Pediatric HIV

Introduction and Etiology

• Definition: Pediatric HIV infection is a chronic viral infection caused by the Human Immunodeficiency Virus (HIV), characterized by progressive destruction of the immune system, specifically CD4+ T lymphocytes, leading to susceptibility to opportunistic infections and malignancies.
• Virology:
  • Family: Retroviridae; Genus: Lentivirus.
  • Types: HIV-1 and HIV-2. HIV-1 is the predominant cause of the global pediatric epidemic. HIV-2 is less pathogenic, less transmissible vertically, and confined primarily to West Africa.
  • Structure: It is an RNA virus containing the enzyme reverse transcriptase. The viral envelope contains glycoproteins gp120 (binding site for CD4) and gp41 (fusion), while the core contains p24 antigen.
• Global Burden: An estimated 1.8 to 2.78 million children worldwide live with HIV, with the vast majority in sub-Saharan Africa. India is also a significant contributor to the global burden.

Epidemiology and Transmission

• Vertical Transmission (Mother-to-Child Transmission - MTCT): Accounts for >90% of pediatric HIV infections.
  • Intrauterine (20-30%): Occurs transplacentally, mostly in late gestation. Suggested by positive PCR within 48 hours of birth.
  • Intrapartum (70-80%): Occurs during labor and delivery via mucosal exposure to infected blood/secretions or micro-transfusions.
  • Breastfeeding (Postpartum): Accounts for 15-20% of transmission risk in untreated populations. Risk increases with mixed feeding and duration of breastfeeding.
• Other Routes:
  • Sexual Transmission: Primary mode in adolescents.
  • Parenteral: Transfusion of infected blood products (now rare due to screening) and use of contaminated needles/syringes.
  • Premastication: Rare reports of transmission via pre-chewed food from an infected caregiver.
• Risk Factors for Vertical Transmission:
  • Viral Factors: High maternal viral load (most critical factor), viral genotype/phenotype.
  • Maternal Factors: Advanced disease (low CD4 count), primary infection during pregnancy/breastfeeding, lack of antiretroviral therapy (ART), sexually transmitted infections.
  • Obstetric Factors: Vaginal delivery (if viral load >1000 copies/mL), prolonged rupture of membranes (>4 hours), chorioamnionitis, preterm delivery, invasive procedures.
  • Infant Factors: Prematurity, breastfeeding, oral thrush, mixed feeding.

Pathogenesis

• Viral Entry: HIV gp120 binds to the CD4 receptor on T-lymphocytes, monocytes, and macrophages. Co-receptors (CXCR4 or CCR5) are required for fusion and entry.
• Replication: Viral RNA is reverse-transcribed into DNA, integrated into the host genome (provirus), and transcribed to produce new virions.
• Infant Immune System:
  • Infants have an immature immune system with higher absolute CD4 counts than adults.
  • Perinatally infected infants experience very high viral loads (often >1 million copies/mL) that persist for the first 2 years, unlike adults who experience a decline after acute infection.
  • This unchecked replication leads to rapid CD4 depletion and early onset of symptoms.
• Immunodeficiency: Progressive loss of CD4+ T cells leads to defects in both cellular and humoral immunity.
  • B-cell Dysregulation: Polyclonal hypergammaglobulinemia is common due to unregulated B-cell activation, yet functional specific antibody responses are impaired.
  • Central Nervous System (CNS): HIV enters the CNS early (via monocytes/macrophages), causing direct neuronal damage, inflammation, and encephalopathy.

Clinical Manifestations

The natural history is bimodal. Manifestations vary from asymptomatic to severe AIDS-defining illnesses.

Patterns of Disease Progression

• Rapid Progressors (15-25%): Associated with intrauterine infection. Present with AIDS, encephalopathy, and failure to thrive in the first few months. High mortality without treatment.
• Slow Progressors (60-80%): Median survival of 6 years or more without treatment. Often infected intrapartum. Present with intermediate symptoms like LIP or recurrent infections.
• Long-Term Non-Progressors (<5%): Remain asymptomatic with normal CD4 counts and low viral loads for >8 years without therapy.

