Abstract
Objectives:
The aim was to investigate whether switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/F/TDF) to bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) may improve neuropsychiatric symptoms and neurocognition.
Design:
Pilot, single-arm, prospective study of persons with HIV (PWH) on the efficacy and safety of switching from EFV/F/TDF to BIC/F/TAF.
Methods:
Participants underwent neuropsychological assessment (NPA) at switch (T0) and after 48 weeks (T1). NPA was carried out through a standardized battery of 12 tests. Neurocognitive impairment (NCI) was defined by a score of at least 1 standard deviation (SD) below the normal mean on at least two tests or ≥2 SD below on one test. Individual z scores were determined, NPZ-12 was calculated as the average of 12 test z scores and change of NPZ-12 was the outcome. HIV-associated neurocognitive disorder (HAND) was classified by Frascati's criteria. Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), and Pittsburgh Sleep Quality Index (PSQI) were administered. Paired-Wilcoxon and McNemar tests were used for comparisons, and logistic regression for associations with NCI changes.
Results:
Out of 126 participants, BAI, BDI-II, and PSQI questionnaires revealed an improvement at T1. NPA revealed NCI in 40.5% of persons at T0 and 42.1% at T1 (P = 0.746). Specifically, at T0, among participants with NCI, 35% improved; among those without, 26% worsened at T1; NPZ-12 score worsened at T1. 5.6% of ANI was observed at T0 and 7.9% at T1. No factor associated with these changes was found.
Conclusion:
Our results suggest switching from EFV/F/TDF to B/F/TAF significantly improves psychiatric symptoms and sleep quality. Neurocognitive performance remained stable, although a decline in NPZ-12 and in specific domains was observed.
Keywords: bictegravir, efavirenz, HIV-associated neurocognitive disorder, neurocognitive impairment, neuropsychological assessment
Introduction
Efavirenz (EFV) played a decisive role in HIV treatment strategies because of therapeutic effectiveness and regimen simplicity, but nowadays, the use of EFV-based combined antiretroviral therapy (cART) remains an alternative option for first-line therapy as stated by some international guidelines for reasons, including neuropsychological tolerability [1,2]. Though the appearance of neuropsychiatric symptoms, usually short-lasting after therapy initiation, well recognized and mostly transient, like abnormal dreams, dizziness, somatization, irritability, and stress can persist in some individuals for several months or years with a proportion of individuals who may experience depression at any time during the treatment with EFV [3]. In contrast, the association between EFV and neurocognitive impairment (NCI) remains unclear and controversial: worst neurocognitive performances have been associated with EFV in some cohort studies [4,5] but not in others [6]. Moreover, replacing EFV seems not to be associated with a change in neurocognitive performance in prospective studies [7,8].
Bictegravir (BIC) is an integrase strand transfer inhibitor (INSTI) approved as first-line in cART-naive and virologically suppressed individuals combined with emtricitabine (FTC) and tenofovir alafenamide fumarate (TAF) in a single tablet regimen (STR) [9].
Whether changes in ART toward more innovative regimens, such as BIC/F/TAF, have an impact on neuropsychological symptoms and/or cognition has not yet been investigated.
Material and methods
The Ebony study (Switching from EFV/F/ tenofovir disoproxil fumarate [TDF] to BIC/F/TAF in virOlogically suppressed PWH in daily or alternate-day regimens) is a pilot, single-center, single-arm, phase IV clinical trial conducted at the Italian National Institute of Infectious Diseases L. Spallanzani Hospital in Rome (Italy) between May 2019 and May 2022. The primary objective was to evaluate the efficacy of switching from EFV/F/TDF, either administered q24 or every other day (q48), to BIC/FTC/TAF 48 weeks after the switch in the total population and comparing patients switching from EFV/F/TDF once daily vs. on AlTernAte Days (ATAD). The secondary objectives were to assess safety, change in immunological status, lipid profile, and neurocognitive performance compared with the baseline. Moreover, other sub-studies were planned, including the assessment of adherence and quality of life (patient self-reported), assessment of pharmacokinetics of BIC, and change in renal function and bone mineral density (BMD) compared with baseline. Herein, we report only the analysis on neurocognitive performance and specifically whether a treatment switch from EFV/F/TDF to B/F/TAF may improve psychiatric symptoms and sleep quality and whether it impacts neurocognition.
