HIV and TB Co-infection in Children

1. Introduction and Epidemiology

The interaction between Human Immunodeficiency Virus (HIV) and Mycobacterium tuberculosis is termed a "syndemic" or a "fatal combination." Each infection accelerates the progression of the other, leading to significantly higher morbidity and mortality compared to either disease alone.

• Epidemiology:

  • People Living with HIV (PLHIV) are approximately 18 times more likely to develop active TB disease than HIV-negative individuals.
  • TB is the leading cause of death among HIV-infected children and adults.
  • In high-burden settings like Sub-Saharan Africa and India, TB accounts for a significant proportion of hospitalizations and deaths in HIV-infected children.
  • The risk of recurrent TB is higher in HIV-infected individuals even after successful treatment.

• Bidirectional Interaction:

  • Effect of HIV on TB: HIV depletes CD4+ T cells, which are essential for containing M. tuberculosis in granulomas. This leads to a higher risk of primary infection progressing to disease, reactivation of latent TB infection (LTBI), and reinfection.
  • Effect of TB on HIV: Active TB disease increases HIV viral replication (increasing viral load), accelerates the decline of CD4 counts, and speeds up the progression to AIDS and death.

2. Pathogenesis

• Immune Mechanisms: Control of M. tuberculosis relies heavily on cell-mediated immunity (CMI), specifically the interaction between macrophages and CD4+ T helper cells (Th1 response producing IFN-γ and TNF-α).
• Impact of HIV: HIV targets and destroys CD4+ T cells. As CD4 counts drop:
  • The body fails to form solid granulomas to contain the bacilli.
  • There is increased hematogenous dissemination of mycobacteria.
  • The sensitivity of diagnostic tests relying on immune response (like TST) diminishes.

3. Clinical Manifestations

The clinical presentation of TB in HIV-infected children depends on the degree of immunosuppression.

• Pulmonary TB (PTB):
  • Early HIV (mild suppression): Signs are similar to HIV-negative children (upper lobe infiltrates, cavitation possible).
  • Advanced HIV (severe suppression): Atypical presentations are common.
    • Less cavitation.
    • More likely to have lower lobe involvement, diffuse interstitial infiltrates, or miliary patterns.
    • Symptom Overlap: Chronic cough, fever, and weight loss are common to both HIV and TB, making clinical diagnosis challenging. Other HIV-related conditions like Lymphoid Interstitial Pneumonitis (LIP), bronchiectasis, and bacterial pneumonia can mimic TB.
• Extrapulmonary TB (EPTB):
  • Significantly more common in HIV-infected children.
  • Common sites: Peripheral lymph nodes, pleura, meninges (TBM), abdomen, and disseminated TB (miliary).
  • TB Meningitis: HIV-infected children have a higher risk of TBM and poorer neurological outcomes.

4. Diagnosis

Diagnosing TB in Children Living with HIV (CLHIV) is complex due to paucibacillary disease, atypical radiology, and anergy.

A. Screening

• Intensified Case Finding (ICF): All CLHIV should be screened for TB at every visit using the 4-Symptom Screen:
  1. Current cough
  2. Fever
  3. Poor weight gain (or weight loss)
  4. History of contact with a TB case
• Interpretation: Presence of any one symptom requires thorough evaluation for active TB. If asymptomatic, the child is a candidate for TB Preventive Therapy (TPT).

B. Diagnostic Tests

1. Microbiological Confirmation (Priority):

   • Specimens: Sputum (expectorated or induced), Gastric Aspirate (GA), or Bronchoalveolar Lavage (BAL).
   • Nucleic Acid Amplification Tests (NAAT):
     • Upfront Test of Choice: Cartridge Based NAAT (CBNAAT/GeneXpert) or TrueNat is the preferred initial diagnostic test for all CLHIV with presumptive TB.
     • Advantages: Higher sensitivity than smear microscopy, detects low bacterial loads, and simultaneously detects Rifampicin resistance.
   • Smear Microscopy: Has poor sensitivity in HIV-infected children and is not the primary diagnostic tool.
   • Culture (Liquid/Solid): Gold standard; useful for drug susceptibility testing (DST) but slow.

2. Radiology:

   • Chest X-ray (CXR) is essential but nonspecific. Hilar adenopathy and infiltrates may be due to other OIs. A normal CXR does not rule out TB in severely immunosuppressed children.

