1. TB/HIV CO-INFECTION
Jantjie Taljaard
Centre for Infectious Diseases (CID)
Department of Medicine - University of Stellenbosch
April 2010

2. Overview
• Epidemiology
• Pathogeneses & Immunology
• Clinical picture
• Diagnosis
• Expanded Clinical case definitions
• TB Prophylaxis

3. The global perspective on TBThe global perspective on TB
• 1/3 of the world’s population has TB infection
• 9 million people globally develops TB disease
• Globally, 2 million TB-related deaths a year
–TB is the leading killer of HIV-infected people
• The number of new TB cases is falling or
stabilized in five of six continents
• 1/3 of the world’s population has TB infection
• 9 million people globally develops TB disease
• Globally, 2 million TB-related deaths a year
–TB is the leading killer of HIV-infected people
• The number of new TB cases is falling or
stabilized in five of six continents

4. African perspective on TB/HIV co-
infection
• Africa is the one continent where TB rates are
rising
• enough to increase global rates
• HIV infection is now the most important
predictor of TB incidence across the African
continent

7. South
Africa
19%
South
Africa
19%

8. “Basic” TB immunology
• Inhalation of mycobacteria
• Alveolar macrophages produce cytokines
• Macrophage activation and enhanced
killing of ingested organisms
• Activation of T-cells → clonal expansion
• T-cells also produce IFN-γ
• Results in granuloma formation →
containment and destruction of infection

9. • The CD4+T-cell subset is central for granuloma
formation and prevention of dissemination
• BUT….this immunological response is unable
to destroy all viable organisms
• The surviving, but dormant organisms causes
latent infection, which is diagnosed by a
positive tuberculin test
(active immunosurveillance maintains the latency of
dormant foci)
“Basic” TB immunology

10. How does HIV impact on TB?
• HIV → CD4+T-cell depletion → defective
immunologic response to M.TB.
• HIV-infected individuals with:
– latent TB are at high risk for reactivation
– recently acquired TB are at high risk for progressive
primary TB
• TB in immunocompromised individuals often
pursues an unusual course

11. Effect of TB disease on HIV
• TB activates CD4+ cells and macrophages
harboring latent HIV increases the ability of
HIV to replicate Increased viral load
– TB accelerates the progression of HIV to AIDS
• TB is the leading killer of HIV-infected
persons
– The life expectancy of a HIV-infected person with
low CD4 count and TB disease is measured in
weeks if treatment is not available

12. Min-Max
25%-75%
Median value
TB diagnosis date
MedianCD4T-lymphocyte(Cells/ul)
0
80
160
240
320
400
480
560
CD4BEFORE CD4AT CD4AFTR
p = 0.03p< 0.01
p = 0.35
CD4+ counts
(p=45)
Int J Tuberc Lung Dis 2001; 5: 225Int J Tuberc Lung Dis 2001; 5: 225--232.232.

13. Alarmingly, fewer than half of TB
cases in HIV-infected patients are
diagnosed before death
1. Mohar A, Romo J, Salido F et al. (1992). AIDS, 6, 467–473.
2. Lucas SB, Hounnow A, Peacock C et al. (1993). AIDS, 7, 1569–1579.
3. Domousa K, N’Dhatz M, Coulibaly G et al. (1995). Med Trop (Mars), 55,
252–254.
4. Rana FS, Hawken MP, Mwachari C et al. (2000). J Acquir Immune Defic
Syndr, 24, 23–29.

14. Factors underlying our failure to rapidly
diagnose and effectively treat TB
• Co-infected patients progress more rapidly from
infection to active disease
– Reduced time available for diagnosis and treatment
• Stigmatization of persons living with HIV/TB
– Reluctance to seek medical assistance
• Limited health-care provision in resource-poor
countries
– Poor access to treatment
• Lack of a sensitive, specific, rapid point-of-care
diagnostic test

15. Pathogeneses

16. • Tuberculosis is transmitted via small droplet
nucluei containing Mycobacterium
tuberculosis bacilli.
• Risk for infection occurs when these droplets
becomes aerolised by
– Coughing, sneezing, talking, singing or
– By aerolising procedures which induce coughing
or access to the respiratory tract such as sputum
induction, bronchoscopy, ventilation,
physiotherapy, open surgery (including post
mortem dissection) etc.

