1. Tuberculosis Treatment
Sample 2
Jennifer Whitaker, MD, MS
Infectious Diseases Midwest Fellows’ Forum, Mayo Clinic, Rochester
April 26, 2014
test

2. Disclosures
Pfizer Educational Grant for Learning and Change

3. Objectives
Review the treatment regimens for latent TB infection (LTBI)
Review the treatment regimens for drug-susceptible TB disease
Review adverse reactions to TB medications

4. Latent TB Infection (LTBI) Treatment
Rationale
To prevent the development of active disease
Component of TB control
Durability of protection against reactivation depends on regional prevalence of TB and risk for reexposure
A decision to test for LTBI is a decision to treat
1965 ATS recommends LTBI treatment for those with previously untreated TB, recent TB skin test converters, young children exposed.

5. Targeted Testing for LTBI
High Likelihood of Exposure to TB
High Risk of Progression to Active TB
Close contacts of a person with infectious TB disease
HIV Infection
Persons who have immigrated from areas of the world with high rates of TB
Recent LTBI test conversion (within past 2 years)
Residents/employees of high-risk congregate settings (correctional facilities, homeless shelters, healthcare facilities)
History of prior, untreated TB or fibrotic lesions on chest radiograph
Those receiving TNF-α antagonists for treatment of autoimmune diseases
Solid organ transplant, lymphoma, leukemia, head and neck cancer, chemotherapy
Chronic kidney disease requiring hemodialysis
Children who have positive LTBI test
High Likelihood of Exposure to TB
High Risk of Progression to Active TB
Close contacts of a person with infectious TB disease
Persons who have immigrated from areas of the world with high rates of TB
Residents/employees of high-risk congregate settings (correctional facilities, homeless shelters, health care facilities)
High Likelihood of Exposure to TB
High Risk of Progression to Active TB
Targeted tuberculosis (TB) testing is used to focus program activities, provider practices, and financial resources on groups at the highest risk for latent tuberculosis infection (LTBI). Once TB disease has been ruled out, those who would benefit from treatment of LTBI should be offered this option regardless of their age.

6. Prior to Treatment Symptom screen Chest X-ray Rule out active disease
Assess for medical conditions and medications that may affect treatment choices
Determine whether patient has ever been treated for LTBI or TB disease
Establish rapport with patient; explain therapy and adverse effects

7. Which LTBI treatment regimens require directly observed therapy (DOT)?
Daily isoniazid x 9 months
Twice weekly isoniazid x 9 months
Daily rifampin x 4 months
Weekly isoniazid + rifapentine
B & D

8. LTBI Treatment Regimens
MMWR. 2011;60(48):
JAMA. 2005; 293:2776.
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
Alternative:
300 mg daily x 6 months
900 mg twice weekly x 9 months (DOT)
900 mg twice weekly x 6 months (DOT)
Isoniazid + Rifapentine
Isoniazid 900 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT)
10-14 kg 300 mg
kg 450 mg
kg 600 mg
kg 750 mg
>50 kg 900 mg (maximum dose)
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
Alternative:
300 mg daily x 6 months
900 mg twice weekly x 9 months (DOT)
900 mg twice weekly x 6 months (DOT)
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
The effectiveness of INH for reducing the incidence of active TB (compared with placebo) is 60 to 90 percent. Effectiveness is affected by medication adherence. Highest efficacy with longer treatment duration, but longer treatment durations also show lower adherence. In those adherent to 9 month regimen, efficacy is >90%.
Will discuss INH/RPT in next slides

9. HIV-infected individuals on antiretroviral therapy A & C A & B
Current CDC recommendations state isoniazid + rifapentine weekly x 12 weeks is an acceptable alternative LTBI regimen for which groups with high risk of developing active TB?
Persons ≥ 12 years old with recent LTBI test conversion, recent exposure to contagious TB, CXR consistent with healed pulmonary TB, or HIV infection but not on antiretrovirals
Pregnant females
HIV-infected individuals on antiretroviral therapy
A & C
A & B
MMWR. 2011;60(48):

