TB Expert Network Conference 9/26/2008

Transcription

1 TB Expert Network Conference 9/26/2008 Case 1-KT1 35 y/o AA male with a history of HIV since Presented in July 2007 to a hospital in Orlando, FL with 1 month history of productive cough, fevers and a 30 pound weight loss. CXR showed a mild peri-hilar and lower lung interstitial pneumonia and left hilar fullness. 1

2 KT AFB sputum smear positive ( Many( AFB on smear ) and, subsequently, cultures positive for pansusceptible TB. Patient placed on 4 drug daily therapy (INH 300mg qd, rifampin 600mg qd, EMB 1200mg qd, PZA 1500mg qd) on 7/16/07 and stayed in the hospital until 7/19/2007 Left AMA to Texas to attend a funeral of a family member. Patient was told to coordinate his care with the local and Texas health departments which he never did. According to the patient he was given some medications when he left the hospital but ran out of them while he was away. 2

3 KT The patient returned to Florida in late August and never sought treatment. However, he re-experienced experienced symptoms and presented himself to another hospital in Orlando on 9/11/

4 7/15/2007 9/11/07 KT Patient was found to be AFB smear (+) ( numerous( AFB ) again, subsequently culture positive with pansusceptible disease. CD4 8 cells/mm3, CD4% 1%, CD4/CD No HIV viral load reported at that time. Patient restarted on 4 TB drugs (INH 300mg qd, rifampin 600mg qd, EMB 1200mg qd, PZA 1500mg qd) on 9/14/08. Given previous history of non adherence, the patient was court ordered to A.G. Holley Hospital on 9/25/07. 4

5 KT No h/o TB exposure. Risk factors include being in jail and in prison but no h/o homelessness. History of HIV since On Kaletra for six months in H/o Pneumocystis jiroveci pneumonia in the past. Denies alcohol abuse. Positive history of using cocaine ten years ago. Denies intravenous drug abuse and silicosis exposure. KT Upon admission to AGH, daily 4 drug therapy continued with Rifabutin 300 mg p.o. qd, INH 300 mg p.o. qd, EMB 1600 mg p.o. qd, PZA 2 g p.o. qd, Vit B6 50mg po qd, in addition to Bactrim and acyclovir. Clinically responded, becoming afebrile with weight gain. Smear negative on admission but initially culture positive, with repeat susceptibility studies on 9/28/07 showing pan-susceptible disease. He became and remained culture negative as of 10/9/

6 9_25_07 AGH admission CXRs KT HIV viral load on admission was 4800 copies/ml, CD4 count 15 cells/ml, CD4% 2%, with CD4/CD8 ratio HIV phenotype and genotype were pansusceptible MRI of Brain was negative On 12/3/07 his viral load was 4300, CD4 count 26 cells/ml, CD4% 3%, with CD4/CD8 ratio On 12/4/07 started on Kaletra (Lopinavir/Ritonavir) 1 tab BID and Truvada (Emtricitabine/Tenofovir Disoproxil Fumarate) 1 tab qd (as( part of a study being performed at AGH with NJH and UM); TB meds switched to INH 900mg thrice weekly, rifabutin 150mg thrice weekly, PZA 3,500mg thrice weekly, EMB 1600mg thrice weekly, Vit B6 50mg thrice weekly 6

7 KT On 1/2/08, developed fever o F accompanied by complaints of body aches but denied abdominal pain, nausea, vomiting, cough Physical exam significant for slightly enlarged liver with edge felt just below right costophrenic margin Symptoms developed 29 days after starting ARVs Blood, urine and sputum cultures negative for bacteria, fungi and AFB WBC 3.8k (61%P, 17L, 16M) Hgb 14.7 plt 280k (no significant change) Chemistries WNL except AST 146 ( 26)( 26),, ALT 191 ( 22),( T Bili 0.5 ( 0.8), Alb 3.3 ( 3.7)( Fevers and symptoms lasted 8 days with a Tmax of o F and then resolved without further interventions (imaging of the abdomen was not performed). LFTs returned to normal 16 days after they initially became elevated