Systemic Manifestations

• General: Failure to thrive (wasting), generalized lymphadenopathy, hepatosplenomegaly, parotitis (distinctive of pediatric HIV), persistent fever, chronic diarrhea.
• Respiratory:
  • Pneumocystis jirovecii Pneumonia (PJP): Most common serious opportunistic infection in infants. Peaks at 3-6 months. Presents with hypoxia, tachypnea, and fever.
  • Lymphoid Interstitial Pneumonitis (LIP): Chronic, slowly progressive lung disease characterized by diffuse reticulonodular infiltrates. Associated with Epstein-Barr Virus (EBV) and indicates a slower disease progression.
  • Tuberculosis (TB): High incidence; more likely to be extrapulmonary or disseminated. Difficult to diagnose due to anergy.
• Neurologic:
  • HIV Encephalopathy: Progressive corticospinal tract signs, loss of developmental milestones, acquired microcephaly, and cognitive impairment.
  • Other: Seizures, meningitis, opportunistic CNS infections (Cryptococcus, Toxoplasma - rare in infants).
• Gastrointestinal: Chronic diarrhea (Crypto/Isospora), oral/esophageal candidiasis, malabsorption, HIV enteropathy.
• Dermatologic: Severe seborrheic dermatitis, recalcitrant fungal infections (tinea), molluscum contagiosum, scabies, herpes zoster.
• Cardiac: Dilated cardiomyopathy, left ventricular dysfunction.
• Renal: HIV-associated nephropathy (HIVAN) presenting as nephrotic syndrome.
• Hematologic: Anemia, neutropenia, thrombocytopenia (often immune-mediated).

Clinical Presentations Requiring Screening for HIV in Children

HIV infection in children can present with a wide spectrum of clinical manifestations, ranging from nonspecific constitutional symptoms to severe opportunistic infections. Screening is indicated when children present with persistent, recurrent, or unexplained symptoms, particularly in settings with a high prevalence of HIV.

General and Constitutional Symptoms

• Failure to Thrive: Unexplained severe wasting, stunting, or severe malnutrition not responding to standard therapy.
• Persistent Fever: Unexplained fever (above 37.5°C), intermittent or constant, lasting for longer than one month.
• Chronic Diarrhea: Unexplained persistent diarrhea lasting 14 days or more.
• Lymphadenopathy: Persistent generalized lymphadenopathy (PGL) is a common early sign.
• Hepatosplenomegaly: Unexplained persistent enlargement of the liver and spleen.

Mucocutaneous Manifestations

• Oral Candidiasis: Persistent oral thrush in infants older than 6–8 weeks of age.
• Parotitis: Unexplained persistent chronic parotid enlargement.
• Skin Infections:
  • Extensive or recurrent molluscum contagiosum.
  • Extensive wart virus infection.
  • Fungal nail infections.
  • Herpes zoster (shingles), especially if multidermatomal or recurrent.
  • Papular pruritic eruptions.
• Oral Hairy Leukoplakia: A specific sign of HIV infection.

Respiratory Manifestations

• Recurrent Bacterial Pneumonia: Severe recurrent presumed bacterial pneumonia.
• Lymphoid Interstitial Pneumonitis (LIP): A chronic lung disease characterized by reticulonodular patterns on X-ray and persistent hypoxia; it is a distinctive marker for pediatric HIV.
• Tuberculosis: Pulmonary or extrapulmonary tuberculosis, especially if disseminated or resistant to therapy.

Neurologic Manifestations

• HIV Encephalopathy: Failure to attain or loss of developmental milestones, loss of intellectual ability, impaired brain growth (acquired microcephaly), or symmetric motor deficits.
• CNS Infections: Central nervous system toxoplasmosis (outside the neonatal period) or cryptococcal meningitis.

Hematologic Abnormalities

• Cytopenias: Unexplained anemia (<8 g/dL), neutropenia (<500/mm³), or chronic thrombocytopenia (<50,000/mm³).

