ART: TB/HIV Co-infection

Principles

PLWH with TB should be started on standard TB therapy with 2 months rifampicin/isoniazid/pyrazinamide/ethambutol followed by 4 months rifampicin/isoniazid (choice of drugs and length of treatment depends on drug susceptibility and site of disease), see Diagnosis and Treatment of TB in PLWH

All persons with TB/HIV co-infection should start ART irrespective of CD4 count. Treatment supervision and adherence evaluation are very important. If the person is already on ART, check for potential DDIs and if these are significant, consider switching to one of the recommended regimens for TB/HIV co-infection

ART initiation

Suggested timing of ART initiation in TB/HIV co-infection according to CD4 count

< 50 cells/µL*: As soon as TB treatment is tolerated and whenever possible within 2 weeks

* Be aware of IRIS reaction in persons starting ART at low CD4 count levels and with early initiation of ART. Prophylactic prednisone for 4 weeks at the time of ART initiation (prednisone 40 mg qd for 14 days, then 20 mg qd for 14 days) can prevent paradoxical TB-associated IRIS in persons with CD4 < 100 cells/μL receiving TB treatment [18]
Corticosteroids should be considered for treatment of symptomatic IRIS, with dosages and duration tailored according to response

≥ 50 cells/µL: Can be deferred up to 8 weeks of TB treatment, especially when there are difficulties with DDIs, adherence and toxicities. Although a RCT showed that early ART (within 2 weeks) did not reduce mortality in TB meningitis, recommendations on ART initiations should be based on the CD4 count in PLWH with TB co-infection [17]

ARV regimens

Table 1. Antiretroviral regimens in TB/HIV co-infection

These recommendations are for PLWH initiating ART with susceptible Mycobacterium tuberculosis infection. When treating MDR-TB or XDR-TB, careful review of DDIs and potential toxicities is mandatory before initiating ART

Regimen Main requirements Footnotes (Additional guidance)
Recommended regimens with rifampicin
2 NRTIs + NNRTI
TDF/FTC or TDF/3TC + EFV
TDF/FTC/EFV
At bed time or 2 hours before dinner   (tenofovir salts)
II  (EFV: suicidality. HIV2 or HIV-1 group 0)
ABC/3TC +EFV HLA-B*57:01 negative
HBsAg negative
HIV-VL < 100,000 copies/mL
At bed time or 2 hours before dinner
III (ABC: HLA-B*57:01)
II  (EFV: suicidality. HIV-2 or HIV-1 group 0)
Alternative regimens with rifampicin
2 NRTIs + INSTI
TDF/FTC or TDF/3TC + DTG bid     (tenofovir salts)
IV (DTG: dosing)
TDF/FTC or TDF/3TC + RAL bid     (tenofovir salts)
V  (RAL: dosing)
ABC/3TC + RAL bid HBsAg negative
HLA-B*57:01 negative
III (ABC: HLA-B*57:01)
  (RAL: dosing)
Other combinations with rifabutin
2 NRTIs + PI/r
TDF/FTC or TDF/3TC + DRV/r, ATV/r or LPV/r With food VI (rifabutin dosing)
ABC/3TC + DRV/r, ATV/r, or LPV/r HLA-B*57:01 negative
HBsAg negative
HIV-VL < 100,000 copies/mL
With food
III (ABC: HLA-B*57:01)
VI (rifabutin dosing)

 

Additional guidance

  1. There are available generic forms of TDF, which instead of fumarate use phosphate, maleate, and succinate salts. They can be used interchangeably. In certain countries, TDF is labelled as 245 mg rather than 300 mg to reflect the amount of the prodrug (tenofovir disoproxil) rather than the fumarate salt (tenofovir disoproxil fumarate)
  2. EFV: not to be given if history of suicide attempts or mental illness; not active against HIV-2 and HIV-1 group O strains
  3. ABC contraindicated if HLA-B*57:01 positive. Even if HLA-B*57:01 negative, counselling on HSR risk still mandatory. ABC should be used with caution in PLWH with a high CVD risk (> 20%)
  4. DTG should be dosed 50 mg bid when given with rifampicin
  5. RAL 400 or 800 mg bid. With RAL 400 bid a large phase 3 study showed non-inferiority at week 24 but failed to show non-inferiority at week 48. With 800 mg bid only limited date from a phase 2 study with potential increases in liver toxicity [19]
  6. See table 2 for guidance on antiretroviral and rifabutin dosing

