tben conf mase edits 9 26 08[1] - global tb...

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TB Expert Network ConferenceTB Expert Network Conference9/26/20089/26/2008

Case 1Case 1--KTKT

35 y/o AA male with a history of HIV since 2002.35 y/o AA male with a history of HIV since 2002.Presented in July 2007 to a hospital in Orlando, FL with Presented in July 2007 to a hospital in Orlando, FL with 1 month history of productive cough, fevers and a 30 1 month history of productive cough, fevers and a 30 pound weight loss. pound weight loss. CXR showed a mild periCXR showed a mild peri--hilar and lower lung interstitial hilar and lower lung interstitial pneumonia and left hilar fullness. pneumonia and left hilar fullness.

2008 TB Expert Network Conference

09/26/2008

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7-15-07

KTKT

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


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KTKT

The patient returned to Florida in late August and never The patient returned to Florida in late August and never sought treatment.sought treatment.

However, he reHowever, he re--experienced symptoms and presented experienced symptoms and presented himself to another hospital in Orlando on 9/11/2007.himself to another hospital in Orlando on 9/11/2007.

9-11-07


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7/15/2007 9/11/07

KTKT

Patient was found to be AFB smear (+) (Patient was found to be AFB smear (+) (‘‘numerous AFBnumerous AFB””) ) again, subsequently culture positive with pansusceptible again, subsequently culture positive with pansusceptible disease.disease.

CD4 8 cells/mm3, CD4% 1%, CD4/CD8 0.02CD4 8 cells/mm3, CD4% 1%, CD4/CD8 0.02

No HIV viral load reported at that time.No HIV viral load reported at that time.

Patient restarted on 4 TB drugs (INH 300mg qD, rifampin Patient restarted on 4 TB drugs (INH 300mg qD, rifampin 600mg qD, EMB 1200mg qD, PZA 1500mg qD) on 600mg qD, EMB 1200mg qD, PZA 1500mg qD) on 9/14/08.9/14/08.

Given previous history of non adherence, the patient was Given previous history of non adherence, the patient was court ordered to A.G. Holley Hospital on 9/25/07.court ordered to A.G. Holley Hospital on 9/25/07.


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KTKT

No h/o TB exposure. Risk factors include being in jail and No h/o TB exposure. Risk factors include being in jail and in prison but no h/o homelessness.in prison but no h/o homelessness.

History of HIV since 2002. On Kaletra for six months in History of HIV since 2002. On Kaletra for six months in 2004. H/o 2004. H/o Pneumocystis jiroveciPneumocystis jiroveci pneumonia in the past. pneumonia in the past.

Denies alcohol abuse. Positive history of using cocaine Denies alcohol abuse. Positive history of using cocaine ten years ago. Denies intravenous drug abuse and ten years ago. Denies intravenous drug abuse and silicosis exposure. silicosis exposure.

KTKT

Upon admission to AGH, daily 4 drug therapy continued Upon admission to AGH, daily 4 drug therapy continued with Rifabutin 300 mg p.o. qD, INH 300 mg p.o. qD, EMB 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 1600 mg p.o. qD, PZA 2 g p.o. qD, Vit B6 50mg po qD, in addition to Bactrim and acyclovir.addition to Bactrim and acyclovir.

Clinically responded, becoming afebrile with weight gain. Clinically responded, becoming afebrile with weight gain. Smear negative on admission but initially culture positive, Smear negative on admission but initially culture positive, with repeat susceptibility studies on 9/28/07 showing with repeat susceptibility studies on 9/28/07 showing panpan--susceptible disease. susceptible disease.

He became and remained culture negative as of He became and remained culture negative as of 10/9/2007.10/9/2007.


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9_25_07 AGH admission CXRs

KTKTHIV viral load on admission was 4800 copies/ml, CD4 count 15 HIV viral load on admission was 4800 copies/ml, CD4 count 15 cells/ml, CD4% 2%, with CD4/CD8 ratio 0.03. cells/ml, CD4% 2%, with CD4/CD8 ratio 0.03.

