Pharmacotherapy for Pediatric HIV Infection

FACULTY:

Anita Siu, PharmD
Assistant Clinical Professor
Ernest Mario School of Pharmacy
Rutgers, The State University of New Jersey
Piscataway, New Jersey
Clinical Neonatal/Pediatric Pharmacotherapy Specialist
K. Hovnanian Children’s Hospital
at Jersey Shore University Medical Center
Neptune, New Jersey

FACULTY DISCLOSURE STATEMENTS:

Dr. Siu has no actual or potential conflict of interest in relation to this program.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To educate health care practitioners about the epidemiology and pathophysiology of pediatric HIV as well as review current prevention and treatment guidelines with antiretroviral therapy.

OBJECTIVES:

At the completion of this article, participants should be able to:

1. Discuss the epidemiology and pathophysiology of pediatric HIV.*
2. Discuss the factors influencing optimal antiretroviral therapy in pediatrics.*
3. Identify the most appropriate initial treatment for HIV-infected children when given a case.*
4. Review the pharmacologic agent used for the prevention of maternal-fetal transmission of HIV.*

*Also applies to pharmacy technicians.

The 2007 Acquired Immunodeficiency Syndrome (AIDS) Epidemic Update Report estimated that 33.2 million people globally are living with the human immunodeficiency virus (HIV), of whom 2.5 million are children under 15 years old.¹ In 2005, the Centers for Disease Control and Prevention (CDC) HIV/AIDS Surveillance Revised Report estimated that 1,424 children under 20 years old were newly diagnosed with HIV in the United States.² At the end of 2005, the CDC reported the prevalence of HIV-infected children to be 7.4 per 100,000 people, while the prevalence of AIDS-infected children was 2.7 per 100,000 people.³

Although the number of newly diagnosed HIV and AIDS cases in pediatrics has declined over the years, clinicians and researchers continue to seek the most appropriate drug regimens to achieve maximal disease control and improve quality of life (QOL). Optimal drug therapy in pediatrics is associated with specific challenges. For example, only 14 agents are approved by the FDA for the treatment of HIV/AIDS in pediatrics, only a few antiretroviral agents are available in liquid formulation, medications usually require weight-based dosing, and children may be more prone to adverse effects than adults. This article reviews the recent National Institute of Health (NIH) guidelines for the management and treatment of HIV-infected children with an emphasis on currently available therapies in pediatrics.

What Is HIV?

HIV is an infection of the ribonucleic acid (RNA) retrovirus. Understanding the pathogenesis of the replicative cycle of HIV helps one understand the mechanism of action of antiviral agents. The outer layer of HIV is composed of glycoprotein 160 (gp160). The subunits of gp160 include gp120 and gp41. Glycoprotein 120 primarily binds to the cluster differentiation 4 (CD4) receptor on the T-helper lymphocytes, while gp41 promotes fusion and absorption, causing the virus to enter the cell. After entering the host cell, the virus uncoats and is ready for replication. Reverse transcriptase catalyzes the viral RNA to form single-stranded DNA, which then synthesizes to double-stranded DNA. This new DNA is known as the proviral DNA. Integrase is the next enzyme that promotes integration of the proviral DNA to the messenger RNA (mRNA). Translation of the HIV proteins occurs, and the single-stranded viral RNA and proteins form the new nucleocapsid. The new HIV is released by budding and is ready to replicate again.

How Is HIV Transmitted?

The three primary modes of transmission are sexual contact, contaminated blood or blood products, and perinatal infection. Among adolescents, transmission of HIV occurs mainly through sexual contact. Sharing blood-contaminated needles by IV drug use or receiving blood transfusions may cause percutaneous and parenteral infection by HIV. Perinatal transmission accounts for 90% of all pediatric HIV infections.² Thirty-five percent of infections occur before birth, and the remaining 65% occur after birth.⁴ Several risk factors associated with an increased risk for maternal HIV transmission include lack of maternal antiretroviral therapy, ruptured membrane for greater than four hours, low maternal CD4 percentage with high viral load, birth weight less than 2,500 grams, and birth of the first twin.⁵ Although uncommon, HIV transmission via breast milk has been reported.⁶ In this particular case, mothers are advised to seek alternatives such as using infant formulas.

