A prospective open-label study to investigate the effects of switching to a darunavir based regimen on low level viremia, immune activation and neurocognitive performance in patients on antiviral therapy.

HIV low-level viremia is a frequently observed clinical phenomenon and a
possible risk for the development of drug resistance. The origin of low-level
viremia is not known, but it is hypothesized that virus production or virus
replication in cellular and anatomical reservoirs are involved. Low-level
viremia may be associated with higher levels of immune activation,
deterioration of neurocognitive performance and periodontitis. These are
frequently observed problems in the HIV-infected population.
In clinical practice darunavir (DRV) is often chosen to prevent the development
of drug resistance in subjects who do not get virologically suppressed by
combination antiretroviral therapy (cART). DRV is a potent HIV protease
inhibitor (PI), with a high genetic barrier and might also be an adequate
compound to reduce low-level viremia, immune activation and the development of
comorbidities.

To suppress low-level viremia to a level below 50cp/mL in patients using cART
by switching their current non-nucleoside reverse transcriptase inhibitor
(NNRTI) or PI to DRV boosted with ritonavir (RTV) (DRV/r).
Secondary objectives are to reduce the risk for development of drug resistance,
to decrease the level of immune activation, to improve neurocognitive
performance and periodontal status and to investigate the source of low-level
viremia in HIV-1 infected patients receiving cART.

A prospective multi-center cohort study of 24 weeks open-label treatment and an
additional 24 weeks of observation, in which a non-randomised intervention is
performed at baseline.

The intervention includes DRV/r according to standard clinical practice.
Subjects pre-treated with PIs will receive twice daily DRV/r 600/100 mg.
Subjects not pre-treated with PI will receive once daily DRV/r 800/100 mg. The
control group will continue with the cART already in use for the duration of
study.

The study will include 6 hospital visits. To a great extent it includes normal
clinical practice regarding clinical history taking, physical examination,
viral load assessment, CD4 count measurements and safety controls in blood to
monitor potential side-effects. The number of visits is to a great extent
similar to patients with persistent low-level viremia. The additional burden
lies in: 3 short questionnaires (about adherence, depression and self-reported
impairment in daily functioning), 2-6 additional blood samples for virological
and immunological analysis and 3 times a set of validated neurocognitive tests
for 40 minutes.
Subjects will be informed about their personal neurocognitive test results
after completion of the study at 48 weeks. Out of ethical considerations,
subjects with cognitive impairment at the end of the study will be offered a
thorough neurocognitive investigation by a clinical neuropsychologist and
offered a revalidation programme to cope with the impairment if deemed
necessary or useful. DRV/r has several common side-effects of which
gastro-intestinal problems (mainly diarrhoea) are most frequently observed.
However, these are all common side-effects for HIV-therapy. Additionally, two
facultative substudies are proposed in which subjects can approve that a lumbar
puncture and/or periodontal examination at baseline and at week 24 will be used
for scientific purposes.
Benefits of participation are that subjects have a lower risk for the selection
of drug resistant variants. It is expected that subjects get an undetectable
viral load, with potential benefits such as lower immune activation and
neurocognitive improvement.