Epidemiological, demographic data, and clinical data were collected and anonymously recorded. The inclusion criteria: stable treatment with EFV/F/TDF and virological suppression (HIV RNA <50 copies/ml) for at least 24 weeks prior to screening, genotypic resistance testing with absence of mutations for any class of antiretroviral drugs, absence of virological failures to INI-containing regimens, creatinine clearance at least 50 ml/min. Participants underwent neuropsychological assessment (NPA) before (T0) and after 48 weeks from the switch (T1). Individuals were classified as impaired or unimpaired based on their performance compared with normative data. NCI was defined according to Frascati's criteria for HAND diagnosis and based on the finding of values below 1 SD of the normative mean on at least two neuropsychological tests or below 2 SDs of the normative mean on at least one test. As reported by the updated research nosology for HAND [10], patients were diagnosed as having asymptomatic neurocognitive impairment (ANI) or mild neurocognitive disorder (MND), if cognitive deficits involved two or more cognitive domains, over at least five analyzed domains, not readily attributable to comorbid conditions, and documented by performances of at least 1 SD below the mean for norms, without interference in everyday functioning if ANI, or with at least mild interference in daily functioning if MND. Finally, HAD was defined by cognitive deficits involving at least two cognitive domains with a performance at least 2 SDs below the mean for norm on neuropsychological test and with a marked interference in everyday functioning. The panel of administered tests and references can be found in the Supplementary Materials.
Ethics
Ebony was approved by the Ethics Committee of ‘INMI Lazzaro Spallanzani’, according to Italian legislation (approval number 73/2018, 15/3/2018; EudraCT 2018-003880-79). The study was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants involved.
Statistical analysis
Descriptive analysis was performed using median and interquartile range (IQR) for continuous parameters and absolute and percentage frequencies for categorical variables. The comparison of proportions between baseline and 48 weeks was made using the McNemar test. Paired Wilcoxon test was used for statistical comparison of continuous values measured at two time points.
The change in BAI and BDI percentage scores and the change in the discrete score of PSQI from baseline to week 48 were calculated, and linear regression was used to study factors associated with the score changes. A high score in these questionnaires is associated with a worsening of psycho-affective condition at week 48. A worsening in neurocognition was defined for those individuals who exhibited an NCI at week 48 that was not present at baseline. Logistic regression was used to investigate the factors associated with the negative change in neurocognitive condition.
Results
One hundred and twenty-six participants were evaluated at T0 and T1. The main characteristics of the study population are summarized in Table 1. Briefly, 13% were women, with a median age of 53 years (IQR 46–57), 90% Caucasian, HIV transmission occurred mainly by unprotected sex (48% MSM and 37% heterosexual), a median time duration of HIV infection of 13 years (9–17), a median time of EFV exposure of 8 years (7–10). Among comorbidities, only 11% of participants had osteopenia at the time of switch, 0.7% kidney disease, and 6% reported neuropsychological disorders.
Table 1.
Main characteristics of study population.
| N = 126 | |
| Female [n (%)] | 17 (13.5) |
| Age, years [median (IQR)] | 53 (46–57) |
| Whites [n (%)] | 114 (90.5) |
| Mode of HIV transmission [n (%)] | |
| Heterosexual | 47 (37.3) |
| MSM | 60 (47.6) |
| IDUs | 6 (4.8) |
| Other/unknown | 13 (10.3) |
| Years of infection [median (IQR)] | 13 (9–17) |
| Years of education [median (IQR)] | 13 (13–17) |
| Pre ART HIVRNA, log10 [median (IQR)] | 4.4 (1.7–4.4) |
| N. of HIV genotype pre-ART | 73 (57.9) |
| CDC stage C [n (%)] | 15 (11.9) |
| At least one comorbidity [n (%)] | 13 (10.3) |
| Osteopenia | 14 (11.1) |
| Kidney diseases | 1 (0.7) |
| Neuropsichological diseases | 8 (6.3) |
| Exposure to efavirenz (years) [n (%)] | 8.3 (7.1–10.2) |
| CNS adverse events after the switch [n (%)] | |
| Headache | 7 (5.5) |
| Insomnia | 4 (3.1) |
| Other | 7 (5.5) |
The proportion of participants with self-reported BAI greater than 85% and BDI-II greater than 85% significantly decreased at T1 (participants with BAI >85% was 17% at T0 vs. 9% at T1; P = 0.008; those with BDI-II >85% were 21% at T0 vs. 14% at T1; P = 0.029; Fig. 1a).
