Combination Therapy With 3BNC117 and 10-1074 in HIV-Infected Individuals
Condition: HIV
Intervention: 3BNC117 and 10-1074; Placebo
Intervention description: Both 3BNC117 and 10-1074 administered intravenously at 30 mg/kg dose level in 250 ml normal saline for 8 infusions at weeks 0, 2, 4, 8, 12, 16, 20, and 24. The two antibodies will be mixed in separate bags of saline for sequential administration.; Placebo is two separate bags of 250 ml normal saline administered intravenously for 8 infusions at weeks 0, 2, 4, 8, 12, 16, 20, and 24. The two separate bags of placebo are administered sequentially.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Treatment Interruption; Neutralizing Monoclonal Antibody

Summary:

      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.

      ...
    

Eligibility criteria:

        -  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).