https://orcid.org/0000-0003-0263-0703
Abstract
Background
Recently, injectable cabotegravir/rilpivirine (ICAB/RPV) became available for HIV treatment. However, there are no real-life data on the impact of switching to ICAB/RPV on sleep disturbances (SD). Therefore, we aimed at assessing and investigating this aspect in our cohort.
Methods
A SD multidimensional assessment (Epworth Sleepiness scale, Insomnia severity Index, Berlin Questionnaire, and Pittsburg Sleep Quality Index, PSQI) was performed to all people who consented before starting ICAB/RPV and 12 wk after the switch. Demographics, life-style habits, laboratory, and clinical data were collected from medical health records.
Results
To June 2023, 46 people were included, 76.1% males, with a median age of 48.5 (IQR: 41–57), 50% had multimorbidity, 13% was on polypharmacy. Median age with HIV and CD4 + T cell count nadir were 10 (5–19.5) years and 360 (205–500) cell/mm3, respectively. The reason to start a long-acting strategy was person’s choice in all cases. Baseline antiretroviral regimens were mostly: tenofovir alafenamide/emtricitabine/rilpivirine (39.1%) and dolutegravir/lamivudine (32.6%). No significant changes were observed in any of the scores for each questionnaire, but for a worsening PSQI. 37% people reported a subjectively improved sleep quality, even if statistically significant changes were not observed in almost all the sleep parameters.
Conclusions
To the best of our knowledge, this is the first study exploring impact of switching to ICAB/RPV on SD. Despite integrase inhibitor have been associated with SD, we did not observed a negative impact on sleep quality after the switch to ICAB/RPV. More studies and with larger number of people are necessary to confirm our results.
Introduction
Treatment of HIV-1 has been completely revolutionized over the last decades; indeed, we have gone from complex regimens, with many tablets, to single tablet regimens, containing two or three molecules. These new regimens are characterized by very high virological efficacy and high tolerability, especially when compared with the regimens used in the early nineties, reducing the clinical issues related to the management of severe toxicities and side effects [Citation1]. However, due to ageing and longer survival, the issue of managing multimorbidity and polypharmacy, preventing drug-drug interactions, remains a challenge for clinicians [Citation2, Citation3].
To date, the class of integrase strand transfer inhibitors (INSTIs) due to its potency and favorable tolerability profile is the most used and INSTIs have become a cornerstone of HIV treatment regimens globally. However, emerging data in people living with HIV (PLWH) suggest the potential association between these drugs and sleep disturbances like insomnia and nightmares, especially for second generation INSTIs [Citation4]. Usually, these adverse events are mild to moderate and among INSTIs dolutegravir is the drug most affected. In a meta-analysis of all randomized controlled trials with dolutegravir (DTG), there was a significantly higher risk of insomnia for DTG vs. other antiretrovirals (6.1% vs 4.5%; p = 0.02) and it is most likely to occur in women, aging people (>60 years old) and individuals starting abacavir at the same time [Citation4, Citation5].
Recently, long-acting (LA) intramuscular injectable cabotegravir and rilpivirine (ICAB/RPV) became available for HIV treatment. Data from clinical trials LATTE-1, LATTE-2, ATLAS-2M and FLAIR reported as most common side effects other than injection site reactions nasopharyngitis, upper respiratory tract infection, headache, and diarrhea [Citation6–8]. Most adverse events were mild or moderate in severity, and less than 2% of participants discontinued treatment owing to an adverse event, confirming the overall tolerability of the regimen. In addition, no new onset of significant sleep disturbances (SD) was observed. However, to date, there are no real-life data on the impact of switching to ICAB/RPV on SD. Therefore, we aimed at exploring the incidence of sleep disorders associated with this new innovative antiretroviral combination and its impact on sleep metrics in a cohort of people who started ICAB/RPV in our HIV out-patient clinic.
Materials and methods
This prospective monocenter cohort study, performed at Infectious and Tropical Diseases Unit of Padua University Hospital (Padua, Italy) included all persons with HIV who switched to ICAB/RPV. Eligible participants were 18 years or older, being on the same antiretroviral regimen for at least 6 months with an undetectable plasma HIV-RNA (i.e. <20 copies/mL) for at least 24 wk, and had CD4 + T cell count >200 cells/μL. As inclusion criteria, we considered all people who, being eligible, started a LA regimen and who consented to comply with the study protocol and were able to complete all the study questionnaires.
By using different validated questionnaires (Epworth Sleepiness scale, ESS, Insomnia severity Index, ISI, Berlin Questionnaire, BQ, for sleep apnea, SA, and Pittsburg Sleep Quality Index, PSQI, a multidimensional assessment for SD was administered to all participants the day before the first ICAB/RPV administration and 12 wk after the switch. Any interruption due to onset of SD was recorded. The presence of SD was assessed by using validated cut-off. In particular, for ESS, an excessive daily sleepiness was considered as present whenever the total score was greater than 10, for ISI the score was deemed altered whenever greater than >15, for PSQI, poor sleep quality was deemed present when the score was >5, and for BQ assessing the risk of sleep apnea, when two or more categories were positive, obstructive sleep apnea was considered present [Citation9–13]. Demographics, life-style habits (regular exercise, alcohol consumption), laboratory, and clinical (comorbidities, polypharmacy) data were collected from medical health records. For life-style habits such as regular exercise and alcohol consumption, we used the WHO definitions [Citation14, Citation15]. We defined multimorbidity and polypharmacy as the presence of two or more non-communicable diseases and the intake of five or more non-antiretroviral drugs in the same person [Citation16, Citation17, Citation18].
