Download Tuberculosis Part 2 2016

Tuberculosis Part 2 2016
(00:04)
#1 Killer of HIV infected = TB
TB = #1 infectious killer on the planet
TB epidemic during the industrial revolution = much larger than the HIV outbreak in the 1980s
> 150 mycobacteria, not all infectious → several are opportunistic infections
1. Mycobacteria avian complex
2. Mycobacterium abscesses
3. Mycobacterium leprous
2 Types of TB Infection: (59) (2:33)
1. Latent TB disease: No S/S of disease; just carry organism w/i you
 Skin test (+)
 Ligra + blood test against TB antigen
2. Active TB disease
Latent TB Infection (LTBI) Treatment WITHOUT Disease Adults (59) (2:34), (60) (4:30) 61 (5:46)
Dose
Frequency
Duration
Notes
300 mg
Daily
9 months;
9 months for those not sick
prefer 6
6 months for those who are sick
Not best drug – need to give it
time to work
900 mg
Twice weekly
15 mg/kg
DOPT = Direct observed
preventative TX
Rifapentine
900 mg +
Weekly
12 doses =
DOT / DOPT Only
(60) (5:46)
INH 900mg
12 weeks
Logical to use in HIV → No
clinical data though
RIF
600 mg
Daily
4 months
Can’t use in HIV → Inducer of
(61)
HIV meds → ↑ clearance → ↓
effectiveness.
Can’t use in cardiac disease if
pt. on drugs that RIF would
cause induction/ ↑ drug
clearance → ↓ effectiveness
?? Substitute
If necessary
RIF 600 mg
Drug
INH
(59)
Latent TB Infection Treatment WITHOUT Disease, Adults, Suspected Resistant, INH & RIF
EMB + LEVO
EMB: 15 mg/kg
Daily
6-12 months
No Trial Data: Latent disease, this drug combo
(62) (6:54)
LEVO: 750 mg
Daily
6-12 months
OR
PZA + LEVO
PZA: 25 mg/kg
Daily
6-12 months
Not well tolerated for latent disease
(62)
LEVO: 750 mg
Daily
6-12 months
Not well tolerated
Resistance: MDR TB = Multi-Drug Resistance TB
Latent Infection: You cannot find disease; can’t get sputum; can’t get blood sample to find pathogen b/c
patient is not bacteremic; No s/s of infection found; base diagnosis on past history of exposure and (+)
skin test.
If patient was in South Africa, working in a health clinic & upon arrival back in US they had (+) TB skin
test, you would suspect MDR TB in this patient: Latent TB, No Active Disease, and Suspect MDR TB.
USE EPIDEMILOGICAL DATA TO MAKE BEST EDUCATED “GUESS” – THEN TREAT ACCORDINGLY.
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Tuberculosis Part 2 2016
TB Active Treatment Goals (63) (9:34)
Patients are sick – can spread disease to others
1. Prevent spread i.e. respiratory isolation
2. Cure current case
3. Find other related cases through public health services
TB Active Treatment (64) (11:16)
TB Drug Susceptible: 60 kg Male
Lecture focusing on daily treatments = most effective = 5 days/week
TB Active Treatment “Daily” (5/7); TB Drug Susceptible (Intensive Phase) (64) (11:16)
Dosing
Dose
Frequency
Duration
5 mg/kg
300 mg
5 x weekly
1st 8 weeks
10 mg/kg
600 mg
5 x weekly
25 mg/kg
1500 mg 5 x weekly
PLUS (Until TB Drug Susceptibility Documented) (65) (12:63)
Ethambutol (65) 20 mg/kg
1200 mg 5 x weekly
Until documented susceptibility
(12:63)
Watch: Renal Function, can overdose on drug
Previous EMB Alternative as 4th Drug (Continuation Phase) (66) (13:27)
Streptomycin
15 mg/kg
900 mg
Weekly
Drug Susceptible TB, After 2 Months TX (66)
Isoniazid
5 mg/kg
300 mg
5 x weekly
6 month minimum total TX
PROVIDED: Patient responded to 1st 2 months of TX.
Rifampin
10 mg/kg
600 mg
5 x weekly
(INH might be: levo, moxy or something else down the
road.)
