Switching from Efavirenz to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Reduces Central Nervous System Symptoms in People Living with HIV
The introduction of antiretroviral therapy (ART) has significantly reduced HIV-related mortality and morbidity worldwide, including in resource-limited countries. In China, the National Free Antiretroviral Treatment Program (NFATP) was launched in 2003, greatly increasing access to ART and leading to a substantial decline in HIV incidence and mortality. Consistent with recommendations from the World Health Organization and national AIDS control programs in several resource-rich countries, the Chinese NFATP currently recommends tenofovir (TDF) + lamivudine (3TC) + efavirenz (EFV) as the preferred first-line antiretroviral regimen due to its efficacy and relative affordability.
However, EFV, a non-nucleoside reverse transcriptase inhibitor, is associated with central nervous system (CNS) adverse events in 40% to 60% of individuals. These adverse events include psychiatric symptoms such as severe depression, anxiety, and suicidal ideation, as well as CNS symptoms like dizziness, insomnia, trouble concentrating, unusual dreams, and daytime drowsiness. These symptoms often prompt regimen switches, especially since many individuals receiving long-term EFV treatment may experience subtler symptoms that significantly affect their quality of life, such as irritability and hallucinations.
Before the availability of potent integrase inhibitors, HIV-positive individuals who did not tolerate EFV were treated with lopinavir/ritonavir (LPV/r), the only NFATP-sponsored protease inhibitor (PI) freely provided by the Chinese government. However, PI-related dyslipidemias have also been reported, with elevations in lipid parameters like total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), which are recognized risk factors for cardiovascular disease.
The fixed-dose combination of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) for HIV treatment was first approved by the US Food and Drug Administration in 2015 and officially introduced in China in 2018. E/C/F/TAF is a single-tablet regimen containing elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg), and tenofovir alafenamide (10 mg). It is effective in treatment-naive and virologically suppressed individuals, with a favorable safety profile. The Chinese Guidelines for HIV/AIDS Diagnosis and Treatment (2018) recommend E/C/F/TAF as the first-line initial ART regimen for people living with HIV (PLWH). E/C/F/TAF is more convenient than LPV/r, as it is taken once daily, and it is more affordable, being the only reimbursement single-tablet HIV drug covered by the Chinese government since January 2020.
This study aimed to assess the CNS effects and efficacy of E/C/F/TAF in Chinese HIV adults experiencing grade two or higher neuropsychiatric and CNS toxicity who switched from an EFV-based regimen to E/C/F/TAF.
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Tianjin Second People’s Hospital Institutional Review Board. Written informed consent was provided by each recruited participant. This observational study was conducted prospectively at Tianjin Second People’s Hospital from January 2020 to June 2021. Inclusion criteria were: age range of 18 to 65 years; HIV infection confirmed by western blotting; on TDF/3TC/EFV regimen for at least 12 months before enrollment; undetectable HIV viral load for at least 6 months; symptomatic CNS-related toxicity associated with EFV at least grade two using the Division of AIDS (DAIDS) criteria; and consent to switch to E/C/F/TAF. Exclusion criteria included: history of CNS opportunistic infections; active CNS infections; history of chronic neurological disorders; severe psychiatric disorders; substance abuse and/or heavy alcohol use; co-infections with hepatitis B and/or hepatitis C; and pregnant and lactating women.
Eligible individuals were switched from TDF/3TC/EFV to E/C/F/TAF (Genvoya®) for the duration of the study period (48 weeks). Participants were followed up at weeks 12, 24, and 48 after the switch. Laboratory assessments were performed at each follow-up visit, including CD4 count, plasma HIV RNA, biochemical blood index, fasting lipid parameters, and complete blood count. Adverse events were monitored at each visit.
Neuropsychiatric toxicity symptoms were measured using a CNS side effects questionnaire on the EFV label and graded according to the DAIDS grading scale. Participants were questioned by a doctor at each visit about any objective neuropsychiatric adverse events. The questionnaire included ten sections ascertaining symptoms such as abnormal dreams, aggression, anxiety, confusion, depression, dizziness, headache, impaired concentration, insomnia, and somnolence. Each symptom score was calculated as follows: none (0), mild (1), moderate (2), or severe (3). The total CNS score was summed for calculating all grades of the neuropsychiatric adverse events.
Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS), which includes the HADS Anxiety (HADS-A) subscale and HADS Depression (HADS-D) subscale. Sleep quality and disturbances were measured using the Pittsburgh Sleep Quality Index (PSQI).
The primary outcome measure was the proportion of participants experiencing grade two or higher CNS toxicity after EFV switch off at weeks 12, 24, and 48. Secondary endpoints included the proportion of participants with HIV RNA <50 copies/mL, the change from baseline in CD4 cell count, and the effects on fasting lipids at week 48 after the switch.
