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Tuberculosis and HIV: Approaches to diagnosis, treatment and prophylaxis .

Tuberculosis and HIV: Approaches to diagnosis, treatment and prophylaxis. Jean Wiliam Pape MD Professor of Medicine Division of International Medicine and Infectious Diseases, Weill Medical College of Cornell University, NY, NY Director, Centres GHESKIO, Haiti

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Tuberculosis and HIV: Approaches to diagnosis, treatment and prophylaxis .

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  1. Tuberculosis and HIV: Approaches to diagnosis, treatment and prophylaxis. Jean Wiliam Pape MD Professor of Medicine Division of International Medicine and Infectious Diseases, Weill Medical College of Cornell University, NY, NY Director, Centres GHESKIO, Haiti First CHART Caribbean Regional Training on the Clinical management of HIV/AIDS; A multidisciplinary team approach. June 17-19, 2004. Montego Bay, Jamaica

  2. Epidemiology of Tuberculosis and HIV in developing countries • 95% of all HIV cases and > 99% of HIV-related deaths • 95% of all TB cases and 98% of the TB-related deaths • > 85% of HIV deaths and 75% of TB deaths are in the economically productive age group (15-50 years)

  3. HIV infection and risk of TB HIV Status Lifetime Risk of Developing TB • Negative 5-10% • Positive 50%

  4. Timeline of HIV Disease in Haiti Before ART Pulmonary TB : most common pre-AIDS manifestation occurring in 40% of the cohort by six years Most common AIDS illness was the wasting syndrome Leading causes of death : wasting syndrome, TB, crytococcal meningitis, toxoplasmosis

  5. CD4 counts in patients with TB

  6. Diagnosis of TB in HIV+ patients • TB disease can occur at any time during the course of HIV infection • Pulmonary TB is still the most common form. Presentation depends on degree of immunosuppression. • Documented bacteriologic diagnosis is more difficult in HIV-infected patients

  7. Diagnosis of TB in HIV+ patients Early HIVLate HIV • Cxray* Upper lobe cavities lower lobe infiltrates but no cavities; • Sputum smear + (70%) - (80%) • PPD + (65%) - (80%) • Blood culture helpful for HIV+ patients who have lower concentration of mycobacteria in sputum • Nucleic acid amplification assays • More reliable on smear + of untreated patients; sensitivity 95%; specificity 98% *8% of patients with pulmonary TB had normal CXR

  8. Causes of bacteremia in patients with the Wasting Syndrome • Definition of the Wasting Syndrome: • weight loss (> 10% body weight from baseline) • chronic diarrhea ( at least 2 loose stools/day for more than 30 days) • or chronic weakness and fever (intermittent or constant for more than 30 days) • Evaluation: Clinical, CXR, Lab: sputum smear, TB culture and blood culture by the BACTEC 9000 machine • Results: • 16/43 had bacteremia (37%); • TB accounted for 50% of all cases

  9. New individuals tested for HIV at GHESKIO (VCT Center)

  10. Screening for TB at HIV VCTs • Methods: • All persons coming for HIV testing presenting with cough had work-up for TB with sputum smear, culture and Chest radiograph • Results:Active TB documented in • 6% of all comers • 33% of all persons with cough • > 500 Active TB cases/year were treated • > 1,000 Persons/year co-infected with HIV and TB were placedon INH prophylaxis Burgess AL, Fitzgerald DW, Severe P, Joseph P, Noel E, Rastogi N, Johnson, WD Jr., Pape J. AIDS. 2001; 15: 1875-1879.

