Antiretroviral treatment in HIV-1 infected pediatric patients: focus on efavirenz

Figures & data

Table 1 When to start antiretroviral treatment in HIV-infected children according to current US, European, and WHO guidelines

Age	Immunologic and clinical criteria	US 2012^10	PENTA 2009^21	WHO 2013^22
< 12 months	• Regardless of clinical symptoms, CD4% or viral load	Treat (AI for < 12 weeks of age; All for > 12 weeks)	Treat all	• Initiate ART in all regardless of WHO clinical stage or CD4 cell count^a
1 to <3 years	• AIDS or significant HIV-related symptoms^Citation13	Treat (AI^*)	Treat CDC stage B or C/	• Initiate ART in all regardless of WHO clinical stage and CD4 cell count
	• Confirmed CD4 <25% or CD4 count <1,000 cells/mm^Citation3, regardless of symptoms or HIV RNA level	Treat (AII)	WHO stage 3 or 4 Treat <25% or < 1,000 cells/mm^Citation3	• Prioritize initiation of ART in all HIV-infected children ≤2 years of age or with severe/ advanced HIV disease (WHO clinical stage 3 or 4) or with CD4 count ≤750 cells/mm^Citation3 or <25%
	• Asymptomatic or mild symptoms^c and CD4 ≥25% or ≥ 1,000 cells/mm^Citation3	Consider^d (BIII)	Consider > 100,000 copies/mL
3 to <5 years	AIDS or significant HIV-related symptoms^b Confirmed CD4 <25% or CD4 count <750 cells/mm^Citation3, regardless of symptoms or HIV RNA level Asymptomatic or mild symptoms^c and CD4 ≥ 25% or ≥ 750 cells/mm^Citation3	Treat (AI^*) Treat (AII) Consider^d (BIII)	Treat CDC stage B or C/ WHO stage 3 or 4 Treat <20% or <500 cells/mm^Citation3 Consider > 100,000 copies/mL
≥ 5 years	AIDS or significant HIV-related symptoms^b Confirmed CD4 ≤500 cells/mm^Citation3, regardless of symptoms or HIV RNA level Asymptomatic or mild symptoms^c and CD4 ≥ 500 cells/mm^Citation3	Treat (AI^*) Treat (AI^* for CD4<350 cells/mm^Citation3 and BII^* for CD4 350-500 cells/mm^Citation3) Consider^d (BIII)	Treat CDC stage B or C/ WHO stage 3 or 4 Treat <350 cells/mm^Citation3 Consider > 100,000 copies/mL	Initiate ART if CD4 cell count is #500 cells/ mm^Citation3 regardless of WHO clinical state - As a priority, initiate ART in all children with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count #350 cells/mm^Citation3 Initiate ART regardless of CD4 cell count - WHO clinical stage 3 or 4 - Active tuberculosis

Notes: 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).

a Initiate in all HIV-infected children younger than 18 months with a presumptive clinical diagnosis of HIV infection;

b CDC Clinical Category C and B (except for single episode of serious bacterial infection);

c CDC Clinical Category A or N or only a single episode of serious bacterial infection;

d data supporting this recommendation are stronger if plasma HIV RNA level is >100,000 copies per mL (BII).

Abbreviations: ART, antiretroviral treatment; HIV, human immunodeficiency virus; PENTA, Pediatric European Network for Treatment of AIDS; WHO, World Health Organization; AIDS, acquired immunodeficiency syndrome; CDC, Centers for Diseases Prevention and Control.

Table 2 List of currently available antiretroviral treatments with US Food and Drug Administration approval by age group

Drug class	Antiretroviral	FDA-approved age
Nucleoside/nucleotide^* reverse transcriptase inhibitors	Abacavir	≥ 3 months
	Didanosine	≥ 2 weeks
	Emtricitabine	Birth
	Lamivudine	Birth
	Stavudine	Birth
	Tenofovir^*	≥ 2 years
	Zidovudine	Birth
Non-nucleoside reverse transcriptase inhibitors	Efavirenz	≥ 3 months
	Etravirine	≥ 6 years
	Nevirapine	Birth
	Rilpivirine	≥ 18 years
Protease inhibitors	Atazanavir	≥ 6 years
	Darunavir	≥ 3 years
	Fosamprenavir	≥ 6 months
	Indinavir	≥ 18 years
	Lopinavir	≥ 2 weeks
	Nelfinavir	≥ 2 years
	Ritonavir	≥ 1 month
	Saquinavir	≥ 2 years
	Tipranavir	≥ 2 years
CCR5 antagonist	Maraviroc	≥ 16 years
Integrase inhibitors	Raltegravir	≥ 18 years
	Elvitegravir	≥ 18 years
Fusion inhibitor	Enfuvirtide	≥ 6 years

Note:

* Tenofovir is a nucleotide reverse transcriptase inhibitor whereas the rest of the drugs in this class are nucleoside analogues.

