Treatment: the basicsnid]/treatment...Denver Health •Vertically integrated health care system •Network of 9 primary care clinics, 17 school-based clinics •Serves approximately

Dr. Michelle Haas

Denver Metro Tuberculosis Program

Denver Public Health

Focus on TB Prevention

Modesto, CA

June 5, 2019 1

Treatment: more of the basics

Focus on TB PreventionJune 5th, 2019

Michelle Haas, M.D.

Associate Director



DISCLOSURES

• I have no disclosures or conflicts of interest to report

Dr. Michelle Haas




Modesto, CA

June 5, 2019 2

Objectives

• By the end of this presentation, participants should be able to:

• Understand the approach to LTBI in special populations

• Be able to discuss the rationale behind latent TB treatment with patients

• Describe examples of operationalizing LTBI management in primary care

Dr. Michelle Haas




Modesto, CA

June 5, 2019 3

Who should get tested?

• Use this tool to identify asymptomatic adults for latent TB infection (LTBI) testing.• Do not repeat testing unless there are new risk factors since the last test.• Do not treat for LTBI until active TB disease has been excluded

DPH 2006-2018: No. of LTBI Patients Starting INH, RIF, 3HP per Quarter

LHS 159/162

3HP 11/11 4R v 9H3HP SAT: 2/15-9/17

EPIC

Dr. Michelle Haas




Modesto, CA

June 5, 2019 4

Patients starting & completing LTBI regimens: DMTB Clinic 2006-2018

Regimen Completed Started* % completed % of Total

9 INH 2344 3919 60 45

4 RIF 2825 3916 72 45

3 HP 692 910 76 10

Total 5861 8745 67 100

*Excluding 347 starting other regimens over the 13 years.

Denver Public Health: Comparison of LTBI Regimen Completion Rates

Dr. Michelle Haas




Modesto, CA

June 5, 2019 5

Denver Health

• Vertically integrated health care system

• Network of 9 primary care clinics, 17 school-based clinics

• Serves approximately 150,000 individuals

• Collects country of birth at registration

• Denver Public Health• Denver Metro

Tuberculosis Program

Evaluating the care continuum in Primary care clinics: Key Objectives

• Evaluate the latent TB care continuum for the adult primary care population• Identified individuals at risk based upon reported birth country

• Identify factors associated with TB screening, offering chest radiograph (CXR) to those who are IGRA or TST positive

• Identify factors that affect treatment initiation and completion

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwj-2LPqrtrTAhUBwWMKHbHTClkQjRwIBw&url=https://www.linkedin.com/company/denver-health&psig=AFQjCNHqmY8QCvuTojjlQzDBO_LmrI8Z9A&ust=1494129081782748

Dr. Michelle Haas




Modesto, CA

June 5, 2019 6

Of individuals estimated to have LTBI, 1024/7503 or 14% have completed treatment

Conclusions/Lessons learned evaluating the LTBI Care continuum in Primary Care

• The largest gap in the LTBI care continuum in primary care is in testing

• LTBI treatment and completion are low

• Having health insurance was associated with increased LTBI testing and treatment

• New key TB program initiative: support primary care providers to offer LTBI care in their clinics

Dr. Michelle Haas




Modesto, CA

June 5, 2019 7

Pilot initiatives in Primary

care clinics

• Transfer of care to medical home after first visit for LTBI in the TB clinic

• Nurse visits at primary care clinics for follow-up

• pharmacist visits for follow-up

• “Complete” LTBI care

• TST or IGRA testing, chest radiographs and LTBI treatment initiation all in one location

• Public Health/primary care clinic collaboration

• TST testing in clinic, IGRA for confirmation of positives

• IGRA+ will be evaluated in TB clinic

Clinical Scenarios

Dr. Michelle Haas




Modesto, CA

June 5, 2019 8

26-year-old woman. Her IGRA is positive & chest radiograph is normal. She has no symptoms.

Risk factors for TB infection include prior residence in a TB endemic area.

Annual risk is estimated at 0.1% or 5.29% by the age of 80

She is hesitant to start LTBI treatment.

9 months daily isoniazid

4 months daily rifampin

12 weekly doses of isoniazid/rifapentine

It depends – we need more information!

What LTBI treatment would you select?