Diagnosis and Surrogate Markers of HIV

Diagnosis of HIV in an infant is primarily determined via virologic assays that include the HIV DNA polymerase chain reaction (PCR) test or the HIV RNA assay. Both assays are highly sensitive for the detection of HIV infection, with sensitivities of 96% at 28 days of life using the HIV DNA PCR and 90% to 100% at two to three months of age with the HIV RNA assay.^7,8 During the first 18 months of life, virologic assays are the preferred method of testing.⁹ The recommended virologic assay-testing schedule for an infant born to an HIV-infected mother is at 14 to 21 days of life, at 1 to 2 months of age, and at 4 to 6 months of age. A repeat assay is recommended for any positive test results. At age 12 to 18 months, the HIV immunoglobulin G or antibody test is performed to confirm negative maternal HIV antibodies. In children with no previous testing and older than 18 months of age, both the HIV antibody test and Western blot are performed.

The two surrogate markers of HIV infection are HIV RNA plasma levels and the CD4 T-lymphocyte count. The HIV RNA plasma levels, also known as viral load tests, quantify the amount of viral RNA found in the blood (copies/mL) and monitor disease progression and effectiveness of drug therapy. Viral load greater than 100,000 copies/mL in older children is a sign of poor prognosis and higher risk of mortality.¹⁰ On the other hand, a declining CD4 count is a marker of disease progression and deteriorating immune system. A CD4 count of less than 15% is an indication of high risk for disease progression and mortality. Immune status depends on the child’s absolute CD4 count, which is dependent on the child’s age (TABLE 1).¹¹

Table 1
Pediatric HIV Immune Categories Based on Specific CD4 Cell Count and Percentage
	<12 months		1-5 years		6-12 years
Immune Category	No./mm3	Percentage	No./mm3	Percentage	No./mm3	Percentage
Category 1: No suppression	1,500	25%	1,000	25%	500	25%
Category 2: Moderate suppression	750-1,499	15%-24%	500-999	15%-24%	200-499	15%-24%
Category 3: Severe suppression	<750	<15%	<500	<15%	<200	<15%
Source: Reference 11.

Treatment of HIV

As of today, 14 antiretroviral agents are indicated for the treatment of HIV-infected children. These agents are classified as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and fusion inhibitors.

Nucleoside Reverse Transcriptase Inhibitors: The first available antiretroviral class, NRTIs, act by competitively blocking the reverse transcriptase enzyme, thus inhibiting HIV viral mitochondrial polymerase and DNA synthesis. Agents in this class that have been approved or studied for use in pediatrics include abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine. The current dosage, administration, dosage adjustments, dosage formulations, and major toxicities found in pediatric HIV-infected patients are summarized in TABLE 2.^12,13 Major toxicities listed in the table are similar to those found in HIV-infected adults. These include peripheral neuropathy, pancreatitis, hepatomegaly, and lactic acidosis. Approximately 5% of children and adults develop hypersensitivity reactions to abacavir requiring discontinuation of the drug.¹⁴

