Tuberculosis

Diagnosis & Treatment of TB in PLWH

Treatment

For standard treatment of TB in PLWH, including appropriate choice of ARVs, see table below and ART in TB/HIV Co-infection

See online video lectures TB and HIV Co-infection-Part 1 and TB and HIV Co-infection-Part 2 from the EACS online course Clinical Management of HIV

Susceptible Mycobacterium tuberculosis

  Drug / Dose(i) Comments*
Initial Phase

rifampicin
+ isoniazid (+ pyridoxine)
+ pyrazinamide
+ ethambutol

(Dosing is weight-based)

Initial phase for 2 months.
Possibility to omit ethambutol,
if M. tuberculosis is known to be fully drug sensitive.
Preventive steroid therapy may be considered to avoid IRIS, see IRIS

Alternative

rifabutin
+ isoniazid (+ pyridoxine)
+ pyrazinamide
+ ethambutol

(Dosing is weight-based)

Initial phase for 2 months.
Possibility to omit ethambutol,
if M. tuberculosis is known to be fully drug sensitive

Continuation Phase

rifampicin/rifabutin
+ isoniazid (+ pyridoxine)

(Dosing is weight-based)

Total duration of therapy:
1. Pulmonary, drug susceptible TB: 6 months
2. Pulmonary TB & positive culture at 8 weeks of TB treatment: 9 months
3. Extrapulmonary TB with CNS involvement or disseminated TB: 9-12 months
4. Extrapulmonary TB with bone/joint involvement and in other sites: 6-9 months

 

An alternative shorter regimen of rifapentine, isoniazid, pyrazinamide and moxifloxacin for 2 months, followed by rifapentine, isoniazid and moxifloxacin for 2 months can be used, if rifapentine is available

* Intermittent regimens (2 or 3 times per week) are contraindicated in PLWH. Missed doses can lead to treatment failure, relapse or acquired drug resistance

For dose details, please see separate table on TB Drug Doses, below

Diagnosis: MDR-TB, XDR-TB

Multidrug Resistant TB (MDR-TB) or Extensively Drug-Resistant TB (XDR-TB)

MDR-TB/XDR TB should be suspected in case of:

  • Previous TB treatment
  • Contact with MDR/XDR-TB index case
  • Birth, travel or work in an area endemic for MDR-TB
  • History of poor adherence
  • No clinical improvement on standard therapy and/or sputum smear positive after 2 months of TB therapy or culture positive at 3 months
  • Homelessness/hostel living and, in some countries, recent/current incarceration
  • In areas with very high MDR/XDR-TB prevalence

MDR-TB: Resistance to isoniazid AND rifampicin

XDR-TB: Resistance to isoniazid AND rifampicin AND fluoroquinolones AND at least one of the following injectable drugs: kanamycin, capreomycin or amikacin

XDR-TB 2021 update: Resistance to isoniazid AND rifampicin AND fluoroquinolones AND at least one additional Group A drug, see below

Rapid detection

Gene Xpert or similar technology has the advantage of rapid detection of rifampicin resistance. Drug susceptibility testing is important for optimising treatment

Treatment of resistant TB

Isoniazid-resistant TB 

Rifampicin-resistant (RR) and MDR/XDR-TB

  • Treatment of MDR/XDR-TB is a specialist area. WHO has recently published new Guidelines

Shorter 9-12 months all oral regimen
Can be used in PLWH with confirmed RR/MDR-TB who have not been exposed to treatment with second-line TB drugs, used in this regimen, for more than 1 month, and in whom resistance to fluoroquinolones has been excluded.

Intensive phase: 4 months (can be extended to 6 months if positive sputum smear at the end of 4 months):
bedaquiline (used for 6 months) + levo-/ moxifloxacin + ethionamide + ethambutol + isoniazid (high-dose) + pyrazinamide + clofazimine

Continuation phase: 5 months:
levo-/ moxifloxacin + clofazimine + ethambutol + pyrazinamide
Treatment compliance is crucial. If needed, each dose of MDR/XDR-TB regimen should be given as DOT throughout the whole treatment period

Surgery
Surgical resection may be part of the management for selected persons with focal pulmonary MDR-/XDR-TB

Longer TB treatment regimens

All three Group A drugs and at least one Group B drug should be included to ensure that treatment starts with at least four TB drugs likely to be effective, and that at least three agents are included for the rest of treatment if bedaquiline is stopped.

If only one or two Group A drugs are used, both Group B drugs are to be included.

If the regimen cannot be composed with drugs from Groups A and B alone, Group C drugs are added to complete it

Drug Choices

Each empiric regimen should be reassessed and modified if needed once drug sensitivity results become available
Group A:

Include all three drugs

  • levofloxacin or moxifloxacin
  • bedaquiline
  • linezolid

Group B:
Add one or both drugs

  • clofazimine
  • cycloserine or terizidone

Group C:
Add to complete the regimen
and when drugs from Groups A
and B cannot be used

  • ethambutol
  • delamanide
  • pyrazinamide
  • amikacin (or streptomycin – only if susceptible)
  • imipenem-cilastatin or meropenem with amoxicillin/clavulanic acid
  • ethionamide or prothionamide
  • para-aminosalicylic acid

Duration of MDR/XDR treatment

For longer treatment regimens, a duration of 18-20 months is suggested, but should be individualized. For details, see WHO Guidelines
For XDR-TB, a 3-drug combination of pretomanid, bedaquiline and linezolid during 6 months (3 additional months if culture positive at 4th month) showed promising results, 88% favourable outcomes at 2 years post treatment

DDIs: ART & MDR/XDR regimens

When treating RR/MDR/XDR-TB careful review of DDIs and potential toxicities is mandatory before initiating ART,
see Drug-drug Interactions between Anti-tuberculosis Drugs and ARVs

