Tuberculosis

Diagnosis & Treatment of TB in PLWH

Treatment

For standard treatment of TB in PLWH, including appropriate choice of ARVs, see table 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

[9]

  Drug / Dose(i) Comments*
Initial Phase

rifampicin + isoniazid + pyrazinamide + ethambutol

(Dosing is weight-based)

- Initial phase for 2 months, then
- Continuation phase (rifampicin + isoniazid)
according to TB type (see below).
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 + pyrazinamide + ethambutol

(Dosing is weight-based)

- Initial phase for 2 months, then
- Continuation phase according to TB type (see below).
Possibility to omit ethambutol, if M. tuberculosis is known to be fully drug sensitive

Continuation Phase rifampicin / rifabutin + isoniazid according to TB type 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


* Intermittent regimens (2 or 3 times per week) are contraindicated in HIV-positive persons. Missed doses can lead to treatment failure, relapse or acquired drug resistance [10].
i. For dose details, please see table TB Drug Doses, below

Diagnosis: MDR-TB, XDR-TB

Multi-Drug Resistant TB (MDR-TB) or Extensively-Drug Resistant 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 quinolones and at least
one at the following injectable drugs: kanamycin, capreomycin or amikacin

Rapid Detection

  • Gene Xpert or similar technology has the advantage of rapid detection of rifampicin resistance. Drug susceptibility testing is important in optimising treatment
  • Some countries/regions have neither of the above and have to use an empirical approach

Treatment of Resistant TB

INH-resistant TB [11]

  • RIF or RFB + Z+ E for 2 months and RIF or RFB + E for 10 months
  • RIF + E + Z + a FQ for 6 months
  • Some experts recommend to add a FQ in the intensive phase and replace E by the FQ in the maintenance phase

Rifampicin-resistant TB and MDR-/XDR-TB

  • Treatment of MDR-/XDR-TB is a specialist area. WHO has recently published new guidelines [12]. Other specialists have different views and practice may vary
  • Initial therapy should include 4 likely effective TB drugs, and treatment should include at least 3 active drugs after bedaquiline is stopped
  • 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

Drug Choices

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

Include all three medicines

 
  • levofloxacin (LFX) or moxifloxacin (MFX)
  • bedaquiline (BED)
  • linezolid (LZD)

Group B: Add one or both medicines

  • clofazamine (CFX)
  • cycloserine (CS) or terizidone (TRD)

Group C:

Add to complete the regimen
and when medicines from
Groups A and B cannot be
used

  • ethambutol (E)
  • delamanid (DLM)
  • pyrazinamide (Z)
  • amikacin (AMK) (or streptomycin (S) – only if susceptible)
  • imipenem–cilastatin (IPM-CLN) or meropenem (MPM) with amoxicillin/clavulanic acid (AMX)
  • ethionamide (ETO) or prothionamide (PTO)
  • p-aminosalicylic acid (PAS)

Duration of MDR/XDR Treatment

  • 6 months of intensive phase using 4 or more drugs, followed by 12-14 months of 3 drugs depending on response
  • In persons with rifampicin-resistant or MDR-TB who have not previously been treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen [13,14]
  • For XDR-TB, a 3-drug combination of pretomanid, bedaquiline, and linezolid during 6 months (3 additional months if culture positive at 4th month) show promising results [15]

DDIs: ART & MDR/XDR Regimen

When treating MDR-TB or XDR-TB, careful review of DDIs and potential toxicities is mandatory before initiating ART

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/day (max 300 mg) po
+ pyridoxine (Vit B6)
25 mg/day po

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

rifampicin
600 mg/day po
or rifabutin** po
(dose according to current cART)
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 cART)
+
isoniazid
5 mg/kg/day (max 300 mg) po
+
pyridoxine (Vit B6)
25 mg/day 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 2/week po
+ isoniazid
900 mg 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 1/week po
+ isoniazid
900 mg 1/week po

3 months, rifapentine is not yet available in Europe

rifapentine***
450 mg (< 45kg)
or 600 mg (> 45kg) /day po
+ isoniazid
300 mg/day po
+ pyridoxine (Vit B6)
25 mg/day po [16]

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

 [12, 17]

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
Rifampin 10 mg/kg qd (usual dose 600 mg) Rifampin is not recommended in persons receiving
PIs, ETR, RPV, EVG/c or TAF, see Drug-drug Interactions between ARVs and Non-ARVs and table on drug-drug interaction relevant ART co-administered with rifampicin and rifabutin
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 30-46 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 30-46 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