A Review of the Efficacy and Safety of Genvoya® (Elvitegravir,Cobicistat,Emtricitabine,and Tenofovir Alafenamide) in the Management of HIV-1 Infection

Abstract

Introduction:

This review evaluates the efficacy and safety of Genvoya® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide [EVG/c/TAF/FTC]), a single-tablet regimen used for the management of HIV-1 infection. Phase II and III randomized clinical trials evaluate the efficacy and safety of EVG/c/TAF/FTC and tenofovir disoproxil fumerate (TDF)–containing arms; renal impairment, bone mineral density, metabolic effects, and other adverse events are topics explored within this review.

Methods:

A MEDLINE with full text and PubMed literature search was conducted for the past 5 years, up to April 2016.

Results:

Virologic suppression was similar between the EVG/c/TAF/FTC and TDF-containing groups (<50 copies/mL) at week 48. The bone mineral density in the hip and spine showed a significant reduction in the TDF-containing groups. The glomerular filtration rate increased in patients in the EVG/c/TAF/FTC arm and there were significant differences in total proteinuria, albuminuria, and tubular proteinuria in patients switching to EVG/c/TAF/FTC. The most common adverse events were diarrhea, nausea, and headache.

Discussion:

The coformulated Genvoya regimen is well tolerated and effective in treatment-naive and virologically suppressed patients. Data seem to suggest it may also be effective and safe in patients with mild to moderate renal impairment. The lower-dosed single-tablet regimen has significantly reduced bone and renal side effects.

Keywords

Genvoya elvitegravir cobicistat emtricitabine tenofovir alafenamide tenofovir disoproxil fumarate HIV-1

Introduction

On November 2015, the US Food and Drug Administration approved Genvoya®, which is made up of elvitegravir 150 mg/cobicistat 150 mg/tenofovir alafenamide 10 mg/emtricitabine 200 mg (EVG/c/TAF/FTC).¹ EVG/c/TAF/FTC is a single-tablet regimen (STR) that contains the same active medications as Stribild (elvitegravir 150 mg/cobicistat 150 mg/tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg [EVG/c/TDF/FTC]), except TDF was replaced by TAF at a much lower dose. In fact, the TAF dose is only 10 mg, which is 30 times less in comparison with the previous TDF formulation.^2,3 EVG/c/TAF/FTC is indicated for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who are treatment naive or as replacement therapy for patients who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on stable antiretroviral therapy (ART) for at least 6 months. Patients must have no history of treatment failure and no known substitutions associated with resistance to the individual components of EVG/c/TAF/FTC.²

Tenofovir (TFV) is a nucleoside reverse transcriptase inhibitor (NRTI) used for the management of HIV-1.⁴ Intracellular phosphorylation converts TFV into the active metabolite tenofovir diphosphate (TFV-DP), which becomes incorporated into viral DNA and causes DNA termination.^5,6 Tenofovir disoproxil fumarate was developed due to the low permeability, bioavailability, and absorption of TFV-DP.⁴ Tenofovir disoproxil fumarate is an ester prodrug of TFV-DP that has markedly improved pharmacodynamics, thus allowing systemic delivery by oral administration.⁶ Tenofovir alafenamide, formerly GS-7340, is a novel prodrug that has demonstrated greater stability in blood and plasma than TDF. Within lymphocytes, it is quickly converted to TFV, thus improving the accumulation of TFV-DP in targeted peripheral blood mononuclear cells (PBMCs).⁴ A lower dosage formulation was developed because TAF therapy results in 4 times higher TFV-DP levels in PBMCs.^7,8

Both EVG/c/TAF/FTC and EVG/c/TDF/FTC STRs are associated with excellent virologic suppression; however, TDF and TAF have evident differences in kidney, bone, and metabolic parameters.^4,5,7,9
-11 Noninferiority clinical data reveal that EVG/c/TAF/FTC has similar efficacy to TDF-containing regimens.^7,9
-11 This review provides a comparative overview and evaluation of the clinical efficacy, safety, and tolerability of EVG/c/TAF/FTC for the management of HIV-1 infection.

