did not differ by age or weight at the time of ART initiation and it was slightly lower in infants on ABC (174/329 [53%]) versus  in those on ZDV (77/138 [56%]) (adjusted odds ratio 1.8; 95% confidence interval (CI) 1.0–3.2).¹²

Pharmacokinetics

Pharmacokinetics in Neonates and Infants

The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1106 trial reported PK data in 25 infants aged <3 months with HIV who were initiated on a median ABC dose of 10 mg/kg (range, 6–‍13 mg/kg) twice daily in combination with 3TC and LPV/r after 1 month of life. Median age was 6 weeks (range, 1.5–‍11 weeks); median weight was 2,250 g (range 1,360–3,320 g); median gestational age was 36 weeks (range, 27–39 weeks). Sparse and pre-dose PK ABC samples were repeatedly obtained throughout 24 weeks of study follow-up. ABC plasma exposures were high compared to the published data in infants aged >3 months and decreased rapidly between 2 and 8 months of age as the infants matured and ABC clearance increased.¹³ In the Tygerberg cohort study from South Africa, 10 healthy term neonates at the median postnatal age of 10 days (range 6–15) who were administered a single ABC dose of 8 mg/kg before 15 days of life had substantially higher exposures than in infants and children and no reported adverse events.¹⁴ Higher ABC exposures in neonates than in infants and children are likely due to slower drug clearance through immature enzyme pathways.

PK modeling of ABC starting at birth has been conducted using pooled data from 308 ABC concentration measurements obtained from three studies administering ABC liquid to 45 young infants (including 21 full-term neonates <15 days of age with intensive PK).¹⁴ Two of these studies, the Pediatric AIDS Clinical Trials Group (PACTG) 321 study and the Tygerberg cohort, performed intensive PK sampling in full-term neonates receiving ABC for HIV prophylaxis. The third study, IMPAACT P1106, described above, performed sparse PK sampling on full-term and low birth weight (LBW; <2,500 g) infants with HIV. LBW infants were older at the first PK assessment, with a median postnatal age of 73 days (range 41–‍190) and weight of 3.8 kg (range 2.4–5.8). ABC PK parameters in neonates were estimated using PK simulations to achieve plasma ABC exposures (area under the curve from time zero to 12 hours after drug administration; AUC_0–12) within the expected adult range (3.2–‍25.2 mcg•hr/mL). The PK model predicted a slow ABC clearance of 2.51 mL/min per kg at birth, which doubled by 4 weeks of age. Simulations predicted that an ABC dose of 2 mg/kg twice daily in full-term neonates from birth to <4 weeks and an ABC dose of 4 mg/kg twice daily in infants aged 4 to 12 weeks would achieve target AUC_0–12; however, data in LBW infants are lacking.¹⁴ Based on these data, the weight-band dosing of ABC for neonates has been developed for neonates from birth to age <1 month and is included in the WHO Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery, and Monitoring.¹⁵ This weight-band dosing for neonates approximates the ABC dosing per kg based on the postnatal age (see Table 1 below). 

For infants aged ≥1 month with weight 3 to <6 kg, the WHO Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery, and Monitoring currently recommend a twice-daily dose of 3 mL (60 mg) of ABC 20 mg/mL solution (range 10–20 mg/kg/dose). The weight-band dosing for neonates and infants within the WHO HIV guidelines is higher than the modeled weight-based dosing for practical considerations in resource-limited settings. As new generic pediatric formulations of ABC become available in resource-limited settings, there is potential for the revision of the WHO guidelines for weight-band dosing of ABC for young infants. 

Based on the PK modeling from three infant studies¹⁴ and the neonatal and infant safety data from the IMPAACT 1106 study and two observational cohort studies (see Safety in Neonates and Infants below), the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV recommends an ABC dose of 2 mg/kg twice daily for neonates from birth to <1 month of age and an ABC dose of 4 mg/kg twice daily for full-term infants aged ≥1 month and <3 months.

Pharmacokinetics in Children

PK studies of ABC in children aged <12 years have demonstrated that metabolic clearance of ABC in adolescents and young adults (aged 13–25 years) is slower than that observed in younger children and approximates clearance seen in older adults.¹⁶

The PKs of ABC administered once daily in children with HIV aged 3 months through 12 years were evaluated in three crossover open-label PK trials of twice-daily versus once-daily dosing of ABC and 3TC (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]).^5,17-20 The data from these three pediatric trials were used to develop a model for ABC PKs; this model predicted that systemic plasma ABC exposure after once-daily dosing would be equivalent to the exposure seen after twice-daily dosing in infants and children aged ≤12 years.^17-21 Both the trials and PK modeling have demonstrated that once-daily dosing with either the tablet or the liquid formulation of ABC produces plasma exposures comparable to those seen with a twice-daily dosing schedule that uses the same total daily dose of ABC.⁵

Dosing

Dosing and Formulations

A total daily dose of ABC 600 mg can be used safely in a person weighing 25 kg.⁵ Doses of the liquid ABC formulation are similar to those used for weight-band dosing with tablet formulations and should be considered for use in younger children who are unable to swallow a pill.²²

In the three ABC dosing pediatric trials described above,^17-20 only children who had low viral loads and who were clinically stable on the twice-daily dose of ABC were eligible to change to once-daily ABC dosing. Efficacy data from a 48-week follow-up in the ARROW trial demonstrated clinical non-inferiority of once-daily ABC (n = 336) versus twice-daily ABC (n = 333) in tablet form combined with a once-daily or twice-daily 3TC-based ARV regimen.¹¹ To date, no clinical trials have been conducted involving children who initiated therapy with once-daily dosing of the ABC liquid formulation. In children who can be treated with pill formulations, initiating therapy with once-daily dosing of ABC at a dose of 16 mg/kg (with a maximum dose of ABC 600 mg) is recommended. However, twice-daily dosing is recommended for infants and young children who initiate therapy with the liquid formulation of ABC. Switching to once-daily dosing with the liquid formulation could be considered when harmonizing with other antiretroviral drugs administered once daily, such as 3TC and dolutegravir (DTG).

