Introduction
Antiretroviral therapy (ART) has transformed pediatric HIV infection from a rapidly fatal disease into a manageable chronic condition. The primary goals of ART in children are to maximally and durably suppress plasma viral load, preserve or restore immune function (CD4 counts), reduce HIV-related morbidity and mortality, and ensure normal growth and development.
Principles of Antiretroviral Therapy
- Combination Therapy: Use at least three drugs from at least two different classes to prevent resistance. Monotherapy or dual therapy is contraindicated for treatment.
- “Treat All” Policy: ART should be initiated in all HIV-infected children regardless of clinical stage, CD4 count, or viral load.
- Early Initiation: Infants <1 year are at highest risk of rapid progression and mortality; immediate ART initiation significantly reduces mortality.
- Adherence: Adherence of >90–95% is required for sustained viral suppression. Pediatric adherence is challenged by palatability, formulation availability, and dependence on caregivers.
Classes of Antiretroviral Drugs
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
- Mechanism: Act as chain terminators during viral DNA synthesis.
- Examples: Zidovudine (AZT/ZDV), Lamivudine (3TC), Abacavir (ABC), Tenofovir (TDF or TAF), Emtricitabine (FTC).
- Role: Dual NRTI backbone is the foundation of first-line regimens.
- Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
- Mechanism: Bind directly to reverse transcriptase enzyme.
- Examples: Nevirapine (NVP), Efavirenz (EFV).
- Note: High rate of resistance; single mutation can confer cross-resistance.
- Protease Inhibitors (PIs):
- Mechanism: Inhibit viral protease, preventing maturation of virions.
- Examples: Lopinavir/ritonavir (LPV/r), Atazanavir/ritonavir (ATV/r), Darunavir (DRV).
- Note: High genetic barrier to resistance; usually “boosted” with low-dose Ritonavir.
- Integrase Strand Transfer Inhibitors (INSTIs):
- Mechanism: Prevent integration of viral DNA into host genome.
- Examples: Dolutegravir (DTG), Raltegravir (RAL).
- Note: DTG has a high barrier to resistance and is increasingly preferred in first-line regimens.
First-Line ART Regimens (NACO/WHO Guidelines)
Regimen selection is stratified by age and weight to ensure appropriate dosing and formulation availability.
1. Children < 6 Years or Weight < 20 kg
- Preferred Regimen: Abacavir (ABC) + Lamivudine (3TC) + Lopinavir/ritonavir (LPV/r).
- Alternative: Zidovudine (AZT) + 3TC + LPV/r.
- Rationale: LPV/r is preferred over NVP for young children, especially those exposed to NVP prophylaxis at birth, due to high rates of NVP resistance.
2. Children 6–10 Years and Weight 20–30 kg
- Preferred Regimen: Abacavir (ABC) + Lamivudine (3TC) + Dolutegravir (DTG).
- Formulation: Pediatric fixed-dose combinations (FDCs) are often used.
3. Children > 10 Years and Weight > 30 kg
- Preferred Regimen: Tenofovir (TDF) + Lamivudine (3TC) + Dolutegravir (DTG).
- Acronym: TLD regimen.
- Note: TDF is generally avoided in pre-pubertal children due to concerns about bone mineral density, but approved for older children/adolescents.
Summary Table of First-Line Regimens (NACO 2021):
| Age / Weight Category | Preferred Regimen |
|---|---|
| < 6 years and < 20 kg | Abacavir (ABC) + Lamivudine (3TC) + Lopinavir/ritonavir (LPV/r) |
| 6–10 years and 20–30 kg | Abacavir (ABC) + Lamivudine (3TC) + Dolutegravir (DTG) |
| > 10 years and > 30 kg | Tenofovir (TDF) + Lamivudine (3TC) + Dolutegravir (DTG) |
Dosing and Administration
- Weight-Based Dosing: Pediatric dosing must be adjusted constantly as the child grows. Weight should be checked at every visit.
- Formulations:
- Syrups/Solutions: Used for infants but often have poor palatability (e.g., LPV/r solution is bitter and contains alcohol).
- Dispersible Tablets: Preferred for ease of administration.
- Fixed-Dose Combinations (FDCs): Simplify regimens and improve adherence.