A total of 196 participants were enrolled and completed the study. The median age of the study population was 37.5 years, and 96.9% were males. At baseline, the median CD4 count was 629 cells/mL, and all subjects had an estimated HIV RNA <50 copies/mL. The median duration on prior EFV-containing regimens was 3.7 years.
At baseline, all subjects had at least one grade two or higher CNS symptom, including abnormal dreams (65.8%), insomnia (55.1%), and anxiety (47.5%). The median CNS toxicity score at baseline was 13. Compared to the baseline CNS toxicity score, the median CNS toxicity score at week 12 significantly decreased to 10 and remained stable at weeks 24 and 48. The proportion of patients experiencing abnormal dreams, headache, dizziness, insomnia, and anxiety significantly decreased at week 12, with the trend remaining similar at weeks 24 and 48. No significant changes were observed in the proportion of individuals experiencing CNS symptoms such as aggression, depression, impaired concentration, and somnolence.
PSQI and HADS-A scores steadily and significantly decreased at weeks 12 and 24 compared with baseline levels. At week 48, the PSQI score remained significantly different compared with the baseline level, while the HADS-A score was not. No significant changes were observed with depression scores from baseline to weeks 12, 24, or 48.
At week 48 after the switch, 100% of participants maintained virologic suppression (HIV RNA <50 copies/mL). No virologic failures were observed during the follow-up period. Median CD4 counts did not show any statistical change at week 48 after the switch.
Increases from before the switch to 48 weeks after the switch were observed in median TC, LDL-C, HDL-C, and TG, and the changes were all statistically significant. No significant difference was found from the baseline in median TC:HDL-C ratio at week 48.
This study suggests that switching from EFV-based regimens to E/C/F/TAF in virologically suppressed PLWH significantly reduces CNS symptoms. The most remarkable improvement was observed in anxiety, dizziness, and sleep-associated symptoms. EFV is still widely used in many resource-limited settings as a first-line ART regimen, and its neuropsychiatric side effects can potentially impact adherence to ART medications, quality of life, and immune system function. These results may provide valuable suggestions for recommendations regarding appropriate regimens for PLWH who suffer from chronic CNS side effects from EFV in China.
Several studies have reported significant improvement in PLWH experiencing ongoing CNS symptoms when switching from EFV-containing regimens to alternative ART regimens. The underlying mechanisms responsible for long-term EFV-associated symptoms remain unclear, but in vitro studies have reported that EFV impairs cellular proliferation and/or cell viability, and EFV-induced neuronal mitochondrial inhibition and autophagy may lead to CNS toxicity-related neuropsychiatric adverse events.
This study found that the severity of depression did not change significantly after the EFV switch, consistent with previous studies indicating that treatment switch may not be effective in resolving all neuropsychiatric disturbances. Further studies on the prevalence of depressive symptoms in PLWH treated with EFV-based regimens are needed.
The CNS toxicity scoring questionnaire has been similarly used in several recent studies, and although there is clinical heterogeneity across the studies, the change of CNS scores showed significant improvement for the EFV switch-off participants. Researchers generally characterized the psychiatric events by asking participants to self-report mood swings instead of using scales, which are beneficial to identify anxiety, depression, and sleep quality and disturbances more exactly than self-reporting.
In this study, the elevation of lipid profiles such as LDL-C was observed to have significance. Previous studies have also shown significantly increased LDL-C and TG levels after switch to TAF, but the degree of elevation depended on the characteristics of the participants and the follow-up time. The risk population which needs lipid-lowering drugs after switching to TAF should be extensively studied in the future. Routine surveillance and evaluation of metabolic parameters, monitoring of ART drug side effects, and behavioral interventions are required to optimize the prevention and management of metabolic disorders in PLWH.
This study has several limitations. First, cognitive function was not assessed. The impact of EFV on cognitive function remains controversial, and the evaluation of the effect of EFV switch off on neurocognitive disorder with a larger sample size and longer follow-up time should be performed in the future. Second, the open-label study design and the subjective measurement of the CNS toxicity grading/scoring questionnaire may introduce bias. In addition, participants’ baseline mental states were not evaluated in this study. Finally, the relatively small sample size, the absence of a control arm, and the fact that most subjects were male limit the generalizability of the results.
In conclusion, switching from EFV-based regimens to E/C/F/TAF was associated with improvements in CNS symptoms, maintenance of viral suppression, and a moderate worsening lipid profile. Although these findings support the use of E/C/F/TAF as an alternative ART medication for virologic suppressed PLWH with EFV-induced complaints, long-term follow-up is expected to further evaluate the benefit of the switch.
doi.org/10.1097/CM9.0000000000001824
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