sa tb guidelines the interface with advanced clinical care

SA TB Guidelines – The interface

with Advanced Clinical Care

Dr Kogie Naidoo (MBCHB, PHD)

Head: CAPRISA Treatment Research Programme

Honorary Lecturer - UKZN Department of Public Heath Medicine

Annual Workshop on Advanced Clinical Care

ICC Durban

6 October 2016

http://www.cdc.gov/

http://www.cdc.gov/

Presentation Outline

• Diagnostic algorithm for DR and DS TB

• Retreatment TB: Revised definitions and

treatment regimen

• ART initiation in TB patients

• Special considerations:

Aluvia with TB treatment

Atazanavir in TB

Ethambutol in Renal failure

Moxifloxacin and streptomycin indications

• TB prevention in HIV infected patients

Currently available TB Diagnostic

tests

Which initial TB diagnostic test does

WHO recommend for HIV + people with

suspected TB?

1. Smear Microscopy

2. Xpert MTB/RIF

3. Culture

Where GeneXpert (GXP) is available,

culture may still be required for:

1. HIV positive TB suspects, who have a negative GXP test

2. TB cases diagnosed as Rifampicin(Rif) resistant on GXP

for susceptibility testing of other drugs

3. Despite a Rif susceptible result, the patient is failing

treatment and treatment adherence is good and thus

resistance to drugs other than Rif is suspected

4. All of the above

TB SUSPECTS

TB and DR-TB contacts, non-contact symptomatic individuals, re-treatment after relapse, failure and default

Collect one sputum specimen at the health facility under supervision

GXP positive

Rifampicin susceptible

GXP positive

Rifampicin resistant

GXP positive

Rifampicin

unsuccessful

GXP negative GXP unsuccessful

Treat as TB

Start on Regimen 1

Send one specimen for

microscopy

Treat as MDR-TB

Refer to MDR-TB

facility

Treat as TB

Start on Regimen 1

Collect one specimen

for microscopy

Culture & DST / LPA

Collect one sputum

specimen for a

repeat GXP

HIV positive HIV negative

Collect one specimen for culture and

LPA or culture and DST (for R and H)

Treat with antibiotics and review after 5

days

Do chest x-ray

Treat with antibiotics

Poor response to

antibiotics

Clinically TB

TB on chest x-ray

LPA/ DST results

Resistant to R

and H/ R only

Good response

No further follow

up

Advise to return

when symptoms

recur

Poor response

Consider other

diagnosis

Refer for further

investigation

Treat as MDR-TB

Refer to MDR-TB Unit

Treat as TB

Start on Regimen 1

Review culture results

Follow up with

microscopy

Collect one specimen for

microscopy, culture and

DST for Rifampicin,

Isoniazid, fluoroquinolone

and Aminoglycoside

Follow up with

microscopy and culture

Where GeneXpert (GXP) is available,

culture may still be required for:

1. HIV positive TB suspects, who have a negative GXP test

2. TB cases diagnosed as Rifampicin(Rif) resistant on GXP

for susceptibility testing of other drugs

3. Despite a Rif susceptible result, the patient is failing

treatment and treatment adherence is good and thus

resistance to drugs other than Rif is suspected

4. All of the above

Streptomycin is indicated for:

1. All categories of DS TB

2. All categories of retreatment TB

3. For patients that cannot tolerate first line

TB medication

4. All of the above

5. None of the above

TB SUSPECTS

TB and DR-TB contacts, non-contact symptomatic individuals, re-treatment after relapse, failure and default

Collect one sputum specimen at the health facility under supervision

GXP positive

Rifampicin susceptible

GXP positive

Rifampicin resistant

GXP positive

Rifampicin

unsuccessful

GXP negative GXP unsuccessful

Treat as TB

Start on Regimen 1

Send one specimen for

microscopy

Treat as MDR-TB

Refer to MDR-TB

Unit

Treat as TB

Start on Regimen 1

Collect one specimen

for microscopy

Culture & DST / LPA

Collect one sputum

specimen for a

repeat GXP

HIV positive HIV negative

Collect one specimen for culture and

LPA or culture and DST (for R and H)

