Pharmacotherapy of pediatric and adolescent HIV infection

Figures & data

Table 1 ART medications approved for use in HIV-infected children. Adapted from the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection³

Agent (Trade name)	Pediatric approval	Age	Formulation	Food requirement	Drug interactions	Major toxicity
Nucleoside reverse transcriptase inhibitors
Zidovudine (Retrovir^®)	1990	0–18 y	Oral solution/tablet/capsule/concentrate for injection	± food	−	GI, hematologic, myositis
Didanosine (Videx and Videx EC^®)	1991	2 wks–18 y	Powder for oral solution delayed release capsules	− food	+	GI, peripheral neuropathy pancreatitis
Lamivudine (Epivir^®)	1995	0–18 y	Oral solution/tablet	± food	−	Headache, fatigue, nausea
Stavudine (Zerit^®)	1996	0–18 y	Oral solution/capsule	± food		GI, headache, rash
Abacavir (Ziagen^®)	1996	3 mo–18 y	Oral solution/tablet	± food	−	GI, hypersensitivity reaction
Emtricitabine (Emtriva^®)	2003	3 mo–16 y	Oral solution/tablet	± food	−	GI, headache, rash
Non-nucleoside reverse transcriptase inhibitors
Efavirenz (Sustiva^®)	1998	3–18 y	Tablet/capsule	− food	+	Neuropsychiatric, rash
Nevirapine (Viramune^®)	1998	0–18 y	Oral suspension/table	± food	+	Rash, hepatotoxicity
Protease inhibitors
Nelfinavir (Viracept ^®)	1997	2–18 y	Powder for oral suspension	+ food	+	Diarrhea
			Tablet	+ food
Ritonavir (Norvir^®)	1997	1 mo–18 y	Oral solution/capsules	+ food	+	GI/lipid
Lopinavir/ritonavir (Kaletra^®)	2000	2 wks–18 y	Liquid/tablet	± food	+	GI
Atazanavir (Reyataz^®)	2003	6–18 y	Capsule	+ food	+	Hyperbilirubinemia
Fosamprenavir (Lexiva^®)	2007	2–18 y	Oral suspension/tablet	± food	+	GI
Darunavir (Prezista^®)	2008	6–18 y	Tablet	+ food	+	GI
Tipranavir (Aptivus^®)	2008	2–18 y	Liquid/capsule	± food	+	GI/lipid
Fusion inhibitors
Enfuvurtide (Fuzeon^®)	2003	6–18 y	Lyophilized powder for injection	± food	−	Injection site reactions

Abbreviations: GI, gastrointestinal; HIV, human immunodeficiency virus; ART, antiretroviral.

Table 2 Indications for treatment of HIV-infected children. Adapted from the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection³

INITIATE TREATMENT

All infants <1 year

Any infant or child with AIDS or significant HIV symptoms (Clinical Category B*,C)

Child ages 1–5 years with CD4 ≤ 25% (regardless of symptoms or HIV RNA level)

Child ≥5 years with CD4 ≤ 350 cells/mm^3

CONSIDER TREATMENT

Child 1–5 years with CD4 ≥ 25% and HIV RNA ≥ 100,000 copies/mL (regardless of symptoms)

Child ≥5 years with CD4 ≥ 350 cells/mm^3 and HIV RNA ≥ 100, 000 copies/mL

DEFER TREATMENT

Child age 1–5 years with no symptoms/mild symptoms** + CD4 ≥25% + HIV RNA ≤ 100,000 copies/mL

Child age >5 years with no symptoms/mild symptoms** + CD4 > 350 cells/mm^3 and HIV RNA < 100,000 copies/mL

Notes: *except single episode of bacterial infection or LIP.

** with a single episode of bacterial infection or LIP.

Table 3 1994 Revised human immunodeficiency virus pediatric classification system; clinical categories (updated February 28, 2008)⁵⁰

Category N: Not symptomatic: Children who have no signs of symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category A.

Category A: Mildly symptomatic: Children with two or more of the following conditions listed in categories B and C:

Lymphadenopathy (≥ 0.5 cm at more than two sites: bilateral at one site)

Hepatomegaly

Splenomegaly

Dermatitis

Parotitis

Recurrent or persistent upper respiratory infection, sinusitis, or otitis media

Category B: Moderately symptomatic: Children who have symptomatic conditions, other than those listed for category A or category C, that are attributed to HIV infection. Examples of conditions in clinical category B include, but are not limited to, the following:

Anemia (<8gm/dL), neutropenia (<1000 cells/mm^3), or thrombocytopenia (<100,000 cells/mm^3) persisting ≥ 30 days

Bacterial meningitis, pneumonia, or sepsis (single episode)

Candidiasis, oropharyngeal (ie, thrush) persisting for >2 months in children aged >6 months