10. Isoniazid (INH) + Rifapentine (RPT)
INH/RPT weekly x 3 mo (DOT) noninferior to 9 mo daily INH (self-administered) in randomized open label trial
N=7731, mostly HIV(-) in Brazil, Canada, Spain, and US
≥ 12 years old (later ≥ 2 yo) + 1 of 4 high-risk groups (recent LTBI test conversion, recent exposure to contagious TB, CXR consistent with healed pulmonary TB, HIV infection and not on ARVs with + LTBI test or close TB contact)
Completion rate was 82% for INH/RPT and 69% for INH (p<0.01)
Hepatoxicity greater in INH than INH/RPT (2.7% vs 0.4%; p<0.001)
Higher rates of permanent drug discontinuation due to an adverse event in the rifapentine/INH group (4.9 % vs. 3.7 %; p=0.009)
Over 33 mo follow up
Data are insufficient to support use of INH-RPT for treatment of LTBI for patients in the following categories: children <2 years of age, HIV infected persons on antiretroviral therapy, presumed infection with INH- or rifampin-resistant TB, and pregnant women. The choice between combination INH-RPT and the other regimens depends on feasibility of directly observed therapy by a trained provider, resources for drug procurement and patient preference
As more data is gathered on this regimen in HIV-infected patients on HAART, recommendations may change. For now, we need more data on interactions between rifapentine and ARV medications.
RIF with pyrazinamide should NOT for treatment of LTBI be used because of the possibility of severe hepatotoxicity
LTBI in pregnancy: INH (safe), not enough data on rifapentine yet.
Other Clinical Trials:
A randomized clinical trial in Brazil compared 12 weekly doses of DOT INH-RPT with 2 months of daily, mostly self-supervised RIF and pyrazinamide (RIF-PZA) in tuberculin skin test–reactive household contacts aged ≥18 years (3). Enrollment was stopped at 399 participants because of hepatotoxicity in RIF-PZA recipients. Patients were followed ≥2 years after treatment. TB was diagnosed in three INH-RPT recipients and one RIF-PZA recipient (incidence rate ratio: 2.8 for INH-RPT versus RIF-PZA, 95% confidence interval [CI] = 0.2–26.8).
A randomized clinical trial in South Africa assigned 1,148 human immunodeficiency virus (HIV)-infected tuberculin skin test–reactive participants aged ≥18 years who were not receiving antiretroviral treatment to one of four regimens: once-weekly INH-RPT or twice-weekly INH-RIF, both by DOT for 12 weeks; and daily self-supervised INH, for 6 months or indefinitely (4). For all four regimens, the median follow-up duration was approximately 4 years. The incidence rates of TB were 1.4–2.0 per 100 person-years, without significant differences between the four regimens. Treatment completion was greater for the two rifamycin-containing regimens, and grade 3 or 4 adverse effects* were more common for INH taken indefinitely.
N Engl J Med Dec;365(23):

11. Isoniazid + Rifapentine
Further study is needed for:
Completion /efficacy without DOT
Durability of protection/ efficacy/toxicity in those with HIV (also with antiretrovirals)
Efficacy/toxicity in other groups without recent infection (prior to TNF-α inhibitors)
Utility where the incidence of TB is high
ACTG study is looking at HIV-infected patients on HAART (excluding protease inhibitors and raltegravir)