More information…

• Is on oral contraceptives

• Doesn’t like taking a lot of pills

• Very active, wears contact lenses when she works out

Dr. Michelle Haas




Modesto, CA

June 5, 2019 9

Patient concerns and questions

Why should I take a medication for a bacteria that is dormant/sleeping?

Am I really infected with TB?

I feel fine, why do I need this medication?

I don’t want to risk lowering the effectiveness of my birth control

I am not sure this test is valid

Suggested messaging

It’s important to stay healthy. Even though the risk is low, having active TB can be life

threatening. If you have active TB in your lungs this can be

passed to other people. This puts your health and the health

of your loved ones at risk

While the TB in your body is “sleeping” it is still an infection that could worsen. Treatment before you get sick will keep

this from happening

No test is perfect. However, these are the best tests we have for TB infection. Most

people who become infected with TB aren’t sure when or how it happened

We can find a regimen that will only minimally interact

with your birth control

Dr. Michelle Haas




Modesto, CA

June 5, 2019 10

Denver Metro TB Clinic: RN offering LTBI

options

• “I generally review/offer all options assuming no medical contraindications.”

• “Patients do generally choose either 4R or 3HP, basically whether they can handle remembering a daily medication vs handle taking 10 pills at once – they usually have a strong preference one way or another!”

• “The only time I will not offer 3HP SAT is if I am worried that the patient doesn’t understand how to take the weekly regimen and may overdose.”

Tips from TB Clinic RN for INH-rifapentine

• Ample hydration prior to 3HP dose and the day after.

• transient nausea, dizziness immediately after dosing can be normal if it self resolves, always recommend dosing at night/after dinner for this reason.

• Taking with food helps with tolerability and adherence

INH-rifapentine (anecdotal):

• If preexisting GERD, daily rifampin may exacerbate that more than a once-weekly regimen. Taking with food greatly seems to greatly increase tolerability

• Urine/body fluid discoloration is alarming, but normal, expected and non-painful.

Rifampin (anecdotal):

• reserved for young women who choose to rely solely on their hormonal BCM (the patient can make this decision!), moderate-significant drug interactions on rifampin (mainly with anticoags, ARVs, and psych meds), or previous rifamycin intolerance.

INH (anecdotal)

Dr. Michelle Haas




Modesto, CA

June 5, 2019 11

Our patient starts isoniazid…She likely does not need laboratory monitoring

• Monthly visits include

• Education regarding purpose of treatment

• Assessment of adherence

• Education regarding drug-related symptoms

▪ Fever

▪ Headache

▪ Rash

▪ Nausea, RUQ pain

▪ Dark urine

▪ Numbness

One month later, another provider checked an ALT which was 105 (upper limit of normal = 40). She feels fine. Which of the following is not indicated?

1. Consider other causes of elevated ALT

2. Continue isoniazid – recheck ALT at intervals

3. Discontinue isoniazid immediately

Dr. Michelle Haas




Modesto, CA

June 5, 2019 12

30-year-old man. His IGRA is positive & chest radiograph is normal. He has no symptoms.

Risk factors for TB infection include being a household contact to a person with MDR-TB.

Risk of developing active TB in the next 2 years is 5%




I have no idea


Contact to MDR-TB: Contact to MDR-TB: little data, some clinical experience

• No standard regimen

• Contact MDR-TB expert

• Follow for 2 years

• “can be considered in selected high-risk contacts of patients with MDR-TB, based on “individualized risk” and “sound clinical justification”

• www.who.int

http://www.who.int/

Dr. Michelle Haas




Modesto, CA

June 5, 2019 13

Contact to MDR-TB: little data, some clinical experience

• Prospective observational study• 1/2019-2/2012• 119 contacts of MDR-TB patients:

• 15 declined• 104 began treatment for MDR

LTBI• 93 (89%) completed

treatment, none developed active TB

• 4 contacts discontinued due to adverse effects

• 3/15 (20%) who declined treatment developed MDR-TB

• 15 unidentified contacts developed MDR-TB Bamrah S. et al. Int J Tuberc Lung Dis. 2014 August ; 18(8): 912–918

12-month fluoroquinolone (FQ) based MDR LTBI treatment

30-year-old man. His IGRA is positive & chest radiograph is normal. He has no symptoms.

Risk factors for TB infection include being a household contact to a person with MDR-TB.

Risk of developing active TB in the next 2 years is 5%

Review index patient’s susceptibilities

Discuss with a clinical expert

More data are coming!