All data were collected in a pseudo-anonymized Excel® electronic spreadsheet. Data were reported as median (interquartile range, IQR) for continuous variables and absolute number (proportion) for categorical variables. Statistical analysis for qualitative data was performed using the chi-squared (χ2) test, quantitative data were analyzed by using Fisher’s exact test, significance was set at p ≤ 0.05. Data were analysed through SPSS v27 (IBM Stat. Corp., Armonk, NY, USA).
This study was conducted in accordance with principles of good clinical practices and Declaration of Helsinki. The study protocol for routine SD assessment in our HIV outpatient’s clinic was approved by the local ethical committee (n.2763, 21.10.2021). All participants provided written informed consent for participation.
Results
To June 2023, 46 persons were included. Demographic and clinical characteristics at enrolment are shown in , 76.1% were males, with a median age of 48.5 (IQR: 41–57) years, 50% had multimorbidity, and 13% was on polypharmacy. Median age living with HIV and CD4 + T cell count nadir were 10 (5–19.5) years and 360 (205–500) cell/mm3, respectively. The reason to start a LA strategy was participant’s choice in all cases. Baseline antiretroviral regimens were: tenofovir alafenamide/emtricitabine/rilpivirine (TAF/FTC/RPV) in 18 cases (39.1%), dolutegravir/lamivudine (DTG/3TC) in 15 cases (32.6%), abacavir/lamivudine + nevirapine (ABC/3TC + NVP) in 3 cases (6.5%), tenofovir alafenamide/emtricitabine/bictegravir (TAF/FTC/BIC) in 2 cases (4.4%), dolutegravir/rilpivirine (DTG/RPV) in 2 cases (4.4%), tenofovir alafenamide/emtricitabine/doravirine (TDF/3TC/DOR) in 1 case (2.16%), %), abacavir/lamivudine + efavirenz (ABC/3TC + EFV) in 1 case (2.16%), tenofovir alafenamide/emtricitabine + raltegravir (TAF/FTC + RAL) in 1 case (2.16%), doravirine/dolutegravir (DOR + DTG) in 1 case (2.16%), dolutegravir + atazanavir/ritonavir (DTG/ATV/r) in 1 case (2.16%), and tenofovir disoproxil fumarate/emtricitabine/rilpivirine (TDF/FTC/RPV) in 1 case (2.16%).
Table 1. Cohort description.
Considering results of the study assessment, at the baseline median time slept per night was 7 h (IQR: 6–8), and 54.4% of participants overall self-reported of suffering from mild to severe insomnia, even though the multidimensional assessment questionnaire did not detect SD in 63% of participants. By contrast, 37% participants reported alterations to one or more questionnaires (BQ 19.5%, ISI = 13%, ESS 15.2%, and PSQI = 13%). One person suffered from a parasomnia (sleepwalking). Considering ISI questionnaire, insomnia was initial, central, and terminal in 41.3%, 45.6%, and 39.1% of cases, respectively. Most participants (73.9%) reported of taking an afternoon nap. 8.7% of the participants were on treatment with hypno-inducing medications. Full outcomes of sleep assessment at the baseline and follow-up time point are reported in . At week 12, all participants maintained an undetectable viral load, and CD4+ T cell count remained stable (median 724 cell/mm3, IQR: 513–915). No statistically substantial and significant differences between baseline and week 12 of follow-up were found in the multidimensional SD assessment. Indeed, both number of people with altered and score and score values for at BQ, ISI, ESS remained substantially stable, as well as the sleep metrics. By contrast we detected a significant number of people who reported an alteration of PSQI at the follow-up point (6, 13% vs. 20, 43.5%, p = 0.002), with a median increase of the score from 4 (IQR: 3–5) to 7 (IQR: 5–8), p = 0.001. In all cases, people who reported an increase of PSQI were already on regimens containing INSTIs. However, at week 12, 37% patients referred a subjective improvement in the quality of their sleep, while no-one disclosed a worsening. Lastly, the viro-immunological profile did not change significantly during the follow-up, with all participants maintaining an undetectable viral load, and a median CD4+ T cell count of 724 (IQR: 513–915) cell/mm3.
Table 2. Sleep metrics and results from screening for sleep disturbances at the baseline and at follow-up.
Discussion
To the best of our knowledge, this is the first study exploring the impact of switching to ICAB/RPV on SD in a real-life setting. SD appear to be considerably common in people with HIV and a meta-analysis, which included twenty-seven studies comprising a total of 9246 participants, estimated the prevalence of SD to be around 58%, and almost 3 times higher than that reported in the general population [Citation19, Citation20].
