Coronavirus 2019 (COVID-19) pandemic

Background:

Human immunodeficiency virus (HIV) affects the immune system. The main function of the immune system is protect you from infections and other diseases such as cancer. HIV attacks and cripples the immune system making people more susceptible to a variety of infections and cancers. Currently, the standard treatment for HIV infection is a daily administration of anti-HIV drugs. These drugs are called combination antiretroviral therapy (ART). ART is very effective at suppressing HIV, but does not cure HIV infection. ART must be taken continuously for life to be effective. ART can stop being effective if not taken correctly and can cause permanent side effects. Researchers want to see if two new products can control HIV infection without the use of ART. The products are the antibodies 3BNC117 and 10-1074.

Objective:

To see if 3BNC117 and 10-1074 are safe and can control HIV levels in the blood of people who are not taking ART or people who stop taking their ART during the study. .

Eligibility:

Adults ages 18-65 with HIV who are:

• on ART and willing to stop treatment for at least 28 weeks
• OR not taking ART with low levels of HIV in the blood

Design:

Participants will be screened with a physical exam, medical history, and blood, heart, and urine tests.

Participants will get the 2 study products or salt water (placebo). A thin tube will be placed in an arm vein. Each product will be given directly into the vein for about 1 hour.

To help collect blood cells to study in the laboratory, participants may have a procedure known as leukapheresis in which blood will be removed through a needle in the arm. Some of the white blood cells will be separated from the blood and used for research studies to see how 3BNC117 and 10-1074 effects HIV and the immune system. The rest of the blood will be returned to the person through another needle in the arm.

Participants will have 18 study visits over 28 weeks. They will repeat some screening tests. They may have leukapheresis again.

At 8 study visits, participants will get the study products or placebo.

All participants will be followed for at least 24 weeks after their last dose of the study infusions. Participants who are in the Group that stops ART will be monitored closely to make sure the levels of virus in their blood do not go to high. If at any time during this the study a person develops HIV-related symptoms, or if the viral levels go up to high levels for more than 4 weeks, ART will be restarted and no further infusions of 3BNC117 and 10-1074 will be given.

...

Recent advances in antibody cloning technologies have led to the discovery of a number of highly potent and 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 Immunodeficiency virus (SIV)-infected animals and block cell-to-cell transmission of laboratory-adapted HIV in vitro. In light of these encouraging outcomes, a number of clinical trials have been conducted in recent years in order to explore the feasibility of achieving sustained virologic suppression using a single bNAb in HIV-infected individuals following analytical treatment interruption (ATI). Despite the fact that repeated administration of a single bNAb was safe and well-tolerated, the vast majority of study subjects experienced plasma viral rebound following ATI, clearly demonstrating that successful passive immunotherapy will require different approach, including the use of a combination of 2 or more bNAbs to achieve extended periods of virologic suppression.

Given a major emphasis on current HIV research lies in the possibility of achieving ART-free virologic remission, it is of great interest to investigate whether a combination of potent HIV- specific bNAbs, such as 3BNC117 and 10-1074, can prevent plasma viral rebound in infected individuals upon discontinuation of ART or suppress viral replication in subjects who are not taking ART.

• INCLUSION CRITERIA:

General Inclusion Criteria for both Groups:

1. Age 18-65 years old.

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

5. 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/1.73m(2) as determined by the National Institutes of Health (NIH) Clinical Center laboratory.
   5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of <2.5 times upper limit of normal (ULN), direct bilirubin within the normal range for the NIH Clinical Center laboratory.

6. Willingness to have samples stored for future research.

   Inclusion criteria specific for Group 1:

7. Institution of ART within 12 weeks of being diagnosed with primary HIV-1 infection

8. Primary HIV-1 infection is defined as meeting at least one of the following criteria:

   1. Detectable plasma HIV-1 RNA levels of >2000 copies/mL with a negative result from an HIV-1 enzyme immunoassays (EIA), or
   2. Positive result from an HIV-1 EIA with a negative or indeterminate result from an HIV-1 western blot or another confirmatory antibody test that subsequently evolves to a confirmed positive result, or
   3. Negative result from an HIV-1 EIA within the past 4 months and HIV-1 RNA levels of >400,000 copies/mL, in the setting of a potential exposure to HIV-1.
   4. Negative result from an HIV-1 EIA within 6 months prior to a positive result from an HIV-1 EIA and an HIV-1 western blot or another confirmatory antibody test.
   5. Presence of low level of HIV antibodies as determined by having a positive EIA or a positive Western blot with a non-reactive detuned EIA according to a serologic testing algorithm for recent infection.

9. Documentation of continuous ART treatment with suppression of plasma viral level below the limit of detection for greater than or equal to 1 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.

10. Willingness to undergo ATI

11. 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.

    Inclusion criteria specific for Group 2:

12. No ART within 24 months of screening.

13. HIV plasma viremia between 200 and 5,000 copies/mL at screening AND at least two documented viral level greater than or equal to 200 copies/mL in the 12 months prior to screening.

At the screening visit, subjects considering enrollment in Group 2 will be advised that current guidelines recommend treatment of all individuals with HIV infection regardless of viral levels and CD4 counts.

Reproductive Risks

Contraception: The effects of 3BNC117 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 intrauterine device (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 each infusion of 3BNC117/10-1074. During the course of the study, if a female subject, or the partner of a male subject suspects or in fact becomes pregnant, the effected 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 vaccine(s) received within 1 year prior to screening.

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

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

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

6. Systemic immunosuppressive medications received within 3 months prior to enrollment (Not excluded: [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 to10 days, with completion in greater than or equal to 30 days prior to enrollment]).

7. 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.

8. 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.

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

10. 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 (Group 1 only).

Co-enrollment Guidelines: Co-enrollment in other trials is restricted to observational studies or those evaluating the use of a licensed medication and is subject to approval of the principal investigator (PI).

Group 2 ART naiive

29 months

The study was terminated early due the the COVID-19 pandemic. The pre-defined samples size of 30 participants (15 per arm) for Group 1 was not not reached prior to closing the protocol.