8 KT Rifabutin dosage increased to 300mg TIW after the drug levels of rifabutin on 150mg TIW came back low HIV studies 1/16/ copies CD % 0.09 TST placed on 2/16/08 was (+) 12 mm; was (-)( ) 12/3/ Expected Rbt Levels Peak µg/ml Rifabutin Levels Rbt300Pre Lop Rbt150 Lop 400 Rbt300 Lop Level Hours Past Dose 8

9 Expected Lopinavir Levels Trough µg/ml Peak µg/ml KT Lopinavir Levels Lopinavir Level Lop400 Rbt150 Lop400 Rbt Hours Post Dose KT Clinically did well, gaining over 89 pounds during the admission. Completed 6 months of TB therapy on 3/14/08 Discharged on Kaletra, Truvada, acyclovir and Bactrim Follow up appointments were arranged with the local health department. 9

10 KT Once patient left AGH, stopped taking ARVs In 6/08 he was arrested and placed in jail Soon after arriving in jail, patient complained of non productive cough and fever. Was transferred to a hospital in Orlando where a CXR was allegedly abnormal (report and film not available). On 6/13/08, underwent a bronchoscopy which was smear negative. The patient also had blood cultures performed. Patient defervesced with? antibiotics and was discharged and returned to jail KT On 6/19/08, patient developed diarrhea and vomiting, RUQ abdominal pain, non productive cough and headache with fevers to o F Transferred to another local hospital and as part of workup was found to have retroperitoneal lymphadenopathy on CT of the Abdomen 10

11 Retroperitoneal LNs LN Biopsy 11

12 KT CT guided biopsy of these lymph nodes were numerous AFB (+) and NAA (+)-path showed scant fibrous tissue and clotted blood without evidence of lymphoid tissue KT HAINS test of LN biopsy revealed no mutations consistent with INH or rifampin resistance (Subsequently LN cultures and susceptibilities confirmed pansusceptible tuberculosis) Patient placed back on INH 300mg qd, rifampin 600mg qd, EMB 1200mg qd, PZA 1500mg qd on 7/1/08 12

13 KT In addition as part of the fever workup: MRI of Brain was negative 6/27/08 Lumbar Puncture showed clear colorless fluid, AFB smear and subsequently AFB culture negative (unfortunately exact results of LP not available) 6/29/08 CT of Chest Showed Small Pericardial effusion but otherwise negative 6/26/08 HIV viral load was 6500 copies/mm3 and CD4 was 4 cells/mm3, 1.8% and

14 KT On 7/1/08, cultures results of the blood and bronchoscopy obtained at the previous hospital were reported to the Orange County Health Dept and then to physicians at the hospital Specimens sent to State Lab for HAINS testing: 2 sets of blood cultures collected previously (6/14/08) at the other o hospital grew TB, no rpob mutation by HAINS, subsequently pansusceptible Bronch Wash which was AFB smear was (-),( culture (+), HAINS (+) rpob mutation and subsequently cultures positive for MTB, with resistance to rifampin and rifabutin Sputum collected on 7/4/08 was smear (-),( NAA (+), HAINS test (+) rpob mutation present and subsequently culture (+) TB, with susceptibilities that confirmed rifampin and rifabutin resistance On 7/3/08 Moxifloxacin 800mg po qd and Amikacin 1gm IV TIW added 14

15 KT Spoliglotyping confirmed that the strain from 9/07 matched the strains from 6/08 from blood, sputum, bronchial wash, lymph node and sputum-consistent with relapse with acquired rifampin resistance ( ). No rpob mutation noted on 9/07 strain KT Given patients prior history of non adherence patient court ordered to AGH on 7/25/08 15