18. RISKS FOR EXPOSURE
1. Number of infectious cases
2. Duration of infectiousness
3. Number/nature of case contact interactions
per unit time

19. RISK FOR INFECTION
(largely exogenous in nature)
1. Number of infected droplet nuclei per unit of air
2. Duration of exposure to this particle density

20. RISKS FOR TB DISEASE
(largely endogenous = integrity of cellular
immunity)
1. Time since infection
– Lifetime risk = 10% (immunocompetent)
– Highest in first 2 years
– Recent infection 10x more likely to produce
disease

21. 2. Susceptibility of the individual
– HIV infection - increases both risk of infection
and reactivation of TB
• Annual risk 10%
• Early “OI” - 3 years
• Increased frequency with progression of HIV disease
– Environmental factors
• Alcohol and smoking….
• Malnutrition – lactovegetarians, Vit D deficiency
• Stress etc….?
– Other medical conditions
• Sillicosis, DM, Malignancies, Renal failure,, Steroid
therapy, Immunosuppressive therapies, Pregnancy
TB DISEASE

22. Disease develops as a consequence of:
1. Progression of primary infection
2. Post primary disease
a. Endogenous reactivation
b. Exogenous re-infection

23. Pathogenesis TB Infection and Disease
EXPOSURE TO TB
LATENT TB INFECTION
(90%)
ACTIVE TB DISEASE
(Progressive primary
disease)
(10%)
POST PRIMARY TB DISEASE
(10% lifetime risk)*
LATENT TB
- Never develop disease
RE-INFECTIONREACTIVATION
PRIMARY INFECTION
(10-30%)
NON INFECTION
(70-90%)
* 10% annual risk if HIV co-infected

24. Clinical PictureClinical Picture

25. Clinical picture of HIV-associated TB
(Influenced by degree of immunodeficiency)
• Early disease
– clinical features resemble those seen in HIV-
negative patients with PTB
– often sputum smear positive
• Progressive disease
– atypical PTB, extrapulmonary TB and disseminated
TB become more common
– often sputum smear negative

26. Management
• CXR

27. Chest x-ray in TB/HIV
• CXR only helps with diagnosis when:
– Negative sputum smears in a patient who continues to
cough despite a full course of broad-spectrum antibiotic
• CXR findings often atypical:
– pulmonary infiltrates throughout the lungs rather than
cavities in the upper lobes
– abnormalities may be due to other conditions
– former TB patients may have been cured and CXR
lesions could incorrectly be read as active TB

28. Common CXR findings in TB/HIV
• Cavitation
• Focal infiltrates in upper and hilar regions
• Hilar adenopathy
• Pleural or pericardial effusions
• Milliary TB

29. Pulmonary Tuberculosis
and withwithout
significant immunosuppression

33. Diagnosis of TBDiagnosis of TB

34. Diagnosis of TB in HIV
• Protocol for diagnosis of TB follows the same
principles, irrespective of the patient’s HIV
status...
BUT
• The diagnosis of TB in HIV+ persons is more
difficult:
– increased frequency of sputum smear negative
disease (pulmonary or extra-pulmonary)
– increased atypical radiology

35. Sputum microscopy
• Two methods available for direct examination
of sputum:
– Conventional carbol-fuschin staining [Ziehl–
Neelsen (ZN)]
– Auramine stains based on fluorescent microscopy
• The sensitivity of conventional microscopy is
highly variable depending on the setting,
ranging from 20 to 80%

36. Conventional Sputum Culture
• Gold standard for diagnosis of TB
– Lowenstein-Jensen solid phase culture
• Increases number of cases by up to 50%
• Can detect cases before they become
infectious
• Process is slow, thereby reducing its immediate
use in clinical practice