12. LTBI Treatment Regimens
MMWR. 2011;60(48):
JAMA. 2005; 293:2776.
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
Alternative:
300 mg daily x 6 months
900 mg twice weekly x 9 months (DOT)
900 mg twice weekly x 6 months (DOT)
Isoniazid + Rifapentine
Isoniazid 300 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT)
10-14 kg 300 mg
kg 450 mg
kg 600 mg
kg 750 mg
>50 kg 900 mg (maximum dose)
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
Alternative:
300 mg daily x 6 months
900 mg twice weekly x 9 months (DOT)
900 mg twice weekly x 6 months (DOT)
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
Alternative:
300 mg daily x 6 months
900 mg twice weekly x 9 months (DOT)
900 mg twice weekly x 6 months (DOT)
Isoniazid + Rifapentine
Isoniazid 900 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT)
10-14 kg 300 mg
kg 450 mg
kg 600 mg
kg 750 mg
>50 kg 900 mg (maximum dose)
Rifampin
Rifampin 600 mg daily x 4 months
Isoniazid + Rifampin
Isoniazid 300 mg daily x 3 months
+ Rifampin 600 mg daily x 3 months
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
Alternative:
300 mg daily x 6 months
900 mg twice weekly x 9 months (DOT)
900 mg twice weekly x 6 months (DOT)
Isoniazid + Rifapentine
Isoniazid 900 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT)
10-14 kg 300 mg
kg 450 mg
kg 600 mg
kg 750 mg
>50 kg 900 mg (maximum dose)
Rifampin
Rifampin 600 mg daily x 9 months
Medication(s)
Recommended Regimen
Isoniazid
Preferred:
Isoniazid 300 mg daily x 9 months
 Efficacy for rifampin x 3 months equaled INH x 6 months. Study comparing Rifampin x 4 months to INH x9 month showed less adverse effects with rifampin x 4 months, but did not study efficacy/effectiveness. Barriers to adoption of routine use of RIF for treatment of LTBI include the possibility of inadvertent treatment of active TB resulting in RIF-resistant disease, concerns about efficacy, and cost . Consider rifampin (in INH shortage), in persons intolerant of INH, persons with INH-resistance,
In a prospective randomized trial among HIV-infected individuals, a three-month regimen of daily INH and RIF provided 60 percent protection. Although this regimen has not been studied in a large trial among HIV-uninfected persons, a meta-analysis of small studies in this population suggests that it is equally efficacious and not more toxic. For circumstances in which RPT is not available and/or directly observed therapy for INH-RPT is not feasible, a three-month daily regimen of INH-RIF may be an acceptable alternative.

13. Pyridoxine and Isoniazid – Who Needs It?
Those at increased risk for peripheral neuropathy
Diabetes mellitus
Alcohol dependence
HIV
Chronic kidney disease
Malnutrition
Pregnant/breastfeeding women

14. Monitoring of LTBI Therapy
Everyone should have initial clinical evaluation prior to starting therapy with monthly clinical monitoring for signs/symptoms of hepatitis and adherence to medication while on therapy
For weekly INH/RPT, ask about signs/symptoms with each dose
Baseline liver enzyme testing in those with:
Underlying liver disease
HIV infection
Pregnant /postpartum (≤ 3 mo after delivery)
Regular alcohol consumption
Medication(s) with potential hepatotoxicity
Routine lab monitoring during treatment for those whose baseline liver function tests are abnormal or those at risk for hepatic disease
Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221.

15. When Should LTBI Therapy be Stopped?
Liver enzymes are:
≥ 3 times upper limit of normal
range and patient has symptoms OR
≥ 5 times upper limit of the normal range and patient has no symptoms

16. Pregnant Women
For most LTBI treatment can be delayed until after delivery, unless they have significant immunocompromising conditions, HIV, or recent TB contact
INH is safe during pregnancy
Preferred LTBI treatment regimen is 9 months of INH with pyridoxine
INH is safe for breastfeeding, give with pyridoxine

17. LTBI Treatment Key Points
Test and treat those at high risk for TB exposure and/or progression to active disease
Isoniazid daily x 9 months or Isoniazid + rifapentine weekly x 3 months with DOT (with caveats) are preferred regimens
LTBI treatment regimens that include weekly or bi- weekly dosing require DOT
Prior to treatment for LTBI, patients need clinical evaluation + CXR to rule out active TB disease
While on therapy patients need monthly clinical monitoring; baseline liver enzymes for those at risk

18. Treatment of Drug-Susceptible TB Disease
Initial Phase
First 8 weeks of treatment
Most bacilli killed during this phase
4 drugs used
Continuation Phase
After first 8 weeks of TB disease
treatment (18 or 31 weeks duration)
Bacilli remaining after initial
phase are treated with at least 2
drugs

19. First Line TB Drug Abbreviations
Rifamycins:
Rifampin (Rifampicin, RIF, R)
Rifabutin (RFB)
Rifapentine (RPT)
Isoniazid (INH, H)
Pyrazinamide (PZA, Z)
Ethambutol (EMB, E)
Streptomycin (SM, S)

20. Mechanisms of Action Rifampin Isoniazid Pyrazinamide Ethambutol
Binds to RNA polymerase and blocks RNA synthesis;
Bactericidal; Sterilizing activity due to activity against semi-dormant bacteria
Isoniazid
Inhibits mycolic acid synthesis
Bactericidal
Pyrazinamide
Potent sterilizing ability within acidic environment of areas of acute inflammation, suppuration
Ethambutol
Cell wall inhibition