  11. Tuberculosis prevention in HIV and PPD positive persons Rate of active tuberculosis cases per 100 person-years Placebo Intervention Author/Place/Date Pape et al/Haiti/1993 INH, X 1 year 10 1.7 Markowitz et al/USA/1997 INH, X 6 mo 4.7 1.6 Whalen et al/Uganda/1997 INH, X 6 mo 3.41 1.08 INH+RIF, X 3 mo 3.41 1.32 INH+RIF+PZA, X 3 mo 3.41 1.73 Halsey et al/Haiti INH, 2X/week, X 6 mo - 1.0 RIF +PZA , X 8 weeks - 3.7 INH = Isoniasid ;RIF = Rifampin; PZA = Pyrazinamide

  12. Effect of preventive INH on the incidenceof active and progression of HIV infection Pape JW et al: The Lancet 342: 1993

  13. PPD Positive Individual PPD Negative Individual Pape JW et al: The Lancet 342: 1993

  14. Duration of Isoniazid prohylaxis and time of recurrence of Tuberculosis Duration of INH prophylaxis Fitzgerald D, Morse MM, Pape JW, Johnson WD Jr CID 2000; 311495-1497

  15. Brazil: tuberculosis in patients with AIDS 1981-2001: before and after ART Source: Brazilian MOH, 2002

  16. Evaluation of TB treatment efficacy 1.- Prior TB therapy 2.- Type of regimen 3.- Compliance 4.- Change of treatment 5.- Mortality 6.- Completion of treatment 7.- Confirmed cured 8.- Recurrence (relapse or reinfection)

  17. Treatment of Tuberculosis in HIV-infected patients • When ARV drugs are not available • When ARV drugs are available

  18. Treating TB in patients with AIDS • Generally response (absence of fever) occur early within 14 days, even in advanced AIDS. • Persistent illness raises concerns about: • Drug-resistant TB. • Compliance issues • Drug reaction to TB meds. • Concomitant infection • an infection other than TB. • Poor absorption of TB drugs. (Rarely occurs in patients with AIDS).

  19. Clinical outcome of HIV-infected patients treated for TB HIV-SEROPOSITIVEHIV-SERONEGATIVE CURE RELAPSE(%)CURE RELAPSE(%) Perriens, Zaire, 1991, 2STH/10TH+84 14 87 5 Kassim,Ivory Coast, 1995, 2HRZ/4HR 87 3 87 3 Perriens, Zaire, 1995,2HRZE/4HR-8HR 96 9/1.9* 97 5.3 Ackah , Ivory Coast, 1995,2HRZ/4HR 93 - 92 - Chaisson, Haiti, 1996,2HRZE/4HR** 97 5.4 94 2.8 Desvarieux, Haiti, 1997, 1HRZ/4HR*** 99 4 88 - *Relapse was 9 and 1.9% respectively for those who received HR for 6 and 10 months. **DOT thrice weekly regimen***Modified DOT + Only regimen which does not contain rifampicin H = Izoniazid; R = RIF; Z = Pirazinamide; E = Ethambutol; T = Thiacetazone; S=Streptomycine

  20. Pulmonary TB treatment outcome of HIV+ patients according to CD4 cell counts* CLINICAL OUTCOME HIV-POSITIVE HIV-NEGATIVE CD4 COUNT (mm3) <200 >500 All groups (N) 71 36 280 Completed therapy (%) 54 64 76 Confirmed cured (%) 95 83 92 Abandonned therapy (%) 37 31 21 *Ackah AN, et al (1995). Response to treatment , mortality, and CD4 lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Cote d’Ivoire. Lancet 345:607-610.

  21. Mortality of HIV-infected patients treated for TB according to CD4 counts and time since starting TB therapy MORTALITY (%) AT 6 MONTHS* AT 18 MONTHS** CD4 CELLS/mm3 < 200 10 67 > 200-500 4 22 > 500 3 8 *Ackah et al , Abidjan, 1995. **Perriens et al, Kinshasa, 1995.