Abbreviation: FDA, US Food and Drug Administration.

Table 3 Comparison of guidelines for preferred first-line antiretroviral treatment in treatment-naïve pediatric patients

US 2012^10	PENTA 2009^21	WHO 2013^22
Infants and children < 3 years
LPV/r + ZDV + (3TC or FTC)	NFV + (ABC or ZDV) + 3TC	LPV/r + (ABC or ZDV) + 3TC
≥ 3 months: LPV/r +	or
ABC + (3TC or FTC)	LPV/r + (ABC or ZDV) + 3TC
Children ≥ 3 years
EFV + (ABC^* or ZDV) + (3TC or FTC)	EFV + (ABC or ZDV) + 3TC	EFV + ABC + 3TC
or	or
LPV/r + (ABC or ZDV) + (3TC or FTC)	LPV/r + (ABC or ZDV) + 3TC
or
ATV/r + (ABC or ZDV) +
(3TC or FTC) if ≥ 6 years
Adolescents
EFV + TDF/FTC	EFV + (ABC or	EFV + TDF +
or	ZDV) + 3TC	(3TC or FTC)
ATV/r + TDF/FTC
or
DRV/r + TDF/FTC
or
RAL + TDF/FTC

Notes:

* HLA-B*5701 genetic tests should be performed before initiating abacavir-based therapy in this setting, and abacavir should not be given to a child who tests positive for HLA-B*5701.

Abbreviations: 3TC, lamivudine; ABC, abacavir; ARV, antiretroviral; ATV, atazanavir; EFV, efavirenz; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; RPV, rilpivirine; ZDV, zidovudine.

Table 4 Studies of virologic and immunologic efficacy of efavirenz in children

Study details	Subjects, n (age range)	EFV dose	Other ARV (previous ART)	Study period	Median baseline HIV RNA (range)	Median baseline CD4 cells/mm^Citation3 (range)	Percent undetectable at last visit	Median increase CD4 cells/mm^Citation3 (range)
Pediatric AIDS Clinical Trials Group (PACTG) 382 Starr et al^Citation30 (USA, RCT)	57 (3.8–16.8) years	mg/day = (weight [kg]/ 70)^0.7 × 600 rounded to the nearest 25 mg increment	NFV + ≥ 1 NRTI (NRTI-pretreated, Pl-naïve and N NRTI-naïve)	48 weeks	4.0 log10 copies/mL (2.6–5.7)	699 (4–2,616)	76% had VL <400 copies/mL and 63% had VL <50 copies/mL	+74 cells/mm^Citation3
Teglas et al^Citation88 (France, retrospective)	33 (10.4–14.9) years	Median dosage 13.3 (1 1.3–16) mg/kg	24: Two NRTIs 9: NRTI + PI (25 pretreated, 8 naïve)	Median 125 (70–277) days	4.7 log10 copies/mL (1.3–6.7)	225 (0–1,262)	48% had VL <200 copies/mL at 6 months	+ 128 cells/mm^Citation3 (–45 to 414)
Engel horn et al^Citation89 (Germany, retrospective)	15 (43–175) months	Median dosage 1 1.7 (7.5–14.8) mg/kg	(7: NRTIs, 8: NRTIs + PI) (pretreated, NNRTI -naïve)	52 weeks	4.7 log10 copies/mL (2.7–6.36)	638 (213–1,358)	60% had VL <50 copies/mL	+321 cells/mm^Citation3 (–162 to 574)
PACTG 382 Starr et al^Citation50 (USA, RCT)	19 (3.1–9.6) years	Liquid formulation mg/day = (weight [kg]/ 70)^0.7 × 720	NFV and one or more NRTI (NRTI-pretreated, PI-naïve and NNRTI-naïve)	48 weeks	4.6 log10 copies/mL	706	63% had VL <400 copies/mL and 58% had VL <50 copies/mL	+366 cells/mm^Citation3 (IQR 178–539)
Fraaij et al^Citation90 (the Netherlands, retrospective)	8 (5.6–15) years	14 mg/kg	LPV/r (NRTI-pretreated)	48 weeks	Inclusion criterion: VL > 1,000 copies/ mL (238–47,975)	530 (IQR 373–655)	88% had VL <500 copies/mL and 50% had VL <50 copies/mL	+665 cells/mm^Citation3 (IQR 580–738)
Funk et al^Citation91 (Germany, retrospective)	10(3.1–8.0) years	12.5–17 mg/kg	2 NRTIs (ARV-naïve)	24 months	5.5 log10 copies/mL (4.11–6.54)	378 (58–1,376)	80% had VL <50 copies/mL	+842 cells/mm^Citation3
PACTG 1021 McKinney et al^Citation92 (USA, prospective)	37(3.2–21.1) years	According to manufacturer’s weight band dosing	FTC + ddl (ARV-naïve)	96 weeks	47,775 copies/mL (3,655–2,370,884)	310 (2–1,893)	85% had VL <400 copies/mL and 72% had VL <50 copies/mL	+329 cells/mm^Citation3
Scherpbier et al^Citation93 (the Netherlands, prospective)	36 (IQR 3.3–10.7) years	According to manufacturer’s weight band dosing	ABC + ddl + 3TC (naive and pretreated children, all NNRT-naïve)	96 weeks	3.6 log10 copies/mL (2.4–4.7)	730 (400–1,050)	67% had VL <50 copies/mL	Not available
French National Agency for AIDS Research and Viral Hepatitis (ANRS) 12103 Barro et al^Citation94	51 (2.5–14.5) years	According to manufacturer’s weight band dosing	ddl + 3TC (ARV-naïve)	12 months	341,032 copies/mL (127,838–761,539)	260 (126–559)	75.5% had VL <300 copies/mL at 12 months	+ 167% at 12 months
Hien et al^Citation95 (Burkina Faso, prospective)				24 months			81.6% had VL <300 copies/mL at 24 months	Mean CD4: 944 cells/mm^Citation3 at 24 months
Lowenthal et al^Citation32 (Botswana, retrospective)	421 (IQR 6.0–10.5) years	According to national guidelines	90.3%: AZT + 3TC 9.7%: 2 NRTIs	Median 69 (IQR 23–87) months	5.2 log10 copies/mL (4.8–5.6)	13% (8–20)	87.2% had VL <400 copies/mL at 60 months	Not reported