Defining Opportunistic Infections (AIDS-Defining Conditions)

• Pneumocystis jirovecii Pneumonia (PCP): A common and serious AIDS-defining illness in infants.
• Cytomegalovirus (CMV) Disease: Retinitis or infection of organs other than liver, spleen, or lymph nodes with onset at age >1 month.
• Esophageal Candidiasis: Candidiasis of the trachea, bronchi, lungs, or esophagus.
• Kaposi Sarcoma: Characteristic malignancy associated with HHV-8.

Adolescent-Specific Indications

• Sexually Transmitted Infections (STIs): Diagnosis of syphilis, gonorrhea, Chlamydia, or genital ulcers should prompt HIV screening.
• High-Risk Behaviors: Sexual activity (especially MSM) or IV drug use.

Classification and Staging

WHO Clinical Staging

• Stage 1: Asymptomatic, persistent generalized lymphadenopathy (PGL).
• Stage 2: Mild symptoms (hepatosplenomegaly, papular pruritic eruptions, fungal nail infections, angular cheilitis, extensive molluscum, herpes zoster, recurrent URI).
• Stage 3: Advanced symptoms (moderate malnutrition, persistent diarrhea/fever, oral candidiasis >2 months, oral hairy leukoplakia, pulmonary TB, LIP, severe bacterial pneumonia).
• Stage 4: Severe symptoms (severe wasting, PJP, recurrent severe bacterial infections, chronic HSV, esophageal candidiasis, extrapulmonary TB, Kaposi sarcoma, HIV encephalopathy, CNS toxoplasmosis).

Immunologic Classification (CDC)

Based on age-specific CD4 counts/percentages:

• No Suppression: CD4 >25% (all ages) or >1500 (<1y), >1000 (1-5y), >500 (>6y).
• Moderate Suppression: CD4 15-24% or 750-1499 (<1y), 500-999 (1-5y), 200-499 (>6y).
• Severe Suppression (AIDS): CD4 <15% or <750 (<1y), <500 (1-5y), <200 (>6y).

Diagnosis

• Infants <18 Months: Antibody tests (ELISA) are not diagnostic due to maternal IgG. Diagnosis relies on virologic assays.
  • Test of Choice: HIV DNA PCR (proviral DNA) or HIV RNA PCR (viral load).
  • Testing Schedule:
    • Birth: Within 48 hours for high-risk infants.
    • 6 Weeks: Routine testing for all exposed infants.
    • Confirmatory Test: A positive PCR must be confirmed with a second sample.
    • Breastfed Infants: Repeat testing 6 weeks to 6 months after cessation of breastfeeding.
  • Exclusion of Infection: Two negative PCRs (one at ≥1 month and one at ≥4 months).
• Children >18 Months: HIV Antibody tests (ELISA/Rapid tests) are used. Confirmation by Western Blot or a second/third distinct ELISA/Rapid test.

Management

The goal is to suppress viral replication, preserve immune function, and prevent opportunistic infections.

Antiretroviral Therapy (ART)

• Initiation: Treat All Policy. ART should be initiated in all HIV-infected children regardless of clinical stage or CD4 count.
• Drug Classes:
  • NRTIs: Zidovudine (AZT), Lamivudine (3TC), Abacavir (ABC), Tenofovir (TDF).
  • NNRTIs: Nevirapine (NVP), Efavirenz (EFV).
  • PIs: Lopinavir/ritonavir (LPV/r), Atazanavir/ritonavir (ATV/r), Darunavir (DRV).
  • INSTIs: Dolutegravir (DTG), Raltegravir (RAL).
• Recommended Regimens (WHO/NACO):
  • Neonates (<4 weeks): AZT + 3TC + NVP (or RAL).
  • Children <20 kg (<6 years): ABC + 3TC + LPV/r (or DTG if age/weight appropriate).
  • Children 20-30 kg (6-10 years): ABC + 3TC + DTG.
  • Children >30 kg (>10 years): TDF + 3TC + DTG (TLD regimen).
• Monitoring:
  • Virologic: Viral load at 6 months, then every 6-12 months. Goal is <50 copies/mL (undetectable).
  • Immunologic: CD4 count every 6 months.
  • Clinical: Growth, development, and signs of OIs or drug toxicity (e.g., anemia with AZT, rash with NVP, lipid abnormalities with PIs).

