Currently Licensed Antiviral Drugs in Pediatrics: A Comprehensive Overview

Introduction

Antiviral drugs play a crucial role in the management of viral infections in pediatric patients. These medications are designed to interfere with various stages of viral replication, thereby reducing the severity and duration of illness, preventing complications, and in some cases, averting the progression of infection. This comprehensive review aims to provide pediatricians with an up-to-date understanding of the currently licensed antiviral drugs for use in children, their mechanisms of action, indications, dosing, and important considerations.

1. Nucleoside and Nucleotide Analogues

1.1 Acyclovir

Acyclovir remains a cornerstone in the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in pediatrics.

Mechanism of Action: Acyclovir is a guanosine analogue that inhibits viral DNA polymerase after phosphorylation by viral thymidine kinase.
Indications:
- HSV encephalitis
- Neonatal HSV infection
- Severe primary or recurrent genital HSV infection
- Varicella in immunocompromised patients
- Herpes zoster
Dosing:
- Neonates: 20 mg/kg/dose IV every 8 hours for 14-21 days
- Children: 10-15 mg/kg/dose IV every 8 hours for 7-14 days
- Oral dosing: 80 mg/kg/day divided into 3-4 doses (maximum 3200 mg/day)
Considerations: Monitor renal function, maintain adequate hydration. Adjust dosing in renal impairment.

1.2 Valacyclovir

Valacyclovir is the L-valyl ester of acyclovir, providing improved oral bioavailability.

Mechanism of Action: Prodrug of acyclovir, converted to acyclovir after oral administration.
Indications:
- Treatment of chickenpox in immunocompetent patients
- Herpes zoster
- Recurrent HSV infections
Dosing:
- Chickenpox: 20 mg/kg/dose (maximum 1000 mg/dose) three times daily for 5 days
- Herpes zoster: 20 mg/kg/dose (maximum 1000 mg/dose) three times daily for 5-7 days
Considerations: Better oral bioavailability than acyclovir. Monitor for signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in immunocompromised patients.

1.3 Ganciclovir and Valganciclovir

These drugs are primarily used for the treatment and prevention of cytomegalovirus (CMV) infections.

Mechanism of Action: Inhibit viral DNA polymerase after phosphorylation by viral and cellular kinases.
Indications:
- Treatment of CMV retinitis
- Prevention of CMV disease in transplant recipients
- Treatment of congenital CMV infection
Dosing:
- Ganciclovir: 5 mg/kg/dose IV every 12 hours for induction, then 5 mg/kg/day for maintenance
- Valganciclovir: 16 mg/kg/dose (maximum 900 mg/dose) orally twice daily
Considerations: Monitor for myelosuppression, particularly neutropenia. Adjust dosing in renal impairment. Valganciclovir provides improved oral bioavailability.

2. Neuraminidase Inhibitors

2.1 Oseltamivir

Oseltamivir is the primary antiviral agent used for the treatment and prophylaxis of influenza A and B infections in pediatrics.

Mechanism of Action: Inhibits viral neuraminidase, preventing the release of newly formed virions from infected cells.
Indications:
- Treatment of acute, uncomplicated influenza
- Post-exposure prophylaxis
Dosing:
- Treatment (5 days):
  - ≥ 12 months and ≤ 15 kg: 30 mg twice daily
  - > 15-23 kg: 45 mg twice daily
  - > 23-40 kg: 60 mg twice daily
  - > 40 kg: 75 mg twice daily
- Prophylaxis (10 days): Same weight-based dosing as treatment, but given once daily
Considerations: Most effective when started within 48 hours of symptom onset. May cause gastrointestinal side effects. Rare neuropsychiatric events reported.

2.2 Zanamivir

Zanamivir is an inhaled neuraminidase inhibitor used for influenza treatment and prophylaxis in children ≥ 7 years old.