Treat with antibiotics and review after 5

days

Do chest x-ray

Treat with antibiotics

Poor response to

antibiotics

Clinically TB

TB on chest x-ray

LPA/ DST results

Resistant to R

and H/ R only

Good response

No further follow

up

Advise to return

when symptoms

recur

Poor response

Consider other

diagnosis

Refer for further

investigation

Treat as MDR-TB

Refer to MDR-TB Unit

Treat as TB

Start on Regimen 1

Review culture results

Follow up with

microscopy

Collect one specimen for

microscopy, culture and

DST for Rifampicin,

Isoniazid, fluoroquinolone

and Aminoglycoside

Follow up with

microscopy and culture

Streptomycin is indicated for:

1. All categories of DS TB

2. All categories of retreatment TB

3. For patients that cannot tolerate first line

TB medication

4. All of the above

5. None of the above

TB Treatment if unable to treat with

standard first line RxMissing drug Possible regimen Duration of treatment

INH Moxifloxacin/ rifampicin/

ethambutol

12 months ±PZA in

intensive phase

Rifampicin Moxifloxacin/ INH/

ethambutol

18 months(PZA or

streptomycin in intensive

phase)

Rifampicin/INH Moxifloxacin/ ethambutol/

streptomycin

18 months

PZA Rifampicin/INH/ ethambutol Nine months

Mechanism of TB treatment

associated DILI

Drug Mechanism Clinical picture

RIF Dose-dependent

interference with

bilirubin uptake

±hypersensitivity

reaction

• Onset: Transient, early in treatment

• Subclinical, Jaundice without

hepatocellular damage,

• ↑Unconj Bil. May potentiate

hepatotoxic effects of other drugs.

PZA Dose-dependent

and idiosyncratic

hepatotoxicity

• Hypersensitivity reactions with

eosinophilia and liver injury or

granulomatous hepatitis.

• More damage in liver with pre-existing

disease.

INH Free radical

generation: toxic

to hepatocytes

• Onset: Within weeks to months.

• Rechallenge does not always elicit a

rapid recurrence of hepatotoxicity

**Alcohol consumption doubles rate of probable INH hepatitis

Definition of DILI

SA HIV Clinician’s Society

DILI guidelines:

ALT level > 120 IU/L and symptomatic

(Nausea, vomiting, abdominal pain,

jaundice) or

ALT level >200 IU/L and asymptomatic

or

Total serum bilirubin concentration > 40

umol/L

Risk factors for DILIModifiable Non-modifiable

• HIV infection

• Hepatitis B Surface

antigen positivity

• Hepatitis C co-

infection

• Malnutrition

• Hypo-albuminaemia

• Abnormal baseline

ALT

• Alcohol use

• Underlying liver

disease

• Age >35 years

• Childhood

• Slow acetylator status

• Female sex

Management of TB DILI

• Limited data

• Most guidelines are based on expert opinion

Principles of TB DILI

management• Moderate to severe liver damage STOP

drugs

• Investigate for other causes of hepatitis

• Confirm the diagnosis of TB

Green card

Intensive phase/ continuation phase

Search for pending TB culture results

Re-investigate for TB

TB Drug Rechallenge in DILI

• If patient presented in liver failure:

TB drug re-challenge is not recommended

• Otherwise, re-challenge

Rates of DILI recurrence in re-challenge is 12 %

• Rechallenge method: Regimen Rechallenge vs Sequential

Drug Rechallenge - latter in full doses vs incremental doses

• RCT data on Rates of DILI recurrence by type of Rechallenge

method: Regimen Rechallenge (14%) vs Sequential Drug

Rechallenge in full (10%) vs incremental (9%) doses

Case 1

• Miss HS is a HIV positive 34 year old female.

• She is clinically stable on an FDC.

• She is diagnosed with TB Lymphadenopathy

based on AFB demonstrated in LN aspirate

following a 2 month duration of fever and LOA.

• She tolerates TB Rx well and has resolution of

constitutional symptoms.

• On routine LFT is as follows:

ALT= 79 IU/L AST= 60 IU/L

Normal Total bilirubin Normal ALP and GGT

What is the most appropriate

management?

