TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE May 8-11, 2018

Curry International Tuberculosis Center, UCSF

300 Frank H. Ogawa Plaza, Suite 520

Oakland, CA; Office (510) 238-5100

TREATMENT OF TUBERCULOSIS

INFECTION

LEARNING OBJECTIVES

Upon completion of this session, participants will be able to:

1. Review recommended treatment options for tuberculosis (TB) infection

2. Describe advantages and disadvantages of treatment regimens for TB infection

3. Understand common side effects for TB infection treatment regimens

INDEX OF MATERIALS PAGES

1. Treatment of Tuberculosis Infection – slide outline Presented by: Amit Chitnis, MD, MPH

1-11

SUPPLEMENTAL MATERIAL

None

TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE May 8-11, 2018

Curry International Tuberculosis Center, UCSF

300 Frank H. Ogawa Plaza, Suite 520

Oakland, CA; Office (510) 238-5100

ADDITIONAL REFERENCES

• Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR 2011;60:1650-1653.

• Centers for Disease Control and Prevention. Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003. MMWR 2003;52:735-739.

• American Thoracic Society, CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221–47.

• CDC. Core Curriculum on Tuberculosis: What the Clinician Should Know. http://www.cdc.gov/tb/education/corecurr/index.htm

• NTNC TB Nursing Manual: http://www.tbcontrollers.org/resources/tb-nursing-manual/#.WA-NDy0rJph

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 1

Amit S. Chitnis, MD, MPH

Tuberculosis Controller

Alameda County Public Health Department

May 9, 2018

Treatment of Tuberculosis Infection

Disclosures

No Disclosures or Conflicts of Interest

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 2

Objectives

Review recommended treatment options for tuberculosis (TB) infection

Describe advantages and disadvantages of treatment regimens for TB infection

Understand common side effects for TB infection treatment regimens

LTBI Treatment Regimens

Medication(s) Frequency Duration DosesTimeframe to

Complete

INH + RPT (3HP)* Weekly 3 months 12 16 weeks

RIF Daily 4 months 120 6 months

INH** Daily6–9

months180–270 9–12 months

*Currently, recommended as by directly observed therapy (DOT); however, anticipate guidancewill change to allow for self-administered therapy (SAT).**INH can be administered twice weekly but must be given by DOT.

MMWR Recomm Rep. 2000;49:1–51. MMWR Morb Mortal Wkly Rep. 2011;60:1650–1653.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 3

Isoniazid for Treatment of TB Infection

Inhibits synthesis of mycolic acid

Well absorbed orally, and peak concentrations achieved 1–2 hours after oral dose

First proposed as a strategy for treatment of TB infection in 1954 by Edith Lincoln, MD

Image obtained from: https://cfmedicine.nlm.nih.gov/physicians/biography_201.html

INH package insert: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008678s028lbl.pdfInt J Tuberc Lung Dis. 2007;11:944–945Am Rev Tuberc 1954;69;682–689

Summary of Select Placebo Controlled Clinical Trials on INH to Prevent TB Disease

Respirology. 2010;15:603–622.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 4

Why is 9 months of INH Recommended?

USPHS household study showed reduction in TB disease greater among persons who took ≥ 80% of pills for ≥ 10 months vs. < 10 months

Reanalysis of Alaska Bethel study found that TB case rates leveled after 9–10 months of INH treatment

Int J Tuberc Lung Dis. 1999;3:847–850.

Why is 6 months of INH Recommended?

IUAT Trial Effectiveness Data in persons with fibrotic pulmonary lesions showed INH taken for 6 months provides substantial protection compared to placebo▪ Also, other studies and meta-analyses support this conclusion

Most cost-effective option from a societal perspective

Int J Tuberc Lung Dis. 1999;3:847–850. JAMA. 1986;255:1579–1583. MMWR Recomm Rep. 2000;49:1–51.Ann Intern Med. 2017;167:248–255.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 5

Adverse Events with Isoniazid

Adverse Event Comment

Hepatotoxcity

• Initially estimated as ~1.3%, but studies in public health clinics found 0.1%–0.3%

• Increased risk with age (~2% aged 50–64 years old)

AsymptomaticElevation in LFTs

• 10%–20% of persons

• LFTs usually return to normal during treatment

Peripheralneuropathy

• <0.2% in healthy, and higher in chronic alcoholics, malnourished, pregnant

• Vitamin B6 supplementation for persons in whom neuropathy is common (e.g., diabetes, ESRD, alcohol, malnutrition, LFTs, HIV); pregnant women; seizure disorders; breastfeeding infants and mothers

Diarrhea• With liquid formulation that contains sorbitol

Other rare • Anemia, Leukopenia, CNS effects, lupus-like syndrome

MMWR Recomm Rep. 2000;49:1–51. Am J Respir Crit Care Med. 2003;167:603–662.

Am J Respir Crit Care Med. 2006;174:935–952.

Rifampin for Treatment of TB Infection

Inhibits bacterial RNA polymerase, enzyme responsible for DNA transcription

Good oral absorption that is improved when taken on an empty stomach

Developed in Dow-Lepetit Research Laboratories in Italy as part of program studying natural metabolites of Nocardia mediterranei that were referred to as rifamycins▪ Approved in U.S. in 1971

Dr. Piero Sensi and team. Image: http://www.nature.com/articles/ja2014104/figures/1

Rev Infect Dis. 1983;5 Suppl 3;S402–S406. MMWR Recomm Rep. 2000;49:1–51.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 6

What Prompted Interest in Short Course Rifampin for TB Infection?