V-QUIN levofloxacin vs. placebo in MDR-contacts

TB CHAMP levofloxacin vs. placebo in children under the age of 5

PHOENIx trial (ACTG): delaminid vs. isoniazid for MDR-TB contacts


Dr. Michelle Haas




Modesto, CA

June 5, 2019 14

Pregnancy, lactation, post-partum period

• Pregnancy does not increase TB risk

• INH and Rifampin

• Safe in pregnancy, no contraindication to breastfeeding

• Trials of INH-rifapentine excluded pregnant women

• Higher hepatitis risk post-partum

• Indications for treatment of LTBI in pregnancy:

• High risk contact

• Immunocompromised

3-year-old boy. His IGRA is positive & chest radiograph is normal. He has no symptoms.

He has never had BCG and was born in the US.

Risk factors include traveling with his parents to visit family/friends in Botswana.





Dr. Michelle Haas




Modesto, CA

June 5, 2019 15

Special Situations: Children

Observational data: Denver Public Health 2006-15, change to 4R as 1st line LTBI Rx

• 4R: 84% - 330/395• 9H: 69% - 536/779 p< 0.001• Similar toxicity: 1.5, 0.8%

• UPDATE from Pediatric Red Book 2018• 3 months of INH-rifapentine if ≥ 2 years old (PK data pending for

under 2)• 4 months rifampin and then INH in that order, all acceptable

• INH x 9 mo. - Intermittent regimens used for DOPT

Gaensbauer J. PIDJ 2017.Red Book: 2018-2021

Patient and parental concerns and questions

Are you sure that this is necessary?

I am worried about my child taking medication

My son is very active and hates taking medication—how will I give this to him?

But he was never around anyone who was sick with TB

Dr. Michelle Haas




Modesto, CA

June 5, 2019 16

Suggested messaging

It’s important for your son to stay healthy. Children are at very high risk for developing active TB and complications

such as meningitis

It’s always challenging to give children medication. We are here to support you. Many children are

happy taking medication with food and/or cherry syrup.

Most children do very well on treatment for latent TB and have

no adverse effects

Most of the time, we can’t pinpoint

when we are infected with TB

3-year-old boy. His IGRA is positive & chest radiograph is normal. He has no symptoms.

He has never had BCG and was born in the US.

Risk factors include traveling with his parents to visit family/friends in Botswana.

4 months daily rifampin was chosen because it was easiest to dose and didn't require directly observed therapy


Dr. Michelle Haas




Modesto, CA

June 5, 2019 17

40 year old woman who was diagnosed with rheumatoid arthritis. Her IGRA is positive & chest radiograph is normal. She has no symptoms.

Her rheumatologist wants to start a TNF-alpha antagonist. She is currently on 10mg of prednisone daily.

She is a current household contact to a person with active smear+ pulmonary TB. During the visit, she reveals that she was already treated for LTBI at the age of 10.




No treatment is indicated


TNF-αlpha antagonists

• Treat if

• TST ≥ 5mm --- or ---

• Positve IGRA --- or ---

• Epidemiologic risk [even if TST and IGRA are negative]—somewhat controversial

• Initiate TNF--α inhibitor after one month of LTBI treatment

• Based on expert opinion

Dr. Michelle Haas




Modesto, CA

June 5, 2019 18

Patient concerns and questions

I am worried about having side effects

Am I really infected with TB again?

I would like to get pregnant and may need to undergo IVF in order to get pregnant

Suggested messaging

It’s reasonable to be concerned about adverse effects of treatment. If you do start treatment, we will do everything possible to support you and monitor

you closely.

I am here to support you and your plans to expand your

family. This includes ensuring you stay as healthy as

possible.

Most of the time, we can’t pinpoint when we are infected

with TB. I don’t know for certain if you were infected

again. But, there is a significant risk to you and your

health

Dr. Michelle Haas




Modesto, CA

June 5, 2019 19

40 year old woman who was diagnosed with rheumatoid arthritis. Her IGRA is positive & chest radiograph is normal. She has no symptoms.

Her rheumatologist wants to start a TNF-alpha antagonist. She is currently on 10mg of prednisone daily.

She is a current household contact to a person with active smear+ pulmonary TB. During the visit, she reveals that she was already treated for LTBI at the age of 10.

Lengthy discussion with rheumatologist and patient.

