TB Intensive Tyler, Texas December 2-4, 2008 Tuberculosis and HIV Co-Infection Lisa Y. Armitige, MD, Ph.D. December 4, 2008 Tuberculosis and HIV Co Infection Lisa Y. Armitige, MD, PhD Assistant Professor of Medicine and Pediatrics Division of Adult Infectious Diseases University of Texas Medical School at Houston
TB and HIV Global (estimates) 1.7 billion infected (1/3 of the world s population) 8 million new cases per year; 2.9 million deaths per year Of 42 million people worldwide infected with HIV, more than a quarter are also infected with Mtb In 1993, TB was given the Centers for Disease Control classification of AIDS defining illness Epidemiology of TB/HIV http://www.euro.who.int/document/tub/pr3s1_tb HIV _ LDitiu_ENG.pdf
Epidemiology of TB/HIV http://www.euro.who.int/document/tub/pr3s1_tb HIV _ LDitiu_ENG.pdf TB/HIV Co Infection Cases in Texas/Houston 2007 No. (%) 2006 No. (%) 2005 No. (%) 2004 No. (%) Texas 145 (12.9) Houston 41 (15.4) 54 (19.5) 29 (11.5) 53 (15.9)
HIV Adults and children estimated to be living with HIV, 2007 Western & Eastern Europe Central Europe & Central Asia 760 000 1.6 million [600 000 1.1 million] [1.2 2.1 million] East Asia 800 000 Middle East & North [620 000 960 000] Africa 380 000 South & South-East [270 000 500 000] Asia Sub-Saharan Africa 4.0 million Latin America 22.5 million [3.3 Oceania 5.1 million] 1.6 million [20.9 24.3 million] [1.4 75 000 1.9 million] [53 000 120 000] North America 1.3 million [480 000 1.9 million] Caribbean 230 000 [210 000 270 000] Total: 33.2 (30.6 36.1) million
HIV Diagnostic tests ELISA Rapid test Western Blot Viral load HIV Replication Cycle
Retrovirus life cycle Fusion inhibitors Maturation inhibitor Coreceptor inhibitors Reverse transcriptase inhibitors Protease inhibitors Integrase inhibitors Goals of HIV Therapy Improved quality of life Reduction of HIV related morbidity and mortality Restoration and/or preservation of immunologic function Maximal and durable suppression of viral load Prevention of vertical transmission Prevention of transmission to sexual partner Preservation of future treatment options Maximizing adherence
Tests used in treatment of HIV positive patients CD4 count HIV RNA viral load test (PCR) HIV genotype test HIV virtual phenotype test HIV phenotype test Use of CD4 Cell Levels to Guide Therapy Decisions CD4 count The major indicator of immune function Most recent CD4 count is best predictor of disease progression CD4 count usually is the important consideration in decision to start ART Important in determining response to ART Adequate response: CD4 increase 100 150 cells/mm³ per year CD4 monitoring Check at baseline (x 2) and at least every 3 6 months
Use of HIV RNA Levels to Guide Therapy Decisions HIV RNA Less important than CD4 count, but may influence decision to start ART, and determine frequency of CD4 monitoring Critical in determining response to ART Goal of ART: HIV RNA below limit of detection (ie, <40 to <80 copies/ml, depending on assay) RNA monitoring Check at baseline (x 2) and at least every 3 4 months in stable patients Immediately prior to initiating therapy 2 8 weeks after start or change of ART Current Antiretroviral Medications NRTI PI Fusion Inhibitor Abacavir Atazanavir Enfuvirtide Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir CCR5 Antagonist Maraviroc Integrase Inhibitor Zidovudine Ritonavir Raltegravir NNRTI Delavirdine Efavirenz Etravirine Nevirapine Saquinavir Tipranavir
Antiretroviral Rules of Thumb NRTIs Backbone of treatment Generally 2 active agents in this category used in most regimens Some, but few, side effects in newer agents NNRTIs Very active against HIV Achilles heel Some psych side effects PIs Very active against HIV More mutations required for resistance to this group Lipid and liver effects Effects of HIV on TB
Pathophysiology of HIV/TB IFN γ production is decreased in parallel with reduction in CD4+ cells, leading to increased risk of reactivation of or infection with Mtb Proinflammatory cytokine production by tuberculous granulomas (especially TNF α) has been associated with increased HIV viremia Outcomes of Exposure to M. tuberculosis Inhalation of Droplet Nuclei Regional replication in lungs, dissemination ~90% ~5% ~5% Killing, clearance of organisms Latent disease Active disease
Outcomes of Exposure to M. tuberculosis in HIV negative and HIV positive patients Inhalation of Droplet Nuclei Regional replication in lungs, dissemination Up to 36% active disease ~90% 10% reactivation ~5% reactivation ~5% per year lifetime Killing, clearance of organisms Latent disease Active disease Clinical Presentation HIV positive vs. HIV negative patients Driven mostly by degree of immunity HIV positive patients are more likely to have: Isolated extrapulmonary localization (53 63% in some studies) Primary infection Pulmonary basilar involvement Tuberculous pneumonia Hilar or mediastinal lymphadenopathies Miliary or disseminated TB Normal CXR (8 20% in some studies) Clinical Microbiology and Infection, Volume 10 Number 5, May 2004
Diagnosis of TB in HIV infected patients Diagnosis * Clinical Microbiology and Infection, Volume 10 Number 5, May 2004
IFN γ gamma release assays (IGRAs) www.cellestis.com Antigens for Gamma Release Assays www.cellestis.com
Quantiferon Gold In Tube ELISPOT S. A. Clark et al. 2007. Clinical and Experimental Immunology
Treatment of LTBI in HIV infected patients Case Scenario A 35 year old HIV+ male is referred to you for a positive TST (12 mm). On questioning, the patient states he was skin tested because one of his roommates was diagnosed with pulmonary cavitary TB. How should you approach this patient? He has 2 other roommates who will see you later this week. They are also HIV+ but were TST negative. How would you evaluate these individuals?
