TB & HIV: What’s New in Tuberculosis

1. TB & HIV: What’s New in Tuberculosis David Ashkin M.D. Florida State TB Controller Medical Executive Director, A.G. Holley State TB Hospital Co-PI, Southeast National TB Center Clinical Associate Professor, Department of Pulmonary and Critical Care, University of Miami, School of Medicine

2. “The Lord shall smite thee with a consumption and with a fever, and with an inflammation…and they shall pursue thee until thou perish.” Deuteronomy 28:22

3. 4

5. TB Case Rates,* United States, 2004 D.C. < 3.5 (year 2000 target) 3.6–4.9 > 4.9 (national average) *Cases per 100,000.

6. Factors Contributing to the Increase in TB Morbidity • HIV epidemic • Increased immigration from high-prevalence counties • Transmission of TB in congregate settings • Deterioration of the health care infrastructure

7. GLOBAL USA Infected Cases 1.7 Billion 10 million (33% Population) (4% Population) Case Incidence 8-10 Million/yr ~18,000/yr Case Prevalence 40-50 Million 30 thousand Deaths 1.8 Million/yr 1,000-2,000/yr MDR Up to 15% <1% (DR and Equador) TUBERCULOSIS

8. TB and HIV at the Turn of the 21st Century • TB kills more people worldwide than ever before • -2-3 million people die every year • -Leading cause of death among HIV infected individuals • -AIDS kills 8000 people a day, of which 5000 die of TB • -one every 10 seconds • -If TB is left unchecked in the next 20 years, almost 1 billion people newly infected and 200 million will develop disease and 35 million will die • TB & HIV kill more individuals than any other infectious diseases • -Most are 25-44 year old individuals (Leading curable infectious killer among young adults) • *Leads to loss of work force • *Leads to orphans • -9 million children are orphaned in Africa The Deadly Partnership TB HIV

9. Transmission Of Tuberculosis

10. Pathogenesis of Tuberculosis

11. Disease Progression • Progression from infection to disease caused by an inability to contain infection • 5-10% of all HIV(-) will progress from infection to disease • Up to 8% per year of PPD(+), HIV(+) pts will progress from infection to disease • The average patient with active TB infects 30 other individuals

12. HIV makes TB worse • Without T cells get immature response • Host response can no longer contain TB organisms that may be present • Taken to Lymph Nodes causing adenopathy and dissemination • Greater chance of rapid progression from infection to disease with recent infection (? If greater chance of acquisition e.g. loss of innate resistance) • May lose innate resistance so have the ability to get re-infected if exposed again • Recent infection with post primary TB more common in HIV infected patients as shown in Genotyping studies from NY and SF • Changes way TB presents-lower lobe, hilar adenopathy, pleural TB, extrapulmonary disseminated disease • With severe immunosuppression may get no response • CT and CXR negative

13. TB in HIV Poorly Formed to No Significant Granuloma Formation in Severely Immunosuppressed HIV (+) Compared to well Formed Granulomas in HIV (-)

14. Tuberculous Granuloma HIV (-) Severely Immunosuppressed HIV (+)

15. Copathogenicity of TB and HIV • (1) TB causes T cells to release IFN-gamma; activated macrophages by TB release TNF and IL-1; those enhance HIV viral replication (-->TB accelerates HIV) • (2) one-year mortality rate for treated HIV-related TB = 20-35% (!! 4 times higher than HIV(-) !!)

16. Key: THINK TB Diagnosis Of Active TB Disease

22. Infection Control • THINK TB, ISOLATE & START MEDS • 6-8 air exchanges/hr • Negative Pressure • Doors Closed • All entering room wear N95 mask • Keep in isolation until 3 negative smears, on medications and responding clinically

24. DIAGNOSIS OF TB DISEASE • Chest X-Ray • 95% of HIV(-) cases with upper lobe infiltrates and/or cavities

25. DIAGNOSIS OF TB DISEASE • Up to 30% of HIV (+), active TB cases will have no infiltrates or cavities

26. TB Disease Diagnosis • Smear • Cheap & rapid • Only 40-60% positive in cases of active TB

27. TB Disease Diagnosis • Culture • Positive ~80% of active TB cases • Takes 6-8 weeks by conventional • Takes 1-3 weeks by liquid media • Sensitivity • Takes 1-2 weeks after positive culture • Nucleic Acid Amplification • Results available in 4-6 hours • Specificity ~98% on smear(+) specimens • Sensitivity 70-80% on multiple respiratory specimens