3. Immunodiagnosis:

   • Tuberculin Skin Test (TST):
     • Cut-off: Induration of ≥5 mm is considered positive in HIV-infected children.
     • Limitation: High rate of false negatives (anergy) due to T-cell depletion. A negative TST does not rule out TB.
   • IGRA (Interferon-Gamma Release Assay): Similar limitations as TST in advanced HIV; generally not superior to TST in this population.

5. Treatment of Co-infection

Management requires concurrent treatment of both infections, managing drug interactions, and monitoring for IRIS.

A. Antitubercular Therapy (ATT)

• Regimen: The standard regimen for drug-sensitive TB is the same as for HIV-negative children.
  • Intensive Phase (2 months): Isoniazid (H) + Rifampicin (R) + Pyrazinamide (Z) + Ethambutol (E).
  • Continuation Phase (4 months): Isoniazid (H) + Rifampicin (R) + Ethambutol (E).
  • Duration: 6 months standard; prolonged to 9-12 months for CNS, bone/joint, or disseminated TB.
• Dosing: Daily therapy is mandatory. Intermittent regimens are contra-indicated in HIV-TB co-infection.
• Pyridoxine (Vitamin B6): Supplementation (10 mg/day) is recommended for all HIV-TB co-infected children receiving Isoniazid to prevent peripheral neuropathy.

B. Antiretroviral Therapy (ART)

• Timing of ART Initiation:
  • General Rule: Start TB treatment first. Initiate ART as soon as tolerability is established, typically within 2 weeks to 2 months of starting ATT.
  • Rationale: Early ART reduces mortality but increases the risk of IRIS. Delaying beyond 8 weeks is associated with higher mortality.
  • Exception (TB Meningitis): Delay ART initiation until 4–8 weeks after starting ATT to reduce the risk of potentially fatal intracranial IRIS events.

C. Drug Interactions and Dose Adjustments

Rifampicin is a potent inducer of the hepatic CYP450 enzyme system, which metabolizes many ARVs (NNRTIs, PIs, INSTIs). This lowers the blood levels of ARVs, risking treatment failure and resistance.

D. Immune Reconstitution Inflammatory Syndrome (IRIS)

• Definition: A paradoxical worsening of pre-existing TB symptoms or the appearance of new TB symptoms after starting ART, despite effective microbiological control, due to recovery of the immune system.
• Types:
  • Unmasking IRIS: Occurs in patients with undiagnosed subclinical TB who start ART. The immune recovery triggers an inflammatory response to the occult bacilli, revealing active disease.
  • Paradoxical IRIS: Occurs in patients already on ATT who start ART. Worsening of fever, lymphadenopathy, or infiltrates.
• Management:
  • Do not stop ART or ATT.
  • Treat symptoms (NSAIDs).
  • Corticosteroids: Prednisolone (1.5 mg/kg for 2 weeks, then tapered) may be used for severe cases (e.g., airway compression, CNS involvement).

6. Drug-Resistant TB (DR-TB) in HIV

• Risk: HIV infection is a risk factor for acquiring MDR-TB and XDR-TB.
• Diagnosis: Rapid molecular testing (LPA or CBNAAT) for Rifampicin and Isoniazid resistance is mandatory for all co-infected children.
• Treatment: Follow standard DR-TB algorithms (Shorter oral Bedaquiline-containing regimen or Longer oral regimens). Bedaquiline and Delamanid can be used with Dolutegravir but require caution and intensive monitoring with Protease Inhibitors.

7. Prevention

A. TB Preventive Therapy (TPT)

• Target: All HIV-infected children >12 months who screen negative for active TB. Infants <12 months if they have a history of contact with a TB case.
• Regimen:
  • 6H: Isoniazid daily for 6 months (10 mg/kg/day).
  • 3HP: Isoniazid + Rifapentine weekly for 3 months (for children >2 years).
• Secondary Prophylaxis: TPT (usually 6 months of Isoniazid) is recommended immediately after completing a successful course of TB treatment in CLHIV to prevent recurrence.

B. Cotrimoxazole Preventive Therapy (CPT)

• CPT prevents Pneumocystis pneumonia, toxoplasmosis, malaria, and severe bacterial infections. It also reduces mortality in children with TB/HIV co-infection and should be continued as per guidelines.

C. BCG Vaccination

• Recommendation: Administer at birth to asymptomatic HIV-exposed infants in endemic areas.
• Contraindication: Do not give BCG to infants with symptomatic HIV infection or AIDS due to the risk of disseminated BCG disease (BCGosis).

D. Infection Control

• Implementation of airborne infection control (AIC) practices in HIV care settings (cough etiquette, ventilation, triage) to prevent nosocomial transmission.