Abbreviations: RCT, randomized controlled trial; EFV, efavirenz; ARV, antiretroviral drugs; ART, antiretroviral treatment; NFV, nelfinavir; NRTI, nucleoside/nucleotide reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitors; LPV/r, lopinavir/ritonavir; 3TC, lamivudine; ddI, didanosine; ABC, abacavir; FTC, emtricitabine; IQR, interquartile range; PACTG, Pediatric AIDS Clinical Trials Group; AZT, zidovudine; VL, viral load.

Figure 1 Pharmacology and pharmacokinetics of efavirenz.

Abbreviations: EFV, efavirenz; C_max, peak concentration; AUC, area under curve; CSF, cerebrospinal fluid.

Table 5 Pharmacokinetic studies of efavirenz in children reporting a high proportion of children with subtherapeutic plasma efavirenz concentrations

Study details	Number of subjects (age range)	Other ARV (Previous ART)	EFV dose	Results
Ren et al^Citation96 (South Africa, case series)	15 (2.3–11.3) years	13: EFV + d4T + 3TC 1: EFV + ZDV + 3TC 1: EFV + ZDV + ddI	Manufacturer’s weight band dosing	Cmin < 1 mg/L in 6 (40%); 5 children had detectable VL, 3 of whom had low EFV concentrations; marked variability of EFV levels
French National Agency for AIDS	48 (30 months to 15 years)	EFV-ddI-3TC (ARV-naïve)	Manufacturer’s weight band dosing	19% (44% of children weighting <15 kg) had Cmin < 1 mg/L
Research and Viral Hepatitis (ANRS) 12103 Hirt et al^Citation47 (Burkina Faso, prospective)				Significantly higher percentage of children with Cmin >1.1 mg/L or AUCs >51 mg/L * hour than of children with lower values had viral load decreases greater than 2 log10 copies/mL after 3 months of treatment
Viljoen et al^Citation97 (South African, prospective)	60 (3–14) years	EFV + d4T + 3TC (ARV-naïve)	200, 250, 300, 350, 400, and 600 mg daily for children weighing 10–14.9, 15–19.9, 20–24.9, 25–32.9, 33–40, and >40 kg, respectively	From 164 samples taken at 1, 3, and 6 months after initiation: Cmin <1 mg/L in 17% Cmin <1–4 mg/L in 58% Cmin >4 mg/L in 25%
Antiretroviral Research for Watoto (ARROW PK Fillekes et al^Citation48 (Uganda, RCT)	41 (3–12) years ^)	EFV + ABC + 3TC	2006 WHO/manufacturer’s recommended dosage	PKI at steady state; PK2 4 weeks after C < 1 mg/L in 7 (17%) at 8 and/or 12 hours after dosing Cmin <I mg/L in 15 of 39 (3%) with C24h median 1.1 (interquartile range 0.7–2.9; range 0.3–18.4) C8h and/or C12h >4.0 mg/L in 12 of 41 (29%)
Cressey et al^Citation98 (Thailand, prospective)	39 (3–17) years	EFV + TDF + 3TC (ARV-naïve)	250, 300, 350, 400, and 600 mg daily for children weighing 15–20, 20–25, 25–32.5, 32.5–40, or >40 kg, respectively	Cmin < 1 mg/L in 6 (15%), including 2 of 4 in the lowest weight band