1. Refer for admission, Stop TB treatment, Stop

ART

2. Continue TB treatment and ART, discharge

from follow up

3. Continue TB treatment and ART, repeat ALT

and Bili in 1 week

4. Continue TB treatment and ART, repeat ALT

and Bili daily

Mild DILI

Clinically well

ALT <200 and Total Bili <40

• Continue TB drugs

• Continue ART if already initiated

• Repeat ALT and Bili in 1 week

• If ALT and bili improving or normal then stop Lab

monitoring

• If ALT and Bili continue to rise, treat as moderate

or severe DILI

Moderate DILI

Clinically well

ALT> 200 irrespective of Total Bili

• Stop TB regimen

• Discontinue Bactrim prophylaxis and other hepatotoxic drugs

• Start ETH/ MOX/ STR if treatment necessary

• Stop ART unless on a stable ART regimen for > 6 months

• Repeat ALT and Bili in 3 (Inpt) or 7 (Outpt) days

• When ALT < 100 and Bili is normal, attempt rechallenge

TB Drugs in Renal failure

• INH, rifampicin, PZA : biliary excretion normal doses

•Streptomycin and ethambutol : can maintain at reduced dose – monitor for uveitis

•Safest regimen: INH, Rifampicin, pyrazinamide X 4 months followed by INH and Rifampicin x 2 months

Managing TB treatment

Interruption

• Less than 1 month: extend treatment for the number of days that patient did not take treatment

• 1-2 months missed: do geneXpert Sensitive: add number of days that patient did not take

treatment.

Resistant: stop treatment: refer to MDR-TB unit

• More than 2 months missed (loss to follow up) do geneXpert Sensitive : restart treatment

Resistant : refer MDR-TB

Integration of TB HIV Services

• Screening for TB and HIV at same visit

• Early initiation of ARVs

• Co-management of Drug toxicities common

to both

• Consideration of Drug interactions

• Early detection and management of TB IRIS

• Initiation of INH prophylaxis

•In TB co-infection, start with TB treatment first, followed by

ART as soon as possible and within 8 weeks

• If CD4 <50 cells/μl initiate ART within 2 weeks of starting TB

treatment, when the patient’s symptoms are improving and TB

treatment is tolerated

• If CD4 >50 cells/μl initiate ART within 2-8 weeks of starting TB

treatment

• In cryptococcal or TB meningitis: Defer ART initiation for 4-6

weeks

TB service One-stop service HIV service

NOTo

Referral

HIV testing

ART

CPT

Condoms

Partiallyintegrated

HIV and TB Services provided together

ART

TB diagnosis and treatment

Co-locatedAdjacent

NOTo

Referral

TB screening

IPT

TB diagnosis

TB treatment

TB contact tracing

Partiallyintegrated

Models for integrated TB and HIV services delivery

Integrated service delivery

Source: WHO

Concerns of co-treating TB and HIV

• Overlapping Toxicity

• Drug Interactions

• IRIS

What are the overlapping drug toxicities with TB treatment and ARVs?

1. Liver Injury

2. Rash

3. Psychosis

4. All of the above

Side-effect Antiretroviral drug TB Therapy

Nausea & vomiting Didanosine, Zidovudine,

Ritonavir

Pyrazinamide

Hepatitis Nevirapine

Efavirenz

Rifampicin

Isoniazid

Pyrazinamide

Peripheral

neuropathy

Stavudine

Didanosine

Isoniazid

Rash

Psychosis

Renal Toxicity

Nevaripine

Efavirenz

EFV

Tenofovir

Rifampicin

Isoniazid

Pyrazinamide

Ethambutol

INH/Ethambutol

Rifampicin

Overlapping Toxicities with co-Rx of HIV and TB

What are the overlapping drug toxicities with TB treatment and ARVs?

1. Liver Injury

2. Rash

3. Psychosis

4. All of the above

Case 2

• Mrs AA is HIV + since 2010. She was

initially started on TDF / 3TC and EFV.

• In 2014, she was changed to ABC / 3TC

and Alluvia due to treatment failure.

• She now presents with night sweats, loss

of appetite and abdominal pain.

• The Gene Xpert test on ascitic fluid is

positive for Rif sensitive MTB

How to do you manage further?

1. Start TB Rx, double the dose of Aluvia

immediately

2. Start TB Rx, double the dose of Aluvia over 2

weeks

3. Double the dose of Aluvia over 2 weeks then

start TB Rx

How to do you manage further?

1. Start TB Rx, double the dose of Aluvia

immediately

2. Start TB Rx, double the dose of Aluvia over

2 weeks

3. Double the dose of Aluvia over 2 weeks then

start TB Rx

Mrs AA improves on TB Rx and completes the

course. Her symptoms and signs have

resolved, and her exit sputum is negative for

AFB. How do you manage further?

1. Reduce Aluvia dose to 2T bd immediately

2. Continue TB Rx for two weeks longer

3. Continue the double dose (4T bd) of

Aluvia until 2 weeks after TB Rx is

completed

Case 3

• Mr E has been on a second line regimen

for a year.

