Sleep and Cognition After Atripla to Stribild Switch

Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) and Stribild
(elvitegravir/emtricitabine/tenofovir disoproxil fumarate/cobicistat) are 2 FDA-approved
'one pill once a day' combination antiretroviral medications given for the treatment of HIV.
Both have a common nucleoside reverse transcriptase inhibitor (NRTI) backbone of tenofovir
(TDF) and emtricitabine (FTC), but differ in the 3rd medication contained in the pill.
Atripla contains a non-nucleoside reverse transcriptase (NNRTI) drug efavirenz (EFV) while
Stribild (elvitegravir/emtricitabine/tenofovir disoproxil fumarate/cobicistat) contains an
integrase inhibitor elvitegravir with the drug cobicistat inactive against HIV but designed
to simply boost the level of elvitegravir.

Both drugs are reasonable well tolerated. However, efavirenz is known to cause 'mental'
side-effects. It is known that the initial use of EFV is associated with central nervous
system (CNS) toxicity. The symptoms of such toxicity include daytime sleepiness, or
alternatively inability to sleep, as well as vivid dreams including nightmares. The majority
of such symptoms are believed to resolve within weeks; however there is controversy as to
whether residual problems persist on a long term basis. Furthermore there are now reports of
long time cognitive dysfunction associated with the use of efavirenz. Whether this is
related to sleep disturbance is not clear. Studies to assess this impact have primarily
involved assessment of sleep and cognitive function in antiretroviral (ART)-naïve subjects
as they are initiated on first time ART that includes EFV. Such studies however are
confounded by a 'return to health' phenomena as HIV per se is known to cause sleep and
cognitive deficits . There is controversy regarding whether use of efavirenz leads to long
term disturbances in sleep and cognition. HIV per se causes sleep and cognitive deficits6
and studies which have tried to assess problems in antiretroviral-naïve subject's pre- and
post- initiation of efavirenz-based regimens may be confounded by a 'return to health'
phenomena.

This proposal aims to assess whether a switch from efavirenz/emtricitabine/tenofovir
disoproxil fumarate to elvitegravir/emtricitabine/tenofovir disoproxil fumarate/cobicistat
will be associated with reversal of sleep and cognitive disturbances. Demonstrating changes
upon withdrawal of drug and substitution of a drug regimen not known to have an impact on
sleep or cognition may represent the best option to determine whether use of EFV is
associated with effects on sleep and cognition beyond the immediate period following
initiation of drug.

Inclusion Criteria:

- HIV infected

- Age 18 to 65 years

- On stable efavirenz/emtricitabine/tenofovir disoproxil fumarate regimen > 12 months

- Documented plasma HIV RNA < 50 copies/ml within 3 months of entry

- Ability and willingness to provide written informed consent

Exclusion Criteria:

- Receipt of any other antiretroviral drugs in addition to
efavirenz/emtricitabine/tenofovir disoproxil fumarate within 6 months of study entry

- Any documented plasma HIV RNA > 100 copies/ml within the past 6 months prior to study
entry

- Chronic hepatitis B as assessed by positive hepatitis B surface antigen [HBsAg]

- Chronic hepatitis C as assessed by positive hepatitis C antibody [HCVab], except with
proof of viral clearance and normal liver function tests

- Other chronic disease which is uncontrolled or likely to interfere with study results

- Acute illness within 2 weeks of entry

- Previously documented history of OSA (obstructive sleep apnea)

- Moderate to high risk of OSA defined as BMI (Body mass index) > 30 plus two of the
following: habitual snoring, gasping/choking, observed apnea while sleeping, neck
circumference > 17 inches

- Severe depression based on the BDI-2 (Beck Depression Inventory - II)

- Chronic daily receipt of medications associated with potential for sleep interference
(i.e. psychoactive drugs, steroids, decongestants, beta blockers)

- Any immunomodulator, HIV vaccine, any other vaccine, or investigational therapy
within 30 days of study entry.

- Anticipated need for medications which are contraindicated as per Stribild package
insert

- Any known contra-indication to use of Stribild (elvitegravir/emtricitabine/tenofovir
disoproxil fumarate/cobicistat)

- Creatinine clearance (Cockcroft and Gault) < 70 ml/min

- The following lab values:

1. Hemoglobin < 9.0

2. Absolute neutrophil count < 500/μL

3. Platelet count < 40,000/μL

4. AST (SGOT) and ALT (SGPT) > 5x ULN

- Active or recent past history (within past 5 years) of illicit substance or alcohol
use or abuse which, in the judgment of the Investigator, will interfere with the
patient's ability to comply with the protocol requirements

- Pregnancy or breast-feeding, intent to become pregnant during the course of the study
or breast-feeding

- Patients, who, in the opinion of the Investigator, are unable to comply with the
dosing schedule and protocol evaluation or for whom the study may not be advisable