A Single Dose of Pembrolizumab in HIV-Infected People

A subset of HIV-infected patients, those with poor immunologic response to combined
antiretroviral therapy (CD4+ T-cell count of less than 300-350 cells/mm^3) despite control of
viremia, are at increased risk for both HIV-related and non-HIV-related complications
compared to immunologic responders. Thus, novel approaches for treating HIV infection are
needed to facilitate management of this patient population.

One potential drug target for HIV treatment is the T-cell receptor PD-1. Binding of PD-1 to
its ligands, PD-L1 and PD-L2, inhibits proliferation of T cells and production of cytokines.
This naturally serves to dampen potentially harmful excessive immune responses. Upregulation
of PD-1 and/or its ligands can be observed in tumors and people with chronic viral infection,
including HIV. This upregulation can inhibit T-cell immune surveillance, which may result in
tumor growth or poor control of infection.

Pembrolizumab is an IgG4 kappa monoclonal antibody that binds to PD-1, thus blocking the
receptor from binding with its ligands. In cancer indications, inhibition of PD-1 induces an
antitumor immune response, which in turn reduces tumor growth. The Food and Drug
Administration has approved pembrolizumab for treatment of unresectable or metastatic
melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and other
cancers. Similarly, in animal models of HIV and in vitro studies, PD-1 blockade was
associated with a decrease in viral load and an increase in CD8+ T cells. A clinical trial to
examine the effects of PD-1 inhibition by pembrolizumab on HIV infection is thus supported by
the data.

The purpose of this study is to evaluate, in a randomized, double-blind, placebo-controlled
study, the safety and tolerability of a single dose of pembrolizumab in HIV-infected
participants who have controlled viremia with a low T-cell count (> 100 cells/mm3 and less
than or equal to 350 cells/mm^3). Study participants will be followed for 96 weeks after
receiving the study drug and will be assessed for adverse events, CD4+ and CD8+ T-cell
counts, PD-1 expression, CD8+ T-cell anti-HIV activity, and viral load. If a single dose of
pembrolizumab appears to be safe and tolerable, then larger multi-dose and efficacy studies
can be planned.

- INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

1. Greater than or equal to 18 years of age.

2. Documented HIV-1 infection (eg, positive standard enzyme-linked immunosorbent assay or
rapid HIV-1/HIV-2 antibody test with a confirmatory test such as western blot, or
documentation of repeated HIV RNA of greater than 1000 copies/mL). Outside
documentation will be acceptable.

3. Absolute neutrophil count greater than 1000/microL.

4. Platelet count greater than 125,000/microL.

5. Hemoglobin greater than 10 g/dL.

6. Aspartate transaminase (AST) and alanine transaminase (ALT) less than 1.5 times the
upper limit of normal (ULN). Total bilirubin less than 1.1 x ULN (unless participant
is taking atazanavir or has Gilbert syndrome).

7. Calculated creatinine clearance (estimated glomerular filtration rate) greater than or
equal to 60 mL/min/1.73 m^2.

8. Thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) within normal
limits. If TSH is not within normal limits then the participant may be eligible if
thyroxine (T4) is within normal limits. Participants will not be excluded if they are
on a stable dose of replacement thyroid medication; dose may be adjusted as needed.

9. No significant underlying pulmonary, cardiac, renal, or hepatic disease, as defined by
a need for drug treatment or ongoing physician care.

10. Under the care of a primary care physician.

11. Willing to comply with study requirements and procedures including storage of
biological specimens for future use in medical research.

12. Willing to allow genetic testing.

13. Able to provide informed consent.

14. Males of reproductive potential must agree to not impregnate a partner beginning 30
days before the dose of pembrolizumab through 120 days postdose. Non-reproductive
potential for males is defined as azoospermia. Males of reproductive potential must
either practice complete and uninterrupted abstinence from heterosexual activity or
use two of the following methods of

contraception with their partners. The 2 methods must include one from each group,
both of which must be consistently used.

- Barrier methods:

- a. Diaphragm with spermicide (cannot be used in conjunction with cervical
cap/spermicide).

- b. Cervical cap with spermicide (only for nulliparous partners).

- c. Contraceptive sponge (only for nulliparous partners).

- d. Male or female condom (cannot be used together).

- Non-barrier methods:

- a. Intrauterine device.

- b. Hormonal contraception: pill (estrogen/progestin or progestin-only), skin
patch, vaginal ring, rod implanted in the skin, or subcutaneous injection.

