Combination Therapy With VRC01 and 10-1074 in HIV-Infected Individuals Undergoing Sequential Treatment Interruptions
Condition: HIV
Intervention: VRC-HIVMAB060-00-AB (VRC01); 10-1074; Normal Saline Placebo
Intervention description: VRC01 is a broadly neutralizing human mAb targeted against the HIV-1CD4 binding site. As single intravenous infusion of VRC01(40 mg/kg) plus10-1074 (30mg/kg) or placebo will be administered after the first analytical treatment interruption phase once the subject's plasma viremia is > or = 200 copies/mL.; 10-1074 is a recombinant, fully human mAb of the IgG1 lambda isotype that specifically binds to the base of the V3 loop within HIV-1 envelope gp-120. A single intravenous infusion of VRC01 (40 mg/kg) plus 10-1074 (30 mg/kg) or placebo will be administered after the first analytical treatment interruption phase once the subject's plasma viremia is > or = 200 copies/mL.; 2 sequential infusions of normal saline placebo in matching volumes to antibody infusions will be administered after the first analytical treatment interruption phase once the subject's plasma viremia is > or = 200 copies/mL.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: HIV Therapy; HIV Neutralizing Antibodies

Summary:

      Background:

      A daily drug combination can keep human immunodeficiency virus (HIV) levels low for a long
      time. But if this combination antiretroviral therapy (ART) stops, HIV levels go back up.
      People can also develop resistance or permanent side effects. Researchers want to see if 2
      new drugs can help control HIV when a person is not on ART.

      Objective:

      To see if VRC01 and 10-1074 are safe and control HIV when a person is not on ART.

      Eligibility:

      Adults 18-65 with HIV

      Design:

      All participants must agree to practice safer sex. Those who can get pregnant will have a
      pregnancy test every visit.

      Participants will be screened with:

      Physical exam

      Medicine review

      Blood and urine tests

      Some participants may need to change their HIV medicine for a brief period of time during the
      study.

      A few weeks later, participants will repeat screening tests and stop taking their HIV
      medicines.

      Interruption phase 1: Participants will have blood tests every 2 weeks, and repeat screening
      tests every 4 weeks.

      Treatment phase: Once their HIV reaches a certain level in the blood, participants will get
      the 2 study drugs or a salt water placebo. They will not know which they get. Each substance
      will be given through a thin tube in an arm vein for about 1 hour. Participants will restart
      their HIV medicines and repeat screening tests every 4 weeks.

      Interruption phase 2: Once the level of HIV in the blood becomes undetectable for 3 months,
      participants will again stop taking their HIV medicines and have blood tests every 2 weeks to
      monitor the level of HIV in the blood.

      Participants will restart their medicines by week 24. They will start sooner if they have
      certain symptoms or blood levels of HIV become too high. They will repeat most screening
      tests 3 times over 24 weeks.
    

Eligibility criteria:

        -  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 lower limit of quantification (LLOQ) for the assay used 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. Aspartate aminotransferase (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 analytical treatment interruption (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 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 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.