Fig. 1.
(a) Comparison of patients’ proportion with Beck Anxiety Inventory greater than 95%, Beck Depression Inventory (BDI-II SA, somatic-affective, BDI-II C, cognitive, BDI-II T, total) greater than 95%; (b) the presence of sleep disturbance according with Pittsburgh Sleep Quality Index (PSQI); (c) NPZ12 score at the time of switch (T0) and after 48 weeks (T1); (d) Mean z score of 12 cognitive tests through 5 different domains at the time of switch (T0) and after 48 weeks (T1).
Also, the proportions of participants not complaining of sleep disorders at baseline improved after the switch (4 vs. 20%), similarly to those who complained of mild disorders (47 vs. 63%); in contrast, the percentages of participants who reported a moderate or severe disorder significantly decreased at 48 weeks after the switch (Fig. 1b).
Overall, the proportion of participants with impaired neurocognitive performances at baseline and after 48 weeks from the switch remained stable. Specifically, NPA revealed NCI in 40.5% of participants at T0 and 42.1% at T1 (P = 0.746).
Among participants with NCI at T0 (51/126), 35% (18/51) improved their performance after the switch, and among those without NCI (75/126) at baseline, 27% (20/75) worsened at w48. At T1, we observed a worsening in NPZ-12 score [median of change between baseline and week 48 = −0.18 (IQR −0.42 to 0.01); P < 0.001] (Fig. 1c) and particularly, in all domains but that of fine motor functioning (Fig. 1d). We observed ANI in 5.6% at T0 and 7.9% at T1. No MND or HAD were found. No significantly associated factors with these changes were found nor with NPZ score (Supplemental Fig. 1).
A few central nervous system (CNS) adverse events were observed, all mild: 7 of 126 participants reported insomnia, 4 headaches, 1 asthenia, 1 seizure episode, 1 temporary amnesia, and 4 participants experienced a neurological complication not drug related.
Discussion
Results from our study showed that in PWH switching from EFV-based to BIC-based regimen, neuropsychological symptoms assessed by self-reported questionnaires for anxiety/depressive symptoms, and sleep quality revealed a significant improvement in a relatively short period of time; this result seemed impressive considering that most of the participants (around 94% of them) had not reported any neuropsychological disorders at the time of the switch; conversely, neurocognitive performance remained stable.
Some authors showed that EFV-treated persons have significantly higher scores for somatization, anxiety, obsessive–compulsive behavior, Global Severity Index, and Positive Symptom Distress Index, but symptom severity appears to decline in about 6–12 months of treatment [11,12]; thus, change in symptomatology related to anxiety, depression, and/or sleep quality after EFV discontinuation was not always found [13] and the risk of discontinuation of EFV-based regimens was not greater than newer INSTI comparators such as raltegravir or dolutegravir [14].
Neuropsychological symptoms and adverse events are often misdiagnosed because they are not systematically investigated during clinical visits or inadequately collected in clinical or cohort studies, just as anxious-depressive symptoms are rarely studied prospectively. In our study, a neuropsychiatric screening methodology using the DSM-V diagnostic criteria [15] was used to screen for anxiety-depressive symptoms, which allowed us to objectively compare two different time points.
Despite the evidence of neuropsychiatric effects, the potential association between EFV exposure and NCI is still debated. Some studies have shown that exposure to EFV is associated with worse neurocognitive performance even after long-lasting drug intake [16]; other authors underline that EFV has led to the reduction in neurocognitive performance by effective virological control, demonstrating that HAND is not a progressive process if viral suppression is achieved [17].
In our study, about 40% of tested participants at baseline and after exposure to EFV were diagnosed with NCI despite suppressed plasma HIV-RNA. Notably, NCI was predominantly mild (MND) or asymptomatic (ANI). Evaluation of NCI predictors has been hampered because other factors could play a role in the pathogenesis of the damage [18].
cART toxicity has been suggested to participate in the pathogenesis of HAND [19], but the underlying mechanisms for possible EFV neurotoxicity are not fully understood, and multiple factors have been suggested, including: the good capacity of the drug to cross the blood–brain barrier [19], the damaging effect of two different EFV metabolites on neuronal cells, particularly on dendritic spines [20], or pharmacokinetic/dynamic factors (including cytochrome p450 polymorphisms), which might be related to increased concentrations of these metabolites and their neurotoxic effect [21].