  22. Adverse reactions in HIV-infected patients treated for TB NUMBER AUTHORS PLACE OF PATIENTS FREQUENCY (%) Kritski et al , 1989 Rio 135 25 Small et al, 1991 San Francisco 125 18 Nunn et al, 1991 Nairobi 93 19 Perriens et al , 1991 Kinshasa 170 27 Perronne et al, 1992 Paris 56 27

  23. Adverse reactions in HIV-infected patients ReactionsMost frequently implicated drugs Rash Thiacetazone, PZA, RIF, Ethambutol Stevens-Johnson Syndrome Thiacetazone Hepatitis INH, RIF, PZA Gastrointestinal Distress RIF, PZA Paresthesias INH Optic Neuritis Ethambutol Arthralgias PZA Anaphylaxis RIF THE MOST FREQUENTLY RESPONSIBLE DRUGS WERE :THIACETAZONE 20%, RIF 12%, PZA 6%, INH 4%, ETHAMBUTOL 2%.

  24. Drug interactions in HIV-infected patients treated for TB Antituberculous drugs INH, RIFDecreased serum levels DECREASE ABSORTION OF RIF KETACONAZOLE FLUCONAZOLE

  25. 233 patients treated for TB Randomized HIV+ (142) HIV- (91) Placebo (74) Isoniazid (68) Placebo (40) Isoniazid (51) • Recurrent TB 12 2 0 1 • Recurrence rate per 100 persons-years (95% CI) 7.8 (4.1-13.3) 1.4 (0.0-3.4) 0.0 (0.0-4.0) 0.7 (0.0-3.9) Fitzgerald D, Desvarieux M, Sévère P, Joseph P, Johnson WD Jr, Pape J.W. The Lancet 2000 356 : 1470-74 Do HIV+ patients with TB respond as well as HIV- TB patients to anti-TB regimens? Effect of 2o INH prophylaxis?

  26. TB recurrence in HIV+ and HIV – patients successfully treated for TB Proportion free of recurrent tuberculosis Time from completion of TB therapy (months) Fitzgerald D, Desvarieux M, Sévère P, Joseph P, Johnson WD Jr, Pape J.W. The Lancet 2000 356 : 1470-74

  27. Effect of post treatment isoniazid prophylaxis on TB recurrence among HIV+ patients Proportion free of recurrent tuberculosis Population free of recurrent tuberculosis Time from completion of TB therapy (months) Fitzgerald D, Desvarieux M, Sévère P, Joseph P, Johnson WD Jr, Pape J.W. The Lancet 2000 356 : 1470-74

  28. TB recurrence rate in HIV + patients after successful TB therapy • All recurrence were in patients with class B / C of CDC at the time of TB diagnosis • They are the ones who should receive post treatment INH prophylaxis

  29. Tuberculosis and Survival of 312 Individuals with Advanced HIV Disease (CD4+ < 15%) p=0,012 Santoro-Lopes, Clin Infect Dis 2002

  30. Tuberculosis: Prophylaxis and Survival INH prophylaxis No prophylaxis 1,0 0,9 0,8 0,7 0,6 Cumulative Survival 0,5 0,4 0,3 0,2 0,1 0,0 0 1000 2000 3000 Days Santoro-Lopes, 2000

  31. Management of relapse and failures RELAPSE : Reinstitution of previously used regimen if organisms were susceptible at onset of treatment, with DOT FAILURE : Use at least 3 drugs not given previously, with DOT

  32. Treatment of HIV-infected patients with TB when ARV drugs are Available • When should ART be started in persons with active tuberculosis? • Before TB, at the same time or after initiation of TB drugs • What medications should be used to treat concomitant HIV and TB? • Maximum efficiency • Avoid toxicity • How should these medications be prescribed? • TB Patient not yet on ART • TB Patient already on ART

  33. When to Initiate ART in Patients with Active TB? Reasons to delay ART during active TB. • Starting HIV treatment during active TB can cause immune reconstitution syndrome (making patient sicker before better). • TB is often the first OI and can occur at time CD4 count is high and may not need to start ART yet. • Increased likelihood of drug side effects or interactions. • In non-HIV patients TB can cause low CD4 cell counts (200 or lower) that increase with TB therapy. • CD4 counts response must be interpreted cautiously.

  34. Paradoxical Response to TB Treatment with Initiation of HIV therapy • Occurs soon after starting antiretroviral therapy. • Characterized by persistent or increasing fever, severe pulmonary inflammation and lymphadenopathy. • May be associated with recovery of +PPD. • May respond to corticosteroids.