21. Current Preferred Regimens for Drug-Susceptible TB disease:
Isoniazid, Rifampin, Pyrazinamide, Ethambutol
Isoniazid & Rifampin are the cornerstones
Both are bactericidal against rapidly dividing mycobacteria
Rifampin also exhibits excellent late sterilizing effect on semi- dormant organisms
Non-INH based regimen = usually 9 months
Non-Rifampin regimen = months (variable)
Pyrazinamide
Potent sterilizing ability
Non-pyrazinamide based regimen = 9 months

22. Standard TB Therapy for Drug-Susceptible Disease
Initial Phase:
4 drugs for 2 months (8 weeks)
Rifampin, isoniazid, pyrazinamide, ethambutol
Okay to stop ethambutol, once it is known that isolate is susceptible to rifampin, isoniazid, and pyrazinamide
ATS/CDC/IDSA. Treatment of Tuberculosis. MMWR 2003.

23. In what cases should the continuation phase of TB therapy be prolonged from 4 months to 7 months?
HIV co-infection
Cavitary disease with positive cultures at end of initiation phase
Initiation regimens of Isoniazid, Rifampin, and Ethambutol, without use of PZA
B and C

24. Standard TB Disease Continuation Therapy
Continuation Phase:
Rifampin & Isoniazid for 4 months (18 weeks)
Six months (26 weeks) total course of therapy
If PZA not used in initiation, then 7 months (31 wk) continuation
Continuation Phase: for cavitary disease AND positive cultures after initiation phase
Rifampin & Isoniazid x 7 months (31 weeks) if cavitary disease at diagnosis and positive cultures after initiation phase at 2 months
Rifapentine should not be used
Nine months (39 weeks) total course of therapy
This practice is based on evidence from USPHS study 22, which demonstrated that among patients on continuation phase twice weekly INH and RIF who had cavitation on initial chest radiograph and positive culture at the two month juncture, nearly 21 percent relapsed [13]. Patients with only one of these factors (either cavitation or positive culture at two months) had relapse rates of 5 to 6 percent; patients with neither risk factor had relapse rates of 2 percent. A prolonged continuation phase for patients with cavitation and positive cultures at two months is supported by a study of patients with silicotuberculosis in whom extending treatment to eight months greatly reduced the rate of relapse (22 to 7 percent)
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.

25. Noncompliance or Abandonment of Therapy is Major Impediment of TB Treatment
Directly observed therapy (DOT) has been shown to:
Facilitate treatment completion rates and bacteriologic evidence of cure
Decrease acquired and primary drug resistance
Decrease relapse rates
CDC and American Thoracic Society (ATS) recommend consideration of DOT for all and
Especially for those with drug resistant organisms, cavitary disease, or HIV infection
Chaulk CP, et al. JAMA. 1998;279(12):943.
Chaulk CP, et al. JAMA. 1995;274(12):945.
Weis SE, et al. N Engl J Med. 1994;330(17):1179.

26. Recommended Treatment Regimens for Drug-Susceptible Organisms
The six-month rifampin-based treatment regimen is supported by USPHS Trial 21, a randomized trial of 1451 patients with pulmonary TB comparing the efficacy of six months of INH and RIF (with PZA for the first two months) with nine months of INH and RIF. Patients in the six-month regimen were more likely to complete therapy (61 versus 51 percent), and relapse rates two years after completing therapy were similar in the two groups (3.5 and 2.8 percent).
Intermittent drug administration facilitates supervision of therapy and has been shown to be as effective as daily administration. Twice weekly dosing is frequently used by public health departments [Regimen 2a] This practice is supported by a study of 160 patients treated with two weeks of daily directly observed therapy (INH, RIF, PZA, and EMB) followed by twice weekly directly observed therapy for a total over 62 doses administered over 32 weeks; the relapse rate was 1.6 percent.
Evidence Ratings:
A=preferred, B=acceptable alternative, C= when A&B cannot be given, E=never
I=randomized controlled trial, II=Clinical trials, not randomized or done in other populations ;
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.

