Research in Tuberculosis: Translation into Practice

Transcription

1 Case History Research in Tuberculosis: Translation into Practice This is a 6-year6 year-old Bosnian male, who presented to ER with one-week history of fever and occasional vomiting. No cough, difficulty breathing or weight loss. Evaluation revealed right lobar pneumonia. Patient was admitted to the hospital and started on IV antibiotics (Ceftriaxone). Michael Lauzardo, MD, MSc Principal Investigator, Southeastern National Tuberculosis Center Assistant Professor, Div. of Pulmonary and Critical Care Medicine, e, University of Florida College of Medicine Deputy Health Officer for TB State of Florida Case History Case Physical Examination PMH No significant illnesses in the past, no surgeries. Social History Patient lives with both parents and a younger sibling. They all immigrated to U.S. from Bosnia about six months PTA. At that time, they all had PPD placed. Both parents tested positive, but elected not to take meds. Both children tested negative. T: P: 154 R: 24 BP: 111/70. O2 Sat. on RA: 96 97%. 97%. Patient was awake, alert, in no apparent distress Chest Markedly decreased BS in the right lung field Rest of exam was within normal limits Case CXR PA Large opacity that filled the lower 2/3 of the right hemithorax, heart slightly displaced to the left, clear left lung field. Right lateral decubitus Mass or large organized pleural effusion without free layering. PAGE 1

2 Case Patient continued having daily fever spikes, but without changes in his respiratory status. Would you do any further evaluation? Repeat TST? Do we need gastric aspirates versus sputum? Spinal tap? Other cultures? Other tests? Case Hospital Course TST was placed and read in 48 hours as 22 mm of induration. Induced sputum/early morning gastric aspirates were obtained. Chest US showed a loculated, organized pleural effusion Surgery was consulted and they performed a video-assisted thoracotomy and decortication. Pleural biopsy and AFB cultures were sent. HIV antibody: negative Case Hospital Course Patient was started on INH, Rif, PZA and Ethambutol. He improved with resolution of fever in three days. He was discharged home to continue meds under DOT. Gastric aspirates X 3 Case Final Results AFB smear and cultures were negative Induced sputum AFB smear was negative Pleural Biopsy Multiple caseating granulomas Pleural fluid/biopsy AFB smear and PCR for M.Tb were negative Sputum and pleural cultures grew M. tuberculosis,, resistant to INH Case Final Diagnosis Tuberculous empyema INH-resistant TB PAGE 2

3 TB Epidemiology A Silent Global Epidemic Infected cases Case incidence Case prevalence Deaths MDR GLOBAL 1.7 billion (33% population) 8-10 million/year million 1.9 million/year Up to 15% (DR and Ecuador) USA 10 million (4% population) ~ 18,000/year 30,000 1,000 2,000/year <1% One-third of the world s s population infected Eight million new cases of active disease per year Two to three million deaths per year One person is newly infected every second and one person dies every 10 seconds Rising incidence of drug-resistant resistant disease Billions of dollars in lost productivity Global TB Rates Tuberculosis in the United States: Epidemic Under Control 14,781 cases (5.1/100,000) 10th year of decline (down 1.3% from 2002) 138 cases (0.9%) of MDR-TB in states meet year 2000 elimination target (< 3.5/100,000) Completion of therapy exceeds 90% Reported TB Cases United States, TB Morbidity United States, Number of Cases Year YEAR *Cases per 100,000 CASES 18,361 17,531 16,377 15,989 15,075 RATE* PAGE 3

4 TB Case Rates United States 2002 Trends in TB Cases in Foreign-Born Persons, United States, Rate: cases per 100,000 D.C. < 3.5 (year 2000 target) > 5.2 (national average) # of Cases Percentage 10, , , , , No. of Cases Percentage of Total Cases Percentage of TB Cases Among Foreign-Born Persons United States Countries of Birth for Foreign-Born Persons Reported with TB, U.S Other Countries (38%) Mexico (25%) Philippines (11%) >50% 25%-49% <25% S. Korea (3%) Haiti (3%) China (5%) India (7%) Vietnam (8%) TB in Foreign-Born United States % of total cases 23.4 cases / 100,000 population Rate ratio: 8.7 relative to U.S.-born 25 states reported > 50% foreign-born cases Number of Cases Number of TB Cases in U.S.-Born vs. Foreign-born Persons, United States * US-Born Foreign-Born PAGE 4

5 Challenges The Global Expansion of Drug Resistant Strains of TB Multi-Drug Resistant (MDR) TB First-line Therapy for Cases of Drug Susceptible TB Defined as resistance to isoniazid and rifampin Created by poorly managed TB programs Non-adherence to therapy Poor quality drugs or supply Leads to bad outcomes Longer treatment (go from months) Toxic regimens Cost increases fold High death rates Disastrous outcomes in HIV settings Isoniazid Rifamycins Pyrazinamide Ethambutol Aminoglycosides Capreomycin Quinolones Thioamides Cycloserine PAS Therapy is standardized 4 drugs for months Safe effective and cheap 95% cure rate Cost about $20 Extensive evidence base of RCTs to support practice Second-line Drugs for Drug Resistant TB Extensively Drug Resistant TB XDR TB Isoniazid Rifamycins Pyrazinamide Ethambutol Aminoglycosides Capreomycin Quinolones Thioamides Cycloserine PAS Need lab testing and or epi information on prevalent resistant strains 4-66 drugs for 2 years Less effective <80% cure rate $3500 to $5000 cost for drugs No clinical trials to support Results from inadequate MDR TB treatment and leads to second-line drug resistance Defined from October 2006 as being: MDR TB plus resistance to at least a fluoroquinolone and any sescond-line injectable (amikacin, kanamycin, and capreomycin) If Fluoroquinolone and injectable are available then outcme of MDR is better (69% cure rate vs 30%) PAGE 5