16 Case 2-DV2 Fifty-one one-year-old white female who presented to an Orange County Hospital ER on June 25, 2007 with a 2-32 week history of cough and fever. She gave a long h/o substance abuse (crack, cocaine, alcohol). Upon her arrival to the ER, she was found to be cachetic, febrile, hypoxic and hypotensive, requiring vasopressors. DV A chest x-ray x showed a right middle lobe infiltrate with a right pleural effusion. A Chest CT scan showed extensive right infiltrates with a small right upper lobe cavity and moderate right pleural effusion. 16

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18 DV AFB sputum smear positive and MTD positive; subsequently found to be pan susceptible TB and a four- drug regimen was started on June 26, Right thoracocentesis (WBC % Lymph, Glucose 57, LDH 115, Protein <2.0, Gm Stain No organisms, AFB smear negative and subsequently culture negative for TB) consistent with reactive TB effusion. The patient was found to be HIV (+) Hospital course also significant for a lower gastrointestinal bleed with bloody diarrhea and a drop in hemoglobin to 6.3 requiring transfusion. The exact etiology of the gastrointestinal bleed was never determined. 18

19 DV Discharged from the hospital on July 12, 2007 to directly observed therapy by the OCHD and arrangements were made for her to live at the Orange County TB shelter. On daily medications until August 26, 2007 at which time the regimen was switched to three times a week with INH and rifampin. During the time that she was on TB medications, she intermittently complained of a pruritic skin rash. Adherent with treatment except for one dose until October 10, 2007, after which she was lost to follow up. DV The patient presented again to the same Orange County Hospital on December 23, 2007 complaining of right back and flank pain, fevers, chills, and weight loss. An abdominal CT scan reportedly showed the possibility of obstruction and inflammation in the right lower ureter. The patient was diagnosed with right hydronephrosis assumed to be due to lower ureter scarring from tuberculosis. U/A with 500 WBC-No urine for AFB sent 19

20 20

21 DV A nephrostomy tube was placed successfully for decompression and was later removed. She also had placement of an indwelling stent. The TB medications were restarted on December 24, 2008 again with complaints of intermittent itching. The patient was committed to A.G. Holley State Hospital on January 7, 2008 for nonadherence with TB therapy. 21

22 DV No h/o TB exposure. Positive history of homelessness and being in jail, but not in prison. Positive history of alcohol abuse and a fifteen-pack pack-year cigarette smoking history. Worked in construction but never did any cement work. Long history of using crack cocaine and marijuana. Denies any intravenous drug abuse. History of Bactrim allergy but the hospital records show that she has been on Bactrim in the past. The patient was diagnosed with HIV in June of She had never been on antiretroviral therapy. She also gives a history of bipolar disorder and she has been on Paxil in the past. DV Upon admission to AGH, the patient appeared chronically ill and weighed 98 pounds. 22

23 DV Started on INH, rifabutin, PZA, and EMB daily. Two days after starting on the TB medications, she started to have a pruritic, macular, papular diffuse rash thought consistent with a drug reaction. Eosinophils were 15%. All of her medications were stopped except for antihistamines. The rash continued despite stopping all medications and the eosinophilia continued. The patient was started on a steroid taper. There was a possibility of contact dermatitis and they stopped all skin products and it seems like after a change in the laundry products used, she got better. 23

24 DV The eosinophilia resolved; no etiology found. On January 13, 2008 TB medications reintroduced, one by one, with occasional complaints of pruritis but no rash appreciated. She was placed on daily rifabutin, PZA, and EMB. DV Patient gained twenty-one pounds during hospital stay. She has been smear and culture negative since January 8, HIV: Quant. 185,080 copies, abs. CD4 14, 2 %, 0.02 The patient refused HIV treatment due to fears of drug reactions. Patient refused to cooperate to allow us to draw TB drug levels 24

25 DV The patient received three months of therapy initially with four drugs for two months daily, and then was switched to INH and rifampin three times a week for one month. (e.g. received ~4 mths of therapy prior to coming to AGH) The patient was smear and culture negative during her hospitalization. Decision was to treat with four drugs for at least four months. Started back on her drug regimen on January 15, 2008, and completed therapy on June 17, 2008 (treatment was somewhat prolonged due to need to remove stent due to discomfort)