27. Key Points: Treatment of TB Disease
Initiation:
RIF/INH/PZA/EMB until susceptibilities confirmed
Can stop EMB if susceptible to RIF/INH/PZA
RIF/INH/PZA for 8 weeks
Continuation:
RIF/INH for 18 weeks
If PZA not used in initiation or if patient has cavitary disease + positive cultures at 8 wks, then RIF/INH continued for 31 weeks
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.

28. Treatment of Culture-negative Pulmonary TB
Continuation phase is shortened to 2 months
Abnormal CXR + positive TST/IGRA or high suspicion for TB disease
Start standard treatment: INH/RIF/PZA/EMB
Attempt to collect appropriate specimen
If no specimen or culture negative, then look at CXR and clinical outcome
Clinical/CXR improvement
Clinical diagnosis of TB
Complete 2 more months of INH/RIF (shortened continuation phase)
CXR unchanged; no clinical improvement after 2 months
Discontinue treatment
Complete therapy for LTBI if indicated (+ LTBI test)
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.

29. Treatment of Extrapulmonary TB Disease
Generally the same treatment as for pulmonary TB
Addition of corticosteroids for:
TB pericarditis
TB meningitis
Recommended that duration of therapy be extended to 9-12 months for TB meningitis
May extend to 18 months for tuberculoma
Adolescents and adults: Prednisone 60 mg/day. Administer initial dose for two weeks, then taper gradually over the next six weeks (ie reduce daily dose by 10 mg each week); total duration approximately eight weeks
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.
Thwaites GE, Nguyen DB, et al. N Engl J Med 2004;351(17):1741.

30. Rifampin Adverse Effects
Most Common:
Rash, generally self-limited. True hypersensitivity rare.
Nausea/vomiting
Hepatotoxicity: (usually cholestatic; bilirubin is a clue)
Orange discoloration of body fluids
Less Common:
Influenza-like syndrome
Cytopenias - WBC, platelets
Nephrotoxicity; interstitial nephritis
Hypersensitivity reactions

31. Rifampin Drug Interactions
Rifampin induces its own metabolism during the first 2 weeks
Induces cyt p450 system & decreases levels of:
Steroids, OCP/estrogen
Protease inhibitors
Warfarin
Antiepileptics
Methadone, morphine
Digoxin, calcium channel blockers, β-blockers
Azoles + many others

32. Isoniazid Adverse Effects
Transient asymptomatic elevation of AST/ALT in 10-15% (usually in 1st 4-8 weeks of therapy) – usually resolves
Hepatotoxicity / hepatitis
Increased in HIV (4x), HCV (5x) or both HIV-HCV (14x) co-infections
Usually in 1st 4-8 weeks of therapy) – typically 0.1-1% risk without underlying liver disease
Rapid improvement (AST/ALT) after stopping drugs - clue to INH toxicity
Peripheral neuropathy – give vitamin B6 (10-50 mg/day) to prevent
Hypersensitivity (fever, rash)
(+) ANA (< 20%)
Lupus-like reaction (<10%)

33. Ethambutol Adverse Effects
Retrobulbar / optic neuritis -  visual field;  red-green color discrimination
Monitoring - Visual acuity & color vision (baseline and monthly)
Other: peripheral neuropathy (rare)
Contraindications:
Pre-existing optic neuritis (from any cause)
Inability (i.e. young pt. age) to report visual disturbances

34. Pyrazinamide Adverse Effects
Hepatotoxicity / hepatitis – modest rises in transaminases; Slow hepatic/transaminase recovery is clue to PZA toxicity
Hyperuricemia – gout is rare (but is often board question)
Arthralgias - particularly of shoulders
Other: GI upset, rash, glucose dysregulation

35. Approach to Hepatitis INH, RIF, & PZA can cause drug-induced liver
injury (ALT > 3x upper limit normal + symptoms or ALT > 5x ULN without symptoms)
Asymptomatic increase in AST occurs in ~20% treated with standard 4-drug regimen
In absence of symptoms, therapy should not
be altered for modest elevations of AST
Frequency of lab monitoring should be increased
In most cases, asymptomatic AST elevations resolve spontaneously

36. Approach to Hepatitis
If drug induced liver injury (AST >3x + symptoms or >5x without symptoms) then stop hepatotoxic drugs
Evaluate for other causes than drugs (viral hepatitis, etc)
Suspect medications should be restarted one by one after AST is <2x ULN
Restart RIF (+EMB) first, if no rise in ALT after 1 week,
Restart INH, if no rise in ALT after 1 week,
If RIF and INH are tolerated & hepatitis was severe, do not restart PZA

37. Sputum Culture Monitoring During Pulmonary TB Treatment
Serial sputum smears every 2 weeks to assess early response
Monthly sputum for AFB smear and culture (until 2 consecutive cultures negative)
Repeat drug-susceptibility tests if culture- positive after 3 months of treatment
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.

