Co-administration of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine and atazanavir in treatment-experienced HIV patients

Abstract

We report the use of elvitegravir 150 mg/cobicistat 150 mg/tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (EVG/COBI/TDF/FTC) once daily, in addition to once-daily atazanavir (ATV) 300 mg, in treatment-experienced patients with human immunodeficiency virus (HIV). Due to limited data available on the co-administration of these agents, our objective was to evaluate and monitor safety and efficacy of this regimen in patients who developed resistance or intolerance to conventional antiretroviral therapy (ART). This short report included offenders incarcerated in the Illinois Department of Corrections who were ≥18 years, HIV-infected, had documented antiretroviral resistance, and received EVG/COBI/TDF/FTC + ATV once daily. Based on previous ART, resistance patterns and current medications, seven patients were initiated on once-daily therapy consisting of EVG/COBI/TDF/FTC and ATV. Due to extensive resistance, two of the seven patients were also started on abacavir (ABC) 600 mg daily in addition to EVG/COBI/TDF/FTC and ATV. Of the seven patients, one had ART changed due to concerns of resistance based on a genotype, one experienced a decline in renal function that warranted a change in therapy, and one is currently virologically suppressed on a combination of EVG/COBI/TDF/FTC, ATV, and ABC. The remaining four patients remain virologically suppressed on EVG/COBI/TDF/FTC + ATV. Therapy consisting of EVG/COBI/TDF/FTC and ATV may be a viable option for some treatment-experienced HIV-infected patients. Further studies evaluating the safety, efficacy, and pharmacokinetics of this therapy are warranted, given the lack of information currently available.

Keywords

Treatment-experienced antiretroviral therapy antiretroviral resistance HIV/AIDS elvitegravir/cobicistat/emtricitabine/tenofovir atazanavir

Introduction

Once-daily antiretroviral therapy (ART) is one measure to improve adherence.^1,2 One meta-analysis evaluated ART adherence rates in over 6000 ART-naïve and experienced human immunodeficiency virus (HIV)-infected adults and demonstrated that higher pill burden was associated with lower adherence and single tablet regimens had higher rates of adherence when compared to twice-daily regimens.³

For treatment-experienced patients, a combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COBI/TDF/FTC) given concomitantly with atazanavir (ATV) offers the benefit of two pills once daily. Traditionally, ritonavir (RTV) was used to increase serum and tissue levels of ATV by inhibiting cytochrome P450 3A4 (CYP3A4). The presence of COBI, another pharmacokinetic booster, in this regimen removes the need for RTV. Compared to RTV, COBI is more selective for CYP3A4, leading to fewer drug interactions and a lower incidence of insulin resistance and lipid changes.^4,5

To date, one study has evaluated co-administration of EVG, COBI, and ATV.⁶ The pharmacokinetics of administering EVG 85 mg and ATV 300 mg/COBI 150 mg to either ATV 300 mg/RTV 100 mg or EVG 150 mg/COBI 150 mg was assessed and demonstrated a 10% decrease (90% CI 73.4 to 112) in the area under the curve (AUC) of ATV, a 20% decrease (90% CI 55.6 to 117) in the ATV trough concentration, and a 17% increase (90% CI 88 to 156) in the AUC of EVG. It stands to reason that administering a higher of dose of EVG (i.e. 150 mg) with COBI 150 mg and ATV 300 mg may lead to greater pharmacokinetic changes than reported and may result in subtherapeutic and supratherapeutic concentrations of ATV and EVG, respectively.

A potential concern with EVG/COBI/TDF/FTC + ATV is the risk of renal dysfunction secondary to the concomitant used of COBI, TDF, and ATV. Although there have been reports of renal dysfunction within a few weeks of initiating TDF,^7–9 the mean onset has been reported between 5 and 11 months.^10,11 In addition to the renal effects of TDF, ATV has been shown to increase the concentration of TDF,^12,13 which may further increase the risk of renal dysfunction.¹⁴ ATV/RTV has been previously shown to cause a significantly greater reduction in estimated glomerular filtration rate (eGFR) (−7.6 mL/min/1.73 m²) than either efavirenz (−5.1 mL/min/1.73 m²) or lopinavir/RTV (−4.8 mL/min/1.73 m²).¹⁵ Additionally, there are nine case reports demonstrating an association between ATV/RTV and tubulointerstitial nephritis.^16–22 In clinical trials, COBI was shown to cause a moderate increase in serum creatinine (SCr), with an accompanying decrease in eGFR.^4,23 However, one study demonstrated that while COBI decreased the eGFR, it did not decrease actual GFR.²⁴ The objective of this report was to evaluate and monitor safety and efficacy of EVG/COBI/TDF/FTC + ATV in patients who developed resistance or intolerance to conventional ART.