26 DV After the patient was discharged, a culture collected while the patient was at AGH on 6/4/2008, was smear (-),( but later culture positive. (Subsequently, culture collected 8/9/2008 also smear negative but culture positive for TB with susceptibilities pending) HAINS test on 6/4/2008 specimen revealed an rpob mutation and susceptibilites subsequently confirmed rifampin and rifabutin resistance. Patient was located in an Osceola Jail and on 8/8/08 was started on INH 300mg qd, rifabutin 300mg qd, EMB 1200mg qd, PZA 1500mg qd, Levofloxacin 500mg qd and SM 1gm IM TIW 26

27 DV CXR taken in jail on 6/25/08 and repeated 8/14/08 described nodular densities and scarring in right mid and lower lung fields which did not change over time (films not available at this time). DV Two weeks after starting TB meds patient started refusing the meds due to the development of a rash Completed her jail sentence on 9/23/08 and transferred to AGH under court order for further therapy 27

28 DV Spoliglotyping matched 2007 to 6/08 (8/08 pending)

29 1/08 9/24/08 29

30 TBTC Study 23 Because intermittent rifabutin-based regimens had not been evaluated in clinical trials of HIV-TB, CDC's TB Trials Consortium (TBTC) initiated TBTC Study 23, which was a single-arm trial of twiceweekly rifabutin-based therapy for treatment of HIV-TB. The TBTC's Data and Safety Monitoring Board (DSMB) advised CDC to suspend enrollment in Study 23 because of the occurrence of five cases of acquired rifamycin resistance among patients enrolled in the study. Although the rate of treatment failure or relapse in the study had been low (preliminary life table rate of 4.1% among the 156 patients with some time at risk), all five patients with failure/relapse had acquired rifamycin resistance. TBTC Study 23 Common features in patients with acquired rifamycin resistance were: very low CD4 cell count (all <60/mm3) at TB diagnosis and receipt of twice-weekly therapy (in four of five) during the intensive phase (i.e., the first 2 months of rifamycinbased short-course therapy for TB); all five received twice-weekly therapy in the continuation phase 30

31 2002 MMWR a relation appears to exist between the frequency of dosing and the risk for acquired resistance. Support for statement: In an earlier study of treatment of HIV-TB using onceweekly rifapentine plus isoniazid, acquired rifamycin resistance was common 1 Acquired rifamycin resistance also occurred in a previous study of HIV-TB treated with twice-weekly rifampin plus In all of these studies, patients with acquired rifamycin resistance had very low CD4 cell counts at the time of TB diagnosis 2 1 Vernon A, Burman W, Benator D, Khan A, Bozeman L, Tuberculosis Trials Consortium. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999;353: El-Sadr W, Perlman DC, Matts JP, et al. Evaluation of an intensive intermittent-induction regimen and duration of shortcourse treatment for human immunodeficiency virusrelated pulmonary tuberculosis. Clin Infect Dis 1998;26: MMWR The consistency of these findings suggests that once- or twiceweekly therapy including isoniazid and a rifamycin increases the risk for acquired rifamycin resistance among TB patients with advanced HIV disease. Additional data are needed to clarify these issues. Until data become available, CDC recommends that persons with HIV-TB and CD4 cell counts <100/mm3 should not be treated with highly intermittent (i.e., once- or twice-weekly) regimens. These patients should receive daily therapy during the intensive phase, and daily or three doses a week during the continuation phase. In this group of patients, CDC recommends directly observed therapy for both daily and three-doses-a-week regimens. 31