Monitoring
1. Clinical Monitoring
- Assess at every visit (monthly initially, then every 3-4 months).
- Parameters: Growth (height/weight), developmental milestones, signs of opportunistic infections (OIs), and WHO clinical staging.
- Adherence: Check pill counts and caregiver report at every visit.
2. Laboratory Monitoring
- Viral Load (Plasma HIV RNA):
- Goal: Undetectable viral load (<50 copies/mL).
- Schedule: At baseline, then at 6 months, 12 months, and annually thereafter (or every 6 months depending on guidelines).
- Response: Expect 5-fold drop by 4-8 weeks; undetectable by 6 months.
- CD4 Count/Percentage:
- Schedule: Baseline and every 6 months.
- Utility: Monitors immune reconstitution and guides need for OI prophylaxis (e.g., Cotrimoxazole).
- Toxicity Monitoring:
- Hemoglobin (AZT), ALT (NVP/EFV), Creatinine (TDF), Lipids (PIs).
Adverse Effects of Common ARVs
| Drug Class | Drug | Common Adverse Effects |
|---|---|---|
| NRTI | Zidovudine (AZT) | Anemia, neutropenia, myopathy, lactic acidosis. |
| Abacavir (ABC) | Hypersensitivity reaction (fever, rash, GI symptoms - potentially fatal upon rechallenge). Screen for HLA-B*5701 if possible. | |
| Tenofovir (TDF) | Renal toxicity (Fanconi syndrome), decreased bone mineral density. | |
| Lamivudine (3TC) | Generally well tolerated; rare pancreatitis. | |
| NNRTI | Nevirapine (NVP) | Rash (Stevens-Johnson Syndrome), Hepatotoxicity. |
| Efavirenz (EFV) | CNS symptoms (insomnia, vivid dreams, psychosis), rash. | |
| PI | Lopinavir/r (LPV/r) | Diarrhea, nausea, metabolic syndrome (hyperlipidemia, hyperglycemia, lipodystrophy). |
| INSTI | Dolutegravir (DTG) | Insomnia, headache, weight gain, hyperglycemia. |
Treatment Failure
Failure is categorized into three types. A single isolated abnormal value should be confirmed before switching regimens.
- Virological Failure: Plasma viral load ≥1000 copies/mL (some guidelines say ≥200) after at least 6 months of therapy, with adherence support. This is the earliest sign of failure.
- Immunological Failure: Persistent decline in CD4 count/percentage or failure to rise despite effective ART (e.g., CD4 <200 or <10% for child 2-5 years).
- Clinical Failure: New or recurrent WHO Stage 3 or 4 events (OIs), failure to thrive, or neuro-regression after >6 months on therapy.
Switching Therapy:
- Requires changing at least two, preferably three, drugs in the regimen.
- Resistance testing (genotype) is recommended before switching if available.
Special Situations
1. TB-HIV Co-infection
- Rifampicin Interaction: Rifampicin induces CYP450 enzymes, significantly lowering levels of NVP, PIs, and INSTIs.
- Regimen Modifications:
- With LPV/r: Requires “super-boosting” (ratio of LPV:Ritonavir increased to 1:1).
- With DTG: Dose of Dolutegravir must be doubled (given twice daily).
- With NVP: Dose escalation is not required, but strict lead-in is avoided, or dose is increased (guidelines vary; some suggest avoiding NVP with Rifampicin if possible).
- Timing: Start ATT first. Start ART within 2 weeks to 2 months. In TB meningitis, delay ART (4-8 weeks) to reduce risk of severe IRIS.
2. Immune Reconstitution Inflammatory Syndrome (IRIS)
- Worsening of pre-existing infection (Paradoxical) or unmasking of occult infection (Unmasking) after ART initiation due to immune recovery.
- Management: Continue ART. Treat the OI. Use corticosteroids for severe inflammation (e.g., CNS IRIS, respiratory compromise).
3. Cotrimoxazole Prophylaxis
- Given to all HIV-exposed infants from 4-6 weeks until infection excluded.
- Continued in HIV-infected children until 5 years old or until immune reconstitution (CD4 >25%) is established. Prevention against Pneumocystis jirovecii pneumonia (PCP) and other infections.