Methods

A medical literature search using PubMed and MEDLINE with full text was conducted for information regarding the management of HIV-1 in patients receiving tenofovir alafenamide [PubMed: (tenofovir alafenamide[Title/Abstract]) AND (Tenofovir disoproxil fumarate[Title/Abstract]) AND (“last 5 years”[PDat]) AND HIV[Title]]l [MEDLINE: (TI tenofovir alafenamide AND tenofovir disoproxil fumarate AND TI hiv)]. Search filters limited publication dates within the last 5 years. The search identified 46 citations in MEDLINE and PubMed. Only randomized, controlled, phase III trials were included in the efficacy section and phase II and III trials were included in the safety sections. Search results are inclusive up to April 2016.

Efficacy

Use of Genvoya in Treatment-Naive HIV-1-Infected Adults

Sax et al combined 2 phase III trials for a prespecified pooled efficacy and safety analysis.⁷ These 2 randomized, double-blinded, phase III noninferiority trials evaluated the efficacy and safety of EVG/c/TAF/FTC and compared TAF to TDF in similar treatment regimens. This trial randomized patients to receive EVG/c/TAF/FTC or EVG/c/TDF/FTC once a day. Baseline characteristics of the study population included primarily young white males with estimated glomerular filtration rate (eGFR) greater than 110 mL/min and CD4 cell counts greater than 200 cells per μL. Over 90% of patients included in the study had symptomatic HIV-1 status and less than 5% of the patients had AIDS. The primary efficacy end point was the proportion of patients with HIV-1 RNA less than 50 copies/mL at week 48. A high success rate was evident in both the EVG/c/TAF/FTC and EVG/c/TDF/FTC groups (800 patients [92%] and 784 patients [90%], adjusted difference: 2%, 95% confidence interval: [CI] −0.7% to 4.7%).

The results of the trial demonstrated significant differences in efficacy in the EVG/c/TAF/FTC group compared to the EVG/c/TDF/FTC group for women (95% vs 87%) and individuals who had a viral load less than 100 000 copies/mL (94% vs 91%); percentage differences were 3.1% (95% CI 0.2-6.0) and 7.9% (95% CI 0.2-15.6), respectively (P = .024). At week 48, CD4 cell counts were significantly higher in the EVG/c/TAF/FTC arm than the EVG/c/TDF/FTC arm (230 and 211 cells/mL; 95% CI: 3-36 cells/mL, P = .024). Virologic failure was defined as plasma HIV-1 RNA greater than or equal to 50 copies/mL and less than 1 log10 reduction from baseline at week 8. It was also defined as 50 copies/mL or more HIV-1 RNA after previous suppression to less than 50 copies/mL or more than a 1 log10 increase in HIV-1 RNA from nadir. Virologic failure was seen in 7 patients (0.8%, n = 866) in the EVG/c/TAF/FTC arm and 5 patients (0.6%, n = 867) in the EVG/c/TDF/FTC arm. Resistance mutation development was similar between the EVG/c/TAF/FTC and EVG/c/TDF/FTC groups. In the study by Sax et al, 1 patient in the EVG/c/TAF/FTC arm and 2 patients in the EVG/c/TDF/FTC arm developed the Lys65Arg reverse transcriptase mutation. Five patients in the EVG/c/TAF/FTC arm and 3 patients in the EVG/c/TDF/FTC arm developed primary INSTI-R mutation.

Limitations of the trial included only involving a small proportion of women and participants with advanced HIV disease and did not include patients with chronic hepatitis B. Another limitation of this study is a low study power that could not detect rare renal adverse events and fractures in patients who have minimal risk factors for renal and bone disease. Based on the results, the authors in this study concluded that the coformulated tablet of EVG/c/TAF/FTC compared to EVG/c/TDF/FTC was noninferior in virologic suppression.