Drug
Isoniazid
Rifampin
Pyrazinamide
4 drugs x 2 months (intensive phase); then, 2 drugs x 4 months (continuation phase)
HIV + Patients: Duration Data (67) (14:26) (68) (15:58)
6 Month Regimens: Prospective Studies: Good Results (HIV; they don’t always have pulmonary disease)
Concerns: Applicability of studies to developed countries
Immune Reconstitution using HAART:??? Effect on relapse rates
Prolonged TX Benefits:
1. ↓ re-infection if re-infection rates are low, prolonged TX may be unnecessary
CDC Guidelines: TX Duration HIV-Related TB (69) (16:39)
Standard 6-month TX: Most patients with drug susceptible isolates
Extended 9-month TX: Patient’s with bone disease often Tx = 9 months
1. Patients with 2 (+) cultures @ 2 months OR
2. Delayed clinical response to TX (Unusual events)
Extended TX for patients with meningitis (70) (18:04)
1. 9-12 months
Extended TX for patients with bone TB (70)
1. 6-9 months
CDC Guidelines: TX Duration HIV-Related TB (69) (70)
Duration TX
Notes
Standard 6 months
Most patients, drug susceptible isolates
Extended 9 months
Patients with 2 (+) cultures @ 2 months OR
Delayed clinical response to TX (Unusual Event)
Extended 6-9 months
Bone TB
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Tuberculosis Part 2 2016
Multidrug Resistance – M. tuberculosis (MDR-TB) (71) (18:14)
Resistant to: INH, RIF
Overall virulence: similar to other isolates
Cause: incomplete or inappropriate treatment regimens
Management:
1. More difficult
2. More expensive than drug susceptible TB ($250,000 MDR-TB)
TB Treatment Pitfalls (72) (19:16) (73) (22:13)
1. Failing regimen & add only 1 drug; i.e. on 3 drugs: INH, RIF, PZA & INH resistant → essentially giving
RIF monotherapy b/c PZA doing its own thing and not protecting the RIF. RIF becomes resistant,
then you add one drug b/c pt. not doing well; THIS IS REALLY BAD – DO NOT ADD JUST 1 DRUG
2. Initial regimen inadequate (i.e. INH + RIF); Remember: 4 drugs x 2 mon. then 2 drugs x 4 months
3. Duration TX inadequate
4. Drug resistance not identified
5. Failure to adjust regimen given drug resistance i.e. did culture – didn’t look @ report (73) (22:13)
6. Failure to recognize/address non-compliance
7. Failure to provide preventative TX per guidelines: INH
Mahmoud A, Iseman M. JAMA 1993;270:65
Treatment of MDR-TB (74) (23:21) (75) (25:04)
1. No standard or twice weekly regimens, use daily regimen
2. Accurate HX of all TB drug usage is essential
Drug-0-Gram Calendar
3. New susceptible data essential
4. Consult with TB experts
5. Verify dose adequacy with serum levels – therapeutic drug monitoring
6. TX Duration: 18-30 months
7. Toxicities:
 Common
 Coach patient through intolerance
8. Directly observed TX (DOT): essential
9. Low serum levels: higher than normal doses indicated
Therapeutic Monitoring (TDM) (76) (26:18)
Goal: Promote optimal drug TX by maintaining drug levels in
“normal range” or a “therapeutic range”
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Tuberculosis Part 2 2016
Therapeutic Range (77) (27:05)
KNOW THIS SLIDE – YOU CAN EXPLAIN PHARMACOLOGY
Y-Axis: Probability
X-Axis: Drug Concentration
Outcomes that can happen:
1. Response
2. Toxicity
Slide above resembles what would be seen with Rifampin
1. Can give large quantities of RIF and there’s no ↑ in the
concentration related toxicity b/c there doesn’t seem to be.
2. RIF has idiosyncratic toxicities but not concentration related
toxicities.
TDM Benefits (78) (28:44) (79) (29:40) (80) (29:59)
Most useful when:
1. Direct relationship b/t serum concentrations & therapeutic response
2. When serum concentration serve as surrogate for drug concentrations @
the site of action i.e. lung tissue for pulmonary TB
3. Narrow drug therapeutic range (79) (29:40)
4. Toxicities / lack of effectiveness put patient @ risk
 Great risk for lack of effectiveness for TB & HIV
5. Ineffectiveness put patient @ risk
TDM + clinical data allows for: (80) (29:59)
 Treat pts. not numbers
 Use numbers to help treat pts.
 Put #’s in context with what is going on with pt.