Methods and materials

A retrospective, Institutional Review Board (IRB)-approved, short report evaluated HIV-positive individuals incarcerated in the Illinois Department of Corrections between May 2013 and May 2015. Inclusion criteria included individuals ≥18 years, HIV-infected, documented antiretroviral resistance, and receiving EVG/COBI/TDF/FTC + ATV once daily. Evaluation of safety and efficacy included data collection of HIV viral load (VL), CD4 cell count/percentage, SCr, and total bilirubin levels (TBIL). Estimated creatinine clearance (eCrCl) was calculated using the Cockroft-Gault equation and actual body weight, except where indicated.

Results

A total of seven patients were identified who received concomitant EVG/COBI/TDF/FTC + ATV. Demographics and results are summarized in Tables 1 and 2, respectively. All seven patients were African American, six patients were male, and the median age of the cohort was 44.1 years (range: 24–57 years). Prior to initiating EVG/COBI/TDF/FTC + ATV, the median duration since HIV diagnosis was 12.9 years (range: 7–19 years). Baseline genotypic data were available in three of the seven patients and are shown in Table 1. Patients received EVG/COBI/TDF/FTC + ATV for a median duration of 10.7 months (range: 2–16 months). Two patients received abacavir (ABC) 600 mg daily in addition to EVG/COBI/TDF/FTC + ATV. Each patient had a detectable VL at baseline with a median of 27,091 copies/mL (range: 308–60,000 copies/mL). At last documented follow-up, four patients had an undetectable VL (<20 copies/mL) and the remaining three patients had a median VL of 46 copies/mL. Baseline CD4 cell count was available for six patients. Median CD4 cell count at baseline and last documented follow-up were 64.3 (range 13–124) and 181.1 (range: 65–396) cells/mm³, respectively.

Table 1.

Patient baseline and follow-up demographics on EVG/COBI/TDF/FTC + ATV.

Case	Gender	Age	Weight at baseline (kg)	SCr at baseline (mg/dL)	SCr at last follow-up (mg/dL)	eCrCl at baseline (mL/min)	eCrCl at last follow-up (mL/min)	EVG/COBI/ FTC/TDF and ATV duration (months)	PR mutations	RT mutations	Additional medications
1	M	37	80.4	1.16	1.27	100.1	99.8	12		L74V, L100I, M184V, V179D	Sulfamethoxazole/trimethoprim, azithromycin, citalopram
2^a	M	24	67.9	0.75	0.83	147.2	141.2	12			Sulfamethoxazole/trimethoprim, sertraline, hydroxyzine, mirtazapine, albuterol, multivitamin
3	M	48	77.3	1.07	1.22	92.3	80.1	9			Sulfamethoxazole/trimethoprim, azithromycin, tramadol, hydrocodone/acetaminophen, multivitamin, iron
4	F	46	106.8	1.35	1.2	61.2	69.2	2	I15I/V, V77I	K65K/R, K70R/E, K103N, V108I/V, M184V	Sulfamethoxazole/trimethoprim, azithromycin, ranitidine
5^a	M	54	109.1	1.71	1.59	60.8	63	16			Sulfamethoxazole/trimethoprim, azithromycin, amlodipine, pravastatin, propylthiouracil, naproxen, aspirin abacavir
6	M	57	63.2	1.26	1.52	57.8	44.3	14			Sulfamethoxazole/trimethoprim
7	M	43	90.9	0.99	1.07	123.7	121.2	10	L10I/L/F, L63P, V77I		Abacavir, dapsone, azithromycin, atenolol, methimazole, beclomethasone, albuterol

Patient initiated on regimen prior to incarceration.

Table 2.

Key laboratory parameters throughout management.