Table 2
Currently Available NRTIs for Pediatrics
Drug (Trade Name)	Abacavir (Ziagen)	Didanosine (Videx)	Emtricitabine (Emtriva)	Lamivudine (Epivir)	Stavudine (Zerit)	Zidovudine (Retrovir)
Abbreviation	ABC	ddI	FTC	3TC	d4T	AZT, ZDV
Dosage	Infants ≥3 mo, children, and adolescents: 8 mg/kg bid (max 300 mg bid)	Neonates ≥8 mo: 50-100 mg/m2 q12hChildren >8 mo: 120 mg/m2 q12hAdolescents: Oral Solution: <60 kg: 125 mg bid; ≥60 kg: 200 mg bidCapsule: <60 kg: 250 mg once daily; ≥60 kg: 400 mg once daily	Infants ≥3 mo– 17 y: Oral Solution: 6 mg/kg once daily (max 240 mg/dose)Capsule (>33 kg): 200 mg once daily	Neonates: 2 mg/kg bidChildren: 4 mg/kg bid (max 150 mg bid)Adolescents: <50 kg: 4 mg/kg bid ≥50 kg: 150 mg bid or 300 mg once daily	Neonates ≥13 days: 0.5 mg/kg q12hNeonates >13 days to children <30 kg: 1 mg/kg q12hAdolescents: 30-59 kg: 30 mg bid ≥60 kg: 40 mg bid	Premature Infants birth–2 wk: PO: 2 mg/kg q12h IV: 1.5 mg/kg q12h >2 wk change to q8hNeonates <6 wk: PO: 2 mg/kg q6h IV: 1.5 mg/kg q6h6 wk–12 y: 160 mg/m2 q8h or 180 mg/m2– 240 mg/m2 q12h>12 y: 200 mg tid or 300 mg bid
Administration	Without regard to food	Take on empty stomach	Without regard to food	Without regard to food	Without regard to food	Without regard to food
Dosage adjustments	Hepatic impairment	Renal impairment	Renal impairment	Renal impairment	Renal impairment	Renal impairment
Dosage formulation	Solution: 20 mg/mL Tablet: 300 mg	Powder (pediatric): 10 mg/mL (ref/ shake well) EC capsules: 125, 200, 250, 400 mg	Solution: 10 mg/mL Capsule: 200 mg	Solution: 10 mg/mL Tablets: 150, 300 mg	Solution: 1 mg/mL (ref/shake well) Capsules: 15, 20, 30, 40 mg	Syrup: 10 mg/mL Capsules: 100 mg Tablets: 300 mg Injection: 10 mg/mL
Major toxicities	More common: N/V/D, fever, HA, decreased appetite Less common: FHR (fever, fatigue, malaise, mouth sores, SOB; occurs during first 2 wk of treatment; resolves within 2 days after discontinuation; never rechallenge) Rare: Pancreatitis, increased LFTs and blood glucose	More common: N/V/D Less common: PN (dose related; numbness, tingling, burning; retinal depigmentation), lactic acidosis, hepatomegaly Rare: Pancreatitis (increased amylase/lipase)	More common: HA, nausea, diarrhea, rash, skin discoloration Less common: Neutropenia, lactic acidosis, hepatomegaly with steatosis	More common: HA, nausea, abdominal pain, diarrhea Less common: Pancreatitis, PN, lactic acidosis, hepatomegaly	More common: HA, GI upset, chills, fever Less common: Pancreatitis, PN, lactic acidosis, hepatomegaly Rare: Increased LFTs	More common: HA, hematologic toxicity (anemia, neutropenia) Less common: Myopathy, cardiomyopathy, liver toxicity, lactic acidosis
NRTIs: nucleoside reverse transcriptase inhibitors; max: maximum; ref: refrigerate; EC: enteric-coated; N/V/D: nausea/vomiting/diarrhea; HA: headache; FHR: fatal hypersensitivity reaction; SOB: shortness of breath; LFTs: liver function tests; PN: peripheral neuropathy; GI: gastrointestinal. Source: References 12, 13.

Non-nucleoside Reverse Transcriptase Inhibitors: Similar to NRTIs, NNRTIs work by noncompetitively binding to reverse transcriptase. Of the three agents in this class, only efavirenz and nevirapine are approved by the FDA for pediatric use (TABLE 3).^15,16 Efavirenz and nevirapine are commonly found in the NNRTI-based regimens along with two additional NRTIs. In children less than 3 years of age, nevirapine is the drug of choice since it is commercially available as a suspension.¹⁵ Efavirenz is recommended for initial therapy in children 3 years of age and older.¹⁶

NNRTIs exhibit less lipodystrophy and dyslipidemia compared to PI-based regimens. However, once viral mutation occurs with one of these agents, the HIV infection becomes resistant to the entire class of NNRTIs. Pruritic maculopapular rash has been reported in pediatrics, presenting within the first three weeks of drug initiation. In more severe cases, nevirapine is more likely to cause Stevens-Johnson syndrome and toxic epidermal necrolysis compared to efavirenz.¹³ Another major toxicity associated with this class is hepatotoxicity causing drug-induced hepatitis. A number of children develop central nervous system toxicity with the use of efavirenz.¹⁵ These children experience confusion, sleep disturbances, nightmares, and hallucinations. When initiating efavirenz, therapy is recommended to be administered in the evening during the first two to four weeks. Over time, these neuropsychiatric adverse effects lessen.

