ART in HIV

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

1. 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.
2. 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.
3. 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.
4. 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):

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

Treatment Failure

Failure is categorized into three types. A single isolated abnormal value should be confirmed before switching regimens.

1. 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.
2. 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).
3. 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.