HIV phenotype and genotype were pansusceptibleHIV phenotype and genotype were pansusceptible

MRI of Brain was negativeMRI of Brain was negative

On 12/3/07 his viral load was 4300, CD4 count 26 cells/ml, CD4% On 12/3/07 his viral load was 4300, CD4 count 26 cells/ml, CD4% 3%, with CD4/CD8 ratio 0.04.3%, with CD4/CD8 ratio 0.04.

On 12/4/07 started on Kaletra (Lopinavir/Ritonavir) 1 tab BIDOn 12/4/07 started on Kaletra (Lopinavir/Ritonavir) 1 tab BID and and Truvada (Emtricitabine/Tenofovir Disoproxil Fumarate) 1 tab qD (Truvada (Emtricitabine/Tenofovir Disoproxil Fumarate) 1 tab qD (as as part of a study being performed at AGH with NJH and UM); TB medspart of a study being performed at AGH with NJH and UM); TB medsswitched to switched to INH 900mg thrice weekly, rifabutin 150mg thrice INH 900mg thrice weekly, rifabutin 150mg thrice weekly, PZA 3,500mg thrice weekly, EMB 1600mg thrice weekly, Vitweekly, PZA 3,500mg thrice weekly, EMB 1600mg thrice weekly, VitB6 50mg thrice weeklyB6 50mg thrice weekly


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KTKTOn 1/2/08, developed fever 101.4On 1/2/08, developed fever 101.4o o F accompanied by complaints of F accompanied by complaints of body aches but denied abdominal pain, nausea, vomiting, coughbody aches but denied abdominal pain, nausea, vomiting, cough

Physical exam significant for slightly enlarged liver with edge Physical exam significant for slightly enlarged liver with edge felt just felt just below right costophrenic marginbelow right costophrenic margin

Symptoms developed 29 days after starting ARVsSymptoms developed 29 days after starting ARVs

Blood, urine and sputum cultures negative for bacteria, fungi anBlood, urine and sputum cultures negative for bacteria, fungi and d AFBAFB

WBC 3.8k (61%P, 17L, 16M) Hgb 14.7 plt 280k (no significant WBC 3.8k (61%P, 17L, 16M) Hgb 14.7 plt 280k (no significant change)change)

Chemistries WNL except AST 146 (Chemistries WNL except AST 146 (↑↑26)26), ALT 191 (, ALT 191 (↑↑22), T Bili 0.5 22), T Bili 0.5 ((↓↓0.8), Alb 3.3 (0.8), Alb 3.3 (↓↓3.7)3.7)

Fevers and symptoms lasted 8 days with a Tmax of 103.3Fevers and symptoms lasted 8 days with a Tmax of 103.3o o F and F and then resolved without further interventions (imaging of the abdothen resolved without further interventions (imaging of the abdomen men was not performed). LFTs returned to normal 16 days after they was not performed). LFTs returned to normal 16 days after they initially became elevated.initially became elevated.

1-2-08


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KTKT

Rifabutin dosage increased to 300mg TIW after the drug Rifabutin dosage increased to 300mg TIW after the drug levels of rifabutin on 150mg TIW came back lowlevels of rifabutin on 150mg TIW came back low

HIV studies 1/16/08 630 copies CD4 56HIV studies 1/16/08 630 copies CD4 56 4.7%4.7% 0.090.09

TST placed on 2/16/08 was (+) 12 mm; was (TST placed on 2/16/08 was (+) 12 mm; was (--) 12/3/07) 12/3/07

Rifabutin Levels

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0 2 4 6 8 12 24

Hours Past Dose

Leve

l

Rbt300Pre LopRbt150 Lop 400Rbt300 Lop 400

Expected Rbt LevelsPeak 0.3-0.9µg/ml


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KT Lopinavir Levels

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

0 2 4 6 8 12 24

Hours Post Dose

Lopi

navi

r Lev

el

Lop400 Rbt150

Lop400 Rbt300

Expected Lopinavir LevelsTrough 1.5-9.5µg/mlPeak 5.0-14.0µg/ml

KTKT

Clinically did well, gaining over 89 pounds during the Clinically did well, gaining over 89 pounds during the admission.admission.

Completed 6 months of TB therapy on 3/14/08Completed 6 months of TB therapy on 3/14/08

Discharged on Kaletra, Truvada, acyclovir and BactrimDischarged on Kaletra, Truvada, acyclovir and Bactrim

Follow up appointments were arranged with the local Follow up appointments were arranged with the local health department.health department.


