WHO: 24 participants with cognitive deficits due to a Human Immunodeficiency Virus (HIV) infection, able to engage in moderate physical activity.

WHY: The Human Immunodeficiency Virus is known to cause deficits in cognitive function, even under effective pharmacological viral load suppression. Cognitive dysfunction in patients with HIV is frequent and has a detrimental impact on their everyday personal and professional life. The purpose of this study is to evaluate two sets of computerized exercises combining cognitive and physical effort to see if they can improve executive function in patients with an HIV infection.

WHAT: Study participants first undergo cognitive and physical assessments. Additional questionnaires will assess mood, everyday life cognition, function and quality. This will be followed by a 6 week training period with 2 training sessions a week. The effect of the physical and cognitive training will be measured in a post-training evaluation session. Six months after completion of the training, the study will evaluate cognitive and physical abilities of participants to study long-term effects of the respective training program.

WHERE: Both the evaluation and the training sessions will be conducted on the premises of the Lausanne University Hospital (Rue du Bugnon 46, 1005 Lausanne, Switzerland)

This is an exploratory Randomized Controlled Trial with the purpose of evaluating the potential of two sets of gamified cognitive and physical exercises in the neurorehabilitation of cognitive deficits due to an infection with the Human Immunodeficiency Virus (HIV).

Upon recruitment, eligible study participants (see 'Eligibility Criteria') receive a detailed oral and written description about the scientific background, aims and methods of the study. Additional information will be provided about potential benefits and risks associated with study participation, as well as about the voluntary nature of participation throughout the study. The participant's written informed consent is required for study enrollment.

After inclusion in the study, participants are randomized into one of two different training programs with equal chance of attribution and without possibility of choosing:

• Program 1 involves brain training and guided, light physical exercise games on a tablet device. The exercise involves movements such as reaching, stepping, and stretching. Warm-up and cool down sessions are mandated prior to and following the tasks.
• Program 2 involves gamified exercises displayed on a large screen. Participants use whole-body movements to complete the tasks. Tasks involve movements such as reaching, stepping, and jogging in place. These movements are tracked by a motion sensor. Warm-up and cool down sessions are mandated prior to and following the training sessions.

Independently of program attribution, participants engage in a pre-training assessment, a six-week training period, a post-training assessment and a 6-month-follow-up assessment.

Before the start of the training, participants are required to perform several cognitive and physical tests (including cyclo-ergospirometry) and fill out a number of questionnaires on subjective cognitive function, mood and quality of life. Additionally, an electroencephalography (EEG) will be performed to measure brain activity. The exercises, the questionnaires and the EEG serve as a baseline evaluation of cognitive, physical and neurophysiological function.

Following the first assessment, study participants engage in a six-week training period. In both programs, participants engage in two weekly trainings of ninety minutes duration each.

After completion of the training period, study participants engage in a post-training assessment to evaluate the effect of training on cognitive and physical performance. This session incorporates the same tasks and questionnaires as in the pre-training visit. An EEG will be used to characterize the training effects on dynamics of the underlying large-scale neuronal networks. The aim of the post-training assessment is to demonstrate immediate training effect of the two programs.

A final follow-up visit is scheduled 6 months after the completion of the last training session. The cognitive and physical testing together with the questionnaires and the EEG will be repeated to examine the long-term effects of the training programs.

Inclusion Criteria:

• Age ≥ 18 years

• Diagnosis of an HIV infection

• Undetectable HIV load in the serum (<50 copies/mL) over the last 6 months prior to study inclusion.

• Z-score ≤ -1.0 in at least one of the three following tests:

  • Color Trail Test (CTT) Flexibility Index
  • subtest Code of the Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV)
  • subtest Digit Span of the WAIS-IV

• Z-score ≤ -1.0 in at least one of the following tests:

  • Symbol Digits Modalities Test (SDMT)
  • Brief Visuospatial Memory Test Revised (BVMT-R)
  • CTT Flexibility Index
  • Stroop Color-Word interference test

Exclusion Criteria:

• Clinically defined cause for cognitive deficits other than HIV
• Diagnosis of severe depression according to a cut-off score of ≥ 27 of the Center for epidemiological studies - depression questionnaire (CES-D; Metral et al., 2020; Radloff, 1977)
• Diagnosis of HIV-associated dementia according to the Frascati Critera (Antinori et al., 2007)
• Current psychotic symptoms according to the Mini-International Neuropsychiatric Interview (M.I.N.I. - L, Sheehan et al., 1998) subscale of psychotic symptoms
• Antidepressive, anxiolytic or cART medication that has been changed over the last month
• Thoracic pain and/or heart palpitations at rest, during or following a physical effort (based on self-report)
• For patients without known and clinically stable cardio-vascular disease: abnormal rest electrocardiogram readings suggestive of second degree type Mobitz or third degree atrioventricular blocking, pathological repolarization (T-wave inversion, ST elevation, abnormal QT lengthening in at least two corresponding leads), or typical features of channelopathies
• Premature termination of maximal effort test due to cardiac problems
• Falls in the past 12 weeks as evaluated in the enrolment interview (Hopkins Falls Grading Scale, Grade >1)
• High risk of falling according a cutoff score > 15 sec in the Four Square Step Test (Dite & Temple, 2002)
• Incapacity to discriminate colors or insufficient visual acuity that cannot be corrected
• Incapacity or unwillingness to provide informed consent
• Insufficient knowledge of French to understand and follow instructions

Masking will affect participants and study personnel, with exception to the personnel supervising the training programs.