SA TB Guidelines – The interface with Advanced Clinical Care

Dr Kogie NaidooHead: CAPRISA Treatment Research

ProgrammeAnnual Workshop on Advanced Clinical Care

Durban, 20 November 2015

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 Atazanivir 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

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 SUSPECTSTB 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 positiveRifampicin susceptible

GXP positiveRifampicin resistant

GXP positiveRifampicin unsuccessful

GXP negative GXP unsuccessful

Treat as TBStart on Regimen 1

Send one specimen for microscopy

Treat as MDR-TBRefer to MDR-TB

Unit

Treat as TB

Start on Regimen 1Collect 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 daysDo 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 TBStart on Regimen 1Review 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

Advantages and Disadvantages of GXP Test

• Detects MTB and Rif resistance

• Rapid TAT• Specific for MTB

complex• Use in CSF, gastric

aspirates, lymph nodes, tissue

• ↓ Risk of cross-contamination & error

• > sensitivity than microscopy

• Cannot be used for monitoring treatment (cannot distinguish between live and dead bacilli)

• Discordant results• Unsuccessful test due

to lab errors, test failure or invalid results. Needs repeat with second specimen

• Expensive • Does not detect INH

resistance

Retreatment TB Definitions• Previously treated: past TB treatment > 4 weeks

& now either relapse, defaulted, or treatment failure(+/- microscopy; PTB/EPTB)

• Relapse: TB again after previous cure/Rx completion – either true relapse or new infection

• Retreatment after failure: Received full course of treatment and remains or becomes smear or culture positive at the end of the treatment period

• Retreatment after default: completes one month of treatment and returns foll a 2 month treatment interruption

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 SUSPECTSTB 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 positiveRifampicin susceptible

GXP positiveRifampicin resistant

GXP positiveRifampicin unsuccessful

GXP negative GXP unsuccessful

Treat as TBStart on Regimen 1

Send one specimen for microscopy

Treat as MDR-TBRefer to MDR-TB

Unit

Treat as TB

Start on Regimen 1Collect 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 daysDo 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 TBStart on Regimen 1Review 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

Missing 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

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

TB Prevalence & Incidence in SA: WHO Global Report 2015

696/100 000

All: 834/100 000HIV+:509/100 000

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

Why start ARVs early?

How early should ART be initiated?

Balance of risks and benefitsFor CD4 count <50 cells/mm3 For CD4 ≥50 cells/mm3

Late integrated therapy↓ AIDS or

death↓IRIS

↓drug switches

Early integrated therapy Late integrated therapy

Early integrated therapy has:68% lower AIDS /death rate overshadows - 5-fold higher risk of IRIS- Increasing trend in drug switches

Early integrated therapy has:No discernable benefit in AIDS /death rate- 2-fold higher risk of IRIS- ↑ drug switches

Early integrated therapy

Recommend: Recommend:

Early ART initiation as soon as possible after TB treatment initiation

Defer ART initiation to start of continuation phase of TB therapy

SA guidelines for HIV-TB co-infected

ACTIVE TB DISEASE, IRRESPECTIVE OF CD4 COUNT

OR CLINICAL STAGE

• 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 Injury2. Rash3. Psychosis4. All of the above

Side-effect Antiretroviral drug TB Therapy

Nausea & vomiting Didanosine, Zidovudine,Ritonavir

Pyrazinamide

Hepatitis NevirapineEfavirenz

RifampicinIsoniazidPyrazinamide

Peripheralneuropathy

StavudineDidanosine

Isoniazid

Rash

PsychosisRenal Toxicity

NevaripineEfavirenz

EFVTenofovir

RifampicinIsoniazidPyrazinamideEthambutol

INH/EthambutolRifampicin

Overlapping Toxicities with co-Rx of HIV and TB

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

1. Liver Injury2. Rash3. Psychosis4. All of the above

Case 1

• 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 Alluvia immediately

2. Start TB Rx, double the dose of Alluvia over 2 weeks

3. Double the dose of Alluvia over 2 weeks then start TB Rx

How to do you manage further?

1. Start TB Rx, double the dose of Alluvia immediately

2. Start TB Rx, double the dose of Alluvia over 2 weeks

3. Double the dose of Alluvia 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 Alluvia dose to 2T bd immediately

2. Continue TB Rx for two weeks longer

3. Continue the double dose (4T bd) of Alluvia until 2 weeks after TB Rx is completed

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 Alluvia dose to 2T bd immediately

2. Continue TB Rx for two weeks longer

3. Continue the double dose (4T bd) of Alluvia until 2 weeks after TB Rx is completed

Case 2

• 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 NVP• NVP clearance may vary between ethnic groups

• Standard NVP dose is effective when co-

administered with RIF

• Increased hepatotoxicity, especially during

the first two months of NVP containing ART

3. 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 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

Major TB-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 patients2. 12 months IPT for all patients3. 6 months IPT for all patients4. 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?

1. 36 months IPT for all patients2. 12 months IPT for all patients3. 6 months IPT for all patients4. 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

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