  35. Major Considerations when ART is given at the Same Time as anti-TB regimen • Drug interactions • Rifampin lowers levels of many HIV drugs. • This may cause HIV therapy to fail. • May select for drug-resistant HIV. • Increased liver toxicity • HIV drugs metabolized by the liver (NNRTIs and protease inhibitors) might cause liver toxicity, complicating management. • Large pill burden 5-7/day

  36. ARV Drugs to avoid during TB Therapy* NNRTIs • **Nevirapine (Viramune) • **Efavirenz (Sustiva) • Delavirdine (Rescriptor) Protease inhibitors* • Nelfinavir (Viracept) • LopinavirR (Kaletra) • Indinavir (Crixivan) • Amprenavir (Agenerase) • Saquinavir (Invirase, Fortovase) • Ritonavir (Norvir) *with Extensive Hepatic Cytochrome P450 (CYP) Metabolism (**may use EFV, or NVP if adjust dose)

  37. Drug Interactions NVP DLV EFV IDV RTV SQV NFV APV LVP <http://www.hivatis.org> NNRTIs PIs

  38. ARV Drugs* that should be used with concomitant anti-TB regimen • AZT (Retrovir) • 3TC (Epivir) • d4T (Zerit) • ddI (Videx) • Abacavir (Ziagen) • Tenofovir (Viread) *without Hepatic CYP Metabolism

  39. Some ARV Regimens that Can be Used with Rifampin All NRTI regimen (no dose adjustment) • (AZT or d4T) + 3TC + (abacavir or tenofovir) • ddI + AZT + abacavir • ddI + 3TC + abacavir • Other NRTI combinations. NRTI + NNRTI regimen • One of above regimens + Efavirenz • One of above + Nevirapine (400 or 600 mg QD)

  40. Recommendation for ART in Patients with Active TB • If the patient is not on ART. • If the patient is already on ART.

  41. Recommendation for ART in Patients with Active TB If the patient is not on ART. • Begin multidrug TB therapy (INH/RIF/EMB/PZA). • Do not begin ART immediately. • Monitor clinical response to TB therapy, especially fever curve over 2 weeks. • Evaluate indications for ART after at least 2-4 weeks of TB therapy. • Consider ART if either: • Patient condition is getting worst or • There is another indication to treat HIV infection.

  42. Recommendation for ART in Patients with Active TB If the patient is already on ART. • In general, continue ART during TB therapy. • If patient is on a protease inhibitor, consider switching to an all-NRTI or an [NRTI + NNRTI] regimen. • Monitor for liver toxicity (ALT or AST) every 2-4 weeks while on therapy, especially if on NNRTIs or protease inhibitors.

  43. Summary: I. Management of tuberculosis in HIV-infected patients with no access to ART 1. HIV-infected patients can be effectively treated with rifampicin- containing short course regimens. Initial efficacy is comparable in HIV+ and HIV- patients but recurrence is higher in HIV+. 2. HIV+ patients should get longer duration of therapy (9 months , CDC) or those with class B/C at time of TB diagnosis could get 6 months of therapy with 1 year of post treatment INH prophylaxis 2. Treatment should be with at least 2 drugs to which the organism is sensitive, including RIFAMPICIN. 3. Compliance is key to success. DOT is the best choice. Modified DOT are acceptable with appropriate incentives. 4. Adverse drug reactions are more common in HIV+ patients. 6. Drug interactions may interfere with the levels of fluconazole, ketaconazole, RIF and PZA. 7. Major determinant of mortality is severity of immune deficiency.

  44. Summary II: Management of tuberculosis in HIV-infected patients with access to ART • TB patient already on ART: • Continue ART; If using protease inhibitors switch to other less toxic regimen • TB patient not on ART: • Begin TB treatment; Delay ART for at least 2-4 weeks if possible • ART regimen recommended: • All NRTI regimen or NRTI + NNRTI regimen • Monitor liver toxicity

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