Mechanism of Action: Similar to oseltamivir, inhibits viral neuraminidase.
Indications:
- Treatment of acute, uncomplicated influenza
- Post-exposure prophylaxis
Dosing:
- Treatment: 10 mg (two 5 mg inhalations) twice daily for 5 days
- Prophylaxis: 10 mg once daily for 10 days
Considerations: Not recommended for patients with underlying respiratory diseases due to risk of bronchospasm. Requires proper inhalation technique for effectiveness.

3. Reverse Transcriptase Inhibitors

3.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs are a crucial component of combination antiretroviral therapy (cART) for pediatric HIV infection.

3.1.1 Abacavir

Mechanism of Action: Guanosine analogue that inhibits HIV-1 reverse transcriptase.
Indications: Treatment of HIV-1 infection as part of cART.
Dosing: 8 mg/kg twice daily or 16 mg/kg once daily (maximum 600 mg/day).
Considerations: Requires HLA-B*5701 screening prior to initiation due to risk of hypersensitivity reaction.

3.1.2 Lamivudine

Mechanism of Action: Cytidine analogue that inhibits HIV-1 and HBV reverse transcriptase.
Indications: Treatment of HIV-1 and chronic hepatitis B infection.
Dosing:
- HIV: 4 mg/kg twice daily or 8 mg/kg once daily (maximum 300 mg/day)
- HBV: 3 mg/kg once daily (maximum 100 mg/day)
Considerations: Well-tolerated. Monitor for lactic acidosis and severe hepatomegaly with steatosis.

3.1.3 Emtricitabine

Mechanism of Action: Cytidine analogue similar to lamivudine.
Indications: Treatment of HIV-1 infection as part of cART.
Dosing: 6 mg/kg once daily (maximum 240 mg/day).
Considerations: Often used in fixed-dose combinations. Monitor for skin discoloration.

3.2 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

3.2.1 Efavirenz

Mechanism of Action: Directly binds to and inhibits HIV-1 reverse transcriptase.
Indications: Treatment of HIV-1 infection as part of cART in children ≥ 3 months and weighing ≥ 3.5 kg.
Dosing: Weight-based, ranging from 200-600 mg once daily.
Considerations: Can cause CNS side effects. Administer on an empty stomach. Potential for drug interactions due to CYP3A4 induction.

3.2.2 Rilpivirine

Mechanism of Action: Similar to efavirenz, inhibits HIV-1 reverse transcriptase.
Indications: Treatment of HIV-1 infection as part of cART in children ≥ 12 years and weighing ≥ 35 kg.
Dosing: 25 mg once daily with a meal.
Considerations: Fewer CNS side effects compared to efavirenz. Requires acid for absorption; avoid co-administration with proton pump inhibitors.

4. Protease Inhibitors

Protease inhibitors (PIs) are another essential class of antiretroviral drugs used in pediatric HIV treatment.

4.1 Lopinavir/Ritonavir

Mechanism of Action: Lopinavir inhibits HIV-1 protease. Ritonavir acts as a pharmacokinetic enhancer.
Indications: Treatment of HIV-1 infection as part of cART.
Dosing: Weight-based, typically 230-350 mg/m² of lopinavir component twice daily.
Considerations: Available as a co-formulation. Monitor for metabolic complications, including lipid abnormalities and insulin resistance.

4.2 Atazanavir

Mechanism of Action: Inhibits HIV-1 protease.
Indications: Treatment of HIV-1 infection as part of cART in children ≥ 3 months and weighing ≥ 5 kg.
Dosing: Weight-based, ranging from 150-400 mg once daily, often boosted with ritonavir.
Considerations: Can cause indirect hyperbilirubinemia. Requires acidic environment for absorption.

5. Integrase Strand Transfer Inhibitors (INSTIs)

INSTIs have become increasingly important in pediatric HIV treatment due to their high efficacy and favorable side effect profile.