Abbreviations: EFV, efavirenz; d4T, stavudine; 3TC, lamivudine; C_min, minimum concentrations; ARV, antiretroviral treatment; ddI, didanosine; ZDV, zidovudine; PK, pharmacokinetic; TDF, tenofovir; ABC, abacavir; WHO, World Health Organization; RCT, randomized controlled trial; ART; VL, viral load.

Table 6 Safety of efavirenz in children

Study details	Subjects, n (age range)	EFV dose	Adverse event		Discontinuation (%)	Time to adverse events
			Grade, n (%)	Type, n (%)
PACTG 382 Starr et al^Citation30 (USA, RCT)	57 (3.8–16.8) years	mg/day = (weight [kg]/ 70)^07 × 600 rounded to the nearest 25 mg increment	None or mild, 26 (46%) Moderate, 25 (44%) Severe, 5 (9%) Life-threatening, 1 (2%)	Rash, 17(30%) Diarrhea, 10(18%) Neutropenia, 7 (12%) Biochemical abnormalities, 7 (12%) Mild dizziness, 8 (14%)	14 (25%)	88% of rashes appeared within 14 days after initiation of EFV (median 9, range 6–205) and lasted for a median of 6 days (range 2–37)
Teglas et al^Citation88 (France, retrospective)	33 (10.4–14.9) years	Median dosage 13.3 (11.3–16) mg/kg	Clinically discernible 15(42%)	Rash, 5 (15%) CNS toxicity, 12(37%)	7(21%)	Rash appeared around day 8 to 10
Engel horn et al^Citation89 (Germany, retrospective)	15 (43–175) months	Median dosage 11.7 (7.5–14.8) mg/kg	Not available	Rash, 3 (20%)	3 (20%)	Rash appeared within 2 weeks and disappeared in 5–7 days
PACTG 382 Starr et al^Citation50 (USA, RCT)	19 (3.1–9.6) years	Liquid formulation mg/day = (weight [kg]/ 70)^0.7 × 720	Grade 3 toxicity, 1 (5%) Grade 2 toxicity, 11 (58%)	Grade 3: Neutropenia, 1 (5%) Grade 2: Diarrhea, 6 (32%) Neutropenia, 6 (32%) Anemia, 2(11%) Rash, 1 (5%)	2(10%)	Not available
Funk et al^Citation91 (Germany, retrospective)	10 (3.1–8.0) years	12.5–17 mg/kg	Not available	Transient rash, 4 (40%) Diarrhea, 1 (10%) Arthralgia, 1 (10%) CNS toxicity, 2 (20%)	None	All adverse events occur during initial phase of treatment
PACTG 1021 McKinney et al^Citation92 (USA, prospective)	37 (3.2–21.1) years	According to manufacturer’s weight band dosing	≥ 1 grade ≥ 1 laboratory abnormality, 37 (100%) ≥ 1 grade 3 or 4 laboratory abnormality, 5 (13%) Grade 3 dizziness, 1 (3%) Grade 3 rash, 1 (3%) Grade 2 rash, 1 (3%)		11 (30%) 5 (13%) due to toxicity or virological failure	CNS toxicity and rash appear within the first 2 weeks of initiation of EFV
Tukei et al^Citation63 (Uganda, prospective)	378 (3–12) years	According to manufacturer’s weight band dosing	Any adverse event, 107 (28.3%) Mild and transient, 102 (81%) Severe or life-threatening, 24(19%)	Gastrointestinal, 47 (12%) CNS-related, 39 (16%) Anemia, 10(3%) Nail discoloration, 8 (2%) Hypersensitivity/skin rash, 7 (2%) Gynecomastia, 1 (0.3%)	None (8 lost to follow-up)	Median duration from start of ART to detection of clinical adverse event was 12 (range 3–24) weeks. There was no significant association between baseline factors (age, sex WHO clinical stage, CD4 cell count, Hb, WBC, ART combination) and the first occurrence of adverse event

Abbreviations: ART, antiretroviral treatment; PACTG, Pediatric AIDS Clinical Trials Group; EFV, efavirenz; RCT, randomized controlled trial; CNS, central nervous system; Hb, hemoglobin; WBC, white blood cells; WHO, World Health Organization.

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