Table 3
Currently Available NNRTIs for Pediatrics
Drug (Trade Name)	Efavirenz (Sustiva)	Nevirapine (Viramune)
Abbreviation	EFV	NVP
Dosage	Children ≥3 y (once daily): 10 to <15 kg: 200 mg 15 to <20 kg: 250 mg 20 to <25 kg: 300 mg 25 to <32.5 kg: 350 mg 32.5 to <40 kg: 400 mg ≥40 kg: 600 mg	Neonates–2 mo: 5 mg/kg or 120 mg/m2 once daily × 14 days, then 120 mg/m2 bid × 14 days, then 200 mg/m2 bidChildren: 150 mg/m2 once daily × 14 days, then 150-200 mg/m2 bid (max 200 mg bid)Adolescents: 200 mg once daily × 14 days, then 200 mg bid
Administration	Take on empty stomach; avoid high-fat meals; capsules day be opened and sprinkled onto liquids or food	Without regard to food
Dosage adjustments	NA	Renal and hepatic impairment
Dosage formulation	Capsules: 50, 100, 200 mg Tablets: 600 mg	Suspension: 10 mg/mL Tablets: 200 mg
Major toxicities	More common: Rash (maculopapular, pruritic); CNS (confusion, sleep disturbances, nightmares, hallucinations) Less common: SJS (rare), N/D	More common: Rash (SJS, toxic epidermal necrolysis); fever, N/D, HA, increased LFTs Less common: Hepatitis, oral lesions, conjunctivitis
NNRTIs: non-nucleoside reverse transcriptase inhibitors; max: maximum; NA: not applicable; CNS: central nervous syndrome; SJS: Stevens-Johnson syndrome; N/D: nausea/diarrhea; HA: headache; LFTs: liver function tests. Source: References 12, 13.

Protease Inhibitors: PIs prevent protein formation necessary for HIV-infection of new cells and replication. Agents in this class that have been approved for or studied in pediatrics include fosamprenavir, indinavir, nelfinavir, ritonavir, and saquinavir (TABLE 4).^12,13 A combination product, lopinavir plus ritonavir, is also available. Ritonavir acts as a potent CYP450 3A4 inhibitor to increase lopinavir’s plasma concentration.

As a class, PIs contain distinctive adverse effects including lipodystrophy, diabetes mellitus, hyperlipidemia, hyper-glycemia, and osteopenia.^17,18 Fosamprenavir, the prodrug of amprenavir, has replaced amprenavir and lacks the potentially toxic, high concentrations of propylene glycol and vitamin E. High amounts of propylene glycol may result in hyperosmolarity, lactic acidosis, respiratory distress, and seizure activity, while excessive vitamin E intake causes necrotizing enterocolitis and bacterial sepsis.¹⁹ Adequate hydration is crucial with the use of indinavir due to the risk of nephrolithiasis. Unfortunately, this may be difficult to maintain at times, especially in pediatric patients.