5.1 Dolutegravir

Mechanism of Action: Inhibits HIV integrase, preventing viral DNA integration into host cell genome.
Indications: Treatment of HIV-1 infection as part of cART in children ≥ 4 weeks and weighing ≥ 3 kg.
Dosing: Weight-based, ranging from 15-50 mg daily.
Considerations: High genetic barrier to resistance. Monitor for neuropsychiatric side effects and weight gain.

5.2 Raltegravir

Mechanism of Action: Similar to dolutegravir, inhibits HIV integrase.
Indications: Treatment of HIV-1 infection as part of cART in full-term neonates and older.
Dosing: Weight-based, available as granules for oral suspension, chewable tablets, and film-coated tablets.
Considerations: Well-tolerated. Can be used in neonates, making it valuable for prevention of mother-to-child transmission.

6. Entry Inhibitors

6.1 Enfuvirtide

Mechanism of Action: Fusion inhibitor that binds to HIV-1 gp41, preventing virus entry into host cells.
Indications: Treatment of HIV-1 infection in combination with other antiretroviral agents in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
Dosing: Children 6-16 years: 2 mg/kg subcutaneously twice daily (maximum 90 mg per dose).
Considerations: Requires subcutaneous administration. Monitor for injection site reactions.

7. Hepatitis C Virus (HCV) Antivirals

Direct-acting antivirals (DAAs) have revolutionized HCV treatment in pediatrics, offering high cure rates with short treatment durations.

7.1 Ledipasvir/Sofosbuvir

Mechanism of Action: Ledipasvir inhibits HCV NS5A protein, while sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase.
Indications: Treatment of chronic HCV infection in children ≥ 3 years old with genotypes 1, 4, 5, or 6.
Dosing:
- Children ≥ 3 years weighing ≥ 17 kg: Weight-based dosing of fixed-dose combination tablet
- Treatment duration: 12 weeks for treatment-naïve patients without cirrhosis or with compensated cirrhosis
Considerations: High efficacy with >95% cure rates. Monitor for fatigue, headache, and nausea.

7.2 Glecaprevir/Pibrentasvir

Mechanism of Action: Glecaprevir is an NS3/4A protease inhibitor, and pibrentasvir is an NS5A inhibitor.
Indications: Treatment of chronic HCV infection in children ≥ 3 years old with any genotype (pan-genotypic).
Dosing:
- Children ≥ 3 years to < 12 years: Weight-based dosing of oral pellets
- Children ≥ 12 years: 300 mg/120 mg orally once daily with food
- Treatment duration: 8-16 weeks depending on prior treatment experience and presence of cirrhosis
Considerations: Excellent pan-genotypic coverage. Contraindicated in patients with severe hepatic impairment (Child-Pugh C).

8. Respiratory Syncytial Virus (RSV) Antivirals

8.1 Palivizumab

Mechanism of Action: Monoclonal antibody that binds to the RSV F protein, preventing viral entry into host cells.
Indications: Prophylaxis against serious lower respiratory tract disease caused by RSV in high-risk infants and children.
Dosing: 15 mg/kg intramuscularly once monthly during RSV season (typically 5 doses).
Considerations: Used for prevention, not treatment. Recommended for preterm infants, infants with chronic lung disease of prematurity, and infants with hemodynamically significant congenital heart disease.

8.2 Ribavirin

Mechanism of Action: Nucleoside analogue with broad-spectrum antiviral activity, including against RSV.
Indications: Treatment of severe RSV infections in immunocompromised patients.
Dosing:
- Aerosolized: 6 g dissolved in 300 mL sterile water, delivered over 12-18 hours daily for 3-7 days
- Oral: 15-20 mg/kg/day divided into 2 doses for 5-10 days (off-label use)
Considerations: Limited evidence for efficacy. Potential for teratogenicity and hemolytic anemia. Use with caution and only in severe cases.

9. Emerging Antiviral Therapies

9.1 Remdesivir

While primarily studied in adults, remdesivir has gained attention for its potential use in pediatric patients with severe COVID-19.

