Short‐course daily isoniazid and rifapentine for latent tuberculosis infection in people living with HIV who received coformulated bictegravir/emtricitabine/tenofovir alafenamide

Abstract

IntroductionShort‐course preventive therapy with 1‐month course of daily administration of isoniazid (300‐mg) plus rifapentine (600‐mg) (1HP) and 3‐month course of weekly administration of isoniazid (900‐mg) plus rifapentine (900‐mg) (3HP) has higher completion rates than 9‐month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).MethodsPLWH testing positive by interferon‐gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL) <200 copies/ml were enrolled. BIC trough plasma concentrations and cytokine profiles were determined before the first dose (day 1/baseline), 24 h after the 14th (day 15) and 28th (day 29) doses of 1HP. PVL were determined on days 15 and 29 of 1HP and every 3 months subsequently after discontinuation of 1HP.ResultsFrom November 2019 to December 2020, 48 PLWH with LTBI were enrolled. One participant (2.1%) discontinued 1HP on day 15 due to fever and generalized rashes with PVL of 72 copies/ml, which was <50 copies/ml in three subsequent determinations while on BIC/FTC/TAF over the 12 months of follow‐up. The percentages of BIC trough plasma concentrations above the protein‐adjusted 95% effective concentration (paEC95 = 162 ng/ml) were 56.3% and 37.0% on days 15 and 29, respectively. The percentage of PVL <200 copies/ml was 91.7% on day 15, 97.8% on day 29 and 100% at both months 3 and 6. After a median observation of 52 weeks (interquartile range, 51–55), all participants continued BIC/FTC/TAF with a median PVL of 20 copies/ml (range 20–331). Except for the participant who discontinued 1HP because of allergic reactions, none of the participants had relevant symptoms or increases of the cytokine levels assessed between baseline and days 15 and 29 of 1HP.ConclusionsBIC/FTC/TAF in combination with 1HP was well tolerated with a high completion rate. BIC trough plasma concentrations were significantly decreased with concurrent use of 1HP among PLWH with LTBI. While transient viral blips were observed during 1HP without causing subsequent treatment failure, such combination should be applied with caution.

Care cascade of tuberculosis infection treatment for people living with HIV in the era of antiretroviral therapy scale-up

“…In a phase 1/2 trial conducted among 61 PLWH concurrently receiving DTG-containing regimens and 3HP, a 36% increase in DTG clearance was observed; however, only one had trough concentration below the 90% maximal inhibitory concentration for DTG and all participants were able to maintain HIV viral suppression during 3HP treatment 13 . In another study of 48 PLWH concurrently receiving BIC/FTC/TAF and 1HP, the proportion of BIC trough concentrations above the 95% effective concentration dropped to 37%; however, more than 90% of participants were able to maintain HIV viral suppression during and after 1HP treatment 14 . Although the findings suggest that viral suppression still could be maintained and no cases of virologic failure occurred after TBI treatment among PLWH receiving InSTI-containing regimens, transient HIV viremia was noted during TBI treatment due to a significant decrease in BIC trough concentration.…”

“…In pharmacokinetic studies, efavirenz or raltegravir can be used with weekly rifapentine without dose adjustment 10 , 11 ; however, clearance of bictegravir (BIC), dolutegravir (DTG), elvitegravir (EVG) and cobicistat (COBI) will be significantly increased when co-administered with rifapentine 12 . Although clinical studies demonstrated that short-course rifapentine-based TBI treatment may not jeopardize the HIV control among PLWH taking BIC- or DTG-containing regimens 13 , 14 , clinicians may still be reluctant to prescribe rifapentine-based TBI treatment due to the concern of drug interactions 5 .…”

Evaluation of drug-drug interaction between rilpivirine and rifapentine using PBPK modelling

“…As seen in the validation study of weekly rifapentine, doravirine 100 mg twice daily could potentially be used with 3HP ( Lam et al, 2020 ). On the other hand, bictegravir is contraindicated ( Arora et al, 2021 ; Liou et al, 2021 ) and there is no data with protease inhibitors or darunavir yet.…”

Complexities of rifamycin use in persons with HIV infection

“…Similarly, 1HP co-administered with fixed-dosed combination bictegravir/emtricitabine/TAF was noted to reduce plasma bictegravir concentrations by approximately 95%, with 25% of the 48 participants studied found to have VL ≥50 copies/ml at day 15 of concurrent therapy. However, by 6 months after completion of 1HP, 100% of participants with VL data were undetectable [22].…”

“…For example, TAF co-administered with rifampin resulted in TAF plasma level reductions of >50% and intracellular tenofovir diphosphate (TFV-DP) concentration decreased by 36%, although intracellular TFV-DP concentrations remained four-fold higher than compared to TDF administered alone [29]. Pharmacokinetic data from the study evaluating bictegravir/emtricitabine/TAF with 1HP found tenofovir plasma levels did not significantly change during rifapentine co-administration however data on intracellular TFV-DP levels were lacking [22]. Additionally, it is not known whether DTG resistance develops during the time of rifapentine-reduced DTG concentration and if this may contribute to HIV treatment failure over the long term.…”