• His regimen includes AZT/3TC/ATZ/rit

because he had severe diarrhoea whilst

on Aluvia.

• He now presents with fever and productive

cough.

• His sputum Gene Xpert is positive for Rif

sensitive MTB.

How do you manage further?

1. Commence TB treatment immediately

2. Double the dose of Atazanavir as you do

for Aluvia

3. Atazanavir may not be given to patients

on TB treatment. Refer to specialist

4. Stop the ART, treat TB, then restart ART

How do you manage further?

1. Commence TB treatment immediately

2. Double the dose of Atazanavir as you do

for Aluvia

3. Atazanavir may not be given to

patients on TB treatment. Refer to

specialist

4. Stop the ART, treat TB, then restart ART

Drug Interactions: 1. RIF and EFV

• Previously reported that Rif caused a 30%

decrease in EFV trough concentrations,

particularly in patients >50kg.

• An increase in EFV dose recommended by FDA

(USA)

• Later reports → clearance of EFV is reduced in

black African patients, due to CYP enzyme

polymorphisms (therefore drug levels actually

increased by 30-50%)

• No increase in EFV dose recommended in SA

2. RIF and PI• PI metabolized by CYP 3A4: induced by Rifampicin and

inhibited by Ritonavir

• Significant reduction of plasma drug levels of most PI’s, except Ritonavir

• LPV/r (Aluvia): Ritonavir boosted Lopinavir (400/100mg)

• Increase Ritonavir to 400mg daily to overcome the enzyme induction – double Aluvia dose

Usual 2T BD, increased to 3T BD for 1 wk then 4T BD

Maintain escalated dose of PI until 2 wks after TB Rx completion

• Rif accelerated Atazanavir/r metabolism, cannot be overcome by boosting with Ritonavir

Referral to higher centre to change PI or change Rifampicin to Rifabutin

TB IRIS

TB diagnosed & treatment started

before ART initiation

No TB diagnosis before ART initiation

ART Initiation

Clinical deterioration of TB as a result of

ART-induced immune recovery =

Paradoxical TB IRIS

Atypical inflammatory presentation of TB as a result of ART-induced

immune recovery = Unmasking IRIS

Lawn Expert Rev Anti Infect Ther, 2011.

TB IRIS incidence, risk factors and

outcomes• Unmasking TB IRIS Incidence 4.8% (most

common )

• Paradoxical TB-IRIS Incidence 18%

• Onset 14 days after ART initiation in 48%

• Hospitalisation 25%

• Mortality 7%, death attributed to TB IRIS 2%

• Increased mortality in CNS IRIS

• Risk Factors: Low CD4 count, Short interval

between TB treatment and ART, Disseminated

TB

TB IRIS Management

• Double-blind, placebo-controlled RCT• Intervention: Prednisone 1.5mg/kg/day x 2 wks then

0.75mg/kg/day x 2 wks• Primary outcome = hospital days• Findings: Steroid arm - fewer days in hospital and fewer

procedures. IRIS associated mortality same in both arms, except CNS disease

• Excl other causes of patient deterioration: MDR TB etc

What are the current guidelines for IPT for patients on ART?

1. 36 months IPT for all patients



4. 36 months IPT for TST positive, 12 months for TST negative, 6 months for TST unknown

INH Prophylaxis

What are the current guidelines for IPT for patients on ART?




4. 36 months IPT for TST positive, 12 months for TST negative, 6 months for TST unknown

Questions

Are patients eligible for more IPT post TB therapy completion?

1. Yes: can be started immediately after TB treatment in all patients

2. No: patients no longer at risk for TB, having just completed TB treatment

3. Yes: can be started immediately after TB treatment but only in patients with documented bacteriologic cure

Summary

• Diagnostic algorithm for DR and DS TB

• Retreatment TB: Revised definitions and

treatment regimen

• ART initiation in TB patients

• Special considerations:

Aluvia with TB treatment

Atazanivir in TB

Ethambutol in Renal failure

Moxifloxacin and streptomycin indications

• TB prevention in HIV infected patients

Acknowledgements

This training was supported by the

Grant or Cooperative Agreement

Number U2G GH001142, funded by

the Centers for Disease Control and

Prevention. Its contents are solely

the responsibility of the presenters

and do not necessarily represent the

official views of the U.S. Centers for

Disease Control and Prevention or

the U.S. Department of Health and

Human Services

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