HIV and Tuberculosis Co-infection

INTRODUCTION

• Global burden (2017): 10 million new TB cases; PLHIV accounted for 10% of all new TB cases; 0.3 million additional TB-related deaths in PLHIV.
• India: Second highest burden of HIV-associated TB globally (9% of global HIV-TB burden); ~110,000 HIV-associated TB patients annually; HIV prevalence among incident TB patients ≈5% (range 0%–45%).

PATHOGENESIS

HIV → TB

• HIV increases risk of progressive primary TB and reactivation of latent TB infection (LTBI)
• Annual risk of reactivation in HIV-TB co-infected persons: 5%–8% (vs. 0.1% in HIV-negative)
• Cumulative lifetime risk in co-infected: 50%–60% (vs. 5%–10% in HIV-negative)
• As CD4⁺ count falls, risk of TB rises markedly

TB → HIV

• Immune activation → increased expression of co-receptors CXCR4 and CCR5 (major co-receptors for HIV entry)
• Increased plasma chemokine levels → enhanced viral entry → elevated viral load locally and systemically
• Accelerated progression to AIDS and death

CLINICAL PRESENTATION

Key Points:

• Extra-pulmonary TB (EPTB) constitutes only 20% in HIV-negative but 45%–56% in HIV-positive individuals (India data)
• In one Delhi study: isolated pulmonary TB in only 38.4%; isolated EPTB in 39.7%; both pulmonary + EPTB in 21.9%
• Involvement of lymph nodes, CNS, pleura, soft tissue, bone marrow, liver, spleen, testes is frequent
• Diffuse pulmonary infiltrates without cavitation, lower lobe involvement, and miliary TB are characteristic of advanced disease

DIAGNOSIS

Sputum Smear

Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) / Xpert MTB/RIF

• Standard of care for TB confirmation in HIV-infected suspects
• Detects both smear-positive and smear-negative pulmonary TB
• Identifies rifampicin resistance (concordance with gene sequencing >97%)
• Turnaround time: 2 hours (vs. 72 hours for LPA; ~2 months for liquid culture + DST)
• Valuable for diagnosis of EPTB, paediatric TB, DR-TB
• Samples from extrapulmonary sites (bone marrow, lymph node, CSF, pleural/ascitic fluid, urine, stool, blood) must be tested by conventional and rapid molecular methods

Additional investigations

• Mycobacterial culture, NAAT, gene-probe-based tests for smear-negative TB
• Chest radiograph, CT scan for atypical presentations

WHO CLINICAL STAGING OF HIV DISEASE

TREATMENT

Principles of Management

1. Start anti-TB treatment immediately without delay on diagnosis
2. Initiate ART as early as possible (within 2–8 weeks) after TB treatment is tolerated
3. All HIV-TB co-infected patients receive ART regardless of CD4⁺ count
4. Co-trimoxazole preventive therapy (CPT) — halves mortality risk

Anti-TB Regimen

• RNTCP Category I or Category II regimens as per guidelines
• Standard short-course chemotherapy regimen applies
• Daily anti-TB treatment preferred over thrice-weekly DOTS in HIV-TB co-infected patients

Antiretroviral Therapy (ART)

• Clinical: Prolong life, improve quality of life
• Virological: Maximum suppression of viral load
• Immunological: Immune reconstitution
• Reduce HIV transmission

• TDF 300 mg + 3TC 300 mg + EFV 600 mg as a single FDC tablet at bedtime
• EFV preferred over NVP in TB co-infection due to minimal drug-drug interaction with rifampicin

• Start anti-TB treatment first
• Initiate ART between 2 weeks and maximum 8 weeks of starting anti-TB treatment
• If CD4⁺ <50 cells/mm³ — simultaneous initiation of anti-TB treatment and ART recommended to reduce mortality

DRUG INTERACTIONS: RIFAMPICIN AND ARVs

• Reduces AUC of efavirenz by 22%–26% — can still be co-administered
• Reduces AUC of nevirapine by up to 31% — usable with dose adjustment
• Reduces AUC of protease inhibitors by 35%–92% → co-administration of rifampicin with PIs is CONTRAINDICATED
• Rifabutin (less potent CYP3A4 inducer) used when PI-based second-line ART is needed alongside TB treatment

Overlapping Toxicities (ARV + Anti-TB drugs):

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

Definition

Types in TB

• Paradoxical IRIS: Transient clinical deterioration after initial improvement on anti-TB treatment, occurring after ART initiation
• Unmasking IRIS: Active TB uncovered in patients with previously unrecognised/occult TB

Incidence

• Occurs in 7%–43% of HIV-TB co-infected patients initiating ART
• Mtb accounts for ~one-third of all HIV-related IRIS events

Clinical features

• Prolonged high-grade fever or reappearance of fever
• Worsening pulmonary infiltrates
• New pleural effusions
• New or worsening lymphadenopathy (mediastinal, cervical, abdominal)
• Hepatomegaly, splenic abscesses, terminal ileitis, arthropathy, cutaneous lesions
• Neurological manifestations (CNS tuberculomas — poor prognosis)

Differentiating IRIS from Treatment Failure

Risk factors for TB-IRIS

• Low baseline CD4⁺ count
• Short interval between TB diagnosis and ART initiation
• Disseminated or EPTB

Management

• Most cases are self-limiting — no change in treatment required
• Mild: NSAIDs
• Moderate–severe: Corticosteroids (prednisolone)
• Occasionally: interruption of ART; rarely needle aspiration, surgical drainage, or laparotomy

HIV-TB AND MDR-TB

THE THREE I's STRATEGY (WHO/NACO)

1. Intensified Case Finding (ICF) — four TB symptom screen (cough, weight loss, fever, night sweats) at every ICTC encounter
2. Isoniazid Preventive Therapy (IPT) — to prevent progression from LTBI to active TB
3. Infection Control (IC) — airborne infection control measures at ART/healthcare settings

NATIONAL PROGRAMME COORDINATION (INDIA)

• RNTCP (Central TB Division) + NACP (NACO) operate under a four-pronged strategy: early detection, prevention, prompt treatment, management of special cases
• PITC (Provider Initiated Testing and Counselling): HIV testing in all TB patients; TB screening in all PLHIV
• National TB-HIV Coordination Committee (NTCC) at national level; State and District Coordination Committees at respective levels
• Free ART programme launched April 1, 2004; by Dec 2015 — ~911,000 PLHIV on free ART
• 78% of TB patients knew their HIV status in 2015; 95% of co-infected patients received CPT; improving trend in ART uptake

SUMMARY

1. Diagnose both early using CBNAAT/Xpert MTB/RIF and HIV testing
2. Start anti-TB treatment immediately
3. Initiate ART within 2–8 weeks (regardless of CD4⁺ count) using TDF + 3TC + EFV
4. Avoid rifampicin + PI combinations — use rifabutin or EFV-based regimens
5. Watch for IRIS (7%–43%), manage with NSAIDs/steroids
6. CPT reduces mortality by 50%
7. Three I's (ICF + IPT + IC) for TB prevention in PLHIV

Source: Sharma SK, Mohan A. Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases, 3rd Ed. (2020), Chapter 35 — "Tuberculosis and Human Immunodeficiency Virus Infection," pp. 466–480 (BB Rewari, Amitabh Kumar, Srikanth Tripathy, Jai P Narain).