Tuberculosis

Latent tuberculosis - Treatment regimens

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

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

Regimen*	Comments
rifapentine** 900 mg x 1/week po + isoniazid 900 mg x 1/week po	3 months. Preferred regimen if rifapentine is available.
isoniazid 5 mg/kg qd (max 300 mg) po + pyridoxine (Vit B6) 25 to 50 mg qd po	6-9 months Consider 9-month duration in countries with high TB prevalence
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
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
** Rifapentine is not approved by EMA
*** Rifabutin is not a WHO recommended regimen

Diagnosis of active tuberculosis

Definitive diagnosis:

clinical symptoms suggestive for pulmonary or extrapulmonary TB AND identification of Mycobacterium tuberculosis by either microscopy (acid fast bacilli), nucleic acid amplification testing, or culture

Clinical diagnosis (WHO):

clinical symptoms suggestive for pulmonary or extrapulmonary TB, supported by radiological findings, suggestive histology and patient’s history AND initiation of anti-TB treatment

Treatment - Drug-susceptible Mycobacterium tuberculosis

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

	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 Corticosteroids are recommended as adjuvant treatment in TB meningitis and TB with CNS involvement(ii)
Alternative Initial phase	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 (only in patients with CD4>100) 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 (see WHO Guidelines, 2022) Evidence on efficacy of this regimen in extrapulmonary TB is limited.

* Intermittent regimens (2 or 3 times per week) are contraindicated in persons with HIV. Missed doses can lead to treatment failure, relapse or acquired drug resistance. Insufficient evidence is available to recommend any ultra-short (<4 months) regimens in HIV patients.

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

ii A recent clinical trial (N Engl J Med 2023;389:1357-1367) did not show statistically significant benefit in use of adjunctive corticosteroids with anti-TB therapy in HIV-associated TB meningitis (HR for death 0.85 [95% CI, 0.66–1.10]). The study, however, did not show any evidence of corticosteroids harm either. The study has some limitations, and it might have been underpowered to detect corticosteroids effect on survival (more than 50% of study population had advanced HIV disease, i.e. CD4 ≤50 cells/mm³; the study was conducted in resource limited settings). The study results do not definitely demonstrate the role of corticosteroids in the  management of TB-meningitis in PLWH. As no harm from their use was seen and there is still uncertainty about their benefit, adjunctive corticosteroids are still recommended in PLWH and TB meningitis. 

Diagnosis of drug-resistant TB - 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 or incomplete 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 - since 2021: 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 optimizing treatment

Treatment of drug-resistant TB

Isoniazid-resistant TB 

• rifampicin/rifabutin + pyrazinamide + ethambutol + levofloxacin or moxifloxacin for 6 months, WHO 2020 recommendations

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

• Treatment of MDR/XDR-TB is a specialist area. WHO has published new Guidelines (2022) 

Currently recommended all-oral regimen:

Can be used in persons with confirmed RR/MDR-TB who have not been exposed to bedaquiline, pretomanid, linezolid for > 1 month

• 6 months of bedaquiline, pretomanid, linezolid (600 mg qd) and moxifloxacin (BPaLM). This regimen may be used without moxifloxacin if resistance to fluoroquinolones (pre-XDR-TB) is documented (BPaL). In this case consider extension of 3 months. Data on the effectiveness of this regimen in extensive pulmonary TB disease or severe extra-pulmonary TB are currently not available (see WHO Guidelines 2022)

Alternative all oral regimen:

Persons and patients groups not eligible to BPaLM regimen may benefit from other all oral regimens. See also the recently released 2024 WHO Key updates to the treatment of drug-resistant tuberculosis

Longer TB treatment regimens (>18 months)

Patients with XDR-TB and those not eligible to or failing all-oral short regimens may benefit from individualized longer treatment.

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. 

The duration of longer regimens must be individualized. For details, see WHO Guidelines 2022.

Treatment compliance is crucial. If needed, each dose of medicines 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-TB

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 ethionamide or prothionamide para-aminosalicylic acid

Pretomanid is recommended but not yet included in Group A drugs

Drug interactions with ART and 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

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	To be used with clavulanic acid
Meropenem		1000 mg tid iv	To be used with clavulanic acid
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 linezolid for 26 weeks Monitor ECG in respect of QT prolongation Peripheral neuropathy is common adverse effect

 
See online lectures for ART from the EACS online course 
https://www.eacsociety.org/education/online-course/