Optimizing Concentrations of Concomitant Antiretrovirals by Reducing Etravirine Doses: Two Case Reports of Complex Drug-drug Interactions

Introduction

HIV therapy rapidly becomes a challenge in the presence of drug–drug interactions (DDIs), especially in patients with multiresistant HIV needing complex antiretroviral (ARV) regimens including CYP3A4 boosters such as ritonavir or cobicistat. We present two patients with intricate HIV treatment regimens who had high etravirine levels and indicate how their DDIs were managed with the assistance of therapeutic drug monitoring (TDM).

Case report 1

A 62-year-old Caucasian male, HIV–HBV-coinfected, treatment-experienced with chronic kidney disease (estimated glomerular filtration rate [eGFR] 42 ml/min/1.73 m²), advanced liver fibrosis (Metavir F3) and severe steatosis was receiving etravirine 200 mg twice daily, darunavir/ritonavir 600/100 mg twice daily and dolutegravir 50 mg once daily with food. He was also taking tenofovir disoproxil fumarate for HBV. He reported 100% adherence. Both HIV and HBV viral load were undetectable. Gradually worsening renal function led to the replacement of tenofovir disoproxil fumarate by tenofovir alafenamide (TAF). In early 2016, due to limited availability and reimbursement of TAF and TAF-containing co-formulations, TAF was available only in Genvoya^™ (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/TAF 10 mg) in Canada. An unconventional regimen was prescribed consisting of Genvoya^™ 1 tablet, etravirine 400 mg and darunavir 800 mg, all taken once daily with food. No darunavir, etravirine or elvitegravir resistance-associated mutations were documented. A regimen containing just Genvoya^™ and darunavir was thought to be sub-optimal due to multiple major reverse transcriptase mutations conferring HIV resistance to tenofovir and emtricitabine.

Important DDI potential warranted TDM (Table 1). 1 month following the change in therapy, a high etravirine concentration, well over our target trough concentration (C_trough; 0.16 mg/l), and an almost undetectable darunavir concentration were recorded [1]. Instead of increasing the darunavir dose, the etravirine dose was reduced to 300 mg daily in hopes of decreasing cytochrome P450 3A4 (CYP3A4) induction. 1 month later, elvitegravir TDM became available and a concentration slightly below our target C_trough (0.13 mg/l) was reported [2]. TDM also showed a lower etravirine concentration, although still high, whereas darunavir remained almost undetectable. Consequently, the etravirine dose was further reduced to 200 mg daily. The etravirine concentration further decreased, the elvitegravir concentration increased threefold, and the darunavir concentration reached twice the protein-adjusted 50% inhibitory concentration (IC₅₀) for wild-type virus (0.055 mg/l) which is below our darunavir C_trough target for patients with viruses without any darunavir mutations of 3x this value [3]. The etravirine dose was further reduced to 100 mg daily. This resulted in a lower etravirine concentration but that remained therapeutic, an unchanged elvitegravir concentration and a darunavir concentration increasing to 2.9-fold the IC₅₀. A repeat TDM showed therapeutic etravirine and elvitegravir concentrations although the darunavir concentration decreased to 1.5x the IC₅₀. As darunavir C_trough has not been shown to be associated with virological response in patients with viruses without darunavir mutations we suggested not to increase the dose [1]. A viral blip (30 copies/ml) occurred when the patient was receiving etravirine 100 mg once daily but the viral load quickly returned to undetectable.