28. 1) Existence of mutant bacilli with innate resistance to antibiotic action General Principles of Chemotherapy for TB Disease

29. DEVELOPMENT OF RESISTANCE INH I I I I I INH I I INH RIF RIF I INH INH

30. “MORE BUGS-MORE DRUGS!!!!!” J. Sbabaro

31. 1) Existence of mutant bacilli with innate resistance to antibiotic action 2)Slow or intermittent growth of mycobacterium which permits the persistence of viable organisms despite prolonged antibiotic treatment, because only actively replicating organisms are killed by antibiotics General Principles of Chemotherapy for TB Disease

32. Treatment of active TB in Patients on Antiretroviral Therapy • Rifabutin (RBT-T1/2~45 hours) preferred over rifampin (Rif-T1/2~5 hours) due to less p450 interactions • Must adjust dosages of ARV and RBT if given concurrently • INH/RBT/PZA/EMB daily for 2 wk (? 2 mth), then tiw for 6 wk (don't drop EMB) then INH/RBT for 4 more mo (RBT toxicity: arthalgia, uveitis, leukopenia) (monitor viral load) • Alternative regimens is not to use a rifamycin or delay ARV therapy

33. Rifamycin Mono-resistance and HIV • CDC Rbt/ARV and other studies have shown that Rbt is highly effective at curing TB in HIV infected patients with ~95% efficacy but 4% (all with CD4<100) on BIW therapy relapsed with rifampin monoresistance • Suggested that long half life of Rbt combined with short half life of INH left Rbt unprotected • However other studies suggested this happened with rifampin also which has shorter half life • Malabsorption of TB drugs seen in those who developed monoresistance • Our study suggested also presence of extrapulmonary disease • ? “More Bugs” in these sites in HIV with low CD4 with selected penetration • Recommend TIW treatment

34. TREATMENT OF ACTIVE TB DISEASE • Start with 4 drugs in all patients • INH, RIF (RBT), PZA and EMB or SM until sensitivities return • If pansensitive, D/C EMB or SM • After 2 months of therapy, D/C PZA • Continue INH & RIF(RBT) for 4 more mths-total 6 mths • Must have culture conversion by 2 months • 6 month regimen good for HIV(-) and (+) • Can use BIW regimen if CD4>100 (? RIF Monoresistance in HIV pts with CD4<100 use TIW) • Monitor adherence and toxicity • DOT preferred, Combination pills for self administered

35. ATS/CDC/IDSA Treatment Guidelines 2003 • Responsibility for successful treatment is clearly assigned to the public health departments • Strong recommendations for initial patient centered case management and DOT • Recommend getting sputum cultures at 2 months to identify potential relapse • Extended treatment for those still with positive cultures at 2 months and cavities on CXR • Role for rifabutin, rifapentine and fluoroquinolones • Treatment completion defined by number of doses as well as duration of therapy

36. “DOT THERAPY WORKS!” • 95% of patients with TB will be cured by DOT • Decreases Morbidity & Mortality and cost (~$1500/pt) • Decreases Spread of Disease • Average patient with TB infects 30 other individuals • Decreases resistance • MDR costs~$250,000 to cure with only ~80% success • 5% of patients with Active TB will be unable to complete therapy; requiring legal interventions and facilities to cure them • In S.F. one non-compliant patient with MDR-TB was responsible for 40 other cases

37. Clinical Significance of Resistance • If pansensitive>95% chance of cure • If resistant to INH>90% chance of cure • If resistant to rifampin>70% chance of cure • If resistant to INH and RIF~50% chance of cure • Before chemotherapy~50% chance of cure

38. Increased MDR resistance among HIV • ? Increased transmission in NY due to poor TB Control Efforts in early phases of epidemic • More chance for congregate settings with individuals who may have MDR (e.g. hospitals, clinics or hospices) • ? More organisms with impaired absorption or altered metabolism