Use of Genvoya in Virologically Suppressed Adults

In this randomized, multicenter, active-controlled, open-label, phase III, noninferiority trial, patients were randomized to receive EVG/c/TAF/FTC or remain on a previous TDF-containing regimen.¹⁰ Similar to the study by Sax et al, baseline characteristics of the study population included primarily young white males with eGFR greater than 100 mL/min. Most patients also had CD4 cell counts >350 cells per μL and were virologically suppressed, defined as HIV-1 RNA <50 copies/mL. All patients were on a TDF-containing regimen for 98 weeks prior to enrollment. These 4 baseline regimens were EVG/c/TDF/FTC, efavirenz/TDF/FTC, atazanavir (ATV)/c/TDF/FTC, or ATV/ritonavir (r)/TDF/FTC. Patients were assigned (2:1) to continue 1 of the 4 TDF-containing regimens or switch to EVG/c/TAF/FTC. This study evaluated whether the efficacy, safety, and tolerability in patients switching to the EVG/c/TAF/FTC regimen were noninferior to patients who remained on a regimen containing TDF. The primary end point was undetectable viral load (HIV-1 RNA <50 copies/mL) at week 48 in patients who received at least 1 dose of the study drug.

Virologic suppression at week 48 occurred in 97% of patients assigned to the EVG/c/TAF/FTC group and 93% of patients in the TDF-containing regimen group (adjusted difference: 4.1%, 95% CI: 1.6-6.7, P = .0002). Virologic failure was similar between the EVG/c/TAF/FTC and TDF-containing arms, 10 patients (1%) and 6 patients (1%), respectively. In the EVG/c/TAF/FTC arm, 1 patient (<1%) had virologic failure at week 8 and developed resistance to the Met184Ile/Met mutation.

Due to the open-label study design, it is important to interpret adverse drug events and study discontinuation rates with caution. Baseline characteristics between the groups were comparable; however, more patients in the EVG/c/TAF/FTC arm than the TDF-containing regimen arms were of Hispanic or Latino ethnic origin (P = .0006).

Use of Genvoya in Renally Impaired Patients

Pozniak et al assessed the safety and efficacy of EVG/c/TAF/FTC in patients with baseline mild to moderate renal dysfunction (eGFR 30-69 mL/min) or bone abnormalities in a single-arm, open-label, phase III clinical trial.¹¹ Baseline characteristics of the study population included primarily older men than the previous studies discussed (median age of about 58 years). Nearly all of the patients had HIV-1 RNA <50 copies per mL and median CD4 count >600 cells per μL. Percentage of patients with comorbidities of hypertension (39%) and diabetes mellitus (14%) was included in the baseline characteristics and nearly half the 242 included patients had significant proteinuria and albuminuria. The primary end point was the change from baseline to week 24 in eGFR_CG, eGFR_CKD-EPI-CysC based on cystatin C, and eGFR_{CKD-EPI-creat} based on serum creatinine. Secondary end points included renal and bone safety assessments, as well as the proportion of patients maintaining virologic control, defined as HIV-1 RNA <50 copies/mL, at 24, 48, and 96 weeks.

Pozniak et al demonstrated that EVG/c/TAF/FTC had comparable efficacy results in patients with renal dysfunction. Of note, although the study continued follow-up until 96 weeks, data were only presented up to week 48. At week 48, 92% of 222 patients maintained an HIV-1 RNA <50 copies/mL. Although the data seem to suggest that patients with mild to moderate renal impairment can safely use EVG/c/TAF/FTC without the need for renal dosage adjustment, it is important to be cognizant that the primary outcome did not look at the efficacy of EVG/c/TAF/FTC, but rather safety. One of the key limitations of this trial was the lack of a control arm and it is difficult to state with certainty whether patients with mild to moderate renal impairment can safely and effectively use EVG/c/TAF/FTC for the treatment of HIV-1. Furthermore, while previous trials have demonstrated favorable effects of EVG/c/TAF/FTC in relation to renal and bone safety, phase III randomized clinical trials all included patients with creatinine clearance (CrCl) greater than 50 mL/min and generally had average baseline eGFR greater than 90 mL/min.

Safety

Renal

Initial treatment of HIV-1 infection includes 2 NRTIs plus a third active drug from a different drug class. Recommended initial treatment options for HIV-1 infection all include abacavir (ABC) or TDF as one of the NRTI backbones within the treatment regimen. ABC carries warnings for coronary artery disease and possible increased risk of myocardial infarction; TDF has risk of renal and bone toxicity.^12
-14 Therefore, TDF or ABC may not be the safest option for patients with an increased risk of chronic kidney disease (CKD) and cardiovascular (CV) disease.

