Impact of Sirolimus and Maraviroc on CCR5 Expression and the HIV-1 Reservoir in HIV-infected Kidney Transplant Recipients

The study will be a pilot, prospective, single-center, open-label, non-randomized,
non-controlled clinical trial. 15 HIV-infected kidney transplant recipients will be enrolled
in the study. Recruitment will be conducted through the renal transplant and infectious
diseases outpatient clinics at the University of Maryland.

The study will include patients with stable glomerular filtration rates (GFRs) >25 with
suppressed HIV with CD4 counts >200. These patients will be recruited from the University of
Maryland's transplant nephrology and infectious diseases clinics. The transplant nephrology
clinic is a multidisciplinary clinic that incorporates nephrologists, pharmacists to aid in
medication management, and coordinators to assist the patients in coordination of care.

All patients will be screened either at the Institute of Human Virology (IHV) Clinical
Research Unit or in the transplant nephrology or infectious disease clinics. At this visit,
all patients will sign an informed consent as approved by our institutional review board
(IRB), have a history and physical examination, and have screening clinical and research labs
drawn. Additional requirements will be Trofile testing prior to enrollment. Eligibility will
be determined based upon these results.

Study drugs will be prescribed (if the patient is not already taking them) starting on day 0
after an interval history and physical examination is performed and safety labs (and
pregnancy tests for women of childbearing potential) are checked. The medications will be
filled by the patient's pharmacy, using their insurance as these are both Food and Drug
Administration (FDA) approved drugs.

Patients will be initially monitored weekly for sirolimus levels and renal function, until
their sirolimus is at the pre-determined (by their transplant nephrologist) steady state.
They will then be followed at week 4, and then every 12 weeks while they are on the new
medication combination. Safety labs (blood counts, renal and liver function), HIV viral
loads, cluster of differentiation 4 (CD4) counts, and rapamycin levels will be reviewed at
each of these visits and if not checked within the specified time period these labs will be
repeated at the study visit. Patients will also be advised about study adherence and
monitored for adverse events.

Safety and adverse event monitoring will occur each study visit. Research nurses will inquire
about adverse events that may or may not be related to study drugs. Any unfavorable medical
occurrences will be recorded, whether or not considered related to the patient's
participation in the research or temporally associated with the patient's participation in
the research. Any grade 3 or 4 AEs and all serious adverse events (SAEs) will be reviewed as
they occur by the study team. Adverse events (AEs) classified as grade 3 or higher occurring
at a frequency greater than that expected by the study team will be reported to the IRB and
principal investigator.

The end of treatment visit will occur at week 96. Clinical safety labs (blood counts, renal
and liver function), HIV viral load, CD4 counts and rapamycin levels will be performed at
this visit if not done in the pre-specified time period. Patients will be given the option,
in conjunction with their transplant nephrologist and their infectious disease provider, to
discontinue or continue the new medications at this time.

Inclusion Criteria:

1. Patient is able to understand and provide informed consent and comply with the study
protocol

2. Diagnosis of HIV infection based on medical record documentation, ELISA and western
blot testing, or a record of a detectable HIV viral load

3. Participant is > or = 18 years

4. CD4 T cell count > or = 200 cells per microliter within 16 weeks prior to enrollment

5. Most recent HIV-1 RNA < 50 copies per milliliter within 16 weeks prior to enrollment

6. Participant must be > or = 6 months post-renal transplant

7. GFR >25 for a minimum of 6 months prior to enrollment

8. On a maintenance immunosuppressive regimen for a minimum of 6 months prior to
enrollment

9. Female participants of child bearing age must have a negative beta-human chorionic
gonadotropin (HCG) pregnancy test within 30 days of enrollment and agree to use
contraception during the study

Exclusion Criteria:

1. Proteinuria at screening defined by spot urine protein to creatinine ratio >1000
milligrams per gram

2. The following active opportunistic infections: Ongoing chronic infections such as
progressive multifocal leukoencephalopathy (PML), disseminated cryptococcosis, chronic
cryptosporidiosis

3. Active malignancy other than superficial skin neoplasms, vulvar intraepithelial
neoplasia (VIN), cervical intraepithelial neoplasia (CIN), or anal intraepithelial
neoplasia (AIN)

4. Any history of augmented immunosuppression with induction immunosuppression regimens
for the treatment of rejection in the 6 months prior to enrollment

5. Known allergy or intolerance to maraviroc or sirolimus

6. Pregnancy or breastfeeding

7. Active substance abuse or mental health concerns that are judged to place a
significant limitation on medication adherence by the PI.

8. Triglyceride elevation at screening > 750; or LDL-c > 160 despite medical treatment

9. Use of any investigational drugs within 30 days prior to screening

10. History of serious adverse reactions to macrolide antibiotics, including anaphylaxis
and related symptoms such as hives, respiratory difficulty, angioedema, and abdominal
pain.

11. Past or current medical problems not listed above which, at the discretion of the
investigator, may pose additional risks from participation in the study, interfere
with the participants ability to comply with study requirements or impact the quality
or interpretation of data obtained from the study

12. Known contraindication to the use of maraviroc or sirolimus

13. Current and ongoing need for concomitant use of rifampin, rifabutin, rifapentine, St.
John's wort, phenytoin, phenobarbital, carbamazepine or dofetilide

14. Any current incompletely healed wounds