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TUBERCULOSIS AND HIV CO-INFECTION
[15 Marks — MD Exam Answer]
Source: Sharma & Mohan — Textbook of Tuberculosis and NTM Diseases, 3rd Ed., Chapter 35
1. INTRODUCTION / DEFINITION
TB and HIV form the "deadly duet" — each disease fuels the other:
- HIV is the strongest known risk factor for progression from latent TB infection (LTBI) to active TB
- Active TB in turn drives HIV disease progression by increasing viral replication
- TB is the most common opportunistic infection (OI) and leading cause of death in HIV-infected patients in India
- TB is classified as WHO clinical stage 3 (pulmonary) or stage 4 (extrapulmonary)
2. EPIDEMIOLOGY
| Parameter | Figures |
|---|---|
| Global new TB cases (2017) | 10 million |
| HIV-associated TB proportion | 10% of all new TB cases |
| HIV-associated TB deaths (2017) | 0.3 million additional deaths |
| India — HIV-TB burden | ~9% of global HIV-TB burden; 2nd highest |
| HIV prevalence among TB patients, India | ~5% (range 0–45% by state) |
| HIV-TB co-infected deaths, India/year | ~42,000 |
| Mortality rate in HIV-TB co-infection | 15–18% (RNTCP data); aggregate case fatality ~40%; >50% in many developing countries |
| Annual risk of TB reactivation in HIV+LTBI | 5–8% (cumulative lifetime risk: 50–60%) vs 5–10% in HIV-negative |
3. PATHOGENESIS
HIV → TB:
- HIV destroys CD4+ Th1 cells — the central immune defence against Mycobacterium tuberculosis (Mtb)
- Increased risk of:
- Progressive primary TB infection
- Reactivation of LTBI
- Re-infection from exogenous sources
- Relapse after treatment
- Risk escalates as CD4+ count falls; most co-infected have WHO stage 3–4 at TB diagnosis
TB → HIV (bidirectional):
- Active TB causes immune activation → upregulates chemokine co-receptors CXCR4 and CCR5 (HIV entry receptors)
- Increased viral entry, replication, and plasma viraemia
- Accelerates progression to AIDS and death
4. CLINICAL PRESENTATION
Depends on degree of immunosuppression (CD4+ count):
| CD4+ count | TB pattern |
|---|---|
| >350 | Similar to HIV-negative: focal infiltrates, cavitation, upper lobe disease |
| 200–350 | Less cavitation, more diffuse infiltrates, adenopathy |
| <200 | Atypical CXR, smear-negative, high rate of EPTB and dissemination |
| <50 | Miliary TB, disseminated disease, bacteraemia |
Extrapulmonary TB (EPTB):
- Only 20% in HIV-negative; rises to 45–56% in HIV/AIDS (India data)
- Sites: lymph nodes, pleura, CNS, bone marrow, liver, spleen, soft tissue, testes, pericardium
- In one Delhi study: pulmonary TB alone only 38.4%; EPTB alone 39.7%; both 21.9%
Key clinical features in HIV-associated TB:
- Fever, weight loss, night sweats, cough (often less productive)
- Atypical radiological presentations
- Miliary and disseminated disease more common
- Higher rate of smear-negative pulmonary TB
5. DIAGNOSIS
Challenges: Atypical presentation, smear-negative disease, EPTB — all more common with HIV.