In the study by Sax et al, the EVG/c/TAF/FTC arm had significantly smaller increases in the eGFR than in the EVG/c/TDF/FTC arm. Glomerular and tubular function was significantly lower in the EVG/c/TAF/FTC arm and had favorable urine protein to creatinine (UPCR) and urine albumin to creatinine (UACR) ratios (P < .001). At 48 weeks, quantitative proteinuria was increased from baseline in the EVG/c/TDF/FTC arm as compared to the EVG/c/TAF/FTC arm, in which smaller increases were noted in the urinary proteins (P < .0001). However, it is important to note that in patients with few risk factors for renal adverse events or bone fractures, the study had low power to detect rare clinical safety events.⁷

In the study by Mills et al, patients who switched to EVG/c/TAF/FTC had decreased serum creatinine, dipstick proteinuria, quantitative tests of total urine protein, urine albumin, and renal tubular proteins. This is significant because individuals with HIV-1 and CKD have increased risk of CV events and may not be able to take TDF or ABC. Mean serum creatinine change in EVG/c/TAF/FTC and TDF-containing regimen were −0.4 µmol/L (SD: 10.14) and 2.9 µmol/L (SD: 9.29), respectively.¹⁰

In the study by Pozniak et al, there were no noted significant changes in estimated CrCl, regardless of baseline renal function or switching to an EVG/c/TAF/FTC. However, there were differences in total proteinuria, albuminuria, and tubular proteinuria in favor of patients switching to EVG/c/TAF/FTC. Most notable, when patients were switched to EVG/c/TAF/FTC, the prevalence of significant proteinuria (UPCR > 200 mg/g) decreased from 42% to 11% and albuminuria (UACR ≥ 30 mg/g) decreased from 49% to 21%. Two of 8 patients experienced kidney-related adverse events. One of these patients had a baseline eGFR of 49 mL/min and had worsening renal insufficiency possibly due to uncontrolled hypertension, vomiting, dehydration, and concomitant use of ramipril and valsartan. Progression of hypertension-related CKD, which was unrelated to the study drug, occurred in the second patient.¹¹

Bone Mineral Density

Patients with HIV-1 infection have lower bone mineral density (BMD) and higher prevalence of osteopenia and osteoporosis, and thus, they have an increased risk of fractures.^7,10 In phase II randomized study by Sax et al, patients in the EVG/c/TAF/FTC arm experienced smaller decreases in BMD. Bone assessment was completed by a dual-energy X-ray absorptiometry (DEXA) scan. Less significant change in BMD was noted at week 24 in the hip (−0.62% vs −2.39%, P < .001) and lumbar spine (−1.00% vs −3.37%, P < .001) in the EVG/c/TAF/FTC arm than the EVG/c/TDF/FTC study arm from baseline. Bone marker turnover at weeks 24 and 48 were lower in the EVG/c/TAF/FTC arm than in the EVG/c/TDF/FTC arm. A marker for bone formation, procollagen type 1 N-terminal propeptide, increased in patients given EVG/c/TAF/FTC by 9% and EVG/c/TDF/FTC by 69% from baseline (P < .001). C-terminal telopeptide, a marker for bone resorption, was 19% higher than baseline in the EVG/c/TAF/FTC arm and 78% higher in the EVG/c/TDF/FTC arm (P < .001).⁹

In phase III noninferiority study by Sax et al, a threshold of 3% was used to assess notable differences in the EVG/c/TAF/FTC and EVG/c/TDF/FTC groups from baseline. Results for DEXA-measured BMD through week 48 for the spine was 26.5% and 45.8% in the EVG/c/TAF/FTC and EVG/c/TDF/FTC arms, respectively. BMD of the hip was 16.8% and 50.1% in the EVG/c/TAF/FTC and EVG/c/TDF/FTC arms, respectively.⁷

In the clinical trial by Mills et al, patients in the EVG/c/TAF/FTC arm had increased mean BMD at the hip (+1.47%) and spine (+1.56%), whereas the BMD of the hip (−0.3%) and spine (−0.44%) decreased in the TDF-containing arm. In the EVG/c/TAF/FTC arm, a significantly greater number of patients recovered from osteopenia or osteoporosis at the hip and spine during the 48 weeks (P < .0001).¹⁰