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Table 1

Antiretroviral plasma concentrations measured through therapeutic drug monitoring

	Month after treatment initiation	Integrase inhibitor a concentration, mg/l	ETV concentration, mg/l	DRV concentration, mg/l	TDM pharmacist recommendations b
Case 1
Target values c		0.13	0.16	0.17
	1	N/A d	1.05 e	0.05 e	↓ ETV dose to 300 mg
	2	0.07	0.71	0.02	↓ ETV dose to 200 mg
	4	0.21	0.47	0.11	↓ ETV dose to 100 mg
	7	0.22	0.18	0.16	No dose change
	11	0.16e	0.19 e	0.08 e	No dose change
Case 2
Target values c		0.30	0.16	0.17
	2	0.26	0.8	2.16	↓ ETV dose to 300 mg
	4	0.29 e	0.86 e	1.78 e	↓ ETV dose to 200 mg
	7	0.93 e	0.44 e	5.00 e	No dose change

a

Case 1: elvitegravir (EVG) concentration, cobicistat concentrations not available; case 2: dolutegravir (DTG) concentration.

b

The initial doses for case 1 were EVG/ cobicistat 150/150 mg, etravirine (ETV) 400 mg and darunavir (DRV) 800 mg daily, whereas those for case 2 were DTG 50 mg, ETV 400 mg and DRV/ritonavir 800/100 mg daily.

c

Our therapeutic drug monitoring (TDM) programme's target concentration at the end of the dosing interval (C_troughs) listed are for viruses without resistance mutations specific to the agents [1–4]. The DRV target C_trough corresponds to 3x the protein-adjusted 50% inhibitory concentration (IC₅₀) for wild-type virus [3].

d

EVG TDM was not yet available at our centre at month 1.

e

For samples drawn in the elimination phase but not exactly at 24 h post-dose, C_trough were extrapolated using the mean elimination half-life for once-daily DRV (18.6 h), DTG (12.1 h), EVG (9.2 h) and ETV (14.1 h). N/A, not available.

Case report 2

A 59-year-old Caucasian male, HIV–HCV-coinfected, HIV treatment-experienced and known for chronic kidney disease (eGFR 60 ml/min/1.73 m²) was taking darunavir/ritonavir 600/100 mg, etravirine 200 mg and raltegravir 400 mg all twice daily. In 2016, viral blips due to suboptimal adherence to his evening dose warranted a modification of his ARVs to dolutegravir 50 mg, darunavir/ritonavir 800/100 mg and etravirine 400 mg all taken daily in the morning with food. The patient's viruses, to our knowledge, had developed no dolutegravir, darunavir and etravirine resistance-associated mutations. He was also started on HCV treatment in the first months of his new ARVs. No significant DDI was detected with his HCV treatment, consisting of a single successful course of ledipasvir/sofosbuvir for 12 weeks. The patient had no hepatic impairment. 1 month after initiating his new ARVs TDM was performed (Table 1). The etravirine level was therapeutic but much higher than the mean population pharmacokinetic curve, while the dolutegravir concentration was subtherapeutic (target C_trough 0.3 mg/l) and the darunavir concentration therapeutic [4]. The TDM pharmacist recommended lowering the etravirine dose to 300 mg daily in hopes of decreasing CYP3A4 and uridine diphosphate glucuronosyltransferase 1A1/1A3 (UGT1A1/1A3) induction. About 2 months later dolutegravir and darunavir concentrations were similar with a lower etravirine level though still high. A further etravirine dose decrease to 200 mg daily was recommended. 3 months later, dolutegravir, etravirine and darunavir concentrations were all therapeutic with the etravirine concentration having decreased by 50%. The patient's HIV viral load was undetectable while on this regimen.