Approach:
- Sputum AFB smear — sensitivity lower in HIV (especially late disease); still first step
- Chest X-ray — lower lobe, mid-zone infiltrates; mediastinal adenopathy; miliary pattern; normal CXR does not exclude TB
- CBNAAT / Xpert MTB/RIF — now standard of care for HIV-infected TB suspects
- High sensitivity and specificity
- Detects rifampicin resistance simultaneously
- Fastest turnaround (~2 hours) vs LPA (72 hrs), liquid culture (2 months), solid culture (4 months)
- Adopted by RNTCP; being expanded to 950 sites
- Mycobacterial culture — for smear-negative, EPTB, drug-resistant cases
- NAAT, Line Probe Assay (LPA) — for drug resistance testing
- Extrapulmonary samples — bone marrow, lymph node, CSF, pleural fluid, ascitic fluid, urine, stool, blood
- HIV testing — all TB patients must be tested for HIV (PITC — Provider Initiated Testing and Counselling)
- CD4+ count + viral load — mandatory at baseline
6. TREATMENT
6A. Anti-TB Treatment
- Same as HIV-negative: Category I (2HRZE/4HR) or Category II as per RNTCP guidelines
- Daily anti-TB treatment preferred (not thrice-weekly)
- Co-trimoxazole preventive therapy (CPT) — halves mortality risk; started along with anti-TB treatment
6B. When to Start ART (Critical Decision)
| Scenario | When to Start ART |
|---|---|
| All HIV+TB patients (regardless of CD4 count or type of TB) | Start anti-TB treatment first; initiate ART as early as possible (within 2–8 weeks) |
| CD4+ <50 cells/mm³ | Start ART within 2 weeks (simultaneous initiation being considered in India) |
| TB meningitis | More cautious timing (risk of severe IRIS) |
- NACO guideline: Start ART after 2 weeks of anti-TB treatment; not later than 8 weeks
- Delayed ART = increased mortality
- Trials supporting early ART: CIPRA HT-001, SMART, HPTN 052, START, CAMELIA, SAPiT
6C. ART Regimens for HIV-TB Co-infection
Preferred first-line FDC (single pill at bedtime):
Tenofovir (TDF) 300 mg + Lamivudine (3TC) 300 mg + Efavirenz (EFV) 600 mg
(Efavirenz preferred over nevirapine due to fewer interactions with rifampicin)
ARV drug classes:
| Class | Drugs |
|---|---|
| NRTI | AZT, 3TC, TDF, d4T, ddI, ABC, FTC |
| NNRTI | NVP, EFV, DLV |
| PI | IDV, NFV, SQV, RTV, ATV, LPV, Darunavir |
| Integrase inhibitors | Raltegravir, Elvitegravir |
| Fusion inhibitors | Enfuvirtide |
| CCR5 antagonist | Maraviroc |
7. DRUG INTERACTIONS (TB + ART)
Rifampicin is the most critical interaction:
- Potent inducer of CYP3A4 → reduces plasma levels of PIs by 15–45% and NNRTIs
- Co-administration of rifampicin + PIs is CONTRAINDICATED
- Efavirenz remains effective (dose may need adjustment)
- Rifabutin (weaker CYP3A4 inducer) used as substitute when PI-based second-line ART required
Overlapping / additive toxicities:
| Toxicity | ART drugs | Anti-TB drugs |
|---|---|---|
| Peripheral neuropathy | Stavudine, didanosine | Isoniazid, ethambutol |
| Hepatotoxicity | NVP, EFV, NRTIs, PIs | INH, rifampicin, PZA |
| Bone marrow suppression | AZT | Rifabutin, rifampicin |
| Skin rash | ABC, NVP, EFV | INH, rifampicin, PZA |
| CNS toxicity | EFV | Isoniazid |
| Ocular toxicity | ddI | Ethambutol, rifabutin |
8. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)
Definition: Paradoxical clinical deterioration after starting ART, due to restored immune responses against Mtb antigens.