Mechanism of Action: Nucleotide analog that inhibits viral RNA-dependent RNA polymerase.
Indications: Treatment of COVID-19 in hospitalized patients ≥ 12 years of age and weighing ≥ 40 kg.
Dosing:
- ≥ 40 kg: 200 mg IV on day 1, followed by 100 mg IV daily for 4-9 days
- < 40 kg: 5 mg/kg IV on day 1, followed by 2.5 mg/kg IV daily for 4-9 days
Considerations: Limited data in pediatrics. Monitor for elevated liver enzymes and potential hypersensitivity reactions.

9.2 Baloxavir Marboxil

Baloxavir represents a new class of influenza antivirals with a novel mechanism of action.

Mechanism of Action: Inhibits cap-dependent endonuclease, an enzyme essential for viral replication.
Indications: Treatment of acute uncomplicated influenza in patients ≥ 12 years of age who have been symptomatic for no more than 48 hours.
Dosing: Single oral dose based on body weight:
- 40 kg to < 80 kg: 40 mg
- ≥ 80 kg: 80 mg
Considerations: Potential for rapid development of resistance. Not yet approved for children < 12 years.

10. Antiviral Drug Resistance

Antiviral drug resistance is an ongoing concern in pediatric infectious diseases. Factors contributing to resistance include:

Prolonged or repeated courses of antiviral therapy
Suboptimal dosing or adherence
Host factors (e.g., immunosuppression)
Viral factors (e.g., high mutation rate)

Strategies to mitigate antiviral resistance include:

Appropriate drug selection based on local resistance patterns
Combination therapy, particularly for HIV and HCV
Adherence support and monitoring
Regular viral load monitoring and resistance testing when indicated

11. Special Considerations in Pediatric Antiviral Therapy

11.1 Dosing and Pharmacokinetics

Pediatric patients require careful consideration of dosing due to differences in pharmacokinetics and pharmacodynamics compared to adults. Factors to consider include:

Age-related changes in drug absorption, distribution, metabolism, and excretion
Body surface area or weight-based dosing
Organ maturity, particularly liver and kidney function
Potential for drug-drug interactions, especially in patients on multiple medications

11.2 Formulations

Appropriate formulations are crucial for ensuring accurate dosing and adherence in pediatric patients. Considerations include:

Availability of liquid formulations or dispersible tablets for younger children
Palatability and taste-masking techniques
Appropriate concentration to allow accurate measurement of small doses
Stability and storage requirements, particularly in resource-limited settings

11.3 Adherence Support

Ensuring adherence to antiviral regimens is critical for treatment success and prevention of resistance. Strategies to support adherence in pediatric patients include:

Age-appropriate education for both patients and caregivers
Use of pill boxes, alarms, or mobile applications as reminders
Simplification of regimens when possible (e.g., once-daily dosing)
Regular follow-up and adherence assessments
Addressing barriers to adherence, such as side effects or psychosocial factors

11.4 Long-term Safety

The long-term safety of antiviral drugs in pediatric patients is an important consideration, particularly for chronic conditions like HIV. Monitoring should include:

Regular assessment of growth and development
Monitoring for metabolic complications (e.g., lipid abnormalities, insulin resistance)
Bone health assessment, particularly with certain antiretroviral regimens
Neurocognitive evaluations
Age-appropriate screening for potential long-term toxicities

12. Future Directions in Pediatric Antiviral Therapy

The field of pediatric antiviral therapy continues to evolve rapidly. Areas of ongoing research and development include:

Novel antiviral agents with improved efficacy and safety profiles
Long-acting formulations to improve adherence and reduce pill burden
Therapeutic vaccines for chronic viral infections
Personalized medicine approaches based on host and viral genetics
Strategies to eliminate viral reservoirs, particularly for HIV
Broad-spectrum antivirals effective against multiple viral families
Improved formulations and delivery systems for pediatric patients

As new antivirals become available, pediatricians must stay informed about their indications, dosing, and potential adverse effects to provide optimal care for their patients.

Currently Licensed Antiviral Drugs in Pediatrics