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KTKT

Once patient left AGH, stopped taking ARVsOnce patient left AGH, stopped taking ARVs

In 6/08 he was arrested and placed in jailIn 6/08 he was arrested and placed in jail

Soon after arriving in jail, patient complained of non productivSoon after arriving in jail, patient complained of non productive e cough and fever. Was transferred to a hospital in Orlando cough and fever. Was transferred to a hospital in Orlando where a CXR was allegedly abnormal (report and film not where a CXR was allegedly abnormal (report and film not available). available).

On 6/13/08, underwent a bronchoscopy which was smear On 6/13/08, underwent a bronchoscopy which was smear negative. The patient also had blood cultures performed.negative. The patient also had blood cultures performed.

Patient defervesced with ? antibiotics and was discharged and Patient defervesced with ? antibiotics and was discharged and returned to jailreturned to jail

KTKT

On 6/19/08, patient developed diarrhea and vomiting, RUQ On 6/19/08, patient developed diarrhea and vomiting, RUQ abdominal pain, non productive cough and headache with abdominal pain, non productive cough and headache with fevers to 104.5fevers to 104.5o o FF

Transferred to another local hospital and as part of workup was Transferred to another local hospital and as part of workup was found to have retroperitoneal lymphadenopathy on CT of the found to have retroperitoneal lymphadenopathy on CT of the AbdomenAbdomen


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Retroperitoneal LNs

LN Biopsy


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KTKT

CT guided biopsy of these lymph nodes were CT guided biopsy of these lymph nodes were ““numerousnumerous”” AFB AFB (+) and NAA (+)(+) and NAA (+)--path showed scant fibrous tissue and clotted path showed scant fibrous tissue and clotted blood without evidence of lymphoid tissueblood without evidence of lymphoid tissue

KTKT

HAINS test of LN biopsy revealed no mutations consistent with HAINS test of LN biopsy revealed no mutations consistent with INH or rifampin resistance (Subsequently LN cultures and INH or rifampin resistance (Subsequently LN cultures and susceptibilities confirmed pansusceptible tuberculosis)susceptibilities confirmed pansusceptible tuberculosis)

Patient placed back on INH 300mg qD, rifampin 600mg qD, Patient placed back on INH 300mg qD, rifampin 600mg qD, EMB 1200mg qD, PZA 1500mg qD on 7/1/08EMB 1200mg qD, PZA 1500mg qD on 7/1/08


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KTKT

In addition as part of the fever workup:In addition as part of the fever workup:

–– MRI of Brain was negativeMRI of Brain was negative

–– 6/27/08 Lumbar Puncture showed clear colorless fluid, 6/27/08 Lumbar Puncture showed clear colorless fluid, AFB smear and subsequently AFB culture negative AFB smear and subsequently AFB culture negative (unfortunately exact results of LP not available)(unfortunately exact results of LP not available)

–– 6/29/08 CT of Chest Showed Small Pericardial effusion 6/29/08 CT of Chest Showed Small Pericardial effusion but otherwise negativebut otherwise negative

–– 6/26/08 HIV viral load was 6500 copies/mm3 and CD4 6/26/08 HIV viral load was 6500 copies/mm3 and CD4 was 4 cells/mm3, 1.8% and 0.03was 4 cells/mm3, 1.8% and 0.03


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KTKTOn 7/1/08, cultures results of the blood and bronchoscopy obtainOn 7/1/08, cultures results of the blood and bronchoscopy obtained ed at the previous hospital were reported to the Orange County Healat the previous hospital were reported to the Orange County Health th Dept and then to physicians at the hospitalDept and then to physicians at the hospital

Specimens sent to State Lab for HAINS testing:Specimens sent to State Lab for HAINS testing:

–– 2 sets of blood cultures collected previously (6/14/08) at the o2 sets of blood cultures collected previously (6/14/08) at the other ther hospital grew TB, no rpoB mutation by HAINS, subsequently hospital grew TB, no rpoB mutation by HAINS, subsequently pansusceptiblepansusceptible