Mutual agreement to start LTBI treatment, would adjust prednisone dose

12 weekly doses of isoniazid/rifapentine was chosen

Patient wanted to finish as quickly as possible


People Living with HIV: LTBI regimens

• INH daily for 9 months + B6 25mg daily

• Rifampin (RIF) given daily for 4 months

–Substantial drug interactions, all medications should be reviewed

•INH-rifapentine once weekly for 12 doses• 2.6% HIV-infected—unclear if on ART in initial studies• Can now be given self-administered or as directly observed therapy• Likely safe if patients are on efavirenz or raltegravir based regimens

Podany, CROI abstract # 455, 2018Weiner M, J antimicrob Chemother 2014

Dr. Michelle Haas




Modesto, CA

June 5, 2019 20

Effect of rifampin on serum concentrations of dolutegravir (DTG) 50mg BID

• INSPIRING Phase 3b non-comparative open label RCT HIV-TB:

• DTG 50mg BID + 2NRTIs during TB tx and 2 weeks post therapy vs. Efavirenz (EFV) + 2NRTIs

• Week 24 of 52:

• 69 received DTG, 44 EFV

• Proportions with VL <50 c/mL:

• DTG 56/69 (81%)

• 5 discontinued due to protocol deviations/LTFU

• EVF 39/44 (89%)

• 2 discontinued due to adverse events

Dooley K et al. J Acquir Immune Defic Syndr 2013;62:21-7Dooley K et al. Clin Infect Dis. 2019 Mar 28

Rifampin Effect on Tenofovir Alafenamide (TAF) Plasma/Intracellular Pharmacokinetics

• Healthy volunteers between the ages of 18-65, n=17

• TAF/FTC once daily x 28 days with food, followed by TAF/FTC once daily with rifampin 600mg daily for 28 days followed by TDF 300mg daily x 38 days

• Intensive PK sampling on day 28, day 56 (TAF/FTC+ rifampin) and 84. • Measured TAF, TFV, FTC and (intracellular) IC TFV diphosphate

• Plasma TAF Cmax and AUC decreased by 45% and 47% respectively

• IC TFV-DP decreased by 40% but still 82% higher than those achieved by standard dose of TDF

Cerrone, M et al. JAC, 2019 Feb 27. oi: 10.1093/jac/dkz068

Dr. Michelle Haas




Modesto, CA

June 5, 2019 21

Rifampin and Raltegravir• Raltegravir concentrations are decreased when co-administered with rifampin

• Increasing the dose to 800mg BID mitigates this interaction

• Unclear if this is necessary to achieve virological suppression: REFLATE TB, Lancet 2014:

Wenning LA, et al. Antimicrob Agents Chemother: 2009

87% completed follow-up at 48 weeks

N=15551 in each armvirological suppression at 24 weeks: Raltegravir 400mg: 39 patients (76%, 95% CI 65–88)

Efavirenz:32 patients (63%, 49–76)

• Phase 3 RCT, open-label, 10 countries participating, n=3,000

• >13 years, living in high TB-burden areas OR who were TST/IGRA positive

• ART with efavirenz or nevirapine; followed for 3 years

• Randomized to 1HP* or 9H*

• Primary endpoint: incidence rates of active TB, TB death or death from an unknown cause

• Results:

• 634 (21%) had positive TST or IGRA

• Primary endpoint:

• N=34 1HP arm; 35 9H arm, for incidence rates of 0.69/100 PY for 1HP and 0.72/100 PY for 9H (IR difference = -0.025, upper 95% CI: 0.31, Table).

• TB incidence rates were higher among those with +TST/IGRA but not different between the two arms

• Treatment completion was 97% with 1 HP vs. 90% in the 9H arm, p<0.01

Swindells, S. et al.*1HP=isoniazid/rifapentine daily x 4 weeks; 9H=isoniazid daily x 9 months

Dr. Michelle Haas




Modesto, CA

June 5, 2019 22

Summary

• Testing and treatment for TB infection (LTBI) should be prioritized for individuals who have lived in areas of ongoing TB transmission

• Identifying risk factors in a systematic way is challenging in clinical practice

• Public Health programs can strengthen TB Prevention efforts by partnering with providers in clinical practice

Thank you!

• Slide contributors

• Randall Reves

• Nicholas Walter

Documents

Treatment: the basicsnid]/treatment...Denver Health •Vertically integrated health care system •Network of 9 primary care clinics, 17 school-based clinics •Serves approximately