Latent tuberculosis

Indication: TST > 5 mm or positive IGRA or close contacts to persons with sputum smear positive tuberculosis. See Assessment of PLWH at Initial & Subsequent Visits

Some national guidelines consider the ethnicity, CD4 count and ART usage to define indication for latent tuberculosis treatment

Regimen* Comments

isoniazid
5 mg/kg qd (max 300 mg) po
+ pyridoxine (Vit B6)
20 mg qd po

6-9 months
Consider 9-month duration in high-prevalent TB countries

rifampicin
600 mg qd po
or rifabutin** po
(dose according to current ART)
4 months, check interactions with ARVs, see Drug-drug Interactions between ARVs and Non-ARVs and table on drug-drug interaction relevant ART co-administered with rifampicin and rifabutin

rifampicin 600 mg/day po
or rifabutin** po
(dose according to current ART)
+
isoniazid
5 mg/kg qd (max 300 mg qd) po
+
pyridoxine (Vit B6)
20 mg qd po

3 months, check interactions with ARVs, see Drug-drug Interactions between ARVs and Non-ARVs and table on drug-drug interaction relevant ART co-administered with rifampicin and rifabutin

rifampicin
600 mg x 2/week po
+ isoniazid
900 mg x 2/week po
+ pyridoxine (Vit B6)
300mg 1/week po

3 months, check interactions with ARVs, see Drug-drug Interactions between ARVs and Non-ARVs

rifapentine***
900 mg x 1/week po
+ isoniazid
900 mg x 1/week po

3 months, rifapentine is not yet available in Europe

rifapentine***
450 mg (< 45kg)
or 600 mg (> 45kg) qd po
+ isoniazid
300 mg qd po
+ pyridoxine (Vit B6)
20 mg qd po

4 weeks, rifapentine is not yet available in Europe

* Other preventive regimens may be considered if high risk of latent infection with MDR/XDR-TB

** Rifabutin is not a WHO recommended regimen

*** Rifapentine is not approved by EMA

TB Drug Doses

First line drugs

Drug name Dose Comments
Isoniazid 5 mg/kg qd (usual dose 300 mg) Max 375 mg qd
Caution: neurotoxicity, add pyridoxine 20 mg qd
Rifampicin 10 mg/kg qd (usual dose 600 mg) Rifampicin is not recommended in persons receiving PIs, DOR, ETR, NVP, RPV, FTR, BIC, CAB, CAB/ RPV LA, EVG/c.
see Drug-drug Interactions between Anti-tuberculosis Drugs and ARVs and ART in TB/HIV Co-infection
Rifabutin without PIs, EFV, RPV 5 mg/kg qd (usual dose 300 mg)  
with PIs 150 mg qd
with EFV 450-600 mg qd
with TAF or EVG/c Not recommended
Pyrazinamide 40-55 kg 1000 mg qd  
56-75 kg 1500 mg qd
76-90 kg 2000 mg qd
> 90 kg 2000 mg qd
Ethambutol 40-55 kg 800 mg qd

Max 1600 mg qd
Caution: optic neuritis
Baseline colour vision should be tested

56-75 kg 1200 mg qd
> 75 kg 1200 mg qd

 

Other Drugs

Drug Name Dose Comments
Levofloxacin 30-45 kg 750 mg qd Max 1500 mg qd
> 46 kg 1000 mg qd
Moxifloxacin 400 mg qd  

Max 800 mg qd (used in the standardized shorter MDR-TB regimen)

Monitor ECG in respect of QT prolongation

Bedaquiline

400 mg qd for 2 weeks

200 mg qd three times weekly for 22 weeks

EFV, ETV: potential reduction of bedaquiline exposure and activity. Not recommended

Boosted regimens: increase in bedaquiline exposure.

Potential risk of QT interval prolongation, ECG monitoring recommended.

Avoid coadministration > 14 days

Linezolid 600 mg qd

Max 1200 mg qd

Caution: hematological side effects and neurotoxicity, including optic neuropathy

Clofazimine 100 mg qd

Alternative: 200 mg for 2 months then 100 mg qd

Caution: skin toxicity

Monitor ECG in respect of QT prolongation

Cycloserine or terizidone 30-45 kg 500 mg qd

Max 1000 mg qd

Caution: neurotoxicity; add pyridoxine, up to 50 mg/250 mg cycloserine

> 46 kg 750 mg qd
Delamanid 100 mg bid for 24 weeks Monitor ECG in respect of QT prolongation
Imipenem/cilastatin 1000/1000 mg bid iv  
Meropenem 1000 mg tid iv  
Amoxicillin/clavulanic acid 500/125 mg tid Only to be used with carbapenems (imipenem/meropenem)
Amikacin 30-35 kg 625 mg qd iv

After initial period can be reduced to thrice weekly

Baseline audiometry should be performed

Caution: monitor renal function, audiometry and
drug levels

36-45 kg 750 mg qd iv
46-55 kg 750-1000 mg qd iv
> 55 kg 1000 mg qd iv
Streptomycin 12-18 mg/kg qd iv Max 1000 mg qd iv
Ethionamide or prothionamide 30-45 kg 500 mg qd Caution: gastrointestinal toxicity;
add pyridoxine, up to 50 mg/250 mg prothionamide
46-70 kg 750 mg qd
> 70 kg 1000 mg qd
Para-aminosalycilic acid 4000 mg bid

In weight > 70 kg can be increased to 4000-6000 mg bid

Caution: gastrointestinal toxicity

Pretomanid 200 mg qd

Use with Bedaquiline and Linezold for 26 weeks

Monitor ECG in respect of QT prolongation

Peripheral neuropathy is common adverse effect