–– Bronch Wash which was AFB smear was (Bronch Wash which was AFB smear was (--), culture (+), HAINS (+) rpoB ), culture (+), HAINS (+) rpoB mutation and subsequently cultures positive for MTB, with resistmutation and subsequently cultures positive for MTB, with resistance ance to rifampin and rifabutinto rifampin and rifabutin

–– Sputum collected on 7/4/08 was smear (Sputum collected on 7/4/08 was smear (--), NAA (+), HAINS test (+) ), NAA (+), HAINS test (+) rpoB mutation present and subsequently culture (+) TB, with rpoB mutation present and subsequently culture (+) TB, with susceptibilities that confirmed rifampin and rifabutin resistancsusceptibilities that confirmed rifampin and rifabutin resistancee

On 7/3/08 Moxifloxacin 800mg po qD and Amikacin 1gm IV TIW On 7/3/08 Moxifloxacin 800mg po qD and Amikacin 1gm IV TIW addedadded


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KTKT

Spoliglotyping confirmed that the strain from 9/07 matched Spoliglotyping confirmed that the strain from 9/07 matched the strains from 6/08 from blood, sputum, bronchial wash, the strains from 6/08 from blood, sputum, bronchial wash, lymph node and sputumlymph node and sputum--consistent with relapse with acquired consistent with relapse with acquired rifampin resistance (000000000003771). No rpoB mutation rifampin resistance (000000000003771). No rpoB mutation noted on 9/07 strain noted on 9/07 strain

KTKT

Given patients prior history of non adherence patient court Given patients prior history of non adherence patient court ordered to AGH on 7/25/08ordered to AGH on 7/25/08


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Case 2Case 2--DVDV

FiftyFifty--oneone--yearyear--old white female who presented to an old white female who presented to an Orange County Hospital ER on June 25, 2007 with a 2Orange County Hospital ER on June 25, 2007 with a 2--3 3 week history of cough and fever. She gave a long h/o week history of cough and fever. She gave a long h/o substance abuse (crack, cocaine, alcohol). substance abuse (crack, cocaine, alcohol).

Upon her arrival to the ER, she was found to be cachetic, Upon her arrival to the ER, she was found to be cachetic, febrile, hypoxic and hypotensive, requiring vasopressors.febrile, hypoxic and hypotensive, requiring vasopressors.

DVDV

A chest xA chest x--ray showed a right middle lobe infiltrate with a ray showed a right middle lobe infiltrate with a right pleural effusion.right pleural effusion.

A Chest CT scan showed extensive right infiltrates with a A Chest CT scan showed extensive right infiltrates with a small right upper lobe cavity and moderate right pleural small right upper lobe cavity and moderate right pleural effusion. effusion.


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6-25-2008


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DVDVAFB sputum smear positive and MTD positive; AFB sputum smear positive and MTD positive; subsequently found to be pan susceptible TB and a foursubsequently found to be pan susceptible TB and a four--drug regimen was started on June 26, 2007. drug regimen was started on June 26, 2007.

Right thoracocentesis (WBC 1540 90% Lymph, Glucose Right thoracocentesis (WBC 1540 90% Lymph, Glucose 57, LDH 115, Protein <2.0, Gm Stain No organisms, AFB 57, LDH 115, Protein <2.0, Gm Stain No organisms, AFB smear negative and subsequently culture negative for TB) smear negative and subsequently culture negative for TB) consistent with reactive TB effusion. consistent with reactive TB effusion.

The patient was found to be HIV (+)The patient was found to be HIV (+)

Hospital course also significant for a lower gastrointestinal Hospital course also significant for a lower gastrointestinal bleed with bloody diarrhea and a drop in hemoglobin to bleed with bloody diarrhea and a drop in hemoglobin to 6.3 requiring transfusion. The exact etiology of the 6.3 requiring transfusion. The exact etiology of the gastrointestinal bleed was never determined. gastrointestinal bleed was never determined.


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DVDVDischarged from the hospital on July 12, 2007 to directly Discharged from the hospital on July 12, 2007 to directly observed therapy by the OCHD and arrangements were observed therapy by the OCHD and arrangements were made for her to live at the Orange County TB shelter. made for her to live at the Orange County TB shelter.