Patients with mild to moderate renal impairment had similar BMD benefits when switched to EVG/c/TAF/FTC. In the study by Pozniak et al, patients who switched from TDF and non-TDF-containing regimens to EVG/c/TAF/FTC had increased mean percentage of BMD in hip (+1.47%) and spine (+2.29%).¹¹

Metabolic Effects

In phase II comparative study by Sax et al, median increases in high-density lipoprotein (HDL) cholesterol (7 vs 3 mg/dL, P = .023) and total cholesterol levels (30 vs 17 mg/dL, P = .007) were higher in the EVG/c/TAF/FTC arm than the EVG/c/TDF/FTC arm. Although not statistically significant, a greater increase in low-density lipoprotein (LDL) cholesterol was observed in the EVG/c/TAF/FTC arm compared to the EVG/c/TDF/FTC arm (17 vs 11 mg/dL, P = .11).⁹ In phase III trial by Sax et al, treatment-naive patients in the EVG/c/TAF/FTC arm had greater increases in total cholesterol, direct LDL, HDL, and triglycerides from baseline compared to the EVG/c/TDF/FTC arm.⁷

Similar to both trials by Sax et al, the clinical trial by Mills et al revealed that in the EVG/c/TAF/FTC arm, fasting lipid concentration increased from baseline but the concentrations remained stable in the TDF-containing arm. More patients in the EVG/c/TAF/FTC arm (8%) than in the TDF-containing arm (6%) began lipid-lowering drugs.¹⁰

In the study by Pozniak et al, patients who were taking a non-TDF regimen at baseline and randomized to EVG/c/TAF/FTC after enrollment in the study had improvement in their fasting lipid panel results. In contrast, patients who used a TDF-containing regimen before being switched to EVG/c/TAF/FTC had increased fasting lipid panel results.¹¹

Other Adverse Events

Some of the most common adverse events (≥5%) reported in phase II and phase III trials by Sax et al were diarrhea, nausea, upper respiratory tract infections, and headache. Study discontinuation was uncommon and similar in the EVG/c/TAF/FTC and EVG/c/TDF/FTC arms. Seven (0.8%) patients and 11 (1.3%) patients in the EVG/c/TAF/FTC and EVG/c/TDF/FTC arms, respectively, discontinued study drugs due to adverse events. Serious adverse events leading to 5 deaths were found to be treatment unrelated.⁷

In the study by Mills et al, upper respiratory tract infections, diarrhea, and nasopharyngitis were the most common adverse events. Drug-related adverse events were higher in the EVG/c/TAF/FTC arm than the TDF-containing arm, 21% versus 16%, respectively. Four patients died and no deaths were treatment related. In the TDF-containing arm, study discontinuation occurred in 3 patients who had jaundice and 5 patients who developed kidney-related adverse events. Two adverse events in the EVG/c/TAF/FTC arm were kidney related. One patient in the ATV/c/TDF/FTC arm had Fanconi’s syndrome, which lead to study discontinuation.¹⁰

The most common adverse events reported in Pozniak et al were diarrhea, upper respiratory tract infection, and arthralgia. Study discontinuation was uncommon and only occurred in 8 (3%) patients.¹¹ See Table 1 for adverse event rates.

Table 1.

Adverse Event Profile of EVG/c/TAF/FTC Versus EVG/c/TDF/FTC.

