TB hiv co infect


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TB hiv co infect

  1. 1. TB/HIV CO-INFECTION Jantjie Taljaard Centre for Infectious Diseases (CID) Department of Medicine - University of Stellenbosch April 2010
  2. 2. Overview • Epidemiology • Pathogeneses & Immunology • Clinical picture • Diagnosis • Expanded Clinical case definitions • TB Prophylaxis
  3. 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. 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
  5. 5. South Africa 19% South Africa 19%
  6. 6. “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
  7. 7. • 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
  8. 8. 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
  9. 9. 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
  10. 10. 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.
  11. 11. 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.
  12. 12. 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
  13. 13. Pathogeneses
  14. 14. • 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.
  15. 15. RISKS FOR EXPOSURE 1. Number of infectious cases 2. Duration of infectiousness 3. Number/nature of case contact interactions per unit time
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. Disease develops as a consequence of: 1. Progression of primary infection 2. Post primary disease a. Endogenous reactivation b. Exogenous re-infection
  20. 20. 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
  21. 21. Clinical PictureClinical Picture
  22. 22. 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
  23. 23. Management • CXR
  24. 24. 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
  25. 25. Common CXR findings in TB/HIV • Cavitation • Focal infiltrates in upper and hilar regions • Hilar adenopathy • Pleural or pericardial effusions • Milliary TB
  26. 26. Pulmonary Tuberculosis and withwithout significant immunosuppression
  27. 27. Diagnosis of TBDiagnosis of TB
  28. 28. 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
  29. 29. 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%
  30. 30. 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
  31. 31. 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.
  32. 32. 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)
  33. 33. 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
  34. 34. 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.
  35. 35. 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
  36. 36. 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
  37. 37. Clinical case definitions for smear negative TB in HIV infected patients
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. Treatment of TB DiseaseTreatment of TB Disease
  42. 42. 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
  43. 43. 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
  44. 44. 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)
  45. 45. Cotrimoxazole in TB/HIV 0 5 10 15 20 25 30 Mortality Hospitalisation /100personyears Placebo Cotrimoxazole Lancet 1999;353:1469
  46. 46. 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
  47. 47. 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
  48. 48. 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
  49. 49. 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
  50. 50. 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
  51. 51. • 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
  52. 52. 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)
  53. 53. 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
  54. 54. 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
  55. 55. 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)
  56. 56. 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)
  57. 57. 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
  58. 58. • 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
  59. 59. 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
  60. 60. 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
  61. 61. Thank you Jantjie Taljaard jjt@sun.ac.za 083 419 1452