Table 4
Currently Available Protease Inhibitors for Pediatrics
Drug (Trade Name)	Fosamprenavir (Lexiva)	Indinavir (Crixivan)	Nelfinavir (Viracept)	Ritonavir (Norvir)	Saquinavir (Invirase)	Lopinavir/Ritonavir (Kaletra)
Abbreviation	f-APV	IDV	NFV	RTV	SQV-S	LPV/RTV
Dosage	Antiretroviral naïve children: 2–5 y: 30 mg/kg bid (max 1,400 mg)>6 y: 30 mg/kg bid (max 1,400 mg) or 18 mg/kg bid (max 700 mg) + RTV 3 mg/ kg bid (max 100 mg)Antiretroviral experienced children: >6 y: 18 mg/kg bid (max 700 mg) + RTV 3 mg/kg bid (max 100 mg)	Children (investigational): 500 mg/m2 q8hAdolescents: 800 mg q8h	Neonates–6 wk (investigational): 40 mg/kg q12hChildren 2-13 y: 45-55 mg/kg bid or 25-35 mg/kg tidAdolescents: 1,250 mg bid or 750 mg tid	Children ≥12 y: 350-400 mg/m2 q12hAdolescents: 600 mg bid	Only use with RTV or LPV/RTVChildren (investigational): 50 mg/kg q8hAdolescents: With RTV: 1,000 mg SQV + 100 mg RTV bidWith LPV/RTV: 1,000 mg SQV + 400 mg LPV/ 100 mg RTV bid	Without NVP, EFV, APV: Children: 230 mg LPV/m2 + 57.5 mg RTV/m2 bid (max 400 mg LPV/100 mg RTV)Adolescents >12 y: 400 mg LPV/100 mg RTV bidWith NVP, EFV, APV: Children: 300 mg LPV/m2 + 75 mg RTV/m2 bid (max 533 mg LPV/ 133 mg RTV bid)Adolescents >12 y: 600 mg LPV/150 mg RTV bid
Administration	Without regard to food	Take on empty stomach; adequate hydration	Take with meal or light snack; tablets can be crushed or dis- solved and mixed	Take with meals; solution can be mixed with milk, pudding, or ice cream	Take within 2 h of meals	Take with meals
Dosage adjustments	Hepatic impairment	Hepatic impairment	N/A	Hepatic impairment	N/A	Hepatic impairment
Dosage formulation	Solution: 50 mg/mL (contains 43 mg amprenavir/mL) Tablets: 700 mg (contains 600 mg amprenavir)	Capsules: 100, 200, 333, 400 mg	Powder: 50 mg/1 g (200 mg per tsp) Tablets: 250, 625 mg (contains EMS)	Solution: 80 mg/mL (room temp) Capsules: 100 mg (ref)	Capsule: 200 mg (ref or room temp × 30 days) Tablet: 500 mg	Solution: 80 mg LPV/ 20 mg RTV per mL (contains alcohol) Tablets: 200 mg LPV/ 50 mg RTV, 100 mg LPV/25 mg LTV
Major toxicities	Others: N/V/D, anemia, rash (SJS ≤1%), perioral paresthesias, anemia, increased cholesterol and blood glucose	Nephrolithiasis (flank pain, with/ without hematuria) Others: Hyperglycemia, hyperbilirubin- emia, anemia, lipodystrophy	Diarrhea, abdominal pain, flatulence Others: Hyperglycemia, asthenia, rash, lipodystrophy	N/V/D, HA, abdominal pain, circumoral/ peripheral paresthesias Others: Increased LFTs, jaundice, lipodystrophy, taste perversion	Others: N/D, abdominal pain, HA, rash, paresthesias, hyperglycemia	Refer to ritonavir Others: Rash, bleeding in hemophiliacs, hepatitis
Max: maximum; NVP: nevirapine; EFV: efavirenz; NA: not applicable; tsp: teaspoon; EMS: ethyl methane sulfonate; temp: temperature; ref: refrigerate; N/V/D: nausea/vomiting/diarrhea; SJS: Stevens-Johnson syndrome; HA: headache; LFTs: liver function tests. Source: References 12, 13.

Fusion Inhibitors: Enfuvirtide is from a new class of antiretrovirals known as fusion inhibitors. Its primary mechanism of action is binding to gp41, preventing fusion of the HIV infection into the host cell. Enfuvirtide is indicated as combination therapy with other antiretroviral agents and is approved for use in children older than 6 years of age. The recommended dosage is 90 mg administered subcutaneously twice a day. Receiving an injection twice a day presents a disadvantage for use in children due to local site reactions. Common adverse effects seen with enfuvirtide include pneumonia, hyper-sensitivity reaction, local injection pain, peripheral neuropathy, decreased appetite, and pancreatitis.²⁰

Initial Drug Therapy: The goals of antiretroviral therapy for HIV-infected children include:

• Achieving maximal suppression of HIV replication
• Delaying the progression to AIDS
• Prolonging patient survival
• Improving the QOL
• Improving medication adherence
• Preventing the incidence of resistance
• Minimizing dose-limiting toxicities of antiretrovirals
• Preventing opportunistic infections

When initiating antiretroviral therapy in infants and children, factors influencing medication adherence need to be considered such as adverse effects, unfavorable taste, complex drug regimens, lack of pediatric-friendly dosage forms, and drug interactions. Combination products are available to reduce pill burden and improve adherence. However, these agents contain fixed dosage forms in tablets or capsules, making it difficult for a child younger than 5 years old to swallow. The U.S. Department of Health and Human Services (HHS) has created guidelines to assist health care professionals in initiating antiretroviral therapy in HIV-infected infants and children.¹³ The younger the age, the greater the risk for disease progression. Therefore, initiation of antiretroviral therapy is recommended in all infants less than 12 months of age regardless of signs and symptoms of HIV, CD4 count, and viral load.²¹

In children 5 years and older, the CD4 count risk to disease progression is similar to adults. The current recommendations for the initiation of therapy based on age, symptoms, CD4 count, and viral load are listed in TABLE 5.

