Elvitegravir (EVG) Cerebrospinal Fluid (CSF) Pharmacokinetics in HIV-Infected Individuals

StribildTM (elvitegravir/cobicistat/emtricitabine/tenofovir) was approved by U.S. Food and
Drug Administration (FDA) in August 2012 as a new multi-class combination drug with potent
antiretroviral activity against HIV-1.1 Two randomized double-blind phase III clinical
trials have demonstrated the non-inferiority as well as the tolerability and safety of
StribildTM compared to AtriplaTM and ritonavir-boosted atazanavir plus TruvadaTM.2,3 Similar
results have been found between ritonavir-boosted elvitegravir and raltegravir in
treatment-experienced patients.4 The safety assessment of StribildTM based on the pooled
data from two comparable clinical trials with a total of 701 subjects in the StribildTM arms
suggested that it distributes into the central nervous system (CNS) because 11-12% of
participants reported relevant adverse events, such as somnolence, headache, dizziness,
insomnia, or abnormal dreams.

The goals of the study are to (1) describe the population pharmacokinetics of elvitegravir
in CSF, and (2) determine the impact of StribildTM on suppressing HIV RNA in CSF,
blood-brain barrier permeability, and Montreal Cognitive Assessment scores. No published
studies have addressed the following questions: 1) What are the concentrations of
elvitegravir in the CSF in patients with HIV-1 disease? 2) Do these concentrations exceed
the 95% inhibitory concentration (IC95) for wild-type HIV-1? 3) How does StribildTM affect
blood-brain barrier and Montreal Cognitive Assessment scores? Through an established
collaborative network, we will address these questions in a prospective, open-label
treatment trial of HIV-infected, treatment-naïve patients.

Inclusion Criteria:

- Adult men or women aged 18-60 years. Able and willing to provide informed consent.

- Presence of HIV-1 infection as documented by a licensed ELISA test kit and confirmed
by Western blot or HIV RNA.

- Naïve to EVG

- Screening plasma HIV-1 RNA ≥ 5,000c/ml and CD4+ T-cell count ≥200cells/mm3.

Exclusion Criteria:

- Presence of primary drug resistance mutations for EVG, tenofovir, or emtricitabine.

- Use of drugs of abuse or alcohol which would interfere with adherence or completion
of this study. While on-study, subjects will be instructed not to consume alcohol for
48 hours prior to pharmacokinetic sampling days.

- Pregnancy or breast-feeding. Women of childbearing potential must have a negative
serum or urine pregnancy test within 14 days prior to study entry and day of entry.

- Chronic, severe, or other medical conditions that, in the opinion of the
investigator, would interfere with the subjects ability to participate in the
protocol.

- Use of prohibited protocol-specified drugs, prescription or over-the-counter, within
14 days prior to study entry.

- Bleeding abnormality or other contraindication to lumbar puncture.

- Moderate or severe cognitive impairment by history or based on Montreal Cognitive
Assessment.

- Laboratory parameters documented within 21 days prior to study entry that would
increase the risk for adverse events:

1. Hemoglobin < 12.5 g/dL for men; < 11.5 g/dL for women;

2. Platelet count < 100,000 platelets/mm3;

3. AST (SGOT) or ALT (SGPT) > 1.5 x the upper limit of normal (ULN);

4. Estimated GFR<70 ml/min

5. Weight less than 50 kg

6. Weight more than 20% over ideal body weight