The limitations of our study are: first, the small number of available NPA. Second, we included all consecutive unselected PWH who switched their current regimen and were available to come back at two different times to perform a complete and comprehensive neurocognitive and neuropsychological screening, so a selection bias might be an issue. Third, we do not have a control group to compare neurocognitive performance and neuropsychologically reported symptoms. Lastly, we were not able to monitor drug concentration to rule out a possible dose-related effect.
The strength of this study undoubtedly lies in the assertion that in an PWH population, reporting few neuropsychological effects at the time of the switch, they actually had a marked improvement in symptoms related to anxiety and depression, as if they were used to living with EFV-induced effects, only able to verify the difference after the therapeutic modification. Furthermore, as no other comorbidities (bone and kidney) were present in most cases, switching to the BIC/F/TAF formulation proved beneficial as well from the point of view of neuropsychological symptoms.
In conclusion, these findings show that a clear improvement of NPA can be obtained in PWH by switching from EFV-based to BIC-based cART; further, a consistent proportion of PWH under EFV-based regimen suffer from NCI, despite its virological efficacy, highlighting the multifactorial nature of the disease [21]; the neurocognitive performance remained stable overtime with a negligible reduction of NPZ-12 and median score performance in four out of five domains, although further investigation might be necessary. BIC/F/TAF has been demonstrated to be a valid alternative to EFV/F/TDF in virologically suppressed patients and with no evidence of previous virological failure, particularly among patients who complain of neuropsychological side effects, even if mild and long-time tolerated.
Acknowledgements
Contributors – conception: A.A., R.B., R.G., C.P. Study design: A.A., R.B., R.G., A.V., G.D.D. Acquisition of data: A.V., G.D.D., R.B., A.C.B., I.M., F.M., M.C., S.O., R.G., J.P., F.D.Z., E.G., R.B., R.G., R.E., V.M., M.P. Statistical analysis: P.L. Data collection: F.M., J.P., M.P. Interpretation of the data: A.V., A.A., C.P., G.D.D., A.C.B. Drafted the article: A.V., C.P., A.A. Review of the article and critical revision for important intellectual content: all the authors. Final approval of the submitted version: all the authors.
Data sharing statement: all data will be available upon reasonable request to the corresponding author
Funding: the study was funded by an unconditional grant from Gilead Sciences.
Conflicts of interest
A.A. has served as a paid consultant to Astra-Zeneca, Gilead Sciences, GlaxoSmithKline, Janssen- Cilag, Merck, Moderna, Mylan, Pfizer, Sharp and Dohme, Roche, Theratotecnologies, and ViiV Healthcare and received research institutional grants from Gilead Sciences, Janssen-Cilag, and ViiV Healthcare, payment or honoraria from Gilead Science and ViiV Healthcare and support for attending meetings and/or travel from ViiV Healthcare and AbbVie. R.B. received grant for speaker's honoraria/advisory board by ViiV Healthcare, MSD, Janssen-Cilag, and Gilead Sciences. M.C. received institutional grant, support for attending meetings and/or travel and speakers’ honoraria from Gilead Sciences. R.G. reports payments to her institution from Gilead Sciences, speakers’ honoraria for ViiV Healthcare, Merck Sharp and Dohme and Gilead Sciences, advisor for Theratechnologies, Janssen-Cilag, and Gilead Sciences. I.M. received institutional research grant and support for attending meetings and/or travel from Gilead Sciences. C.P. received personal fee from Gilead Sciences for a case presentation and a travel grant and served on an advisory board for Janssen-Cilag. A.V. received an institutional grant from Gilead Sciences, speakers’ honoraria/educational activities from Merck Sharp & Dohme, Janssen-Cilag, Gilead Sciences, AstraZeneca, and served an advisor for Janssen-Cilag. The other co-authors declare no conflicts of interests for this work.
Supplementary Material
Footnotes
Supplemental digital content is available for this article.
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