Table 5
Current Recommendations for Initiation of Antiretroviral Therapy
Age	Criteria	Recommendation
<12 months	Regardless of clinical symptoms, immune status, or viral load	Treat
1 to <5 years	AIDS or significant HIV-related symptomsaCD4 <25%, regardless of symptoms of HIV RNA levelsb Asymptomatic or mild symptomsc and • CD4 ≥25% and • HIV RNA ≥100,000 copies/mLAsymptomatic or mild symptomsc and • CD4 ≥25% and • HIV RNA <100,000 copies/mL	TreatTreatConsider Deferd
≥5 years	AIDS or significant HIV-related symptomsaCD4 <350 cells/mm3Asymptomatic or mild symptomsc and • CD4 ≥350 cells/mm3 and • HIV RNA ≥100,000 copies/mLAsymptomatic or mild symptomsc and • CD4 <350 cells/mm3 and • HIV RNA <100,000 copies/mL	TreatTreateConsider Deferd
a CDC Clinical Category C and B (except for the following Category B conditions: single episode of serious bacterial infection or lymphoid interstitial pneumonitis). b Data are stronger for those with CD4 percentage <20% than for those with CD4 percentage between 20%-24%. c CDC Clinical Category A or N or the following Category B conditions: single episode of serious bacterial infection or lymphoid interstitial pneumonitis. d Clinical and laboratory data should be reevaluated every 3-4 months. e Data are stronger for those with CD4 percentage <200 than for those with CD4 counts between 200-350 cells/mm3. Source: Reference 13.

The gold standard is combination therapy with three antiretroviral agents, from at least two classes of drugs (TABLE 6).¹³ Combination therapy slows disease progression, improves survival, improves immunologic response with greater reduction in viral load, and prevents virus mutation leading to drug resistance. Drug regimens are categorized as preferred, alternative, for use in special circumstances, not recommended, and insufficient data to recommend. Preferred regimen indicates that clinical trials demonstrated favorable efficacy and toxicity in pediatrics. Alternative regimen shows that efficacy results may not outweigh the potential adverse consequences associated with the combination and may include additional toxicities and drug interactions. Pediatric data on the efficacy and safety of alternative regimens are also limited. When the preferred or alternative regimen cannot be used, combination antiretroviral therapy in the special circumstances category is utilized. Agents in the not recommended category are not considered for initial therapy due to overlapping toxicities, undesirable virologic response, and antagonistic drug effects. Antiretrovirals listed as insufficient data to recommend lack pediatric pharmacokinetic and safety data.

