Which tuberculosis (TB) medications are contraindicated when used together?

TB Medication Contraindications

Rifampin is absolutely contraindicated with ritonavir-boosted saquinavir, and with the protease inhibitors atazanavir, darunavir, fosamprenavir, saquinavir (unboosted), and tipranavir due to severe hepatotoxicity risk and loss of antiviral efficacy. 1

Absolute Contraindications Between TB and HIV Medications

Rifampin Contraindications

Rifampin must never be combined with:

• Ritonavir-boosted saquinavir - causes severe hepatocellular toxicity 1
• Atazanavir, darunavir, fosamprenavir, saquinavir (unboosted), or tipranavir - rifampin substantially decreases plasma concentrations of these protease inhibitors, resulting in loss of antiviral efficacy and development of viral resistance 1
• Praziquantel - prevents achievement of therapeutically effective blood levels; rifampin must be discontinued 4 weeks before praziquantel administration 1

Historical Rifabutin Contraindications (Now Modified)

Previously, rifabutin was contraindicated with ritonavir and delavirdine, but updated CDC guidelines now permit rifabutin use with ritonavir at substantially reduced doses (150 mg two or three times per week instead of 300 mg daily). 2

Drug Interaction Mechanisms

The contraindications exist because:

• Rifampin is the most potent CYP450 inducer among rifamycins, dramatically reducing blood levels of protease inhibitors and NNRTIs 2, 3
• Full enzyme induction occurs within 1 week of starting rifampin and persists for approximately 2 weeks after discontinuation 3
• The combination of rifampin with most protease inhibitors results in 80-95% reductions in protease inhibitor concentrations 4, 5
• Even ritonavir boosting cannot overcome rifampin's induction effect - studies show 87% reduction in indinavir and 94% reduction in ritonavir concentrations when combined with rifampin 5

Permitted Combinations (Not Contraindicated)

Rifampin CAN be used with specific antiretroviral regimens:

• Efavirenz plus two NRTIs 2
• Ritonavir (alone, not boosting other PIs) plus one or more NRTIs 2
• Ritonavir combined with saquinavir (hard-gel or soft-gel capsule) as dual protease inhibitor therapy 2

All nucleoside reverse transcriptase inhibitors (NRTIs) - zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir - have no contraindication with any rifamycin because they are not metabolized by CYP450. 2

TB Medications Without Contraindications

Isoniazid, pyrazinamide, ethambutol, and streptomycin have no contraindications with protease inhibitors, NNRTIs, or NRTIs - these first-line TB drugs are not CYP450 inducers. 2

Critical Clinical Pitfalls

Common errors to avoid:

• Never assume ritonavir boosting will overcome rifampin induction - even low-dose ritonavir used to boost other protease inhibitors cannot prevent subtherapeutic levels when rifampin is added 5
• Remember the 2-week washout period - rifampin's enzyme-inducing effects persist for at least 2 weeks after the last dose, so protease inhibitors or NNRTIs should not be started until 2 weeks post-rifampin 2
• Do not substitute rifabutin for rifampin in HIV-negative patients - rifampin remains the preferred agent for TB treatment in patients not taking contraindicated antiretrovirals 2
• Prioritize TB treatment over HIV treatment modifications - active TB requires immediate, uncompromised treatment with rifampin-containing regimens for optimal morbidity and mortality outcomes 2