32 Question 1 Question 2 32

33 TBTC 23 Among patients with HIV-related TB treated with directly observed therapy, there are two consistent associations in this and previous studies with the occurrence of acquired rifamycin resistance: the presence of severe immunodeficiency (CD4 lymphocyte count 100 cells/mm3) and the use of once or twice-weekly therapy. Acquired rifamycin resistance has been reported with twice-weekly rifabutin plus isoniazid (4.7% in the present study) and with twice-weekly rifampin plus isoniazid (2.0, 3.7, and 1.7%) (5, 29, 30). In contrast, the rate of acquired rifamycin resistance among HIV-infected patients treated with daily (5 7 d/wk) rifampin-based therapy (29, 31, 32), or rifabutin based therapy (29, 31) has been very low. The interpretation of these data from different clinical trials and observational cohorts is difficult. We conclude that there is a risk of acquired rifamycin resistance with rifabutin or rifampin when given twice weekly, but whether the risk is higher with one of these agents is not clear. Burman et. al Am J Respir Crit Care Med Vol 173. pp , 2006 TBTC 23 Burman et. al Am J Respir Crit Care Med Vol 173. pp ,

34 NYC Study No patient who was treated with a rifabutin-based regimen alone and 1 patient who was treated with a rifabutin- and rifampinbased regimen had ARR. This finding differs from the findings of previous studies in which intermittent dosing of rifabutin or previous treatment with rifabutin was suspected to be the probable cause of development of rifampin monoresistance [10, 11, 18]. The difference may be the result of the fact that none of the patients in the present study began receiving intermittent dosing with rifabutin during the intensive phase. Second, intermittent rifampin therapy significantly increased the risk of ARR only when intermittent dosing was begun during the intensive phase. Ref 29-Li et. al. Clinical Infectious Diseases 2005; 41:83 91 Li et. al. Clinical Infectious Diseases 2005; 41:

35 TBTC 23- Leap of Faith? Although use of twice-weekly therapy was associated with acquired rifamycin resistance among patients with low baseline CD4 lymphocyte counts, our study did not include a group randomized to more frequent dosing. Evaluating the relationship between dosing frequency and the success of treatment of HIV-related TB should be a high priority for future randomized studies. Burman et. al Am J Respir Crit Care Med Vol 173. pp , 2006 TBTC 23- Leap of Faith? Among patients in this trial who enrolled in a pharmacokinetic substudy, patients with low concentrations of rifabutin were at increased risk of acquired rifamycin resistance, even after adjusting for baseline CD4 cell count and dosing frequency (33). Thus, it appears that three factors are closely associated with acquired rifamycin resistance: severe immunodeficiency, highly intermittent dosing, and low concentrations of the rifamycin component of the regimen. These associations suggest that, in the relative absence of immune control, low concentrations of the rifamycin near the end of the prolonged dosing interval allow mycobacterial replication and selection for rifamycin resistance. Burman et. al Am J Respir Crit Care Med Vol 173. pp ,

36 2002 MMWR Recommendations Recommended changes focused on intermittent dosing No further explanations for associations with low CD4 count and/or low rifamycin levels Rifabutin Pharmacokinetics-TBTC 23 In summary, our study offers strong evidence that an important factor in the pathogenesis of acquired rifamycin resistance is the abnormal pharmacokinetics of the drugs used to treat tuberculosis. The relationship between drug pharmacokinetics and acquired rifamycin resistance was strongest for low rifabutin AUC0 24, but data also suggested a relationship with low isoniazid AUC0 12. Additional clinical trials are required before these results can be translated into clinical practice. Weiner et. al. Clinical Infectious Diseases 2005; 40:

37 Weiner et. al. Clinical Infectious Diseases 2005; 40: Question 3 37

38 Relapse in Florida Recurrence of tuberculosis was not significantly associated with tuberculosis drug levels High percentage of lower than expected drug levels (60%) had lower than expected levels of isoniazid or rifampin, which raises the concern that the expected drug levels derived from healthy volunteers may not represent the therapeutic range among patients with tuberculosis. Limbo-how low is low All patients (10) who relapsed and developed resistance (MDR) were non adherent Narita et al Clinical Infectious Diseases 2001; 32:515 7? Role of Extrapulmonary TB in HIV Is lower CD4 count marker for: Increased risk of extrapulmonary disease Increased number of organisms (e.g. Smear +)? Penetration of drugs into these areas (?? Protected sites ) 38