	Sax et al⁷		Mills et al¹⁰		Pozniak et al¹¹
	TAF, n = 866 (%)	TDF, n = 867 (%)	TAF, n = 959 (%)	TDF, n = 477 (%)	TAF < 50 mL/min, n = 80 (%)	TAF ≥ 50 mL/min, n = 162(%)
Patients with any AE(s)
Death	5 (<1)	3 (<1)	4 (<1)	0	0	0
Serious AE	N/A	N/A	65 (7)	35 (7)	9 (11)	20 (12)
Study discontinuations due to AE	7 (<1)	11 (<2)	9 (1)	12 (3)	6 (8)	2 (1)
Most common AE(s)
Diarrhea	147 (17)	164 (19)	96 (10)	42 (9)	10.4 (13)	17.8 (11)
Nausea	132 (15)	151 (17)	50 (5)	16 (3)	4.8 (6)	14.6 (9)
Headache	124 (14)	108 (13)	69 (7)	20 (4)	2.4 (3)	14.6 (9)
Upper respiratory tract infection	99 (11)	109 (13)	151 (16)	54 (11)	2.4 (3)	19.4 (12)
Nasopharyngitis	78 (9)	80 (9)	88 (9)	39 (8)
Cough	67 (8)	60 (7)	64 (7)	25 (5)	4 (5)	9.7 (6)
Vomiting	62 (7)	54 (6)
Arthralgia	61 (7)	39 (5)	59 (6)	24 (5)	6.4 (8)	16.2 (10)
Back pain	60 (7)	57 (7)	52 (5)	25 (5)	3.2 (4)	13 (8)
Insomnia	57 (7)	48 (6)	50 (5)	30 (6)
Rash	55 (6)	46 (5)
Pyrexia	45 (5)	41 (5)
Dizziness	44 (5)	37 (4)			8 (10)	6.5 (4)
Syphilis			46 (5)	30 (6)
Bronchitis			58 (6)	26 (5)	7.2 (9)	13 (8)
Depression			42 (4)	30 (6)
Osteopenia			56 (6)	22 (5)	8.8 (11)	11.3 (7)
Sinusitis			48 (5)	25 (5)
Fatigue					4 (5)	9.7 (6)
Pain in extremity					4 (5)	13 (8)
Renal cyst					4.8 (6)	9.7 (6)

Abbreviations: AE, adverse event; N/A, not applicable; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumerate.

Discussion

The efficacy and safety results from phase II and III clinical trials in this review article conclude that EVG/c/TAF/FTC has an improved bone and renal safety profile without compromising the efficacy of HIV-1 treatment. Elvitegravir/c/TAF/FTC’s ability to increase CrCl/GFR is uncertain since the clinical trials have inconsistent results; however, EVG/c/TAF/FTC does show marked improvement in proteinuria, albuminuria, and tubular function.^7,9
-11,15

Osteopenia and osteoporosis are costly adverse effects of TDF-containing regimens. The risk factors for osteopenia and osteoporosis include smoking, insufficient intake of calcium and vitamin D, Caucasian ethnicity, family history, excessive alcohol consumptions, and long-term use of corticosteroids or proton pump inhibitors.¹⁶ It is our opinion that patients with medical history of fractures or those who have or are at risk for developing osteopenia or osteoporosis at baseline should be started or switched to EVG/c/TAF/FTC in order to reduce the risk of decreased BMD. It is the opinion of the authors that EVG/c/TAF/FTC is a better choice for HIV-1 treatment than a TDF-containing regimen in patients diagnosed at a young age. Patients diagnosed in their 30s have a longer life expectancy than those in their 50s. For this reason, the medication used in this population should have as few adverse effects as possible.

The increase in total cholesterol levels seen in the aforementioned clinical trials should be further investigated. Lipid abnormalities are an established risk factor for CV events and should be managed with appropriate therapy in patients who experience this adverse effect while taking EVG/c/TAF/FTC for HIV-1 infection. It is the opinion of the authors that lipid abnormalities should not preclude patients from continuing EVG/c/TAF/FTC therapy.

A limitation of this review is that this review is observational and there was no statistical analysis completed to compare the results of the trials presented. There were a few limitations that were present in all clinical trials. The clinical trials discussed in this article included patients with different ethnicities, but a large percentage of the included patients were white men. The rates of HIV-1 acquisition continue to increase within black and Hispanic/Latino gay/bisexual men, whereas rates within the white gay/bisexual population are at a decline.¹⁷ There are certain differences within these populations that effect their rate of HIV-1 transmission that is unaccounted for in all of these trials.

Conclusion

Phase III clinical trials discussed in this article demonstrate EVG/c/TAF/FTC’s noninferiority in efficacy to EVG/c/TDF/FTC and TDF-containing regimens.^7,10,11 The high stability of TAF and decreased TFV systemic exposure result in lower renal toxicity and BMD.⁷ Phase II and III studies show a more favorable renal and BMD profile in patients treated with EVG/c/TAF/FTC compared with EVG/c/TDF/FTC and other TDF-containing regimens. Increases in total cholesterol, LDL levels, and HDL levels were seen in the EVG/c/TAF/FTC arm compared to the TDF-containing arms.^7,9
-11

Footnotes

Declaration of Conflicting Interests

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

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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