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TB and HIV
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TB and HIV

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  1. TBandHIV Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK

  2. Chemopreventative therapyTreatment and side effects What with… when…IRISMDRTB

  3. TB and HIV • Chemopreventative therapy • Is it useful in HIV ?

  4. INH for TB/HIVTuberculin skin test positive patients Tuberculin skin test positive patients Favours control Favours isoniazid All Studies 0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10 20 Risk ratio & 95% CI

  5. Risk ratio & 95% CI Tuberculin skin test negative patients Favours control Favours isoniazid 0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10 Isoniazid (INH) for TB/HIVTuberculin skin test negative patients All Studies

  6. Effect of INH on TB incidence in HIV+ % reduction in TB incidence, INH vs. placebo * all TST+ TST- / anergic 90 * 60% * * 70 * * 42% * 50 * 30 10 -10 Uganda Zambia Kenya Zambia US Mexico Haiti pooled *P<0.05 -30 Bucher, AIDS 1999;13:501

  7. Efficacy of other TBPT regimes in HIV+ NB RX deaths in HIV neg with2RZ3

  8. Adherence (%) Year Country Proportion of Individuals Dropping Out of Preventative Therapy (PT) in Feasibility Studies HIV+ persons entering the PT process (%) Those entering the process who started PT (%) HIV seroprevalence in study population (%) 1995 Uganda 1995 Rwanda 1995 Zambia 1997 Thailand 1998 Uganda 1999 Brazil 23 53 47 100 100 100 15 95 34 100 51 100 30 12 38 89 38 75 62 - - 69 70 61

  9. Who should receive TB preventive therapy? • effect of TBPT only demonstrated in TST+ • Proportion HIV patients TST+ small • TST difficult to perform • requires return after 48hrs • requires skilled staff • lack of tuberculin • risk of transmission of blood-borne pathogens • ? not required if high prevalence of latent TB (prisoners, miners, household contacts etc)

  10. Secondary preventive therapyPost treatment prophylaxis • In industrialised countries, risk of relapse and reinfection after TB treatment low, hence “secondary PT” not required • in regions with high TB prevalence, risk of reinfection may be significant

  11. Contribution of reinfection to recurrent TB in gold miners in South Africa Incidence of recurrent TB 20 all HIV-pos HIV-neg 15 10 5 0 all recurrence relapse reinfection Sonnenburg et al, Lancet 2001;358:1687 & Lancet 2002;359:1619-1620

  12. Efficacy of secondary TB preventive therapy

  13. Advantages of secondary TBPT • in settings of high TB transmission: • eligible patients easier to identify • HIV test done at TB diagnosis • sputum smear done routinely at treatment completion - no need to re-screen for active TB • if giving primary TBPT, why exclude people with previous TB? • But ? lifelong

  14. Effect of CD4 count on risk of TBamong HIV-infected people Incidence of TB (per 100 pyrs) 20 >350 200-350 <200 15 10 5 0 Italy US South Africa Antonucci JAMA 1995;274:143; Markowitz Ann Int Med 1997;126:123; Badri Lancet 2002;359:2059

  15. Effect of HAART on TB incidence

  16. Operational use of TB secondary prophylaxis • In countries with significant rates of reinfection • For patients enrolling into HIV treatment programmes whose CD4 is < 200 • Once CD4 has risen prophylaxis stopped

  17. Issues in initiating antiretroviral therapy in HIV patients with TB

  18. Drug-drug interactions TB/HIV Absorption CYP3A4 Metabolism PIs NNRTIs Metabolism Elimination

  19. Drug-drug interactions TB/HIV Absorption Rifampicin ↑CYP3A4 Metabolism PIs NNRTIs Metabolism Elimination

  20. Rifampin Effects on HIV Drugs • Protease inhibitors • Saquinavir 80 % decrease • Ritonavir 35 % decrease • Indinavir 92 % decrease • Nelfinavir 82 % decrease • Amprenavir 81 % decrease • Nonnucleoside reverse transcriptase inhibitors (NNRTI) • Nevirapine 37 % decrease • Efavirenz 26 % decrease • Reverse transcriptase inhibitors • No effect