39 TB Drug Levels at AGH AGH INPATIENT BETWEEN 7/1/95 AND 6/30/97 CRITERIA TAKING INH, RIF, PZA, EMB AND/OR OFLOXACIN STANDARD ORAL DOSES DRUG LEVELS AT BOTH 2 HRS AND 6 HRS 39

40 AGH INPATIENTS POPULATION TOTAL PATIENT POPULATION = 236 STUDY POPULATION = 116 PTS (48%) SUB-POPULATION = 64 (27%) (ON ALL 4 FIRST-LINE ORAL AGENTS) Sub-Population Stats Diseases n % HIV GI DZ Diabetic Renal Disease Alb<

41 DRUG LEVELS SUB-POPULATION PATIENTS = 64 DRUG LEVELS = 256 INH RIF PZA EMB DRUG LEVELS 4 FIRST LINE DRUGS n = 64 PATIENTS DRUG ABOVE EXPECTED BELOW INH % 34% 59% RIF % 27% 73% PZA % 95% 5% EMB % 58% 41% TOTALS n = 256 2% 53% 45% 41

42 PATIENTS WITH LOW LEVELS LEVEL RANGES BY PATIENT 64 PATIENTS 256 LEVELS BELOW RANGE # PATIENTS % PTS # RX BELOW PATIENTS WERE ON 4 DRUGS 28 PATIENTS WERE ON 5 DRUGS PZA % EXPECTED LEVELS % OF EXPECTED LEVELS PZA 25 MG/KG n=3 (20MCG/ML) % OF RANGE NUMBER EXPECTED MCG/ML SAMPLES 75-99% % % %

43 EMB % EXPECTED LEVELS % OF EXPECTED LEVELS EMB 25 MG/KG n=26 (2MCG/ML) % OF RANGE NUMBER EXPECTED MCG/ML SAMPLES 75-99% % % % INH % EXPECTED LEVELS % OF EXPECTED LEVEL INH 300 MG/DAY n=35 (3MCG/ML) % OF RANGE NUMBER EXPECTED MCG/ML SAMPLES 75-99% % % %

44 RIF % EXPECTED LEVELS % OF EXPECTED LEVELS RIF 600 MG/D n=47 (8MCG/ML) % OF RANGE NUMBER EXPECTED MCG/ML SAMPLES 75-99% % % % RESISTANCE PRESSURE LOW PRESSURE -> > NO RESISTANCE High pressure -> > kills organism with no chance to develop resistance Moderate pressure -> > organism can mutate to survive 44

45 ARR in FL cases of RMR-all HIV (+)-no RMR among HIV (-)( CD4 count was 37 cells/mm3 (p<0.05) All had evidence of extrapulmonary disease on relapse (and possibly prior on initial) (p<0.05) 80% had evidence of non adherence None were treated with highly intermittent therapy during first two months and 4/6 treated with daily throughout with rifampin/rifabutin 356 patients HIV (+) ARR in FL Most patients (>95%) treated with daily or TIW No ARR observed 45

46 SO WHAT!!!! 46

47 Post 2002 MMWR Recommendations? Most TB Programs switched to less intermittent regimens The recommendations places a potentially greater demand for DOT No studies since to see if the recommendations have been effective in reducing/halting acquired rifampin mono-resistance (ARMR) Question 4 47

48 So What Next???? Further studies are needed to answer this very important question that has implications for patient care as well as utilization of Public Health Resources Has the incidence of RMR changed since suggested changes implemented? Is there a group that needs further interventions (e.g. CD4<100)? Does dosing schedule make a difference (daily vs. intermittent)? Does pharmacokinetics play a role and if so how? Do we need drugs with longer half lives/better penetration? TB Hotline TB-INFO 48