Cardiomyopathy

Cytomegalovirus infection with onset before age 1 month

Diarrhea, recurrent or chronic

Hepatitis

Herpes simplex virus (HSV) stomatitis, recurrent (ie, more than two episodes within 1 year)

HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month

Herpes zoster (ie, shingles) involving at least two distinct episodes or more than 1 dermatome

Leiomyosarcoma

Lymphoid interstitial pneumonitis (LIP) or pulmonary lymphoid hyperplasia complex

Nephropathy

Nocardiosis

Fever lasting >1 month

Toxoplasmosis with onset before age 1 month

Varicella, disseminated (ie, complicated chickenpox)

Category C: Severely symptomatic: Children who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome (below) with the exception of LIP (which is a category B condition)

Serious bacterial infections, multiple or recurrent (ie, any combination of at least two culture-confirmed infections within a 2 year period) of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abcess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abcesses, and indwelling catheter-related infections)

Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)

Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes)

Cryptococcosis, extrapulmonary

Cryptosporidiosis or isosporiasis with diarrhea persisting >1 month

Cytomegalovirus disease with onset of symptoms at age >1 month (at a site other than liver, spleen, or lymph nodes)

Encephalopathy (at least 1 of the following progressive findings present for at least two months in the absence of a concurrent illness other than HIV infection that could explain the findings): a) failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; b) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by computerized tomography or magnetic resonance imaging (serial imaging required for children <2 years of age); c) acquired symmetric motor deficit manifested by 2 or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance

Herpes simplex virus infection causing a mucocutaneous ulcer that persists for >1 month; or bronchitis, pneumonitis, or esophagitis for any duration affecting a child >1 month of age

Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes)

Kaposi’s sarcoma

Lymphoma, primary in brain

Lymphoma, small, noncleaved (Burkitt’s), or immunoblastic or large cell lymphoma of B-cell or unknown immunologic phenotype

Mycobacterium tuberculosis, disseminated or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)

Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)

Pneumocystis jiroveci pneumonia

Progressive multifocal leukencephalopathy

Salmonella (nontyphoid) septicemia, recurrent

Toxoplasmosis of the brain with onset at >1 month of age

Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings: a) persistent weight loss >10% of baseline; OR b) downward crossing of atleast two of the following percentile lines on the weight-for-age chart (eg, 95th, 75th, 50th, 25th, 5th) in a child ≥1 year of age; OR c) <5th percentile on weight-for-height chart on two consecutive measurements, ≥ 30 days apart PLUS 1) chronic diarrhea (ie, >2 loose stools per day for ≥30 days), OR 2) documented fever for ≥30 days, intermittent or constant)

Table 4 Initial therapy for HIV-infected children. Adapted from the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection³

A. NNRTI-BASED REGIMEN:
Preferred regimen	Alternative regimen
Efavirenz + 2 NRTIs (≥3 years)	Nevirapine + 2 NRTIs (≥3years) (child unable to swallow capsule)
Nevirapine + 2 NRTIs (<3 years)
B. PI-BASED REGIMEN
Preferred regimen	Alternative regimen	Special circumstances
Lopinavir/ritonavir + 2 NRTIs	Atazanavir/ritonavir + 2 NRTIs (children ≥6 years)	Fosamprenavir (unboosted) + 2 NRTIs (children ≥2 years)
	Fosamprenavir/ritonavir + 2 NRTIS (children ≥6 years)	Atazanavir (unboosted) + 2 NRTIs (for treatment-naïve adolescents >3 years and >39kg)
	Nelfinavir+ 2 NRTIs (children ≥2 years)
C. TRIPLE NRTI REGIMEN		Zidovudine + Lamivudine + Abacavir
Dual NRTI backbones for use in above regimens (A and B)
Preferred regimen	Alternative regimen	Special circumstances
Lamivudine + Abacavir*	Zidovudine + Abacavir*	Stavudine + Lamivudine
Emtricitabine + Abacavir*	Zidovudine + Didanosine	Stavudine + Emtricitabine
Didanosine + Emtricitabine
Zidovudine + Lamivudine
Zidovudine + Emtricitabine
Tenofovir** + Lamivudine
Tenofovir** + Emtricitabine

Notes: *HLA B*5701 genetic testing recommended prior to therapy with use of abacavir contraindicated in patients found to be HLA B*5701-positive.

** For Tanner Stage 4 or post-pubertal adolescents only who are unable to tolerate ritonavir + 2 NRTIs (boost with ritonavir if tenofovir used). Saquinavir/ritonavir + 2 NRTIs for post-pubertal adolescents who weigh enough to receive adult doses).

Working Group on Antiretroviral Therapy and the Medical Management of HIV-Infected Children22009Guidelines for the Use of Antiretroviral Agents in Pediatric HIV InfectionAccessed March 31, 2009. Available from: http://AIDSinfo.nih.gov.contentfiles/PediatricGuidelines.pdf

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Centers for Disease Control and Prevention1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age1994(No. RR-12)110

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