6 XDR TB Outbreak, South Africa patients in TB/ARV integration study 14 deaths of which 10 were MDR 6 of 10 isolates were resistant to all the drugs tested Suggested that the facility likely had high rates of resistance Prompted a survey from Jan 2005 through March 2006 South Africa Drug Resistance Survey Of 542 M. TB cultures 221 (41%) were MDR TB 53 (10%) XDR TB 52 of the 53 patients died within 25 days of the diagnosis All were HIV positive and those that died included those on anti- retroviral therapy XDR likely has spread to neighboring African countries TB Drug Resistance Global Burden of Drug Resistant TB The XDR outbreak in South Africa led to prevalence surveys of national labs The global burden of MDR or XDR TB is now estimated to be over 450,000 Over 28 countries now have confirmed cases of XDR with likely spread in sub-saharan Africa in populations with high rates of HIV From NEJM 356;7:2007 HIV and TB: Twin Epidemics HIV / TB Co-Infection PAGE 6

7 HIV and TB The twin epidemics of HIV and TB are the single biggest threat to global TB control The WHO strategy of DOTS fails to decrease the incidence of TB in settings of high HIV prevalence Expansion of ARV therapy is good overall for TB control efforts however, it may lead to drug interactions that may worsen MDR TB epidemic May lead to a paradoxical worsening of the TB burden by improving survival in HIV positive individuals who would be at risk for TB Poverty and TB Responding to the Challenges Technological Advances Whole Blood Gamma Interferon Assay for LTBI Quantiferon gold recently approved by FDA utilizing early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP 10) [present in TB and bovis absent from BCG and most NTM except kansasii, szulgai and marinum) by ELISA May be able to discern reaction to BCG and NTM More studies needed to discern role in LTBI diagnosis PAGE 7

8 Vaccine History BCG was developed by Albert Calmette and Camille Guerin who attenuated a strain of M. bovis by growing it on culture medium for 13 years. Virulence was monitored in animal models. In 1921 it was first administered widely in France where it reduced infant mortality from TB by 90%. BCG Today Now one of the most widely used vaccines Very effective at reducing mortality in infants Protective effect lasts no more than years at best Efficacy has been shown to be highly variable (0-80%) in protecting against TB disease Reasons for this are unclear but likely involve the relationships between M. tuberculosis, BCG, and other environmental non- tuberculous mycobacteria Immunology of TB Vaccine Summary Unexpected advances in the field of immunology and vaccine development hold great promise for the delivery of the most important new tool for the elimination of TB. Without a vaccine, the elimination of TB is likely impossible. The current vaccine candidates are not ideal but even a less than ideal vaccine can potentially become a cost-effective valuable tool that can be applied globally. Doherty et al. Clin Micro Rev Vol. 18, p Diagnosis of TB in Low-Resource Settings Microscopic-Observation Drug-Susceptibility Testing MODS MODS is a rapid low-cost technique in which broth cultures are examined microscopically to detect characteristic growth In a recent study in Peru the MODS assay was compared head- to-head with two reference methods Of 3760 sputum samples, 401(10.7%) yielded positive cultures for MTB Sensitivity of detection was 97.8% for MODS Agreement between MODS and reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, and 99% for both PAGE 8

9 The Effect of DOTS Expansion Global Collaborations in the Fight Against TB Goals of the STOP TB Partnership PAGE 9

10 New TB Drug Pipeline Developing New Drugs for TB Early Bactericidal Activity In EBA studies, newly diagnosed patients with acid-fast bacillus (AFB)-positive, pulmonary tuberculosis are treated for periods ranging from 2 to 14 days with single drugs or drug combinations. During this period, quantitative counts of viable tubercle bacilli li from carefully collected sputum specimens are made, with the EBA traditionally expressed as log-decrease in colony forming units/ml sputum/day over the first 48 hours, Generally this technique is used as a proof of concept. Usually follows in-vitro and animal studies. What are clinical trial phases? Phase 1 clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase 2 clinical trials, the treatment is given to a larger group of people (40-100) to see if it is effective and to further evaluate its safety. Phase 3 studies, the study drug or treatment is given to large groups of people (more than 200) to further determine its effectiveness, monitor side effects, and compare it to commonly used treatments, Nitroimidazoles Diarylquinoline (TMC207) Effective against DS-TB and MDR-TB as well as other clinically important Mycobacterial species Has a novel mechanism of action Phase I studies among healthy males was very well tolerated Phase II studies about to begin in MDR-TB patients PAGE 10

11 Pyrrole (LL3858) Currently being evaluated in a Phase I study in India with healthy volunteers. Mechanism of action is uncertain but has MIC s s for DS-TB and MDR-TB are similar, The sterilizing activity of this agent in the spleen and lungs of o mice is faster than that of the conventional INH/RIF/PZA regimen. Also has some effect against non-tb mycobacterial species. Quinolones Originally looked at to treat MDR-TB. More interest now in its role to shorten the regimen. Report from Chennai India showed remarkable sputum conversion rates at 2 months (92%-98% 98% rather than expected 80% with conventional therapy). An Alternative View: Back to the Future Who says that currently available drugs are not sufficient for treating drug resistant TB? In the 1960 s s it took 8 years to get a new drug to market, now it takes 20 years. The data to justify the current dosing is weak and there is little le evidence to support our current strategies Would it not make sense to fund studies to evaluate the dose used in currently used regimens while we wait for new drugs? Conclusion PAGE 11