Combination Therapy With VRC01 and 10-1074 in HIV-Infected Individuals Undergoing Sequential Treatment Interruptions

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Exploratory Study of Combination Therapy With VRC-HIVMAB060-00-AB (VRC01) and 10-1074 in HIVInfected Individuals Undergoing Sequential Treatment Interruptions

Conditions
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HIV

Intervention / Treatment
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* Biological: VRC-HIVMAB060-00-AB (VRC01)
* Biological: 10-1074
* Biological: Normal Saline Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: 18-65 years of age. HIV-1 infection and clinically stable. 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. CD4+ T cell count >450 cells/mm(3) at screening. 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: The blips are <400 copies/mL, and Succeeding viral levels return to levels below the limit of detection on subsequent testing. Laboratory values within pre-defined limits at screening: Absolute neutrophil count >1,000/mm(3). Hemoglobin levels >10.0 g/dL for men and >9.0 g/dL for women. Platelet count >100,000/mm(3). Estimated or a measured glomerular filtration rate >60 mL/min/1.73 m(2) as determined by the NIH Clinical Center (CC) laboratory. 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. Willingness to have samples stored for future research. Willingness to undergo analytical treatment interruption (ATI) 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: 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. HIV immunotherapy or HIV vaccine(s) received within 1 year prior to screening. Any prior history of receiving 10-1074 or VRC01. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza, pneumococcal polysaccharide) received within 2 weeks prior to study enrollment. Receipt of other investigational study agent within 28 days of enrollment. Any active malignancy that may require systemic chemotherapy or radiation therapy. 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]). History or other clinical evidence of: Significant or unstable cardiac or cerebrovascular disease (e.g., angina, congestive heart failure, recent stroke or myocardial infarction). 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. 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. Pregnancy or breast-feeding at time of screening. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single infusion of VRC01 and 10-1074<br>Single infusion of 40 mg/kg VRC-HIVMAB060-00-AB (VRC01) in 100 mL of saline and 30 mg/kg of 10-1074 in 250 mL of saline when viral load is >/= 200 copies/mL in HIV-infected individuals undergoing antiretroviral treatment interruption. | Biological: VRC-HIVMAB060-00-AB (VRC01)<br>* 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.<br>Biological: 10-1074<br>* 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.<br>|
| Placebo Comparator: Single infusion of Normal Saline<br>Single infusion of 100 mL and 250 mL of normal saline when viral load is >/= 200 copies/mL in HIV-infected individuals undergoing antiretroviral treatment interruption. | Biological: Normal Saline Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days From Start of the Second Treatment Interruption Until the Subject Meets Criteria to Restart ART | Number of days from start of the second analytical treatment interruption (ATI) until the subject meets criteria to restart Antiretroviral Therapy (ART) before Week 16 [a confirmed >30% decline in baseline CD4+ T Cell count or an absolute CD4+ T Cell count in the setting of detectable HIV viremia (>40 copies/mL); a sustained (>4weeks) HIV RNA level of > 1000 copies/mL, or any HIV related symptoms or pregnancy.] | From start of second Analytical Treatment Interruption (ATI) until up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Grade 3 or Higher Related Adverse Events | Percent of participants with grade 3 or higher adverse events, including serious adverse events, that were probably or definitely related to study agent | From the start of the initial infusion through follow-up phase week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Therapy, HIV Neutralizing Antibodies