Factors such as chronic inflammation, psychiatric conditions, neurocognitive impairment, alcohol and substance consumption, and adverse effects of antiretroviral drugs contribute to the development of sleep disturbances in this population [Citation5, Citation21, Citation22]. Among antiretroviral drugs, EFV and DTG have the greatest impact on sleep [Citation5, Citation23, Citation24]. Vivid dreams, difficulties in falling asleep, and a lot of sleep interruptions are frequently reported after beginning EFV therapy. Symptoms improved in few weeks post EFV initiation, even though in some persons they may persist, compromising the quality of life and occasionally leading to drug withdrawal. SD with DTG seems to be less common. In recent cohort studies including more than 6000 participants in different countries, DTG was discontinued because of neuropsychiatric events mainly regarding SD and insomnia in a range of 1.4–7.2% of participants [Citation4].
The recent introduction in the clinical practice of ICAB/RPV offered for the first time a LA option for HIV maintenance therapy, providing convenience and improved adherence compared to daily oral medications.
To date, no real-life research specifically assessed evolution of sleep quality and SD after an antiretroviral switch to ICAB/RPV. However, studies investigating the efficacy and safety of these medications have reported sleep-related adverse events, including insomnia, abnormal dreams, and sleep disorders [Citation6–8].
Our study did not reveal any changes in scores measured by four validated questionnaires on SD, but one (PSQI). These results even in a limited number of individuals seem to confirm the this switch is reasonable to have not an impact on the overall sleep quality, and that the safety profile may be comparable to that reported in the randomized studies of switching to a dolutegravir plus rilpivirine combination regimen [Citation25].
Indeed, sleep plays an essential role in physical and mental health, and we strongly believe that it would be crucial to consider this issue when prescribing ICAB/RPV, particularly for people who are already at higher risk of suffering from SD.
The exact mechanisms through which antiretroviral drugs, including ICAB/RPV may contribute to SD in people with HIV are not fully understood. Potential factors include genetic predisposition, neurochemical alterations, high drug exposure, direct effects on sleep regulatory systems, interactions with other medications, and underlying comorbidities [Citation26]. Interestingly, we observed a significant increase in PSQI score and in a significant number of people, but it was not associated with a relevant clinical condition. Indeed, despite this score was altered in the follow-up in a significantly higher number of people compared to the baseline, no persons complained about a subjective perception of sleep quality worsening. This is in line with previous results that showed how changes in sleep questionnaire may not reflect a clinical improvement or worsening [Citation27]. On the other hand, it can be speculated that the enthusiasm for a new therapy with the absence of a daily need for oral intake, selected almost in all cases by the participants, and a short duration of observation, did not allow us to detect even sub-clinical disturbances. Indeed, being the study focused over the 12 wk after the switch, we are not able to foresee what may happen in the long-term.
This study is also somewhat limited by the study design and by the small number of participants. Moreover, 50% people came from INSTI or efavirenz containing regimens, so the impact on SD of people who were naïve to INSTI could have been under shadowed. However, in our study the evaluation of SD was performed through validated measures that are pragmatic tools for routine clinical settings since inexpensive and easy to be administered.
To optimize treatment outcomes for individuals on ICAB/RPV, healthcare providers should be vigilant in assessing and managing SD. This may involve comprehensive sleep evaluations, personal education on sleep hygiene practices, and, if necessary, the incorporation of adjunctive therapies such as cognitive-behavioral therapy for insomnia. Close monitoring of potential drug-drug interactions, particularly with medications that may exacerbate SD, is also crucial.
Finally, even if we did not detect any relevant clinical impact on sleep in our cohort, it must be underlined that clinicians should be aware of the considerably occurrence of SD per se and the possible impact of some antiretroviral drugs, specifically related to INSTI and non-nucleos(t)ide reverse transcriptase inhibitor classes, in the worsening of sleep quality. Effective interventions like the assessment of sleep-related symptoms regularly and appropriate measures should be implemented to improve sleep quality and reduce the mental and physical consequences from its disturbance in this population. Further research is also warranted to better understand the underlying mechanisms and develop targeted interventions for improving sleep outcomes in individuals receiving the innovative ICAB/RPV therapy. Lastly, further research is needed to elucidate the specific etiology and the effects of chronic immune activation involved on sleep-wake physiology.
Ethical approval
Participants signed a written informed consent for participation. Local Ethics Committee approved the study protocol (n.2763, 21.10.2021).
Acknowledgments
We want to thank all the staff (doctors and nurses) working in the Padua HIV clinic. This study was presented at EACS 2023 as poster presentation (n.290)
Disclosure statement
MM received research grant from Gilead, fees for advisory board from ViiV Healthcare, speaker’s honoraria from Gilead, ViiV Healthcare, MSD; AC, LS, DL received speaker’s honoraria from Gilead, ViiV Healthcare, MSD; all the other authors declare no conflict of interests.
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References
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