On daily medications until August 26, 2007 at which time On daily medications until August 26, 2007 at which time the regimen was switched to three times a week with INH the regimen was switched to three times a week with INH and rifampin. and rifampin.

During the time that she was on TB medications, she During the time that she was on TB medications, she intermittently complained of a pruritic skin rash. intermittently complained of a pruritic skin rash.

Adherent with treatment except for one dose until October Adherent with treatment except for one dose until October 10, 2007, after which she was lost to follow up. 10, 2007, after which she was lost to follow up.

DVDVThe patient presented again to the same Orange County The patient presented again to the same Orange County Hospital on December 23, 2007 complaining of right back Hospital on December 23, 2007 complaining of right back and flank pain, fevers, chills, and weight loss.and flank pain, fevers, chills, and weight loss.

An abdominal CT scan reportedly showed the possibility of An abdominal CT scan reportedly showed the possibility of obstruction and inflammation in the right lower ureter.obstruction and inflammation in the right lower ureter.

The patient was diagnosed with right hydronephrosis The patient was diagnosed with right hydronephrosis assumed to be due to lower ureter scarring from assumed to be due to lower ureter scarring from tuberculosis. U/A with 500 WBCtuberculosis. U/A with 500 WBC--No urine for AFB sentNo urine for AFB sent


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12-23-07

DVDV

A nephrostomy tube was placed successfully for A nephrostomy tube was placed successfully for decompression and was later removed. She also had decompression and was later removed. She also had placement of an indwelling stent.placement of an indwelling stent.

The TB medications were restarted on December 24, The TB medications were restarted on December 24, 2008 again with complaints of intermittent itching.2008 again with complaints of intermittent itching.

The patient was committed to A.G. Holley State Hospital The patient was committed to A.G. Holley State Hospital on January 7, 2008 for nonadherence with TB therapy. on January 7, 2008 for nonadherence with TB therapy.


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DVDV

No h/o TB exposure. Positive history of homelessness and No h/o TB exposure. Positive history of homelessness and being in jail, but not in prison. Positive history of alcohol being in jail, but not in prison. Positive history of alcohol abuse and a fifteenabuse and a fifteen--packpack--year cigarette smoking history. year cigarette smoking history. Worked in construction but never did any cement work. Worked in construction but never did any cement work. Long history of using crack cocaine and marijuana. Denies Long history of using crack cocaine and marijuana. Denies any intravenous drug abuse. History of Bactrim allergy but any intravenous drug abuse. History of Bactrim allergy but the hospital records show that she has been on Bactrim in the hospital records show that she has been on Bactrim in the past. the past.

The patient was diagnosed with HIV in June of 2007. She The patient was diagnosed with HIV in June of 2007. She had never been on antiretroviral therapy. She also gives a had never been on antiretroviral therapy. She also gives a history of bipolar disorder and she has been on Paxil in the history of bipolar disorder and she has been on Paxil in the past. past.

DVDV

Upon admission to AGH, the patient appeared chronically Upon admission to AGH, the patient appeared chronically ill and weighed 98 pounds.ill and weighed 98 pounds.


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1-7-2008

DVDV

Started on INH, rifabutin, PZA, and EMB daily. Two days after Started on INH, rifabutin, PZA, and EMB daily. Two days after starting on the TB medications, she started to have a pruritic, starting on the TB medications, she started to have a pruritic, macular, papular diffuse rash thought consistent with a drug macular, papular diffuse rash thought consistent with a drug reaction. Eosinophils were 15%. reaction. Eosinophils were 15%.

All of her medications were stopped except for antihistamines.All of her medications were stopped except for antihistamines.

The rash continued despite stopping all medications and the The rash continued despite stopping all medications and the eosinophilia continued.eosinophilia continued.

The patient was started on a steroid taper. The patient was started on a steroid taper.

There was a possibility of contact dermatitis and they stopped There was a possibility of contact dermatitis and they stopped all skin products and it seems like after a change in the laundrall skin products and it seems like after a change in the laundry y products used, she got better.products used, she got better.


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DVDV

The eosinophilia resolved; no etiology found. The eosinophilia resolved; no etiology found.