Recent data from the IMPAACT 2019 clinical trial of dispersible and immediate-release ABC/DTG/3TC tablets in children with HIV has validated the FDA-approved dosing in infants and children weighing 10 to <25 kg and established newly proposed dosing of this fixed-dose combination (FDC) (3 tablets once daily of ABC 60 mg, DTG 5 mg, and 3TC 30 mg dispersed in 15–20 mL of water) in infants aged ≥3 months weighing 6 to <10 kg.(Food and Drug Administration 2023) ABC/DTG/3TC dispersible FDC dosing was developed based on PK and safety data in each weight band at the originally selected dosing, which aligned with WHO weight band dosing for the individual ARV agents. Follow-up through 24 weeks confirmed the safety, tolerability, and virological efficacy of both formulations.²³

Toxicity

Safety in Neonates and Infants

Data from the PACTG 321, the IMPAACT P1106 trial, and two observational European and African cohorts provided reassuring data on the safety of ABC in infants when initiated at <3 months of age, including infants with weight <3 kg.^12,13,24 The IMPAACT P1106 trial reported 24 weeks of safety data in 27 infants in whom repeated dosing of ABC was initiated at the median age of 60 days. Fifteen infants (55.6%; 90% CI, 38.3–72.0) met the safety endpoint of death or a Grade 3 or higher adverse event (AE). None of the AEs were related to ABC, and none led to interruptions or adjustments of ABC dosing. No hypersensitivity reactions were reported with the multi-dose treatment.¹³ In two cohorts of neonates (<‍1 month of age) who received a single ABC dose, ABC was well tolerated; all reported AEs in the PACTG 321 study were unrelated to ABC, and no AEs were reported in the Tygerberg cohort.^14,25 The European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC) reported safety outcomes among 139 children from 13 cohorts in 11 countries in Europe who initiated ABC at age <3 months. By 12 months on ABC, 3.6% (n = 4) had discontinued ABC because of an ART safety concern and 11.8% (n = 15) discontinued ABC for any reason.²⁴ Another observational study of nine cohorts from the IeDEA Southern Africa collaboration compared safety outcomes (measured as ABC discontinuations and their reasons) between infants who started ABC aged <28 days (n = 232) and those aged ≥28 days (n = 605), and between infants who started ABC with weight <3 kg (n = 53) and those with weight ≥3 kg (n = 784) at the time of ABC initiation.¹²ABC discontinuations at 6 and 12 months were not significantly different in infants who started ART aged <28 days versus ≥28 days or in infants who weighed <3 kg versus ≥3 kg. ABC discontinuations were less frequent than ZDV discontinuations (adjusted hazard ratio 0.14, 95% CI 0.10–0.20).¹²

Safety in Children and Adolescents

ABC has less of an effect on mitochondrial function than the NRTI ZDV^7,8 and less bone and renal toxicity than tenofovir disoproxil fumarate.^26,27

Systematic review and meta-analysis of the 54 full-text articles on the observational and experimental studies conducted in infants, children, and adolescents with HIV who are aged 10 to 19 years and that included data on safety, efficacy, or both, and were published in English or French between 2009 and 2022 reported that toxic effects due to ABC use in infants, children, and adolescents remain rare and manageable.²⁸

Several observational cohort studies, including contemporary cohort analyses, suggest that an increased risk of cardiovascular disease (CVD) events—such as myocardial infarction, stroke, and invasive cardiovascular procedure—exists in adults who are currently using ABC or who have recently used ABC (see Cardiovascular Risk in Nucleoside Reverse Transcriptase Inhibitor Options as Part of Initial Therapy in the Adult and Adolescent Guidelines); however, other studies have not substantiated this finding. Limited data are available on the CVD risks associated with ABC use in children. One cohort study of South African adolescents (385 participants with HIV and 63 participants as HIV-negative controls) with a median age of 12 years reported an association between ABC exposure and insulin resistance, which was evaluated using homeostatic model assessment. These findings suggested that the use of ABC may be a CVD risk factor for young people with perinatally acquired HIV.²⁹ In a recent prospective study of 101 virally suppressed (≤400 copies/mL) youth aged 10 to 18 years with HIV and 97 uninfected controls from Uganda, the baseline common carotid artery intima-media thickness (IMT) was slightly higher in participants with HIV than in controls (P < 0.01), and pulse wave velocity (PWV) did not differ between groups. In longitudinal analyses, the longer ART duration was associated with lower PWV in youth with HIV (β =.008 [95% CI, -.008 to .003]), while ABC use was associated with greater IMT in youth with HIV (β =.043 [95% CI, .012–.074]). These findings suggest that in adolescents with HIV, early prolonged ART may prevent progression of subclinical vascular disease, while prolonged ABC use may increase it. ³⁰

References

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