Combination Therapy With VRC-HIVMAB060-00-AB (VRC01) and 10-1074 in HIV-Infected Individuals Undergoing Sequential Treatment Interruptions

Recent advances in antibody cloning technologies have led to the development of a number of
highly potent and human immunodeficiency virus (HIV)-specific broadly neutralizing monoclonal
antibodies (bNAbs) from B cells of HIV-infected individuals. It has been shown that certain
bNAbs can prevent acquisition of the virus, suppress viral replication, delay and/or prevent
plasma viral rebound following treatment interruption in simian/human immunodeficiency virus
(SHIV)-infected animals. Preliminary data from clinical trials indicates that bNAbs may delay
plasma viral rebound following interruption of antiretroviral therapy (ART) and block
cell-to-cell transmission of laboratory-adapted HIV in vitro.

In the above studies, suppression of plasma viremia was dependent on maintaining neutralizing
serum levels of bNAbs via repeated intravenous (IV) infusions. A recent pre-clinical study in
an acute SHIV-macaque model suggests a limited course of passive immunotherapy with two bNAbs
(10-1074 and 3BNC117) given shortly after infection, can result in prolonged suppression of
plasma viremia that is not dependent on the continuous presence of the bNAbs18. Based on CD8+
T cell depletion studies, it appears that the prolonged suppression of plasma viremia
observed in these animals resulted from the induction of potent antiviral CD8+ T cell
immunity by the short course bNAb treatment. The mechanism by which bNAb therapy could induce
such a response is unclear but could involve the early formation of unique bNAb-SHIV immune
complexes that subsequently induce an effective and durable T cell response to the virus.

In light of these encouraging preclinical outcomes, it is of considerable interest to
investigate whether treatment with a single infusion of two bNAbs (VRC01 and 10-1074) which
target different epitopes of HIV gp120 (CD4 binding site and V3 glycan, respectively), during
transient plasma viremia can induce long-lasting anti-HIV immunity capable of controlling
plasma viremia in the absence of ART.

- INCLUSION CRITERIA:

1. 18-65 years of age.

2. HIV-1 infection and clinically stable.

3. General good health and has an identified primary health care provider for
medical management of HIV infection and is willing to maintain a relationship
with a primary health care provider for medical management of HIV infection while
participating in the study.

4. CD4+ T cell count >450 cells/mm(3) at screening.

5. Documentation of continuous ART treatment with suppression of plasma viral level
below the limit of detection for greater than or equal to 2 years. Individuals
with blips (i.e., detectable viral levels on ART) prior to screening may be
included provided they satisfy the following criteria:

1. The blips are <400 copies/mL, and

2. Succeeding viral levels return to levels below the limit of detection on
subsequent testing.

6. Laboratory values within pre-defined limits at screening:

1. Absolute neutrophil count >1,000/mm(3).

2. Hemoglobin levels >10.0 g/dL for men and >9.0 g/dL for women.

3. Platelet count >100,000/mm(3).

4. Estimated or a measured glomerular filtration rate >60 mL/min/1.73 m(2) as
determined by the NIH Clinical Center (CC) laboratory.

5. AST and alanine transaminase (ALT) levels of <2.5 times upper limit of
normal (ULN), direct bilirubin within the normal range for the NIH CC
laboratory.

7. Willingness to have samples stored for future research.

8. Willingness to undergo ATI

9. Willingness for both male and female subjects to agree to use barrier protection
methods or abstinence during the ATI phase of the study to decrease the risk of
HIV transmission.

Reproductive Risks

Contraception: The effects of VRC01 and 10-1074 on the developing human fetus are unknown.
For this reason, men and women of childbearing potential must agree to use adequate
pregnancy prevention. This includes the use an effective method of contraception (i.e.
condom with spermicide, diaphragm with spermicide, hormone-eluting IUD, hormone-based
contraceptive with condom) for the study duration. Subjects should also agree to use a male
or female condom while off ART. Pregnancy prevention must be practiced continuously for the
duration of study participation. Females of childbearing-age must have a negative pregnancy
test result prior to receiving the infusions of VRC01 and 10-1074/placebo. During the
course of the study, if a female subject, or the partner of a male subject suspects or in
fact becomes pregnant, the affected subject should inform the study staff immediately, as
well as the woman s primary care physician.

EXCLUSION CRITERIA:

1. Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface antigen
(HBsAg), or chronic hepatitis C virus (HCV) infection, as evidenced by a positive test
for HCV RNA. Subjects with a positive test for HCV antibody and a negative test for
HCV RNA are eligible.

2. HIV immunotherapy or HIV vaccine(s) received within 1 year prior to screening.

3. Any prior history of receiving 10-1074 or VRC01.

4. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza,
pneumococcal polysaccharide) received within 2 weeks prior to study enrollment.

5. Receipt of other investigational study agent within 28 days of enrollment.

6. Any active malignancy that may require systemic chemotherapy or radiation therapy.

7. Systemic immunosuppressive medications received within 3 months prior to enrollment
(Exceptions: [1] corticosteroid nasal spray or inhaler; [2] topical corticosteroids
for mild, uncomplicated dermatitis; or [3] oral/parenteral corticosteroids
administered for non-chronic conditions not expected to recur [length of therapy less
than or equal to 10 days, with completion in greater than or equal to 30 days prior to
enrollment]).

8. History or other clinical evidence of:

1. Significant or unstable cardiac or cerebrovascular disease (e.g., angina,
congestive heart failure, recent stroke or myocardial infarction).

2. Severe illness, malignancy, immunodeficiency other than HIV, or any other
condition that, in the opinion of the investigator, would make the subject
unsuitable for the study.

9. Active drug or alcohol use or any other pattern of behavior that, in the opinion of
the investigator, would interfere with adherence to study requirements.

10. Pregnancy or breast-feeding at time of screening.

11. Documented multiclass antiretroviral drug resistance that, in the judgment of the
investigator, would pose a risk of virologic failure should additional mutations
develop during the study.