Rifampin Drug-Drug Interactions with Newer Antiretrovirals (TAF, Bictegravir, Dolutegravir)

Treatment of tuberculosis (TB) in HIV-infected persons remains challenging, in part because of drug interactions between rifampin and some ARVs that may compromise antiretroviral therapy (ART). Three studies presented at CROI provide clinicians with additional guidance on how to manage certain interactions.

Tenofovir alafenamide

Tenofovir alafenamide (TAF), unlike tenofovir disoproxil fumarate (TDF), relies on drug transporters that are influenced by rifampin; therefore current DHHS guidelines do not recommend coadministering the two agents. At the 2017 European AIDS Conference, researchers presented data from a study in which TAF 25 mg was dosed twice daily with rifampin 600 mg orally once daily.(1) This strategy resulted in a reduction in the plasma TAF area under the curve (AUC) of approximately 15% when compared with the AUC when TAF was given without rifampin. The AUC of tenofovir diphosphate (TFV-DP), the active metabolite, was reduced 24% in PBMCs, although its trough levels were still higher than those typically observed when TDF is given alone.

A study presented at CROI this year aimed to discover whether standard dosing of TAF 25 mg once daily would be sufficient when given with rifampin.(2) Healthy volunteers (n = 23) were given the combination pill TAF/FTC 25/200 mg once daily with food for 28 days. Rifampin 600 mg once daily on an empty stomach was added on days 29-56. On days 57-84, TAF and rifampin were stopped and TDF 300 mg was given once daily. Two subjects discontinued the study due to adverse effects. Plasma TAF AUC was reduced by 55% with the addition of rifampin. The intracellular AUC of TFV-DP was reduced by 36%; however, this AUC was still 76% higher than that achieved with use of TDF alone.

Pharmacokinetic studies have already shown that there is no interaction between TDF and rifampin. While the two studies of TAF + rifampin discussed above found that rifampin does lower plasma level of TAF, they also found that levels of the active tenofovir metabolite were higher than those achieved with TDF alone and thus may be adequate for treatment of HIV. To date, there are no clinical outcome studies to confirm the efficacy of TAF in patients who take rifampin. But, for HIV patients on rifampin-based TB therapy who are not able to take TDF for treatment of their HIV, TAF (given twice daily or possibly even once daily) may be an acceptable alternative, if they have close medication adherence and no resistance mutations that may compromise the ART regimen.

Bictegravir

Bictegravir (BIC) at a dosage of 75 mg once daily should not be coadministered with rifampin because the BIC AUC is reduced by 75%.(3) A new study presented at CROI evaluated whether administering bictegravir 75 mg twice daily might help offset the interaction.(4) A group of 52 healthy volunteers was divided into two cohorts. The first cohort was a control group that received a combination tablet containing BIC 50 mg/TAF 25 mg/emtricitabine 200 mg once daily for 28 days. (Of note, although the 75 mg BIC formulation mentioned previously was evaluated in Phase II clinical trials, a 50 mg formulation was subsequently developed; it reportedly is bioequivalent to the earlier 75 mg formulation.) The second cohort received BIC/TAF/FTC twice daily plus rifampin 600 mg daily for 28 days. Despite the increased frequency of dosing, plasma bictegravir AUC was still 60% lower when coadministered with rifampin than when given without rifampin. Plasma trough levels of BIC were also reduced significantly (~80%). Based on these data, clinicians should continue to heed the recommendations to avoid coadministration of BIC with rifampin.

Dolutegravir

Pharmacokinetic data support the use of dolutegravir 50 mg orally twice daily when given concurrently with rifampin.(5) An abstract presented at CROI describes 24-week clinical and laboratory follow-up from the INSPIRING study, and further supports the clinical use of this combination.(6) INSPIRING was an open-label randomized study that examined initiation of HIV treatment in persons who were taking rifampin-based TB therapy. Of the 113 persons who enrolled, 69 were assigned to receive dolutegravir + 2 NRTIs; they received dolutegravir 50 mg twice daily during the rifampin phase, and then 50 mg once daily after completion of therapy with rifampin. The other subjects were assigned to receive efavirenz + 2 NRTIs. At week 24, reduction of HIV viral load to <50 copies/mL was achieved in 81% (95% confidence interval [CI]: 72-90) of participants on dolutegravir and 89% of participants in the efavirenz arm. This difference was attributed to a higher rate of discontinuations in the dolutegravir group that were not related to medications, such as loss to follow-up and deviations from study protocol. There were few discontinuations due to immune reconstitution inflammatory syndrome (IRIS) in the dolutegravir arm (6%) and in the study overall. The INSPIRING study suggests that dosing dolutegravir 50 mg twice daily when given with rifampin is sufficient for treatment of HIV. As integrase inhibitors become first-line HIV therapy globally, clinicians should be mindful to increase the dolutegravir dosage appropriately when treating HIV in the setting of TB therapy.

References

1. Custodio JM, West S, Lutz J. Twice-daily administration of tenofovir alafenamide in combination with rifampin: potential for tenofovir alafenamide use in HIV-TB coinfection. In: Program and abstracts of the 16th European AIDS Conference; October 25-27, 2017; Milan, Italy. Abstract PS13/4.

2. Cerrone M, Alfarisi O, Neary M, et. al. Rifampin effect on tenofovir alafenamide (TAF) plasma/intracellular pharmacokinetics. In: Program and abstracts of the 2018 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston. Abstract 28LB.

3. Biktarvy [package insert]. Foster City, CA: Gilead Sciences; 2018.

4. Custodio JM, West SK, Collins S, et. al. Pharmacokinetics of bictegravir administered administered twice daily in combination with rifampin. In: Program and abstracts of the 2018 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston. Abstract 34.

5. Tivicay [package insert]. Brentford, Middlesex, TW8 9GS, United Kingdom: Viiv Healthcare; 2018.

6. Dooley K, Kaplan R, Mwelase N, et al. Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults at week 24. In: Program and abstracts of the 2018 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston. Abstract 33.