12.5 Drug interactions

12.5.1 Antituberculous and antiretrovirals

Rifamycins and antiretrovirals

Interactions between rifamycins and 2 groups of antiretrovirals (ARVs) ⎯ NNRTIs and protease inhibitors (PIs) ⎯ must be expected due to liver enzyme induction of the rifamycins.
For possible combinations of ARVs and rifamycins, see Table 12.1.

Patients receiving NVP when TB is diagnosed:
– If rifabutin is available, give 2 months of HZE-Rfb followed by 4 months of H-Rfb.
– If rifabutin is not available, replace NVP with EFV 600 mg. When the TB treatment is completed, NVP may be resumed1 .
– If rifabutin is not available and EFV is contraindicated, see options in previous section.

Patients receiving protease inhibitors (PI):
– When PIs and rifamycins are given to the same patient, PI serum levels can decrease to sub-therapeutic levels, while the serum levels of rifamycins could rise to toxic levels.
– Rifabutin is a less potent enzyme inducer than rifampicin; rifabutin is the preferred drug in patients using PIs.
– If rifabutin is not available, dosages of lopinavir and ritonavir (LPV/r) must be significantly increased in patients taking both LPV/r and rifampicin (see Table 12.1). Liver enzymes should be monitored.

Table 12.1 Possible combinations of ARVs and rifamycins


Rifampicin

Rifabutin

NNRTIs

Nevirapine (NVP)

Do not combine unless Rfb is not available and there are no other options.

Rfb: 300 mg/day
NVP: usual dose

Efavirenz (EFV)

May be combined.
R: usual dose
EFV: 600 mg/day


NRTIs

Abacavir (ABC)




May be combined without dose adjustments.




Didanosine (ddI)

Lamivudine (3TC)

Stavudine (d4T)

Zidovudine (AZT)

Tenofovir (TDF)

Pls

Indinavir (IDV)

Do not combine

Rfb: 300 mg/day
IDV: 1 g every 8 hours

Nelfinavir (NFV)

Do not combine

Rfb: 300 mg/day
NFV: usual dose

Lopinavir/ritonavir (LPV/r)

May be combined if Rfb is not available.
LPV/r: double dose of LPV/r (800 mg/ 200 mg twice daily)
R: usual dosage

Rfb: 150 mg/day4
LPV/r: usual dose

Atazanavir/ritonavir (ATZ/r)

Do not combine

Rfb: 150 mg/3 times a week5
ATZ/r: usual dose

Bedaquiline and antiretrovirals6,7

Data from drug-drug interaction studies with bedaquiline and ARVs to date are extremely limited.
– NNRTI: EFV (enzyme inducer) is estimated to decrease bedaquiline concentrations by 50%. Nevirapine does not significantly affect bedaquiline concentrations.
– NRTI are unlikely to affect bedaquiline concentrations.
– PI: ritonavir is an enzyme inhibitor. The use of ritonavir-boosted lopinavir (LPV/r) with bedaquiline may result in a significant accumulation of bedaquiline and its metabolites. This combination is therefore not recommended.

The following ART regimens can therefore be considered in association with bedaquiline:
1) 2 NRTIs + nevirapine: e.g. AZT/3TC or FTC/NVP or TDF-3TC-NVP;
or
2) 3 NRTIs: e.g. AZT/3TC/ABC.

Fluoroquinolones and didanosine

Buffered didanosine contains an aluminium/magnesium-based antacid that, if given with a fluoroquinolone, can result in its decreased absorption. If it is not possible to avoid prescribing these drugs together, didanosine should be given 2 hours apart fluoroquinolone administration. The enteric-coated formulation of didnosine can be given without such precaution.

Other drug-drug interactions can occur between anti-TB drugs and ARVs, further complicating treatment. Most of the drugs used in the treatment of DR-TB have not had drug-drug interaction studies performed with ARVs.

12.5.2 Other interactions

Rifampicin can interact with drugs commonly used in opportunistic infections.

Interaction occurs with fluconazole. Rifampicin may decrease blood levels of fluconazole by as much as 25-50%. The two drugs can be taken 12 hours apart (i.e. rifampicin in the morning, fluconazole in the evening) without dosage adaptation. However, the patient’s clinical condition should be carefully monitored, as the dosage of fluconazole may need to be increased if clinical improvement is suboptimal.
For the treatment oral candidiasis, miconazole mucoadhesive tablets (gum patches) can be used (no interaction with rifampicin).



Footnotes
Ref Notes
1

If a patient is changed from EFV back to NVP on completion of TB treatment, no lead-in dosing of NVP is necessary.