Mouse model of tuberculosis infection

RIF had higher bacteriologic clearance than INH for 6 months, and was comparable to RIF and Pyrazinamide for 2 months

Am Rev Respir Dis. 1989;140:1189–1193.

Treatment Completion and Safety of Rifampin Compared to Isoniazid

Lower occurrence of clinically significant, serious adverse events, or grade 3 or 4 adverse events of hepatoxicity with RIF 4 months compared to 9 months of INH (0%–1.7% vs. 1.4%–5.0%)

Respirology. 2010;15:603–622. Arch Intern Med. 2006;166:1863–1870. Chest. 2006;130:1712–1717. Am J RespirCrit Care Med. 2004;170:445–449. Ann Intern Med. 2008;149:689–697.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 7

Effectiveness of Rifampin for 4 months

Am Rev Respir Dis. 1992;145:36–41.

679 elderly men in Hong Kong with silicosis randomized to: Placebo; INH 6 months; 3 months of INH + RIF; 3 months of RIF

Followed for 5 years to see if active TB disease developed

Significant differences in treatment arms vs. placebo

No difference between treatment arms, but RIF had lowest TB occurrence

Large multicenter trial comparing INH 9 months to RIF 4 months just completed

Adverse Events with Rifampin

Adverse Event Comment

Orange Discoloration of Fluids

• Universal side effect

Hepatotoxcity• Infrequent when given alone (<1%)

• More common when given with INH (~3%) or other drugs (~1%)

AsymptomaticElevation in Bilirubin

• Rare and occurs in 0.6% of patients

Rash or other dermatologic manifestations

• Pruritis with or without rash common (~6%), and is generally self-limited

• True hypersensitivity is rare (0.07%–0.3%)

Flu-like syndrome• Rare and occurs in 0.4%–0.7% of patients; more common with

intermittent administration

Other rare• Immune mediated reactions are rare (< 0.1%) and include

thrombocytopenia, hemolytic anemia, and acute renal failure

Am J Respir Crit Care Med. 2003;167:603–662.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 8

INH and Rifapentine (RPT) for TB Infection

RPT has similar mechanism of action as RIF, but substantially longer half-life (~17 hours)

Three randomized clinical trials provide evidence to support INH and RPT (3HP)▪ Brazil – 12 weekly doses of 3HP by DOT vs. 2 months RIF/PZA mostly

self administered

▪ South Africa – 3HP 12 weekly doses by DOT vs. INH/RIF biweekly for 12 weeks by DOT vs. at least 6 months of INH SAT

▪ Multicenter trial – 3HP 12 weekly doses by DOT vs. INH for 9 months SAT

MMWR Morb Mortal Wkly Rep. 2011;60:1650–1653.

Prevent TB Study Results

INH-RPTN=3,986

INHN=3,745

P-value

Effectiveness 1.9 per 1,000 4.3 per 1,000 Non-inferior

Completion 82.1% 69.0% P<0.001

Hepatotoxicity 0.4% 2.7% P<0.001

Possible Hypersensitivity

3.8% 0.5%P<0.001

N Engl J Med. 2011;365:2155–2166.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 9

Further Studies of INH-RPT

Children aged ≥2 years old▪ Non-inferior to 9 months of INH

HIV▪ Non-inferior to 9 months of INH

▪ Unable to receive ART in first 90 days

Self-administered therapy ▪ Non-inferior to INH-RPT

JAMA Pediatr. 2015;169:247-255. AIDS. 2016;30:1607-1615. Ann Intern Med. 2017;167:689-697.

Who is 3HP NOT Indicated For?

Children under age 2 years of age

HIV infected persons taking ARV’s

Individuals taking medications that may have drug-drug interactions

Infected with INH or RIF resistant isolate

Pregnant women or women planning to become pregnant during treatment

Previous adverse events or hypersensitivity to INH or Rifampin

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 10

Advantages and Disadvantages to LTBI Treatment Options

Regimen Advantages Disadvantages

INH-RPT ▪ Less hepatotoxicity than INH

▪ Greater adherence than INH

▪ Multiple drug interactions

▪ Pill burden

▪ Flu-like/hypersensitivity syndrome

RIF ▪ Less hepatotoxicity than INH

▪ Greater adherence than INH

▪ Multiple drug interactions

▪ Less evidence of efficacy in clinical trials; however, substantial experience in public health setting

INH ▪ Efficacy 60%–90% depending on duration

▪ Fewer drug interactions

▪ Completion rates are low

▪ Hepatotoxicity risk

▪ Clinic time required for 9 monthly visits

Clinical and Laboratory Monitoring During TB Infection

Clinical monitoring indicated for all patients, and should occur monthly while on treatment for TB infection▪ Education on signs and symptoms of adverse events

▪ Instruction on when to stop treatment and seek urgent clinical evaluation

Routine baseline or follow-up laboratory testing not indicated except for following▪ HIV infection

▪ Liver disease or hepatitis

▪ Alcohol use

▪ Pregnancy or post-partum within past 3 months

▪ Consider in persons aged > 50 years old or who use Statins

MMWR Recomm Rep. 2000;49:1–51.

Treatment of tuberculosis infection

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 11

Thank You!

Amit.Chitnis@acgov.org

Phone Number: 510.667.3054