37. Does induction of sputum with nebulised
saline increase diagnostic yield?
• High-income countries
– A single specimen of induced sputum is
comparable in diagnostic yield with a BAL specimen
from fiberoptic bronchoscopy
– The yield is further increased with repeat
specimens
Anderson C, Inhaber N, Menzies RL. (1995). Am J Resp Crit Care Med, 152, 1570–74
Conde MB, Soares LM, Mello CQ et al. (2000). Am J Respir Crit Care Med, 162, 2238–40
• South Africa
– In a study of smear-negative TB in HIV patients in
Cape Town
• 72% of cultures from sputum induction in 110 patients
were positive for M. tb, including 56% of cases that did
not have pulmonary infiltrates on CXR
Wilson D, Nachega J, Morroni C, Chaisson R, Maartens G. (2006). Int J Tuberc Lung Dis, 10, 31–38.

39. Rapid Mycobacterial Culture
• Automated systems based on fluorescence
such as BACTEC 9000 and MGIT
(Mycobacterial Growth Indicator Tube)
• Microscopic observation drug susceptability
(MODS) assay – characteristic “cording growth
pattern”
• Time to culture positivity:
– MODS - median 7 days (IQR 6–8)
– Automated - 13 days (IQR 10–16)
– Solid-phase culture - 26 days (IQR 21–33)

40. Rapid Mycobacterial Culture (MODS)
• MODS assay represents a major potential
advance in rapid culture-based diagnosis of
TB, especially in resource-poor countries with
basic laboratory facilities.
• However:
– further studies needed to address the
performance of MODS in smear-negative TB cases

41. Nucleic acid amplification tests (PCR)
• Many meta-analyses studying the
performance of PCR for diagnosis of smear-
positive and smear-negative TB
– The main use of PCR tests is restricted to
confirming the presence of M. tb in smear positive
sputum samples in a low TB burden setting
Greco S, Girardi E, Navarra A, Saltini C. (2006) Thorax 61, 783–790.

42. Nucleic acid amplification tests (PCR)
• Current NAA tests exhibit poor sensitivity in
those with smear-negative TB
Sarmiento OL, Weigle KA, Alexander J, Weber DJ, Miller WC. (2003. J Clin
Microbiol, 41, 3233–3240.
• Furthermore:
– Wide variation in reported performance suggests
that they may also be highly operator dependent
– Such tests are unable to distinguish live from dead
mycobacteria

43. TST and interferon-gamma release
assays in rapid diagnosis of active TB
QuantiFERON-TB gold and ELISPOT assay
• In populations with high rates of TB they
cannot distinguish between LTBI and active
infection

44. Clinical case definitions for smear
negative TB in HIV infected
patients

45. Adapted and reproduced with permission of G Maartens.
*CDC case definition:
Bilateral interstitial infiltrate, exertional dyspnoea (onset <3
months), hypoxia or desaturation 5% or more on effort.
Smear-negative tuberculosis case definitions PPV (%)
Pulmonary
• Cough for >21 days +
•Pulmonary opacification or nodular infiltrate on CXR + PJP
excluded (using CDC clinical case definition) * +
•No resolution after Rx with broad spectrum antibiotics
who are started on anti-TB Rx after cultures are sent.
92

46. Lymphadenopathy
Peripheral
Significant asymmetrical nodes (long axis 3 cm) + fever >38°C on two
occasions OR drenching sweats for 2 weeks
Visceral
Visceral nodes (mediastinal / hilar / abdominal nodes on imaging) + fever
38°C on 2 occasions OR drenching sweats for 2 weeks
94
94–96
Serositis
Pleural effusion:
Lymphocytic exudate
Pericardial effusion:
Effusion on ultrasound + fever 38°C on two occasions OR drenching
sweats for 2 weeks
Ascites:
Lymphocytic exudate + fever 38°C on two occasions OR drenching
sweats for 2 weeks
85
90
100
Constitutional syndrome
Wasting (BMI < 18.5) OR documented weight loss >5% body weight
within a month + fever >38°C on two occasions OR drenching sweats for
2 weeks
36