Supportive Care

• Nutrition: Aggressive management of malnutrition; vitamin/micronutrient supplementation.
• Immunization:
  • Live Vaccines (BCG, OPV, MMR, Varicella): Generally contraindicated in severe immunosuppression (CD4 <15%).
  • BCG: Give at birth to asymptomatic exposed infants. Do not give to symptomatic HIV-infected infants.
  • MMR/Varicella: Safe in children with CD4 >15%.
  • Inactivated Vaccines: Safe. Pneumococcal, Hib, Influenza, Meningococcal, Hepatitis B, and HPV vaccines are strongly recommended.

Prophylaxis for Opportunistic Infections

• Pneumocystis (PJP):
  • Drug: Cotrimoxazole (TMP-SMX).
  • Indication: All HIV-exposed infants starting at 4-6 weeks until infection is excluded. All HIV-infected infants <1 year. Children >1 year if CD4 <15% or symptomatic (Stage 2/3/4).
• Tuberculosis (TB): Isoniazid Preventive Therapy (IPT) for all HIV-infected children >12 months without active TB.
• Mycobacterium Avium Complex (MAC): Azithromycin or Clarithromycin for children with severe immunosuppression (CD4 <50-75 cells/uL).

Prevention of HIV

Prevention of Mother-to-Child Transmission (PMTCT)

Vertical transmission can occur during pregnancy (intrauterine), labor and delivery (intrapartum), or breastfeeding (postpartum). Without intervention, transmission rates range from 15% to 45%, but effective interventions can reduce this to less than 2%.

1. Antenatal Interventions

• Universal Screening: All pregnant women should be tested for HIV as early as possible. Repeat testing in the third trimester or at delivery is recommended for high-risk populations or those who tested negative initially but have ongoing risk factors.
• Maternal Antiretroviral Therapy (ART):
  • Treat All Policy: All HIV-infected pregnant women should initiate lifelong combination ART (cART) immediately, regardless of CD4 count or clinical stage, to suppress viral load.
  • Viral Suppression: The most critical factor in preventing transmission is maintaining a maternal viral load <1,000 copies/mL (ideally undetectable) near delivery.
  • Recommended Regimen: Current guidelines (NACO/WHO) recommend a fixed-dose combination of Tenofovir (TDF) + Lamivudine (3TC) + Dolutegravir (DTG) (TLD regimen) once daily. Alternative regimens include TDF+3TC+Efavirenz (EFV).

2. Intrapartum Interventions

• Mode of Delivery:
  • Vaginal Delivery: Safe and recommended if the mother is on effective ART with a suppressed viral load (<1,000 copies/mL).
  • Elective Cesarean Section: Recommended at 38 weeks (before onset of labor/rupture of membranes) for women with a viral load >1,000 copies/mL or unknown viral load to reduce the risk of intrapartum transmission.
• Obstetric Management:
  • Avoid artificial rupture of membranes (AROM) unless medically indicated.
  • Avoid invasive procedures like fetal scalp monitoring, scalp blood sampling, and instrumental delivery (vacuum/forceps) as they increase exposure to maternal blood.
  • Avoid routine episiotomy.

3. Infant Antiretroviral Prophylaxis

Postnatal prophylaxis for the infant depends on the risk stratification of the infant.

• Low-Risk Infants: Born to mothers who received ART during pregnancy with suppressed viral load (<1,000 copies/mL).
  • Regimen: Daily Nevirapine (NVP) or twice-daily Zidovudine (AZT).
  • Duration: Typically 6 weeks (or 4 weeks in some guidelines if mother suppressed >4 weeks before delivery).
• High-Risk Infants: Born to mothers who received no antenatal ART, received only intrapartum ART, had unsuppressed viral load (>1,000 copies/mL), or acquired infection during pregnancy/breastfeeding.
  • Regimen: Multi-drug prophylaxis is required.
    • Option A: AZT + NVP (dual prophylaxis) for 12 weeks (if breastfeeding) or 6 weeks (if replacement feeding).
    • Option B (Presumptive Therapy): Zidovudine + Lamivudine + Nevirapine (or Raltegravir) for 6 weeks.
  • Duration: Minimum 6 weeks, often extended to 12 weeks or throughout breastfeeding in high-risk scenarios.