On January 13, 2008 TB medications reintroduced, one by one, On January 13, 2008 TB medications reintroduced, one by one, with occasional complaints of pruritis but no rash appreciated. with occasional complaints of pruritis but no rash appreciated. She was placed on daily rifabutin, PZA, and EMB. She was placed on daily rifabutin, PZA, and EMB.

DVDV

Patient gained twentyPatient gained twenty--one pounds during hospital stay. one pounds during hospital stay.

She has been smear and culture negative since January 8, She has been smear and culture negative since January 8, 2008. 2008.

HIV: Quant. 185,080 copies, abs. CD4 14, 2 % , 0.02 HIV: Quant. 185,080 copies, abs. CD4 14, 2 % , 0.02

The patient refused HIV treatment due to fears of drug The patient refused HIV treatment due to fears of drug reactions.reactions.

Patient refused to cooperate to allow us to draw TB drug Patient refused to cooperate to allow us to draw TB drug levelslevels


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DVDV

The patient received three months of therapy initially with The patient received three months of therapy initially with four drugs for two months daily, and then was switched to four drugs for two months daily, and then was switched to INH and rifampin three times a week for one month. (e.g. INH and rifampin three times a week for one month. (e.g. received ~4 mths of therapy prior to coming to AGH)received ~4 mths of therapy prior to coming to AGH)

The patient was smear and culture negative during her The patient was smear and culture negative during her hospitalization.hospitalization.

Decision was to treat with four drugs for at least four Decision was to treat with four drugs for at least four months. Started back on her drug regimen on January 15, months. Started back on her drug regimen on January 15, 2008, and completed therapy on June 17, 2008 2008, and completed therapy on June 17, 2008 (treatment was somewhat prolonged due to need to (treatment was somewhat prolonged due to need to remove stent due to discomfort). remove stent due to discomfort).

6-10-08


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1-7-2008 6-10-08

DVDV

After the patient was discharged, a culture collected while After the patient was discharged, a culture collected while the patient was at AGH on 6/4/2008, was smear (the patient was at AGH on 6/4/2008, was smear (--), but ), but later culture positive. (Subsequently, culture collected later culture positive. (Subsequently, culture collected 8/9/2008 also smear negative but culture positive for TB 8/9/2008 also smear negative but culture positive for TB with susceptibilities pending)with susceptibilities pending)

HAINS test on 6/4/2008 specimen revealed an rpoB HAINS test on 6/4/2008 specimen revealed an rpoB mutation and susceptibilites subsequently confirmed mutation and susceptibilites subsequently confirmed rifampin and rifabutin resistance.rifampin and rifabutin resistance.

Patient was located in an Osceola Jail and on 8/8/08 was Patient was located in an Osceola Jail and on 8/8/08 was started on INH 300mg qD, rifabutin 300mg qD, EMB started on INH 300mg qD, rifabutin 300mg qD, EMB 1200mg qD, PZA 1500mg qD, Levofloxacin 500mg qD 1200mg qD, PZA 1500mg qD, Levofloxacin 500mg qD and SM 1gm IM TIWand SM 1gm IM TIW


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DVDV

CXR taken in jail on 6/25/08 and repeated 8/14/08 CXR taken in jail on 6/25/08 and repeated 8/14/08 described nodular densities and described nodular densities and ““scarringscarring”” in right mid in right mid and lower lung fields which did not change over time (films and lower lung fields which did not change over time (films not available at this time).not available at this time).

DVDV

Two weeks after starting TB meds patient started refusing Two weeks after starting TB meds patient started refusing the meds due to the development of a rashthe meds due to the development of a rash

Completed her jail sentence on 9/23/08 and transferred Completed her jail sentence on 9/23/08 and transferred to AGH under court order for further therapyto AGH under court order for further therapy


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DVDV

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

9-24-08


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1/08 9/24/08


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TBTC Study 23TBTC Study 23Because 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 twice-weekly 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 23TBTC 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 rifamycin-based short-course therapy for TB);

– all five received twice-weekly therapy in the continuation phase


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2002 MMWR 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 once-weekly 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;353:1843—72 El-Sadr W, Perlman DC, Matts JP, et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virusrelated pulmonary tuberculosis. Clin Infect Dis 1998;26:1148--58

2002 MMWR2002 MMWR“The consistency of these findings suggests that once- or twice-weekly 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. ”


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Question 1 Question 1

Question 2Question 2


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TBTC 23TBTC 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 350–356, 2006

TBTC 23TBTC 23



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NYC StudyNYC Study“No patient who was treated with a rifabutin-based regimen alone

and 1 patient who was treated with a rifabutin- and rifampin-based regimen had ARR. This finding differs from the findings of previous studies in which intermittent dosing of rifabutin orprevious 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; 41:83–91


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TBTC 23TBTC 23--””Leap of Faith?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.”