Table 6
Recommended Antiretroviral Regimens for Initial Therapy in HIV-infected Children
NNRTI-based Regimens
Preferred	Children ≥3 y: 2 NRTIs plus efavirenza Children <3 y or who can’t swallow capsules: 2 NRTIs plus nevirapinea
Alternative	Children ≥3 y: 2 NRTIs plus nevirapineb
PI-based Regimens
Preferred Alternative	2 NRTIs plus lopinavir/ritonavirChildren >6 y: 2 NRTIs plus fosamprenavir plus low-dose ritonavir
Use in Special Circumstances
	Children 2-6 y: 2 NRTIs plus fosamprenavir 2 NRTIs plus low-dose ritonavir plus atazanavir or indinavir or saquinavir; only in post-pubertal adolescents who weigh enough to receive adult doses Zidovudine plus lamivudine plus abacavir
Two-Drug NRTI Backbone Options (for use in combination with additional drugs)
Preferrred	Abacavir plus (lamivudine or emtricitabine) Didanosine plus emtricitabine Tenofovir plus (lamivudine or emtricitabine); (Tanner Stage 4 or post-pubertal adolescents only) Zidovudine plus (lamivudine or emtricitabine)
Alternative	Abacavir plus zidovudine Zidovudine plus didanosine
Use in special circumstances	Stavudine plus (lamivudine or emtricitabine)
Insufficient Data to Recommend
	Low-dose ritonavir-boosted PI regimens with the exceptions of lopinavir/ritonavir, fosamprenavir/ritonavir in children >6 y and low-dose ritonavir in combination with atazanavir, indinavir, or saquinavir in post-pubertal adolescents who can receive adult dosesc Dual (full-dose) PI regimens NRTI plus NNRTI plus PIb Tenofovir-containing regimens in children in Tanner Stage 1-3 Enfuvirtide (T-20)-containing regimens Darunavir-containing regimens Tipranavir-containing regimens Maraviroc-containing regimens Raltegravir-containing regimens Etravirine-containing regimens
aEfavirenz is currently available only in capsule form and should be used in children ≥3 years old with weight ≥10 kg; nevirapine would be the preferred NNRTI for children under age 3 years or who require a liquid formulation. bWith the exception of efavirenz plus nelfinavir plus one or two NRTIs, which has been studied in HIV-infected children and shown to have virologic and immunologic efficacy in a clinical trial; however, nelfinavir is not recommended for initial therapy until future notice because of the presence of ethyl methane sulfonate, a toxic byproduct of the manufacturing process in nelfinavir formulations. cWith the exception of lopinavir/ritonavir and fosamprenavir in combination with low-dose ritonavir in children >6 years old, data on the pharmacokinetics and safety of low-dose ritonavir-boosted PI combinations are limited; use of other boosted PIs as components of initial therapy is not recommended, although such regimens may have utility as secondary treatment regimens for children who have failed initial therapy. The use of low-dose ritonavirboosted atazanavir (or saquinavir or indinavir) can be considered in the special circumstance of initial therapy of post-pubertal adolescents who weigh enough to receive standard adult doses. NNRTI: non-nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; PI: protease inhibitor. Source: Reference 13.

Prevention of Maternal-Fetal Transmission

During pregnancy, HIV testing and counseling are recommended as the standard of care in the U.S.²² When maternal HIV infection is identified, optimal drug therapy is initiated for the mother and the newborn. The risk of maternal-fetal transmission from a mother receiving no antiretroviral therapy ranges from 14% to 39%.²³ Most HIV transmissions to newborns occur during or near the time of birth; therefore, treatment during this time frame is optimal. Recent guidelines from the Public Health Service Task Force suggest that combination antiretroviral regimen rather than monotherapy with zidovudine is indicated for the prevention of maternal-fetal transmission.²⁴

Zidovudine: Since 1994, zidovudine has been the drug of choice for preventing HIV transmission to the newborn. Zidovudine readily crosses the placenta, exhibiting maternal cord blood concentrations greater than antiretroviral activity.²⁵ Due to their immature livers, newborns have a reduction in hepatic glucuronoconjugation. In addition, renal clearance is prolonged, causing an increase in serum half-life. Although both liver metabolism and renal clearance were delayed in newborns, the total body clearance of zidovudine significantly increased with age.²⁶

The Pediatric AIDS Clinical Trial Group (PACTG) 076 randomized 363 HIV-infected mothers to determine whether a three-part regimen (antepartum, intrapartum, and postpartum) with zidovudine would decrease the risk of maternal-fetal transmission.²⁷ During the pregnancy, taking zidovudine as part of the antiretroviral regimen is recommended in mothers not receiving highly active antiretroviral therapy (HAART). During delivery, injectable zidovudine was administered at 2 mg/kg for the first hour followed by 1 mg/kg/hour until delivery. After birth, the newborns continued zidovudine for an additional six weeks (see TABLE 2).^28,29 Results revealed significant reduction of maternal HIV transmission by 67.5% with overall decrease of perinatal transmission by 3% to 4%. Adverse effects were similar in both groups. To date, the CDC reports no difference in the rate of congenital abnormalities in infants exposed to zidovudine in utero, and the risk of perinatal HIV infection has diminished to less than 2%.³⁰ Although other prophylactic agents have been studied, zidovudine remains the standard of care in the U.S.

Summary

More investigational studies are needed to further expand optimal antiretroviral therapy in pediatric patients. Although this review has focused on the initial drug therapy in HIV-infected children, HHS has established further guidelines on how to change antiretroviral regimens due to treatment failure. Although pediatric HIV management resembles adult HIV management, pharmacists need to consider the multiple factors affecting ideal medication regimens in pediatrics.

REFERENCES

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