47. 1 Weight gain of 5%
2 Haemoglobin increase of 1g/dl
3 Reduction in CRP
4 Increase in Karnofsky performance score of 20
(or 10 if baseline was ≥ 80)
5 Symptom count ratio > 0.5
(number of symptoms better or resolved at 8 weeks
follow-up/total number of symptoms at baseline
> 1 of these response criteria at week 8 of follow-up =
97.5% confirmed TB
Wilson D, Nachega J, Morroni C, Chaisson R, Maartens G. (2006). Int J Tuberc Lung Dis, 10, 31–38.
Criteria that defines a clinically
relevant response to TB treatment

48. Treatment of TB DiseaseTreatment of TB Disease

49. o Use multiple drugs in combination tablets
o Patients must be DOT supported
o Use standardised treatment regimens
o Cure patients the first time round!!
o Give the correct drugs for the correct period of time
(6 months short course)
o No trials of therapy should be given – once decision
to start Rx has been taken Rx must be completed
o NTBCP protocols must be followed

50. Probability of Survival during TB
Treatment
0.7
0.75
0.8
0.85
0.9
0.95
1
HIV neg
HIV pos
Probabilityofsurvival
0 30 60 100 160 180
Days
Nunn P et al
Am Rev Respir Dis 1992;146:849-54

51. 3.8
4
4.2
4.4
4.6
4.8
5
5.2
5.4
PRE O.I. POST
Effect of opportunistic infections
Viral load (log10)
(Donovan 1996)

52. Cotrimoxazole in TB/HIV
0
5
10
15
20
25
30
Mortality Hospitalisation
/100personyears
Placebo Cotrimoxazole
Lancet 1999;353:1469

53. TB & ARV’s
the challenges
1.1. ComplexComplex drugdrug--drug interactionsdrug interactions
2.2. IncreasedIncreased pill burdenpill burden
3.3. SharedShared toxicitytoxicity
4.4. ParadoxicalParadoxical deteriorationdeterioration of TB due toof TB due to
immune reconstitutionimmune reconstitution

54. Shared toxicity
•• Overlapping toxicity isOverlapping toxicity is commoncommoncommoncommoncommoncommoncommoncommon
•• Leads toLeads to difficult managementdifficult managementdifficult managementdifficult managementdifficult managementdifficult managementdifficult managementdifficult management
decisionsdecisions
•• Most common shared sideMost common shared side--effects:effects:
–– Peripheral neuropathiesPeripheral neuropathies
–– NauseaNausea
–– RashRash
–– HepatitisHepatitis

55. Common shared toxicity of HAART
and anti TB drugs
TOXICITYTOXICITYTOXICITYTOXICITY TB DRUG/STB DRUG/STB DRUG/STB DRUG/S ARTARTARTART
Peripheral
neuropathy INH
Stavudine (d4T)
Didanosine (ddI)
Rash RIF
INH
PZA
NNRTI’s
Nausea
PZA
Didanosine (ddI)
Zidovudine (AZT)
Protease inhibitors
Hepatitis RIF
INH
PZA
NNRTI’s

56. Drug interactions
•• Rifampicin in a powerfulRifampicin in a powerful enzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducerenzyme inducer
–– enhanced metabolism of PIenhanced metabolism of PI’’s (excepts (except
Ritonavir) and to a lesser extent, NNRTIRitonavir) and to a lesser extent, NNRTI’’ss
•• Rifampicin levels areRifampicin levels are not significantlynot significantly
affectedaffected by HAARTby HAART
•• Antiretroviral drugsAntiretroviral drugs cancancancancancancancan be usedbe used
concomitantly with Rifampicinconcomitantly with Rifampicin

57. HAART interactions with
Rifampicin
NRTI’s & NtRTI’s No interactions
Efavirenz Non significant reduction in EFV
levels
Nevirapine Significant reduction in NVP
levelsLopinovir/Ritonovir
(400mg/100mg) plus
Ritonovir 300mg
(Can also give double
dose LOP/rit)
No significant interactions
All other PI’s Marked reduction in PI levels -
AVOID