Patient 1	Feb 2014	Mar 2014	Jun 2014	Aug 2014	Nov 2014
Viral load (copies/mL)	45,817	98	234	37	46
CD4 cell count (cells/mm³)	61^a	85 (8%)	133 (9%)	110 (9%)	124 (12%)
SCr (mg/dL)		1.16		1.37	1.27
eCrCl (mL/min)		100.1		89.1	99.8
TBIL (mg/dL)		3.4		3.5	2.4
Patient 2	Mar 2014	Aug 2014	Nov 2014
Viral load (copies/mL)	55	21	45
CD4 cell count (cells/mm³)	124 (8%)	288 (12%)	396 (17%)
SCr (mg/dL)	0.75	0.96	0.83
eCrCl (mL/min)	147.2	123.1	141.2
TBIL (mg/dL)	0.6	4.0	2.7
Patient 3	Feb 2014	Mar 2014	May 2014	July 2014
Viral load (copies/mL)	60,000	60	<20	<20
CD4 cell count (cells/mm³)	49^a	60 (7%)	192 (9%)	124 (9%)
SCr (mg/dL)		1.07	1.08	1.22
eCrCl (mL/min)		92.3	96.8	80.1
TBIL (mg/dL)		2.2	0.7	0.3
Patient 4	Dec 2013	Jan 2014	Feb 2014	Mar 2014	Apr 2014
Viral load (copies/mL)	45,469		49	47
CD4 cell count (cells/mm³)	70 (3%)		86 (4%)		92 (4%)
SCr (mg/dL)	1.35	0.98	1.12		1.20
eCrCl (mL/min)^b	61.2	74.5	74.5		69.2
TBIL (mg/dL)		0.3	1.4	0.6
Patient 5	Sept 2013	Nov 2013	Feb 2014	May 2014	Jun 2014	Sept 2014	Dec 2014	Jan 2015
Viral load (copies/mL)	37,556	<20	<20	<20		<20		<20
CD4 cell count (cells/mm³)	13 (1%)	43 (2%)	58 (4%)	89 (4%)		130 (7%)		145 (8%)
SCr (mg/dL)		1.71	1.62	1.64	1.86	1.59	1.57	1.59
eCrCl (mL/min)^b		60.8	63.5	61.5	54.2	63.7	63.8	63.0
TBIL (mg/dL)		1.5	2.0	2.9	2.1	2.1	2.3	2.1
Patient 6	May 2013	July 2013	Sept 2013	Nov 2013	Feb 2014	May 2014	Aug 2014	Nov 2014
Viral load (copies/mL)	182	308	<20	<20	<20	<20
CD4 cell count (cells/mm³)	209 (14%)		214 (13%)	186 (15%)	149 (10%)	253 (13%)	256 (14%)	322 (14%)
SCr (mg/dL)	1.26		1.31	1.34	1.37	1.52	1.52	1.38
eCrCl (mL/min)	53.6		54.0	54.4	52.9	46.0	44.3	52.5
TBIL (mg/dL)	2.1		2.0	2.0	1.0	1.3	1.1	2.0
Patient 7	Apr 2014	May 2014	Jun 2014	Aug 2014	Mar 2015
Viral load (copies/mL)	<20	437	21	<20	<20
CD4 cell count (cells/mm³)	73 (10%)	69 (11%)	80 (8%)	74 (9%)	65 (7%)
SCr (mg/dL)	0.99	1.00	1.10	1.09	1.07
eCrCl (mL/min)	123.7	122.5	114.0	106.2	121.2
TBIL (mg/dL)	1.1	0.4	0.6	1.3

TBIL: total bilirubin levels; eCrCl: estimated creatinine clearance; SCr: serum creatinine.

CD4 percentage not available.

eCrCl was calculated using adjusted body weight (ABW) rather than actual body weight.

Compared to baseline, median SCr at last documented follow-up increased from 1.18 to 1.24 mg/dL (+5.1%). Corresponding median eCrCl decreased from 91.9 mL/min at baseline to 88.4 mL/min at last documented follow-up (−3.8%). Four patients remain virologically suppressed on EVG/COBI/TDF/FTC + ATV, and another on a combination of EVG/COBI/TDF/FTC, ATV, and ABC. Of the remaining two patients, one had ART changed due to concerns of resistance based on a genotype and one experienced a decline in renal function that warranted a change in therapy.