Incidence: 7–43% of HIV-TB co-infected patients on ART
Two types:
- Paradoxical IRIS — TB was known; patient improves on anti-TB treatment, then worsens after ART started
- Unmasking IRIS — previously unrecognized occult TB "unmasked" after ART initiation
Risk factors:
- Low baseline CD4+ count
- Short interval between TB diagnosis and ART initiation
- Disseminated or EPTB
Clinical features:
- High-grade prolonged fever, worsening pulmonary infiltrates, new/increased lymphadenopathy
- New pleural effusions, hepatomegaly, splenic abscesses, arthropathy, cutaneous lesions
- Terminal ileitis, neurological disease (poor prognosis)
Onset: As early as 5 days; most within 2–6 weeks of ART
Distinguishing IRIS from Treatment Failure:
| Feature | IRIS | Treatment Failure |
|---|---|---|
| CD4+ count | ↑ | ↓ |
| Viral load | ↓ | ↑ |
Management:
- Most cases: self-limiting; symptomatic (NSAIDs)
- Moderate–severe: corticosteroids
- Rarely: temporary interruption of ART
- Do NOT stop anti-TB treatment
9. PREVENTION (Three I's Strategy)
Under the intensified HIV-TB package:
- Intensified Case Finding (ICF) — active TB screening at all HIV settings (4-symptom score: cough, weight loss, fever, night sweats)
- Isoniazid Preventive Therapy (IPT) — for LTBI in PLHIV; 6 months INH (300 mg/day)
- Infection Control (IC) — airborne precautions at ART centres and healthcare facilities
10. NATIONAL PROGRAMME COORDINATION (India)
"Four Pronged Strategy" — NACP + RNTCP:
- Early detection of TB in HIV patients and HIV in TB patients
- Prevention (Three I's)
- Prompt treatment (anti-TB + ART + CPT)
- Management of special cases (DR-TB, IRIS, pregnant women)
Key agencies:
- NACO (National AIDS Control Organisation) — National AIDS Control Programme (NACP)
- CTD (Central TB Division) — RNTCP
- National TB-HIV Coordination Committee (NTCC) at national level
- National Technical Working Group (NTWG) for policy oversight
- Integrated Counselling and Testing Centres (ICTC) — co-located HIV/TB testing at 7,500+ sites
ART Programme outcomes (India):
- Free ART since April 2004
- ~9,11,000 PLHIV on free ART (as of 2015)
- ~4,50,000 lives saved by ART till 2014
- 78% of TB patients knew HIV status (2015)
- 95% of co-infected patients received CPT (2015)
11. TREATMENT FAILURE CRITERIA (for ART)
| Type | Criteria |
|---|---|
| Clinical failure | New/recurrent WHO stage 4 condition after ≥6 months of ART |
| Immunological failure | CD4 falls to pre-therapy baseline; 50% fall from on-treatment peak; CD4 persistently <100 cells/mm³ |
| Virological failure | Plasma viral load >1,000 copies/mL after ≥6 months of ART |
12. PROGNOSIS
- ART reduces mortality by 64–95% in drug-susceptible HIV-TB
- CPT halves mortality risk
- Sputum culture conversion rate: similar to HIV-negative when on effective ART + anti-TB treatment
- However, overall mortality remains higher than HIV-negative TB patients
- Drug-susceptible HIV-TB: good outcomes with timely, coordinated treatment
SUMMARY BOX (Quick Recall)
| Topic | Key Point |
|---|---|
| Most common OI in HIV in India | Tuberculosis |
| Annual reactivation risk HIV+LTBI | 5–8% |
| EPTB rate in HIV/AIDS (India) | 45–56% |
| Preferred first-line ART with TB | TDF + 3TC + EFV (single FDC, bedtime) |
| When to start ART | Within 2–8 weeks of anti-TB Rx |
| Rifampicin + PI | CONTRAINDICATED |
| IRIS onset | 2–6 weeks after ART |
| IRIS tx | NSAIDs; corticosteroids for moderate-severe |
| Three I's | ICF + IPT + IC |
| CFR of HIV-TB | ~40% (>50% in some developing countries) |
References: Sharma SK, Mohan A. Textbook of Tuberculosis and NTM Diseases, 3rd Ed. (2020), Chapter 35 — BB Rewari, Amitabh Kumar, Srikanth Tripathy, Jai P Narain; Fishman's Pulmonary Diseases (HIV and TB Co-pandemics); Harrison's Principles of Internal Medicine 22E
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