Managing Drug Interactions in HIV and TB Coinfection Is Complex

Tuberculosis (TB) is a serious health concern, especially when coupled with HIV. Individuals with HIV are more likely to become sick if they are coinfected with TB. Infections among individuals with TB include those in the following categories:

• Active (disease mainly affects the lungs and is spread individual to individual through airborne transmission)
• Extensively drug resistant (TB that is resistant to isoniazid and rifampin, plus any fluoroquinolone and a second-line injectable drug)
• Latent (the individual is infected with Mycobacterium tuberculosis but without symptoms and cannot spread it to others and may never develop active TB)
• Multidrug resistant (there is drug resis- tance to the 2 most potent TB medications, isoniazid and rifampin)^1,2

It is estimated that up to 13 million individuals in the United States have latent TB, but the incidence in individuals with HIV is not known. In 2020, of 6960 individuals in the United States who had diagnoses of active TB, 300—or 4.3%—had HIV.³ Consequences of untreated TB, along with HIV, can lead to significant morbidity and mortality. Consequently, medication initi- ation for the management of HIV and TB tends to be complex, because concomitant drug interactions often affect treatment.

Rifamycin derivatives, such as rifabutin and rifampin, are core components of first-line TB treatment regimens. Unfortunately, they have the potential to cause drug-drug interactions through either enzymatic and/or transporter induction, not only with established first-line agents for the treatment of HIV but also those newly approved. This review will summarize rifamycin drug-drug interactions with novel agents and combinations, such as fostemsavir, tenofovir alafenamide (TAF), and 2-drug regimens (2DR).

Historically, TAF has been contraindicated with rifamycin, and tenofovir disoproxil fumarate (TDF) has been the preferred formulation. However, newer pharmacokinetic data suggest that concurrent therapy with TAF may be acceptable. This is particularly important, because TAF is often a key component of many first-line regimens for patients who have just received diagnoses of TB.

The results of one study show that coadministration of rifampin and TAF led to a decrease in plasma tenofovir area under the curve (AUC) and concentration at 24 hours by 54% and 55%, respectively.⁴ However, intracellular tenofovir diphosphate (TFV- DP) AUC remained 4-fold higher than those of TDF administered alone. Because the TFV-DP AUC at the site of action was higher, this shows promise for maintaining efficacy when rifampin and TAF are coadministered. Data regarding clinical outcomes are lacking, so coadministration of rifampin and TAF should only be considered when benefits outweigh risks.

Fostemsavir is a novel agent for the treatment of multidrug-resistant HIV. Rifampin significantly reduces concentrations and exposure of the active metabolite temsavir, so coadministration is contraindicated.⁵ Rifabutin may be considered an alternative, because it only lowers temsavir AUC and minimum concentration by 30% and 41%, respectively.⁵ However, there are limited clinical data on efficacy with coadministration, and in the setting of multidrug- resistant HIV, these decreases may contribute to virologic failure of a fostemsavir-containing regimen.

Although there are pharmacokinetic data examining the effect of rifamycin on individual components of 2DR, there is a paucity of clinical data on the management of TB with 2DR. Dolutegravir, a cornerstone agent in oral 2DRs, continues to be evaluated for its role in HIV and TB coinfection.⁶ Dolutegravir/rilpivirine may be considered in the presence of rifabutin, but a supplemental dose of rilpivirine 25 mg daily with a meal must be given, because of decreased concentrations of rilpivirine in the presence of rifabutin. No significant changes in concentrations were observed when rifabutin was coadministered with dolutegravir.^7,8

Similarly, dolutegravir/lamivudine may be considered in the presence of rifabutin and does not require supplemental dosing for either agent.⁹ Neither rifampin nor rifapentine should be coadministered with dolutegravir/rilpivirine, because of the extensive enzymatic induction of rilpivirine metabolism. As for dolutegravir/lamivudine, a supplemental dose of dolutegravir 50 mg separated 12 hours from dolutegravir/lamivudine may be considered, although formal studies have not been conducted.⁹ The additional dose of dolutegravir 50 mg should be continued 2 weeks after stopping rifampin or rifapentine, because inducing properties may continue even after discontinuing a strong inducer.

The newest 2DR is long-acting injectable cabotegravir/rilpivirine. No drug-drug interaction studies have been completed between the rifamycins and the long- acting injectable cabotegravir/rilpivirine formulation, and it is unclear whether any dosage adjustments could overcome the potential interaction.¹⁰ If a patient requires a rifamycin while on injectable therapy, transition to an alternative regimen should be considered.

Conclusion

Managing drug-drug interactions in HIV/TB coinfection can be complex. As new studies are published and recommendations may change, best practices call for referring to resources such as the US Department of Health & Human Services HIV guidelines or the University of Liverpool HIV drug interaction checker.^11,12

Melissa Badowski, PharmD, MPh, FCCP, FIDSA, BCIDP, BCPS, AAHIVP, is a clinical associate professor at the University of Illinois Chicago College of Pharmacy.

Rajeev Shah, PharmD, AAHIVP, BICDP, is a clinical pharmacy specialist, infectious diseases, at Lifespan in Providence, Rhode Island, and an assistant professor of medicine at the Warren Alpert Medical School of Brown University in Providence.

References

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7. Juluca. Prescribing information. ViiV Healthcare. 2017. Accessed February 9, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210192s000lbl.pdf

8. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013,62(1): 21-27. doi:10.1097/QAI.0b013e318276cda9

9. Dovato. Prescribing information: ViiV Healthcare. 2019. Accessed February 9, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211994s000lbl.pdf

10. Cabenuva. Prescribing information. ViiV Healthcare. 2021. Accessed February 9, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf

11. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Clinicalinfo.hiv.gov. Updated January 20, 2022. Accessed January 10, 2022. https://clinicalinfo. hiv.gov/en/guidelines/adult-and-adolescent-arv

12. HIV drug interactions. University of Liverpool. Updated February 11, 2022. Accessed February 9, 2022. https://www.hiv-druginteractions.org

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.