Discussion

This is the first clinical evaluation on co-administration of EVG 150 mg, COBI 150 mg, and ATV 300 mg. When co-administered with ATV, the recommended regimen is EVG 85 mg, ATV 300 mg, and RTV 100 mg. The only previous study that evaluated the use of EVG, COBI, and ATV combined EVG 85 mg with COBI 150 mg and ATV 300 mg.⁶ This resulted in decreased systemic exposure to ATV and increased systemic exposure to EVG. The EVG dose was likely reduced due to ATV inhibition of CYP3A4 and uridine 5'-diphospho-glucuronosyltransferase-glucuronosyltransferase (UGT) 1A1, which along with UGT1A3, are the main metabolic pathways of EVG.²⁵ The mechanism responsible for the decreased ATV systemic exposure has yet to be defined. The main metabolic pathway of ATV is CYP3A4 and to a lesser extent, cytochrome P450 2C9 (CYP2C9), whereas, EVG is a moderate inducer of the CYP2C9 enzyme.^25,26

Patients receiving sulfamethoxazole/trimethoprim (SMZ/TMP) for opportunistic infection prophylaxis may be at greater risk for renal dysfunction since SMZ/TMP is excreted primarily through the kidneys. It was previously implicated as an agent that increased the risk of drug-induced nephrotoxicity in HIV-infected patients.¹⁰ In our study, six out of seven subjects received SMZ/TMP. Additionally, all patients received Pneumocystis jirovecii pneumonia prophylaxis as well as five patients receiving azithromycin prophylaxis against Mycobacterium avium-intracellulare. This demonstrated advanced immunosuppression in this patient population.

According to the prescribing information for EVG/COBI/TDF/FTC, treatment should not be initiated in patients whose eCrCl is < 70 mL/min.²⁵ Initiation of EVG/COBI/TDF/FTC + ATV occurred in one patient with an eCrCl is < 70 mL/min due to a lack of previous ART compliance and their options for salvage therapy that offered a low pill burden. This patient remained on this regimen for 11 months since the benefits outweighed the risks.

In patient four, baseline eCrCl was 61.2 mL/min prior to the initiation of EVG/COBI/TDF/FTC + ATV. Her therapy was changed after her genotypic data became available and revealed reverse transcriptase mutations K65K/R and M184V. These mutations could reduce susceptibility to TDF and FTC but patient’s VL decreased significantly to 47 copies/mL. Despite near virologic suppression and reduced pill burden, the decision was made to optimize therapy with etravirine (ETR), darunavir (DRV)/RTV, and dolutegravir (DTG). Of note, one month after starting EVG/COBI/TDF/FTC + ATV, eCrCl was 74.5 mL/min. For reference, eCrCl one month after ART change to once-daily ETR, DRV/RTV, and DTG remained stable.

Patient six began EVG/COBI/TDF/FTC, ATV, and ABC in July 2013. In May 2013, eCrCl was 57.8 mL/min and in September 2013, it was 55.6 mL/min. In August 2014, ART was changed to DTG, lamivudine/ABC, and ATV/RTV due to a continuously down-trending eCrCl. Until this change, the patient received TDF as part of ART since 2002.

Of the remaining four patients currently virologically suppressed on EVG/COBI/TDF/FTC + ATV, the development of nephrotoxicity is still a potential concern. TDF-associated nephrotoxicity has been reported more than three years after initiation.^11,27 This reinforces the importance of regularly monitoring renal function in patients receiving TDF-based ART. In cases such as ours, initiating or continuing treatment with EVG/COBI/TDF/FTC when the patient’s eCrCl was below specified cutoffs may be acceptable given that the patient was closely followed with routine laboratory monitoring.

Conclusion

EVG/COBI/TDF/FTC + ATV may be considered in treatment-experienced individuals for the management of HIV-1 infection. Important factors to consider prior to initiation are current and previous HIV genotype(s) and ART, concurrent medications, and baseline and routine renal function assessments. Further research and pharmacokinetic data are still needed in this relatively unstudied combination of agents, but initial results have provided evidence that this regimen may be a viable option for some treatment-experienced patients who have developed resistance or intolerabilities to conventional forms of ART.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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