  21. TB Treatment RegimensRIFAMPICIN / HAART HAART Dose TB Dose therapy 3/4NRTI No change RIF No change rit/saq 1000mg/100 mg RIF 600 mg 3/7 rit/saq 1600mg/100 mg RIF 600 mg od nevirapine 200 mg bd RIF 600 mg 3/7 nevirapine 300 mg bd RIF 600 mg od efavirenz 800 mg od RIF 600 mg od

  22. Patients n Regimen South Africa Argentina/Thailand/ Brazil Hong Kong 2RHZE/4HE(2) **2RbHZE/4RbHE(2) 106 98 3.8 5.1 175 171 174 2HRZE/4HR **2RbHZE/4RbH *2RbHZE/4RbH 0.6 1.2 1.2 2HRSZ(3) +4HR(3) 4HRp(1) 4HRp(1)*2-3 190 199 203 3.2 7.5 9.4 Every 2nd or 3rd dose omitted RBT(Rifabutin)/Rifapentine for Treatmentof Pulmonary Tuberculosis Bacteriological relapse % Rifabutin dosage 300mg/day Rifabutin dosage 150mg/day R = rifampicin, Rp = rifapentine, Rb = rifabutin E = ethambutol, Z = pyrazinamide, H = isoniazid

  23. TB Treatment RegimensRifabutin HAART Dose TB Dose therapy 3/4NRTI No change RBT No change nelfinavir 1750 mg bd RBT 150 mg od indinavir 1000 mg tds RBT 150 mg od amprenavir 1200 mg bd RBT 150 mg od Boosted PI No change RBT 150 mg 2-3/7 nevirapine 200 mg bd RBT 300 mg od efavirenz 600 mg od RBT 450 mg od

  24. Antiretroviral Therapy Options • Triple or Quad NRTI with Rifampicin • EFV* with Rifampicin • NVP plus intermittent Rifampicin • Ritonavir + saquinavir with Rifampicin • EFV* with Rifabutin • Protease inhibitor (IDV, NFV, APV)* with Rifabutin • Boosted PI plus Rifabutin* Intermittent 2-3/7 • ? In complex regimens eg Boosted PI plus NNRTI *Dose adjusted

  25. TB • 109 HIV +ve patients with TB • Only risk factor for TB relapse was low CD4 count • 98 HIV +ve patients on 2 NRTIs + EFV + rifampicin • Co-administration of EFV + rifampicin was well-tolerated and immunologically effective • 98 HIV +ve patients on 2 NRTIs + EFV 600mg + rifampicin • 80% had TB resolution • EFV 600mg was sufficient to treat HIV/TB patients on rifampicin Nettles R et al. 10th CROI, Boston MA, February 2003. Abs 137; Patel A et al. 10th CROI, Boston MA, February 2003. Abs 138; Pedral-Samapio D et al. 10th CROI, Boston MA, February 2003. Abs 784

  26. Peripheral Neuro Rash Hepatitis 31 (22%) 3.6 52% d4T 19 (13.6%) - 74% nevirapine efavirenz 11 (7.8%) - 91% isoniazid rifampicin n Onset months <2 months AVR association TB and HIV Adverse Events Dean et al AIDS 2001

  27. AIDS + Drug absorption Median AUC HIV + HIV - P AIDS N13 14 - INH 1248 1062 0.5 PZA 22392 23117 0.5 RIF 3604 1665 0.001 Taylor IUTBLD NB No diff in, TMAX,CMAX 2 hr value NOT reflect CMAX 1998

  28. How Long to Treat? TB / HIV

  29. Duration of Treatment HIV/ TB Patients: Data • 4/6 studies show acceptable (< 5 %) relapse rate with 6-month course • 2 studies showed > 9 % relapse with 6-month course • Relapse vs. re-infection