38. Clinical Monitoring During Pulmonary TB Treatment
Periodic (minimum monthly) evaluation to review adherence and identify adverse reactions
Repeat chest x-ray:
After 2 months treatment for patients with negative cultures
As clinically indicated for worsening
At end of treatment

39. Diagnostic Monitoring During Pulmonary TB Treatment
Liver enzymes at baseline; HIV testing at baseline; hepatitis testing if indicated; monthly liver enzymes if indicated
Renal function and CBC if abnormalities at baseline
Visual acuity and color vision at baseline if EMB used and monthly
If EMB used > 2 months or
EMB dose > mg/kg or
EMB with renal failure

40. TB Treatment in Pregnancy/Breastfeeding
INH considered safe in pregnancy/breastfeeding
Risk of hepatitis increased in peripartum period
Pyridoxine (25 mg/day) recommended if INH is administered during pregnancy, administer to infant if breastfeeding
RIF & EMB considered safe in pregnancy & breastfeeding
PZA - little information in pregnancy, generally avoided in US
Safe for breastfeeding
Benefits of PZA may outweigh the risk (drug resistant cases)
WHO & IUATLD recommend this drug for use in pregnant women with tuberculosis

41. Key Points: TB Drug Adverse Effects
INH, RIF, & PZA can cause drug-induced liver
injury
ALT > 3x upper limit normal + symptoms or ALT > 5x without symptoms
Stop medications if this occurs until liver enzymes are <2x upper limit of normal
EMB can cause optic neuritis
Monitor visual acuity & color vision
Pyridoxine is given with INH to prevent peripheral neuropathy
PZA may exacerbate gout; generally avoid in pregnancy

42. References
Blumberg HM, Leonard MK Jr, Jasmer RM. Update on treatment of tuberculosis and latent tuberculosis infection. JAMA 2005; 293:2776.
CDC. Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection. MMWR 2011; 60(48):1650.
Person AK, Sterling TR. Treatment of latent tuberculosis infection in HIV: shorter or longer? Curr HIV/AIDS Rep September ; 9(3): 259–266.
Targeted tuberculin testing and treatment of latent tuberculosis infection. (ATS/CDC/IDSA). Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221.
Sterling TR, Villarino ME, Borisov AS, et al. TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med Dec;365(23):
ATS; CDC; IDSA.Treatment of Tuberculosis. MMWR 2003 Jun 20;52(RR-11):1-77.
Chaulk CP, et al. JAMA. 1998;279(12):943.
Chaulk CP, et al. JAMA. 1995;274(12):945.
Weis SE, et al. N Engl J Med. 1994;330(17):1179.
Thwaites GE, Nguyen DB, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351(17):1741

43. Which LTBI treatment regimens require directly observed therapy (DOT)?
Daily isoniazid x 9 months
Twice weekly isoniazid x 9 months
Daily rifampin x 4 months
Weekly isoniazid + rifapentine
B & D
JAMA 2005; 293:2776
MMWR Dec 9;60(48):

44. HIV-infected individuals on antiretroviral therapy A & C A & B
Current CDC recommendations state isoniazid + rifapentine weekly x 12 weeks is an acceptable alternative LTBI regimen for which groups with high risk of developing active TB?
Persons ≥ 12 years old with recent LTBI test conversion, recent exposure to contagious TB, CXR consistent with healed pulmonary TB, or HIV infection but not on antiretrovirals
Pregnant females
HIV-infected individuals on antiretroviral therapy
A & C
A & B
MMWR. 2011;60(48):

45. In what cases should the continuation phase of TB therapy be prolonged from 4 months to 7 months?
HIV co-infection
Cavitary disease with positive cultures at end of initiation phase
Initiation regimens of Isoniazid, Rifampin, and Ethambutol, without use of PZA
B and C