Short Communication: The Impact of Switching from Atripla to Darunavir/Ritonavir Monotherapy on Neurocognition,Quality of Life,and Sleep: Results from a Randomized Controlled Study

Introduction

Even though Efavirenz (EFV) is no longer a recommended starting regime in some clinical guidelines, it is still one of the most commonly prescribed antiretroviral drugs in the world. In combination with two nucleoside reverse transcriptase inhibitors, it is recommended as a first-line regimen for the treatment of HIV-1 infection. ^{1 –3} However, it has been associated with mood changes, anxiety, abnormal dreams, dizziness, and suicidal ideation. ⁴ Central nervous system (CNS)-associated side effects generally resolve after 4 weeks of treatment, ⁵ but some patients experience ongoing symptoms ⁶ and subclinical CNS side effects (such as changes in cognition only detected by neuropsychological testing) that may be underestimated. Higher levels of anxiety and abnormal dreams were reported in patients on stable EFV containing HAART than in controls. ^7,8

Boosted darunavir (DRV/r) monotherapy is a class sparing ART regimen, able to suppress HIV replication in plasma. ⁹ It is not clear whether this suppression is as potent in the CNS or whether switching from Atripla to this regimen will impact neurocognition.

Our objective was to investigate whether a treatment switch from Atripla^® (tenofovir, emtricitabine, and EFV) to DRV/r monotherapy may improve neuropsychological performance, quality of life, and sleep function.

We report results from a substudy of the MIDAS trial (ISRCTN 11504121). The main study investigated the changes in bone mineral density and renal function in virologically suppressed patients who were randomized to continue Atripla or to switch to DRV/r (800/100 mg) for 48 weeks. ¹⁰ In this substudy, a battery of tests was performed at baseline and week 48 to assess three neurocognitive domains using the Trail making test part A (TMT-A), Trail making test part B (TMT-B), and Grooved pegboard test (GPT), which evaluate attention, executive functioning, and fine motor function, respectively. We also performed the International HIV Dementia Scale (IHDS), a screening test to identify individuals at risk for HIV dementia, and quality of life (Medical Outcomes Study HIV Health Survey [MOS-HIV] ¹¹ and EQ-5D-3L ¹² ), and depression and anxiety (Hospital Anxiety and Depression Scale [HADS]) assessments at each visit. Sleep was evaluated using a validated four-item questionnaire (Jenkins Sleep Evaluation Questionnaire) at week 48 only.

Continuous variables were summarized using mean (standard deviation [SD]) or median (interquartile range [IQR]), depending on distribution. Frequency (percentage [%]) was reported for categorical variables. The treatment effect on the outcome of mean change in cognition and quality-of-life score at 48 weeks was estimated using repeated measures mixed effects models with an unstructured variance-covariance matrix to assess mean difference between arms. Non-normally distributed variables were transformed to approximate normality. Covariates such as age, ethnicity, HIV transmission risk, viral load, CD4 cell count, years diagnosed with HIV, and years on ATP were assessed for inclusion in the model using a forward stepwise approach. Interactions between treatment and other variables were investigated. Sleep scores between arms at 48 weeks were compared using Wilcoxon rank-sum tests. All analyses were performed on an intention-to-treat basis and conducted using STATA (version12).

Seventy subjects were randomized in the main study of whom 26 in the DRV/r arm and 31 in the Atripla arm consented to take part and were included in the present analyses. No significant differences in baseline characteristics were observed between subjects entering this substudy and the overall population in the main study. The mean (SD) age was 42.7 (9.0) years, mean (SD) CD4 cell count was 537 (194) cells/mm³, 84% male, 67.2% men who have sex with men. The median time (IQR) since HIV diagnosis was 6.4 (3.9–10.1) years and median (IQR) time on Atripla was 3.5 (2.5–3.9) years. None of the included patients presented reported cognitive complaints.

No significant difference in the change in scores from week 0 to week 48 between the two arms was observed in neurocognitive outcomes, IHDS, quality-of-life (MOS-HIV and EQ-5D-3L), and HADS score. By contrast, the HADS score was significantly better in the DRV/r arm. At week 48, sleep quality appeared significantly better than in continued Atripla (Table 1).

One patient in the DRV/r arm presented with a HIV-associated acute meningoencephalitis while not fully suppressed in blood plasma (HIV RNA plasma: 217 copies/ml, HIV cerebrospinal fluid [CSF] viral load: 9,450 copies/ml). All symptoms resolved upon reintroduction of Atripla.

We report the changes in neurocognitive performance in HIV-infected virologically suppressed subjects who switched from Atripla to DRV/r. Although no significant differences were observed in neurocognitive performance or self-assessed quality-of-life questionnaires, patients on the DRV/r arm had a lower anxiety score and reported significantly better quality of sleep than subjects who remained on Atripla.

These results are consistent with data from other prospective studies, in which patients switched from triple therapy to boosted protease inhibitor (bPI) monotherapy and in which no difference in the incidence of neurocognitive impairment was observed. ^{13 –15}

Long-term EFV therapy can be associated with neuropsychiatric symptoms, mainly depression and anxiety. In agreement with our results, recent studies have shown that treatment switch could be effective in resolving those disturbances. ^16,17

Moyle et al. demonstrated that EFV had a modest but persistent impact on sleep and suggested that increases in stage 4 deep sleep and rapid eye movement may account for pronounced dream recollection, whereas reduced stage 2 sleep lowers morning energy levels. ¹⁸ In another study, 36 patients were prospectively switched from EFV to nevirapine. Of the 20 patients who reported neuropsychiatric symptoms (with or without sleep disturbances) at baseline, 15 experienced complete resolution after switching to NVP. ¹⁹

Current EACS guidelines suggest that in well-selected patients, especially those with a history of long-term viral suppression, no history of virological failure on PIs and good treatment compliance could be considered for bPI monotherapy. ¹ In our study, despite no difference between arms in neurocognitive performance after 48 weeks of follow-up, one subject experienced symptomatic CSF viral escape. This could not be prevented despite careful selection of candidates for bPI monotherapy, raising further questions about the clinical usefulness of this strategy.

Viral replication in the CSF has been previously reported in patients receiving bPI monotherapy, ^{20 –22} suggesting a greater risk of viral escape in those receiving monotherapy. The consequences of a long-term persistent low level CSF viral replication, however, are not fully evaluated, but it might be the cause of neurocognitive decline. ²³

In our study, we found no changes in quality-of-life measures after 48 weeks of follow-up. Similar results were observed in a randomized clinical trial published recently. In that study, the investigators found no differences in quality-of-life markers after a treatment switch from stable cART to PI monotherapy for a median of 44 months. ²⁴

The results in this study should be interpreted cautiously as there are some important limitations such as lack of baseline sleep data and no objective measures of sleep.

In addition, important data related to confounding factors such as educational level could not be included in the analysis. The TMT-B has age-specific norms, so the absence of these data may be related to lack of significance.

In conclusion, switching to DRV/r monotherapy did not affect neurocognitive function or quality of life but improved anxiety, and sleep quality was significantly better than in continued Atripla.