  30. HIV and TB Duration Rx and Relapse Duration months F/U months Relapse/ failure 51 50 2* 1 6 9 * = new infection by RFLP

  31. Duration of Treatment HIV/ TB Patients: • 6-month course for drug-sensitive, uncomplicated cases • Longer course for cases with CNS disease • Longer course for MDRTB and with non-Rifampicin regimens

  32. Examples of TB regimens used innew TB cases INITIAL PHASE CONTINUATION PHASE 2 ERHZ 4 RH 2 SRHZ 4 R3 H3 2 S3 R3 H3 Z3 6 EH 6 R3 H3 Z3 plus S3or E3 Don’t use twice weekly regimens in patients with CD4 counts <100

  33. Antiretroviral Therapy and TB When to start HAART?

  34. TB and HIV: Immediate vs. Delayed HAART Arguments for delaying potent HIV therapy until TB is treated: 1. HIV is a chronic disease. 2. Adherence may be compromised. 3. Toxicity management is more complex. 4. Immune restoration may produce “paradoxical reactions.”

  35. TB and HIV: Immediate vs. Delayed HAART Arguments for initiating potent HIV therapy at the onset of TB: 1. TB is associated with immune activation, increased HIV replication, and HIV disease progression. 2. Potent antiretroviral therapy can reduce HIV RNA levels, improve immune function and slow HIV disease progression. 3. HIV therapy reduces risk of developing other opportunistic infections

  36. Don’t Wait till it’s too lateFurther AIDS 27/188 TB/HIV patients developed further AIDS On HAART =3 Not on HAART= 24 median CD4 in this group was 70 cells 90% had median CD4 <100 4 months post TB 16 died only 4 on HAART (3 short term) Dean et al AIDS 2001

  37. TB and HIV:Immediate vs. Delayed HAART • TB treatment must be given urgently. • The urgency of HIV treatment depends on predictors of HIV disease progression especially the CD4 cell count. • <100 cells/mm3 - HAART ASAP • 100-200 cells/mm3 - HAART after 2 months • >200 cells/mm3 - HAART after TB RX finished

  38. Immune Reconstitution Inflammatory Syndrome (IRIS)

  39. IRIS • Worsening of original disease • No evidence of bacteriological relapse or recurrence* • May have high fevers – must exclude concomitant disease • Related to start of ARV not to TB Rx • May respond to steroids /IL-2 and GM-CSF • Often prolonged • Recurrent aspiration –not biopsy * NB not always the case

  40. IRIS • Thought to be due to increased proliferation of peripheral bloodmononuclear cells and interferon- response to tuberculous antigens • ?genetic predisposition • Lack polymorphism in the cytokine gene TNFA-308*2. • Increased levels of IL-6 have also been found.

  41. IRIS • TB and severe immunosuppresion • Rx HAART • Some patients expand abnormal/anergic T cell clone • leads to abnormal response decrease IL-2 and cell signalling • Rx with IL-2 and GM-CSF can lead to resolution of IRIS Pires et al submitted

  42. MDR - TB outbreaks • Factors responsible • Inadequate control programmes • Inadequate compliance • Infection control procedure breakdown • Immunosuppressed convergence • Index of suspicion low • Inadequate lab. communication • Infectiousness prolonged

  43. MDR – TB outbreak • Argentina 162 HIV Unit 8 8 102 Resistant to 10 drugs Resistant to 6 drugs

  44. MDR -TB • Mortality • 87 died prior to Rx starting • 49 died on standard Rx • 10 died on tailored Rx • 16 alive on tailored Rx • Epidemiology • 77/92 indistinguishable RFLP TYPE • all 77 contact with index case • Control • cohort nursing • contact tracingcost of 1case =£60000 in UK

  45. HIV and TB Thanks to SE TB research group LSTMH Dr Alison Grant ICSM Dr Imami Chelsea and Westminster Hospital Prof Gazzard