Discussion

Both cases present ARV combinations resulting in a high DDI potential. In case 1, darunavir and elvitegravir levels were considered subtherapeutic. Instead of increasing darunavir and elvitegravir dose or dosing frequency, a reduction in the etravirine dose by 75% allowed therapeutic elvitegravir levels and improved darunavir levels. Elvitegravir and etravirine are substrates of CYP3A4 and etravirine is a moderate inducer of CYP3A4 [5,6]. Elvitegravir is also a minor substrate of UGT1A1/1A3, etravirine a substrate of CYP2C19 and darunavir a substrate of CYP3A4 and p-glycoprotein (P-gp) [5–7]. On the other hand, cobicistat is an inhibitor of CYP3A4 and P-gp and increases darunavir and elvitegravir concentrations [8]. Co-administration of etravirine with darunavir and cobicistat has been shown on average to decrease cobicistat C_trough and elimination half-life by 66 and 32%, respectively, and decrease darunavir C_trough by 56% (either directly and/or indirectly by decreasing cobicistat levels) [7]. Compared to data with once-daily darunavir/ritonavir/etravirine, CYP3A4 inhibition by cobicistat appears less potent than ritonavir in the presence of inducers, in particular, at the end of the dosing interval [7,9]. Due to a drug–drug–gene interaction, the decrease of darunavir levels by etravirine induction may be accentuated in patients that are CYP3A5 expressers [10]. Unfortunately, pharmacogenetic testing was not available for these patients. Decreases in elvitegravir and darunavir levels by etravirine can also potentially be caused by UGT1A1/1A3 and P-gp induction, respectively, as etravirine induction is pregnane-X-receptor (PXR)-mediated and thus induction of these enzymes and transporter are also expected [6,11]. Elvitegravir has also been shown to decrease darunavir C_trough by an average of 21% [12]. The final result of this concomitant induction-inhibition of CYP3A4, P-gp and UGT1A1/1A3 was difficult to predict. We believe the high etravirine concentrations caused more potent induction as PXR activation by etravirine is known to be concentration-dependant [11]. The cause for the high etravirine levels in case 1 is unclear but could include advanced liver fibrosis/steatosis, renal impairment and CYP2C19 polymorphism [13]. Non-HIV concomitant medications cannot explain high etravirine levels in this patient.

Though the product monograph of Genvoya^™ warns that it should not be co-administered with other ARVs, in treatment-experienced patients with multiresistant virus and multiple comorbidities and past toxicities, treatment options become very limited and non-traditional regimens are sometimes needed as was the case here. Attempting to manage the interaction by adding a second 150 mg dose of cobicistat (Tybost^™) 12 h apart from Genvoya^™ to allow more consistent CYP3A4 inhibition throughout the dosing interval would have been interesting but cobicistat alone is not available in Canada. Another simpler strategy to prevent this interaction would have been to replace etravirine with rilpivirine, which is a less potent CYP3A4 inducer, in particular, at the therapeutic dose of 25 mg [11,14]. The medical chart does not document why this strategy was not retained for our patient. QTc interval prolongation may have been feared as cobicistat is expected to increase rilpivirine concentrations by CYP3A4 inhibition and rilpivirine QTc prolongation is concentration-dependent [14].

In case 2, dolutegravir levels were subtherapeutic. Literature reports that etravirine decreases dolutegravir C_trough by an average of 88%, likely by inducing UGT1A1, CYP3A4 and P-gp. Combination of daily dolutegravir with twice-daily etravirine and darunavir/ ritonavir offsets the interaction partially as dolutegravir C_trough decreases by an average of only 37% [15]. In our case, darunavir/ritonavir was given once daily which means the lower ritonavir dose could have compensated the interaction less. Further, etravirine concentrations were higher than expected which might imply more potent induction as discussed above [11]. Again, the cause for the high etravirine concentration is unclear but could be due to some of the reasons highlighted in case 1. Decreasing the etravirine dose by half allowed dolutegravir levels to increase and become therapeutic. Replacing etravirine by rilpivirine could have limited these interactions. Due to limited data in 2016, dual therapies such as darunavir/ritonavir/dolutegravir or dolutegravir/rilpivirine were not considered at the time for our patient but could now be viable options [16,17].

Darunavir, elvitegravir and dolutegravir concentrations responded similarly to an etravirine dose decrease. We believe this alleviated etravirine induction. TDM allowed safe etravirine dose decreases by verifying that etravirine levels remained adequate for virological suppression. This not straightforward approach to managing the low darunavir, elvitegravir and dolutegravir concentrations allowed us to preserve a simplified once-daily regimen instead of recommending dose increases which might have required twice-daily dosing, potentially decreasing adherence and quality of life.