TBTC 23TBTC 23--””Leap of Faith?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.”



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2002 MMWR Recommendations2002 MMWR Recommendations

Recommended changes focused on intermittent dosingRecommended changes focused on intermittent dosing

No further explanations for associations with low CD4 No further explanations for associations with low CD4 count and/or low rifamycin levelscount and/or low rifamycin levels

Rifabutin PharmacokineticsRifabutin Pharmacokinetics--TBTC 23TBTC 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; 40:1481–91


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Weiner et. al. Clinical Infectious Diseases 2005; 40:1481–91



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Relapse in Florida 1996Relapse in Florida 1996--19971997

“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? Role of Extrapulmonary TB in HIV

Is lower CD4 count marker for:Is lower CD4 count marker for:

–– Increased risk of extrapulmonary diseaseIncreased risk of extrapulmonary disease

Increased number of organisms (e.g. Smear +)Increased number of organisms (e.g. Smear +)

? Penetration of drugs into these areas ? Penetration of drugs into these areas ((““? Protected sites? Protected sites””))


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TB Drug Levels at AGHTB Drug Levels at AGH

CRITERIACRITERIA

AGH INPATIENT BETWEEN AGH INPATIENT BETWEEN

7/1/95 AND 6/30/977/1/95 AND 6/30/97

TAKING INH, RIF, PZA, EMB AND/OR OFLOXACINTAKING INH, RIF, PZA, EMB AND/OR OFLOXACIN

““STANDARDSTANDARD”” ORAL DOSESORAL DOSES

DRUG LEVELS AT BOTH 2 HRS AND 6 HRSDRUG LEVELS AT BOTH 2 HRS AND 6 HRS


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POPULATIONPOPULATION

AGH INPATIENTSAGH INPATIENTS

–– TOTAL PATIENT POPULATION = 236TOTAL PATIENT POPULATION = 236

–– STUDY POPULATION = 116 PTS (48%)STUDY POPULATION = 116 PTS (48%)

–– SUBSUB--POPULATION = 64 (27%)POPULATION = 64 (27%)

(ON ALL 4 FIRST(ON ALL 4 FIRST--LINE ORAL AGENTS)LINE ORAL AGENTS)

SubSub--Population StatsPopulation Stats

57.857.83737Alb< 3.5Alb< 3.5

10.910.977Renal DiseaseRenal Disease

7.87.855DiabeticDiabetic

46.946.93030GI DZGI DZ

31.331.32020HIVHIV

%%nnDiseasesDiseases


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DRUG LEVELSDRUG LEVELS

SUBSUB--POPULATIONPOPULATION

–– PATIENTS = 64PATIENTS = 64

–– DRUG LEVELS = 256DRUG LEVELS = 256

INHINH

RIFRIF

PZAPZA

EMBEMB

DRUG LEVELSDRUG LEVELS

DRUG ABOVE EXPECTED BELOW

INH 4 22 386% 34% 59%

RIF 0 17 470% 27% 73%

PZA 0 61 30% 95% 5%

EMB 1 36 272% 58% 41%

TOTALS 5 136 115n = 256 2% 53% 45%

4 FIRST LINE DRUGSn = 64 PATIENTS


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PATIENTS WITH LOW LEVELSPATIENTS WITH LOW LEVELS

64 PATIENTS 256 LEVELS

# PATIENTS % PTS # RX BELOW5 7.8 0

20 31 116 25 220 31 34 6.25 45 7.8 0

BELOW RANGE

35 PATIENTS WERE ON 4 DRUGS28 PATIENTS WERE ON 5 DRUGS

LEVEL RANGES BY PATIENT

PZA % EXPECTED LEVELSPZA % EXPECTED LEVELS

n=3 (20MCG/ML)% OF RANGE NUMBER

EXPECTED MCG/ML SAMPLES

75 - 99% 15 - 19.99 1

50 - 74% 10 - 14.99 0

25 - 59% 5 - 9.99 1

0 - 24% 0 - 4.99 1

% OF EXPECTED LEVELSPZA 25 MG/KG


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EMB % EXPECTED LEVELSEMB % EXPECTED LEVELS



