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Tuberculosis – Drug-drug Interactions

Drug-drug Interactions

  • The majority of interactions between TB and HIV therapies are through induction or inhibition of metabolic enzymes in the liver or intestine; most notably enzymes of the CYP450 family1,2

– the CYP3A4 isoform metabolises many drugs, including Protease Inhibitors (PIs) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
– rifamycins (such as rifampicin and rifapentine) are potent inducers of CYP3A4 and have clinically important interactions with PIs and NNRTIs

  • Currently recommended first-line ART regimens for TB patients are those that contain efavirenz, as its interactions with anti-TB therapies are minimal compared with other NNRTIs.3,4

– efavirenz and nevirapine are the two NNRTIs recommended by the WHO for co-administration with TB therapies3
– efavirenz should not be used during the first 1–2 trimesters of pregnancy5

  • For individuals who require an ART regimen containing PIs, rifampicin should not be administered; substitution with rifabutin is recommended.1,3

– if rifabutin is not available, the use of rifampicin and a boosted antiretro¬viral regimen containing lopinavir or saquinavir with additional ritonavir dosing can be used

  • this regimen should be closely monitored3

The complexity of DDIs between TB and HIV drugs requires expertise in the use of both antiretroviral and anti-TB drugs.1

  • The British HIV Association recommends that rifamycin-based TB regimens should be used whenever possible
  • Co-administration guidance for antiretrovirals is given below. There are few long-term clinical outcome data to support use of these TB/HIV drug combinations1

NRTI: nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI: non nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; TDM: therapeutic drug monitoring.

Table compiled from information provided in British HIV Association Guidelines for the Treatment of TB/HIV Coinfection 20111and the University of Liverpool HIV drug interactions website.4

  • TDM of NNRTIs and PIs should be performed when drug regimens are complex
  • Drug levels of anti-tuberculosis drugs should be measured when there is clinical concern regarding absorption or response to TB therapy1

While not recommended as preferred therapy, if rifabutin is not available and efavirenz is ineffective, TB treatment with rifampicin may be combined with:

  • a HIV treatment regimen composed of four NRTIs (as long as the medications retain antiviral activity)
    • this may be an acceptable alternative for patients unable to take NNRTIs, or in those with NNRTI-resistant HIV5
  • a combination of two NRTIs with raltegravir (800 mg twice daily)
    • published data for this regimen has been reported in the treatment of 8 patients in real-life clinical practice6

 

Simultaneous malaria and TB treatment

  • Malaria and TB are endemic diseases in many resource-poor countries and frequently occur simultaneously.7

– DDIs between rifampicin or rifabutin and antimalarial agents are likely as they share hepatic metabolic pathways

  • in many cases DDIs are likely due to common metabolic pathways. However these interactions have not been studied or confirmed in patients.7

 

– in addition, co-trimoxazole and fansidar (sulfadoxine/pyrimethamine) should not be administered concurrently given their redundant mechanisms of action and synergistic worsening of adverse drug reactions8

– in addition, halofantrine should not be co-administered with any PIs or delavirdine
– interactions may also occur between halofantrine and other NNRTIs4

For more information on DDIs:

Click here to access the HIV drug interactions website
Download the Centers for Disease Control and Prevention guidelines on ‘Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis’.

View a summary of concomitant use of anti-TB medications and ART in the EACS Guidelines.9

Access British HIV Association guidelines for the treatment of TB/HIV coinfection 2011.1

References

  1. British HIV Association. Guidelines for the Treatment of TB/HIV Coinfection 2011.  Accessed 25 November 2011.
  2. Harries AD, Zachariah R, Lawn SD. Providing HIV care for co-infected tuberculosis patients: a perspective from sub-Saharan Africa. Int J Tuberc Lung Dis 2009;13:6–16. 
  3. World Health Organization. Treatment of Tuberculosis Guidelines Fourth Edition (2010).  Accessed 30 November 2011.
  4. HIV drug interactions website. Accessed 9 February 2012.
  5. Department of Health and Human Services Centers for Disease Control and Prevention. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis. Accessed 26 November 2011.
  6. Mena A, Vázquez P, Castro Á, et al. Clinical experience of raltegravir-containing regimens in HIV-infected patients during rifampicin-containing treatment of tuberculosis. J Antimicrob Chemother 2011;66:951–952. 
  7. Sousa M, Pozniak A, Boffito M. Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs. J Antimicrob Chemother. 2008;62:872–878. 
  8. Peters PJ, Thigpen MC, Parise ME, et al. Safety and toxicity of sulfadoxine/pyrimethamine: implications for malaria prevention in pregnancy using intermittent preventive treatment. Drug Saf 2007;30:481–501. 
  9. European AIDS Clinical Society. Guidelines Version 6.0. Accessed 17 April 2012.