15. Participants must meet criteria for INR, defined as follows:

- a. Has been on a cART regimen for at least 12 months and on a stable regimen for
at least 4 weeks.

- b. Has evidence of viral suppression, defined as viral load less than 40
copies/mL, and documented suppression (below detection limits of the utilized
assay) for at least 12 months. A viral load of less than 500 copies/mL once in
the year preceding screening will be allowed if there is documentation of a viral
load less than 40 copies/mL on subsequent testing and at screening.

- c. CD4+ T-cell count greater than 100 cells/mm^3 and less than or equal to 350
cells/mm^3.

EXCLUSION CRITERIA:

1. Has used an investigational drug agent or investigational device within 12 weeks of
baseline. However, ARVs obtained through expanded access programs are permitted.

2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

3. Known allergy to any component of the pembrolizumab formulation.

4. Systemic steroid therapy or other immunosuppressive therapy in the 3 months prior to
enrollment. (Inhaled or topical corticosteroids are permitted.)

5. Has used an immunotherapeutic agent (eg, cyclosporine, tacrolimus, mycophenolate
mofetil, azathioprine, sirolimus, therapies targeting tumor necrosis factor- ) within
6 months of baseline necrolysis. Replacement therapy (eg, T4.) is not considered a
form of systemic treatment.

6. Has received any vaccine, live or inactivated, within 30 days of baseline, or plans to
receive any vaccine within 16 weeks of receiving pembrolizumab.

7. Has active autoimmune disease or a history of autoimmune disease that has required
systemic treatment (eg, with use of disease-modifying agents, corticosteroids, or
immunosuppressive drugs). Such autoimmune diseases include for example psoriasis,
systemic lupus erythematosus, autoimmune uveitis, autoimmune hepatitis, inflammatory
colitis, rheumatoid arthritis, Guillain-Barr(SqrRoot)(Copyright) syndrome,
Stevens-Johnson syndrome, or toxic epidermal necrolysis. Replacement therapy (eg, T4.)
is not considered a form of systemic

treatment.

8. Has known history of, or any evidence of active, non-infectious pneumonitis.

9. Malignancy requiring systemic therapy, or a history of malignancy that required
systemic therapy within the past 5 years. However, cutaneous basal cell carcinoma or
cutaneous Kaposi sarcoma not requiring systemic therapy will not be exclusionary.

10. Has known active hepatitis B (HBV) or potential for HBV reactivation (eg, hepatitis B
surface antigen [HBS] reactive, HBV DNA positive, or isolated anti-core antibody
positive; individuals who are anti-HBS antibody positive with or without anti-core Ab
are eligible).

11. Has known active hepatitis C (HCV; eg, HCV RNA [qualitative] is detected). Patients
who have sustained virologic response (SVR) to anti-HCV treatment are eligible if at
least 24 weeks have passed since achieving SVR.

12. Females of reproductive potential or who are pregnant or breastfeeding.
Non-reproductive potential for females is defined as any of the following:
postmenopausal; surgical sterilization at least 6 weeks before screening; or a
congenital or acquired condition that definitively prevents conception. Further,
postmenopausal is defined as at least 12 consecutive months with no menses at age 50
or older, or at least 12 consecutive months with no menses at age 45 - 49 plus a high
follicle-stimulating hormone level in the postmenopausal range, in participants not
using hormonal contraception or hormone replacement therapy.

13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the study.

14. History or other clinical evidence of:

- a. Significant or unstable cardiac disease (eg, angina, congestive heart failure,
myocardial infarction).

- b. Significant pulmonary disease (eg, chronic obstructive pulmonary disease,
asthma requiring systemic therapy).

- c. Severe illness, chronic liver disease, malignancy, immunodeficiency other than
HIV, active systemic infection (other than HIV) requiring therapy.

15. Opportunistic infection requiring maintenance therapy, including toxoplasmosis, fungal
infections other than candida (eg, cryptococcosis, histoplasmosis,
coccidioidomycosis), atypical mycobacterial infection. Secondary Pneumocystis,
candida, and HSV prophylaxis will be permitted.

16. Active or history of tuberculosis (TB), or positive TB QuantiFERON Gold test.

17. Known osteoporosis or diabetes mellitus.

18. Hemoglobin A1c greater than 6%.

19. Fasting triglyceride greater than 300 mg/dL.

20. Any condition that, in the opinion of the investigator, would make the participant
unsuitable for the study.