Drug-drug interactions

Table 2. Drug-drug interactions relevant to ART co-administered with rifampicin and rifabutin

  Rifampin Rifabutin
NRTIs
TDF No significant effect No significant effect
TAF

Administer TAF bid

Note: TAF qd results in intracellular levels of tenofovir diphosphate which are still higher than those achieved with TDF. Additional clinical data are needed to assess the efficacy of TAF qd in presence of rifampicin

Expected to decrease TAF. Based on TAF-rifampicin DDI study, consider administration of TAF bid
NNRTIs
EFV 600 mg or alternative 400 mg EFV levels by ↓ 20–30%
EFV at standard dose not weight dependent
Rifampicin at standard dose
Rifabutin levels ↓ by 38%
Rifabutin increase dosed to 450 mg daily
EFV at standard dose
NVP NVP levels ↓ 20–55%
No change in rifampicin
Not recommended
Use standard dose but little data so not recommended
ETR No data available Use standard doses but little data so not recommended
 RPV RPV levels ↓ 90%
Do not use
RPV levels ↓ 50%
Double dose RPV/but not recommended
DOR DOR levels ↓ 56% with steady state rifampicin
Do not use
Increase DOR to 100 mg bid. Maintain bid dosing for at least another 2 weeks following cessation of rifabutin due to persisting inducing effect
PLs
 ATV 80% ↓ level ATV
Do not use
Reduce rifabutin to 150 mg 3 times per week
 ATV/r ↓ level ATV
Do not use
Reduce rifabutin to 150 mg qd
 DRV/r No data
Do not use
Reduce rifabutin to 150 mg qd
 LPV/r 75% ↓ level LPV
Higher doses cause hepatototoxicity
Advice not to use
(If no other option use 400 mg bid RTV or double dose boosted LPV)
Reduce rifabutin to 150 mg qd
Pl/c No data
Do not use
No data
Do not use
INSTI
EVG/c EVG levels ↓
Do not use
Reduce rifabutin to 150 mg 3 times per week
RAL RAL levels ↓ 60%
400 or 800 mg bid can be used but with caution
Use standard doses
DTG Use 50 mg bid Use standard doses
BIC Decrease trough levels by 80%
Do not use
Decrease by 38%
Do not use
CCR5 Inhibitors
MVC Use with caution
MVC levels ↓
Double MVC dose to 600 mg bid
Use standard doses
FI
ENF (T20) No interaction
Use standard doses
No interaction
Use standard doses

Non-rifamycin regimens

Tuberculosis can be treated with regimens that do not contain rifamycins. Their use should be contemplated only in persons with serious toxicity to rifamycins where desensitisation has failed, or in persons with rifamycin-resistant isolates. Although non-rifamycin regimens have fewer drug-drug interactions, such regimens are inferior to a rifampicin-based regimen for fully drug-sensitive TB treatment

Non-rifamycin treatment regimens used for one year when coadministered with streptomycin have shown high relapse rates of greater than 15%. Poorer outcomes have also been seen in cases where rifampicin is used for the initial two months before the regimen is switched to isoniazid and ethambutol in the continuation phase

In countries where neither DTG nor rifabutin are available, following combinations could also represent a short-term alternative until anti-TB treatment has been completed

  • Rifampicin plus double dose LPV/r or with RTV super boosted (400 mg bid) + LPV
  • For other regimens based on 2 NRTIs plus NVP, RPV, DOR, ETV or MVC, consultation with an HIV specialist is recommended