58. • If TB present before starting ART
– Time of initiation of ARVs depends on CD4 count and
clinical condition (Use efavirenz instead of nevirapine)
•• CD4CD4CD4CD4CD4CD4CD4CD4++++++++ > 350> 350> 350> 350> 350> 350> 350> 350 –– does not need ART yet.does not need ART yet.
•• CD4CD4CD4CD4CD4CD4CD4CD4++++++++ < 350< 350< 350< 350< 350< 350< 350< 350 –– delay ART untildelay ART until after intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phaseafter intensive phase
of TB treatment has been completedof TB treatment has been completed unless patientunless patient
very illvery ill
•• CD4CD4CD4CD4CD4CD4CD4CD4++++++++ <100<100<100<100<100<100<100<100 –– delay ART until sure that TBdelay ART until sure that TB
medication is tolerated,medication is tolerated, afterafterafterafterafterafterafterafter ±±±±±±±± 2 weeks2 weeks2 weeks2 weeks2 weeks2 weeks2 weeks2 weeks
TB treatment and HAART

59. Paradoxical worsening of TB
•• MoreMore commoncommoncommoncommoncommoncommoncommoncommon in HIVin HIV--infected patients.infected patients.
•• Typical in largeTypical in large lymph nodeslymph nodeslymph nodeslymph nodeslymph nodeslymph nodeslymph nodeslymph nodes or CNSor CNS
tuberculomastuberculomastuberculomastuberculomastuberculomastuberculomastuberculomastuberculomas..
•• RRelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ARTelated to initiation of ART, especially if, especially if
commenced within intensive phase of TBcommenced within intensive phase of TB
treatment = Immune reconstitutiontreatment = Immune reconstitution
inflammatory syndrome (IRIS)inflammatory syndrome (IRIS)

60. Mechanism?
•• Host immune responseHost immune responseHost immune responseHost immune responseHost immune responseHost immune responseHost immune responseHost immune response????????
–– Increased antigen releaseIncreased antigen release –– TB therapyTB therapy
–– Immune reconstitutionImmune reconstitution –– ART/HAARTART/HAART
•• In patients who initiate HAART if CD4In patients who initiate HAART if CD4++ < 50< 50

61. TB Prophylaxis
TB prophylaxis leads to 60% decrease ofTB prophylaxis leads to 60% decrease of
clinical TB inclinical TB in HIV+ patients with PPD skin testHIV+ patients with PPD skin test
≥≥≥≥≥≥≥≥ 5mm5mm

62. Efficacy of INH Preventive Therapy
among HIV-positive, TST-
positive(>5mm) Persons
0
2
4
6
8
1 0
1 2
H a it i Z a m b ia U g a n d a K e n y a
TBrate(%peryear)
IN H P la c e b o
Isoniazid (INH) reduces active TB rate by 60%
(but only among TST-positive persons)

63. Eligibility for TB prophylaxis
• Although the benefit of IPT is greater in people with
a positive TST
– Not practical to do TST on all patients
– Many anergic due to immunosuppression
• All HIV+ people not on ART and no features of
active TB are eligible
– Screen for TB with good history of symptoms and
clinical examination
• Patients with signs and symptoms suggestive of TB
must first be investigated for TB (CXR + culture)

64. WHO IS NOT ELIGIBLE FOR TB PREVENTIVE
THERAPY?
• Active liver disease or active alcohol abuse
• Active TB in past 2 years
• Patients already on ART

65. • Patients who receive TB preventive therapy
and who require to start HAART
– can complete their TB preventive therapy even if
the ARV treatment is started
– there is no interaction between INH and the
current ART regimens used

66. RECOMMENDED REGIMEN
• INH: 5 mg/kg/day (maximum 300 mg per
day) for 6 months
– Protects against TB for another 12 months
• Additional Pyridoxine to prevent peripheral
neuropathy (25 mg od)
• No definite evidence to support other drug
regimens
• High risk groups to be targeted
– Miners, Prisoners, Health care workers

67. HIV infection is the biggest single
challenge to TB control efforts on the
African continent
TB is the biggest single challenge in
reducing HIV/AIDS related morbidity
and mortality on the African continent

68. Thank you
Jantjie Taljaard
jjt@sun.ac.za
083 419 1452