39. TB Treatment Monitoring • Observe for response-weight gain, coughing less, improved appetite, decreased fevers, AFB smears decreasing • Repeat cultures at two months • Observe for drug toxicities • INH • hepatitis with transaminase elevation-monitor for clinical signs of hepatitis and at least monthly LFTs • Peripheral neuropathy-monitor clinically, give B6 • Rifampin • Red color to urine, sweat, tears • Myalgias-NSAIDS prn • Cholestatic hepatitis-monitor for clinical signs of hepatitis and at least monthly LFTs • Pancytopenia-CBC monthly • Rifabutin-same as rifampin except uveitis more common • Ethambutol • GI upset-? Metoclopramide (try not to give TB meds with food) • optic neuritis (esp in pts with decreased renal function)-monitor clinically, monthly color vision and visually acuity • Pyrazinamide • hepatitis with transaminase elevation-monitor for clinical signs of hepatitis and at least monthly LFTs • Increased uric acid (gout)-monitor clinically and if symptomatic and elevated uric acid-allupurinol • CXRs not routinely recommended for f/u • Therapeutic Drug Monitoring not routinely recommended

40. * If CD4 count is greater than 100 cells/mm3, may consider BIW administration of RBT with APV, fos-APV, IDV, NFV, EFZ and NVP Adapted from MMWR 1/23/04

41. Paradoxical Responses

42. “Paradoxical Response” • Soon after ARVs are started (2-6 weeks) in patients with HIV and TB, paradoxical responses (Immune Reconstitution with Inflammatory Response Syndrome-IRIS) may frequently be seen ( ~25% esp. in patients with an initially high HIV viral load who experience a marked drop post ARVs) • These “paradoxical responses” frequently arouse concerns of uncontrolled TB due to drug resistance and/or noncompliance, drug fever or alternative diagnosis, they are distinct from these and may represent an enhanced antituberculous immune response after the initiation of anti-retroviral therapy • Clinicians should be aware of this phenomenon although other possibilities for a worsening clinical state must first be excluded • Potentially many will regain their ability to react to PPD

43. How Can we Prevent TB among HIV patients? • Detect HIV early (Strongest determinant for patients progressing from infection to disease) • Test all patients who are HIV (+) annually with PPD test (>5mm) (Risk of progressing from infection to disease in HIV infected patients is 8-10%/year as opposed to 5-10%/lifetime in HIV(-) ) • Problems • Anergic • Routine Anergy Testing not recommended • ? Treat those with TB risk factors presumptively for LTBI • ? Treat with ARV and repeat PPD in 3 months

44. Diagnosis of TB Infection:Tuberculin Test

46. Whole Blood Gamma Interferon Assay for LTBI • Quantiferon recently approved by FDA • May be able to discern reaction to BCG and NTM • More studies needed to discern role in LTBI diagnosis

47. How Can we Prevent TB among HIV patients? • Assure that those with PPD (+) complete LTBI treatment!!! • Assure that all HIV (+) with active TB are on DOT and complete therapy before the development of resistance and worsening of immune function!!

48. “Treatment of Latent Tuberculosis Infection” (Formerly Known as Preventive Therapy) • Treatment of latent TB infection • for HIV(+), 9 mo INH (instead of 12 mo) • Short Course Treatment of LTBI no longer routinely recommended • RIF for 4 months as effective as INH for 9 months

49. WHAT CAN YOU DO TO COMBAT TUBERCULOSIS • CONTACT LOCAL HEALTH DEPARTMENT TO HELP ARRANGE A PLAN OF THERAPY FOR PATIENT-HEALTH DEPARTMENTS ARE RESPONSIBLE FOR THE CURE OF TUBERCULOSIS PATIENTS • BEGIN 4 MEDICATIONS ON ALL PATIENTS UNTIL SENSITIVITY OF ORGANISMS RETURNS • EDUCATE PATIENT ABOUT TUBERCULOSIS AND IMPORTANCE OF ADHERENCE TO MEDICATIONS • CONSIDER HAVING PATIENT SIGN ACKNOWLEDGEMENT FORM • MONITOR FOR EFFECTIVENESS OF THERAPY, ADHERENCE AND SIDE EFFECTS • CONSIDER DOT THERAPY • IF DOT THERAPY FAILS CONSIDER COURT ORDERED DOT • INVOLUNTARY COMMITMENT

50. A.G. HOLLEY TB HOTLINE 1-800-4TB-INF0