Risk reduction by treatment of Latent TB Infection (LTBI) in HIV infected patients Churchyard et al. JID 2007:196 (Suppl 1) S52 LTBI treatment MMWR August 8, 2003 / Vol. 52 / No. 31
Treatment of TB in HIV infected patients ATS recommendations for treatment of tuberculosis * * Morbidity and Mortality Weekly Report June 20, 2003 / Vol. 52 / No. RR 11
ATS recommendations for extrapulmonary TB treatment duration Rifamycins Have significant interaction with all ARVs except nucleoside analogues (other than AZT) and enfuvirtide Once or twice weekly regimens show high rate of rifampin resistance in HIV patients with CD4 cell count <100 Most common locus of interaction is the cytochrome P450 system, especially CYP2C19 and CYPD6 isotypes As inducers, rifampin > rifapentine > rifabutin Also upregulates synthesis of cytosolic drug metabolizing enzymes including glucuronosyl transferase (involved in metabolism of AZT/reltegravir)
Effect of Rifampin on Serum Efavirenz Levels Effect on plasma level of efavirenz by Effect of increasing efavirenz dose with rifampin co administration rifampin co administration López Cortés et al. Clin Pharmacokinet 2002; 41 (9): 681 690 Effect of Efavirenz Dosing with rifampin on treatment outcomes Manosuthi et al AIDS 2005, 19:1481 1486 Manosuthi et al AIDS 2006, Vol 20 No 1
Rifampin and PIs Note: Decrease in serum rifampin is NOT overcome by low dose ritonavir Clinical Microbiology and Infection, Volume 10 Number 5, May 2004 Newer drugs and rifampin Maraviroc has a substantial reaction with rifampin An increased dose of maraviroc is recommended when co administered with rifampin but no clinical studies have been done Trough concentrations of raltegravir are decreased by ~ 60 % when co administered with rifampin Rifampin is PREDICTED to substantially decrease concentrations of etravirine, but this has not been proven
Rifabutin Has much less effect than rifampin on drugs metabolized by CYP3A Requires dosage adjustment due to effects by many other drugs (such as ritonavir). Concerns regarding adequate dosing if patient is not compliant with PI medication PIs (especially if boosted with ritonavir) cause a marked increase in serum rifabutin serum concentrations and toxicity Rifabutin dose should be decreased when using PI based regimens Rifabutin Good virological and immunological outcomes when administered with PI based HAART Treatment of choice when pt cannot tolerate NNRTI based treatment (though no head tohead studies) Expensive
Case Scenario A 28 year old Latin male with HIV presents with a 2 ½month history of productive cough, night sweats, fevers, fatigue and 30 lb weight loss. The patient has been under the care of an ID physician for his HIV and has been stable on a PI containing regimen. The patient has been working construction out of state and has not been able to visit his doctor until now. He has been compliant with his HIV meds and his current laboratory studies show a CD4 count of 281 and viral load <50. Two of 3 sputums collected on consecutive days are positive for AFB Which anti TB regimen do you start him on? What do you do with his HIV meds?
Overall Treatment Outcomes * * Ronan. A. M. JID 2006:193 (15 May) 1439
When Should HIV Treatment Be Added to the TB Treatment? Indications for Initiating ART: Chronic Infection Clinical Category and/or CD4 Count History of AIDS defining illness CD4 <350 cells/mm³ Pregnant women HIV associated nephropathy Hepatitis B coinfection, when HBV treatment is indicated* Recommendation Initiate ART *Treatment with fully suppressive drugs active against both HIV and HBV is recommended. DHHS guidelines @www.aidsinfo.nih.gov
Indications for Initiating ART: Chronic Infection Clinical Category and/or CD4 Count CD4 >350 cells/mm³, asymptomatic, without conditions listed above Recommendation Optimal time to initiate ART is not well defined. Consider individual patient characteristics and comorbidities. When should treatment be started when patient is being treated for TB? Considerations Treatment of HIV improves outcomes in patients with TB Decreased death or relapse Multiple medications with multiple potential toxicities that are overlapping If the CD4 count is < 200, generally most ID physicians would treat for HIV with treatment for TB If the CD4 count is > 200 Arguments to start both treatments concurrently Arguments to delay the start of HAART
When should treatment be started when patient is being treated for TB? Blanc et al. S46 JID 2007:196 (Suppl 1) Case Scenario A 30 year old black woman presents with fever, chills, night sweats and a 20 lb weight loss over the past month. She has large anterior cervical lymph nodes and a left lower lobe infiltrate. Biopsy of one of the lymph nodes reveals granulomas and AFB which are probe positive for Mtb. After further testing, the patient is found to be HIV positive with a CD4 count of 80. The patient is started on 4 drug therapy and, once stable on anti TB drugs, is started on HAART with efavirenz. Two months into treatment, the patient has worsening cough, a return of fevers, night sweats and worsening LAD. How do you proceed with this patient?
Immune Reconstitution Inflammatory Syndrome (IRIS) * * Manosuthi et al. 2006. Journal of Infection, p. 1 7 IRIS Manosuthi et al. 2006. Journal of Infection, p. 1 7
IRIS Meintjes Lancet Infect Dis 2008;8: 516 23 One more thing
Co trimoxazole prophylaxis Nunn et al. BMJ 2008;337;a257 Thanks!! Questions?