Tuberculosis and HIV: key issues in diagnosis and management Julian Elliott Infectious Diseases Unit, Alfred Hospital Centre for Population Health, Burnet Institute julian.elliott@alfred.org.au
Outline TB and HIV interaction Reducing the burden of TB and HIV TB and HIV testing Co-management of TB and HIV
Egger CROI 2007
Comparison of mortality in the months after starting HAART in low-income and high-income settings. ART-LINC and ART-CC Lancet 2006
Egger CROI 2007
Tuberculosis is the most important cause of illness for people living with HIV
Effect of HIV on risk of active TB Increased progression from primary or latent TB infection to TB disease HIV negative: 10% lifetime risk HIV positive: 10% annual risk
HIV prevalence and TB notifications (all forms), Zimbabwe Reid Lancet 2006
Estimated TB incidence rates Dye Lancet 2006
HIV is the most important cause of progression to active TB and increasing TB incidence
CD4 900 800 700 600 500 400 300 200 100 0 Natural Course of HIV Infection Infection TB Asymptomatic 0 1 2 3 4 5 1 2 3 4 5 6 7 8 9 10 11 Months Years Symptomatic TB AIDS PCP MAC Antonucci JAMA 1995; Badri Lancet 2002; Sonnenberg JID 2005
Incidence of TB during ART, Cape Town Lawn AIDS 2005
Williams Science 2003
Treatment of latent TB infection (Isoniazid) Outcome RR 95% CI Incidence of any TB 0.64 0.51, 0.81 PPD + 0.38 0.25, 0.57 PPD - 0.83 0.58, 1.18 PPD? 0.81 0.49, 1.34 Incidence of confirmed TB 0.73 0.49, 1.08 Incidence of death 0.95 0.85, 1.06 Incidence of AIDS 0.88 0.60, 1.28 Woldehanna Cochrane Database Syst Rev 2004
Currie BMC Public Health 2005
TB control is essential for reducing TB incidence and increasing survival of people living with HIV
Survival of people with HIV and TB Manosuthi JAIDS 2006
HIV testing of patients with TB Very low HIV testing rates in Western Pacific Region: 0.6% in 2005 Traditional approach has been VCCT Provider Initiated Testing and Counseling: 81% Rwanda; 64% Kenya Cambodia (BMC); 47% sites without VCCT vs 76% sites with VCCT Nong IUTLD KL 2007; WPR TB/HIV framework 2008
Options for HIV testing WPR TB/HIV framework 2008
Access to HIV testing and ART is essential for the survival of people with HIV and active TB
WHO algorithm for diagnosis of TB in ambulatory HIV patients WHO guidelines for SNTB/EPTB 2006
Cain IUTLD 2007
Diagnosis of TB in people with HIV Classic symptoms, sputum and if possible Chest X-ray Critical but less accurate, especially if CD4 is low Jones ARRD 1993; Samb IJTLD 1997; Siddiqi Lancet ID 2003; Elliott IJTLD 1993; Karstaedt IJTLD 1998; Johnson IJTLD 1998
Additional TB diagnostic methods Assay Performance Fluorescence microscopy Bleach/centrifugation Liquid culture Serology Nucleic acid amplification tests Adenosine deaminase (ADA) Phage-based assays Line probe assays More sensitive than conventional Can improve sensitivity More sensitive and rapid Poor High specificity, modest sensitivity Accurate for pleural effusion Poor with clinical specimens Accurate and rapid for RIF resistance Perkins JID 2007; Pai PLoS Med 2008
TB screening is HIV care: rapid assessment experienced clinician improved algorithms quality controlled diagnostics
Cotrimoxazole Report Design Setting Mortality reduction Wiktor Lancet 1999 RCT Cote d Ivoire 48% Badri Lancet 1999 RCT South Africa 53% Zachariah AIDS 2003 Observational Malawi 19% Grimwade AIDS 2005 Observational South Africa 29% Nunn unpublished RCT Zambia 16% Mermin Lancet 2004 RCT (all PLHA) Uganda 46% Chintu Lancet 2004 RCT (children) Zambia 43% Mermin AIDS 2005 RCT (family) Uganda 63% <10yrs
Cain WPR TB HIV Framework meeting, Phnom Penh 2008 Mortality by time to start of ART 12.0 10.0 Hazard ratio for mortality 8.0 6.0 4.0 2.0 0.0 30 40 50 60 70 80 90 100 110 120 Days until antiretroviral therapy was initiated bac culture Expon. (bac) Expon. (culture)
Drug interactions with rifampicin With first line ART Nevirapine Efavirenz With other ART regimens Protease inhibitors Triple/quadruple nucleosides Newer agents Challenges First line ART failure Pregnant women Patel JAIDS 2004; Pedral-Sampaio BJID 2004; Manosuthi IAC 2004; Sheehan IWCPHT 2005; Almond IWCPHT 2005;Autur IAC 2004; Oliva AIDS 2003; Ribera JAIDS 2001; Dean AIDS 1999; Van Cutsem IAS 2005; van Oosterhout IAC 2006; Avihingsanon CROI 2007; Justesen CID 2004; la Porte AAC 2004; Losso Antivir Ther 2004
Overlapping toxicities Toxicity TB drug HIV drug Neuropathy Ethambutol Stavudine Didanosine Hepatotoxicity Pyrazinamide Nevirapine Isoniazid Efavirenz Rash Pyrazinamide Nevirapine Efavirenz Abacavir
Immune reconstitution inflammatory syndrome Restoration of immune response to pathogens Paradoxical variant = deterioration in pre-existing clinical illness Unmasking variant = onset of clinical illness after start/change of ART Commonly fever, respiratory, lymph node Usually in first 3 months of ART start/change More common if start ART earlier Difficult to differentiate from other causes Corticosteriods can be used for serious cases Narita AJRCCM 1998; Breen Thorax 2004;; Lawn Lancet Infect Dis 2005; French AIDS 2004
Starting ART within 2-3 weeks of start of anti-tb therapy especially if CD4 < 100 cells/µl is likely to result in more morbidity, but less mortality
Survival after sputum collection in patients with XDR tuberculosis with confirmed dates of death Gandhi Lancet 2006
TB infection control Joshi PLoS Med 2006
Two diseases One person