4. Infant Feeding Practices

• Resource-Rich Settings: Replacement feeding (formula) is recommended to eliminate the risk of postnatal transmission via breast milk.
• Resource-Limited Settings (e.g., India, Africa):
  • Exclusive Breastfeeding (EBF): Recommended for the first 6 months because formula feeding is associated with higher mortality from diarrhea and malnutrition (lack of AFASS criteria—Affordable, Feasible, Acceptable, Sustainable, Safe).
  • Maternal ART: The mother must continue ART to maintain viral suppression, which keeps transmission risk <1%.
  • Avoid Mixed Feeding: Strictly avoid mixed feeding (breast milk + other fluids/solids) as it damages the gut lining and significantly increases transmission risk.
  • Weaning: Should be gradual over 2–4 weeks around 12 months (or up to 24 months per WHO). Abrupt cessation is discouraged.

Prevention of Blood-Borne Transmission

• Blood Safety: Screening of all blood donors for HIV antibodies has virtually eliminated transfusion-associated HIV in developed nations.
• Injection Safety: Use of sterile, single-use, disposable needles and syringes. Avoidance of sharing needles in adolescent IV drug users.
• Premastication: Caregivers with HIV should avoid premasticating (pre-chewing) food for infants, as cases of transmission via blood in saliva have been reported.

Prevention of Sexual Transmission in Adolescents

Adolescents (13–24 years) represent a growing population of new infections.

• Behavioral Interventions:
  • Comprehensive sex education regarding safer sex practices and risk reduction.
  • Consistent and correct use of condoms (barrier protection).
• Biomedical Interventions:
  • Pre-exposure Prophylaxis (PrEP): Daily oral Tenofovir + Emtricitabine is approved for adolescents (weighing >35 kg) at high risk of acquiring HIV. Injectable Cabotegravir is also approved for those >12 years.
  • Male Circumcision: Associated with a 50–60% reduction in HIV acquisition risk in young men.
  • Treatment as Prevention (TasP): Effective ART in HIV-positive partners eliminates transmission risk (Undetectable = Untransmittable).

Post-Exposure Prophylaxis (PEP)

• Indication: For children or adolescents exposed to HIV via percutaneous injury (needlestick), mucous membrane exposure, or sexual assault.
• Timing: Must be initiated as soon as possible, ideally within 24–72 hours of exposure.
• Regimen: A three-drug regimen is recommended for 28 days.
  • Children <2 years: Zidovudine + Lamivudine + Raltegravir (or Lopinavir/ritonavir).
  • Children 2–12 years: Tenofovir + Emtricitabine + Raltegravir.
  • Adolescents ≥12 years: Tenofovir + Emtricitabine + Dolutegravir.
• Follow-up: HIV testing at baseline, 4–6 weeks, and 3 months post-exposure.

General Preventive Measures for HIV-Exposed Children

• Cotrimoxazole Prophylaxis: Administer to all HIV-exposed infants starting at 4–6 weeks of age to prevent Pneumocystis jirovecii pneumonia (PCP). Continue until HIV infection is definitively excluded (typically 18 months or after cessation of breastfeeding).
• Immunization:
  • Inactivated Vaccines: Safe and recommended per national schedule (e.g., DTaP, Hib, HepB, IPV, Pneumococcal).
  • Live Vaccines (BCG, MMR, Varicella):
    • BCG: Give at birth to asymptomatic HIV-exposed infants. Contraindicated in symptomatic HIV-infected infants due to risk of disseminated BCG disease.
    • MMR & Varicella: Contraindicated in severe immunosuppression (CD4 <15%). Safe and recommended in children with CD4 >15%.
    • OPV: IPV is preferred. OPV is generally contraindicated in symptomatic HIV infection.

Prognosis

• Without treatment, >50% of infected children die by age 2 years.
• With early diagnosis and ART, mortality is reduced by >90%, and children can survive into adulthood with a chronic manageable condition.
• Prognosis depends on baseline CD4 count, viral load, and age at diagnosis.