 Assessment of pt. status
 Timely therapeutic interventions
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Tuberculosis Part 2 2016
Drug Interactions (81) (30:29) (82)
Gene
CYP 3A4
Enzyme
P450
Drug Interactions
Inducer
Rifampin
Rifapentine
Rifabutin
Carbamazepine
Phenytoin
Efavirenz
Nevirapine
St. John’s Wort
Inhibitor
Clarithromycin
Erythromycin
Fluconazole
Itraconazole
Voriconazole
Amprenavir
Ritonavir
Saqunavir
Cobicistat
Inducers: RIF’s; Anti-seizure drugs; Non-nucleoside reverse transcriptase inhibitors (NNRTI’s)
Inhibitors: Sit on the enzyme preventing it from working: Erythromycins; azols; protease inhibitors;
boosters of protease inhibitors i.e. Ritonavir & Cobicistat. In the presence of inhibitors, the drug
clears slower so dosing frequency of the TB drugs can be less frequent i.e. daily instead of 3-4/day
RIfamycins Effects on Protease Inhibitors Serum Levels (AUC) (83) (32:30) (84) (32:59)
RIfamycins Effects on Protease Inhibitors Serum Levels (AUC)
PI
Notes on Interactions
Rifabutin
Rifampin
Darunavir/ritonavir
Main protease inhibitors (PI)
↓ 46 %
↓ (no data)
Ritonavir
Main protease inhibitors (PI)
NR
↓ 35%
Fosamprenavir/Ritonavir
Main protease inhibitors (PI)
↓ 14%
↓ 82% (Can’t use with PI’s)
Lopinavir / Ritonavir
Main protease inhibitors (PI)
No Effect
↓ 75%(Can’t use with PI’s)
Atazanavir / Ritonavir
Main protease inhibitors (PI)
No Effect
↓ 90% (Trough) (Can’t use w. PI’s)
Measure Rifabutin levels
↑ 45%
NR
Darunavir (84) (32:59)
Ritonavir
Measure Rifabutin levels
↑ 400%
Unchanged
Amprenavir
Measure Rifabutin levels
↑ 400%
NR
Lopinavir/Ritonavir
Measure Rifabutin levels
↑ 300%
NR
Atazanavir
Measure Rifabutin levels
↑ 250 %
NR
Rifampin is NOT a 3A4 Substrate; Rifabutin IS a substrate of 3A4 – it is an inducer & substrate of 3A4
Rifamycins Effect on NNRTI’s Serum Concentration (AUC) (85) (33:42)
Rifamycin Effect on NNRTI’s Serum Concentration (AUC)
NNRTI
Etravirine
Rilpivirine
Efavirenz
Rifabutin
↓ 35% (Trough) → OK to use
↓ 45% → OK to use
Unchanged → OK to use
Rifampin
↓ “Large” %→ Undesirable
↓ 80% → Undesirable
↓ 13% → OK Here
1998 Oct 1998(47); RR 20 CDC & Subsequent Updates (86) (34:01)
PK: Drug Interactions (87) (34:28)
1. www.hiv-druginteractions.org/
2. http://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/default.htm
3. HIV Insight @UCSF
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Tuberculosis Part 2 2016
Overlapping Side Effect Profiles: 1st Line TB Drugs & Antiretroviral Drugs (88) (34:36)
Overlapping Side Effect Profiles: 1st Line TB Drugs & Antiretroviral Drugs
Side Effect
Possible Causes
Anti-TB Drugs
Antiretroviral Drugs
Skin Rash
PZA, RIF, INH
NVP, DVL, EFV, ABC
N/V
PZA, RIF, RBT, INH AZT, RIT, AMP, IDV
Hepatitis
PZA, RIF, RBT, INH NVP, PIs, Immune Reconstitution
Leukopenia, Anemia
RBT, RIF
AZT
TB kills you faster than HIV → treat TB 1st
TB is spread airborne → HIV is not
The sicker the HIV pt., the lower the CD4 count, the higher the viral load →the more
you want to start the TB & HIV drugs @ the same time → overlapping side effect profiles.
ADRs During TX for HIV-TB (89) (37:30)
Frequency of ADRs:
1. 54 % (99/167) had ADRs
2. 34 % interrupted TB or HIV TX
Common ADRs:
1. Peripheral Neuropathy: 21 %
More common with stavudine
2. Skin rash: 17 %
 TB Drugs: 16
 Co-trimoxazole: 7
 Nevirapine: 2
 Other drugs: 4
3. Hepatitis: 6%
 TB drugs: 6
 Unknown: 5
AIDS 2002;16:75-83
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Tuberculosis Part 2 2016
Paradoxical Reactions: HIV-Related TB (IRIS → Immune Reconstitution Inflammatory Syndrome) (90)
(37:53) (91) (38:47)
Paradoxical reactions: Bring the immune system back → suddenly pt. gets worse
Immune system so compromised, body didn’t recognize the TB. Now you bring the
Immune system back → CD4 count goes ↑ → viral load goes ↓ → immune system
Recognizes something is going on → lets go after it → get an inflammatory response that
can be exaggerated → can be health / life threatening
1. Hectic fever
2. New/worsening adenitis: Peripheral or central nodes
3. New/worsening pulmonary infiltrates; including respiratory failure
4. New/worsening pleuritic, pericarditis, ascites
5. Intracranial tuberculosis, worsening meningitis
6. Disseminated skin lesions
7. Epididymitis
8. Hepatosplenomegaly
9. Soft tissue abscesses
10. Enlarging adenopathy compromising function
i.e. airway, GI Tract
11. Expanding CNS lesion
12. Acute respiratory failure
13. Acute adrenal insufficiency
14. Bowel perforation
15. Large soft-tissue abscesses
Summary (92) (39:22)
1. MDR-TB should be suspected with (+) sputum smears for AFB
 Foreign born patients’ i.e.
 Baltic States – formerly part of Soviet Union
 Russia
 Dominican Republic
 Brazil
 South Africa
2. Easier to remove extra drugs than to add ones that should have been started initially
 If pt. acutely ill, broaden # of drugs (pallet) → get them controlled → wait for
susceptibility data → then make decisions
3. Direct observation of TX should be the rule → needs to be 100 %
 There are new electronic ways to do this
 Wirelessly observed therapy
4. Therapeutic drug monitoring may assist confirming compliance (delivering the therapy)
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