75 - 99% 1.5 - 1.99 7

50 - 74% 1.0 - 1.49 13

25 - 49% 0.5 - 0.99 6

0 - 24% 0 - 0.49 0

% OF EXPECTED LEVELSEMB 25 MG/KG

INH % EXPECTED LEVELSINH % EXPECTED LEVELS



75-99% 2.25 - 2.99 13

50 - 74% 1.5 - 2.24 9

25 - 49% 0.75 - 1.49 9

0 - 24% 0 - 0.74 3

% OF EXPECTED LEVELINH 300 MG/DAY


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RIF % EXPECTED LEVELSRIF % EXPECTED LEVELS



75 - 99% 6 - 7.99 11

50 - 74% 4 - 5.99 12

25 - 49% 2 - 3.99 10

0 - 24 % 0 - 1.99 14

% OF EXPECTED LEVELSRIF 600 MG/D

RESISTANCE PRESSURERESISTANCE PRESSURE

LOW PRESSURE LOW PRESSURE --> NO RESISTANCE> NO RESISTANCE

High pressure High pressure --> kills organism with no chance to develop > kills organism with no chance to develop resistanceresistance

Moderate pressure Moderate pressure --> organism can mutate to survive> organism can mutate to survive


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ARR in FL 1998ARR in FL 1998--20012001

6 cases of RMR6 cases of RMR--all HIV (+)all HIV (+)--no RMR among HIV (no RMR among HIV (--))

CD4 count was 37 cells/mm3 (p<0.05)CD4 count was 37 cells/mm3 (p<0.05)

All had evidence of extrapulmonary disease on relapse All had evidence of extrapulmonary disease on relapse (and possibly prior on initial) (p<0.05)(and possibly prior on initial) (p<0.05)

80% had evidence of non adherence80% had evidence of non adherence

None were treated with highly intermittent therapy during None were treated with highly intermittent therapy during first two months and 4/6 treated with daily throughout first two months and 4/6 treated with daily throughout with rifampin/rifabutinwith rifampin/rifabutin

HIV (+) ARR in FL 2004HIV (+) ARR in FL 2004--20052005

356 patients356 patients

Most patients (>95%) treated with daily or TIWMost patients (>95%) treated with daily or TIW

No ARR observedNo ARR observed


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SO WHAT!!!!SO WHAT!!!!


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Post 2002 MMWR RecommendationsPost 2002 MMWR Recommendations

? Most TB Programs switched to less intermittent ? Most TB Programs switched to less intermittent regimensregimens

The recommendations places a potentially greater The recommendations places a potentially greater demand for DOTdemand for DOT

No studies since to see if the recommendations have No studies since to see if the recommendations have been effective in reducing/halting acquired rifampin been effective in reducing/halting acquired rifampin monomono--resistance (ARMR)resistance (ARMR)



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So What Next????So What Next????

Further studies are needed to answer this very important Further studies are needed to answer this very important question that has implications for patient care as well as question that has implications for patient care as well as utilization of Public Health Resourcesutilization of Public Health Resources

–– Has the incidence of RMR changed since suggested Has the incidence of RMR changed since suggested changes implemented?changes implemented?

–– Is there a group that needs further interventions (e.g. Is there a group that needs further interventions (e.g. CD4<100)?CD4<100)?

–– Does dosing schedule make a difference (daily vs. Does dosing schedule make a difference (daily vs. intermittent)?intermittent)?

–– Does pharmacokinetics play a role and if so how?Does pharmacokinetics play a role and if so how?

–– Do we need drugs with longer half lives/better Do we need drugs with longer half lives/better penetration?penetration?

TB HotlineTB Hotline11--800800--4TB4TB--INFOINFO


09/26/2008

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