Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials

Gilbert, Peter B.; Juraska, Michal; deCamp, Allan C.; Karuna, Shelly; Edupuganti, Srilatha; Mgodi, Nyaradzo; Donnell, Deborah; Bentley, Carter; Sista, Nirupama; Andrew, P.; Isaacs, Abby; Huang, Yunda; Zhang, Lily; Capparelli, Edmund V.; Kochar, Nidhi; Wang, Jing; Eshleman, Susan H.; Mayer, Kenneth H.; Magaret, Craig A.; Hural, John; Kublin, James G.; Gray, Glenda; Montefiori, David C.; Gomez, Margarita; Burns, David; McElrath, M. Juliana; Ledgerwood, Julie E.; Graham, Barney S.; Mascola, John R.; Cohen, Myron S.; Corey, Lawrence

doi:10.1515/scid-2016-0001

Cited by 76 publications

(96 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both test 20 or 30 mg/kg of VRC01 transfused 10 times at 8‐week intervals. The primary test for efficacy is prevention of acquisition by week 80 (the time of the last transfusion) . Goals for the AMP trials are to learn whether passive transfer can prevent HIV infection in homosexual and heterosexual partners and, if it can prevent infection, define the level of Ab that is needed to protect these cohorts.…”

Section: Vaccines and Amp In Ongoing Efficacy Trialsmentioning

confidence: 99%

“…The passive transfer approach uses repeated transfusions to achieve and maintain protective levels of a bnAb. 75 Challenges faced by this approach include: (i) the repetitive transfusions required to maintain protective levels of a bnAb (estimated at 10-20 μg/mL for the VRC01 bnAb); (ii) the cost of manufacturing recombinant Ab; (iii) the need for skilled medical personnel to administer the passive Ab; and (iv) the time required for the recipient to be transfused with a protective dose of Abs. AMP is being actively pursued to assess whether it can provide protection to an at-risk population; and, if so, the level of Ab needed to provide protection.…”

Section: Passive Transfer Of Ab To Achieve Bnab Antibody-mediated Prmentioning

confidence: 99%

See 1 more Smart Citation

HIV/AIDS Vaccines: 2018

Robinson

2018

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV) has infected 76 million people and killed an estimated 35 million. During its 40‐year history, remarkable progress has been made on antiretroviral drugs. Progress toward a vaccine has also been made, although this has yet to deliver a licensed product. In 2007, I wrote a review, HIV AIDS Vaccines: 2007. This review, HIV AIDS Vaccines: 2018, focuses on the progress in the past 11 years. I begin with key challenges for the development of an AIDS vaccine and the lessons learned from the six completed efficacy trials, only one of which has met with some success.

show abstract

Section: Vaccines and Amp In Ongoing Efficacy Trialsmentioning

confidence: 99%

Section: Passive Transfer Of Ab To Achieve Bnab Antibody-mediated Prmentioning

confidence: 99%

HIV/AIDS Vaccines: 2018

Robinson

2018

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

show abstract

“…Over the past decade, many anti‐HIV antibodies have been isolated from HIV‐infected individuals that broadly neutralize most strains of HIV. Several of these broadly neutralizing monoclonal antibodies (mAbs) have been developed for potential use to prevent HIV infection via passive administration and has generated optimism that highly efficacious vaccines that elicit broadly neutralizing antibodies against HIV can be developed …”

Section: Introductionmentioning

confidence: 99%

Assessing pharmacokinetic marker correlates of outcome, with application to antibody prevention efficacy trials

Gilbert

Zhang

Rudnicki

et al. 2019

Statistics in Medicine

Self Cite

View full text Add to dashboard Cite

The Antibody Mediated Prevention efficacy trials are the first studies to evaluate whether passive administration of a broadly neutralizing monoclonal antibody can prevent human immunodeficiency virus (HIV) acquisition. The trials randomize 4600 HIV‐negative volunteers to receive 10 infusions of the monoclonal antibody VRC01 or placebo. The primary objective compares the incidence of HIV infection between the study groups. The secondary objective assesses whether and how a marker defined as the serum concentration of VRC01 over time associates with the instantaneous rate of HIV infection, using a two‐phase sampling design, a pharmacokinetic model for the time‐concentration curve, and an estimator of HIV infection times. While a Cox model with a time‐dependent covariate constitutes an important approach to this problem, the low interindividual versus intraindividual marker variability limits its power, motivating us to develop two alternative methods that condition on outcome status: (1) an indirect method that checks whether HIV‐infected cases have unexpectedly long times from the most recent infusion to the estimated infection date and (2) a direct method that checks whether the marker itself is unexpectedly low at estimated infection dates. In simulations and a pseudo Antibody Mediated Prevention application, we find that method (2) (but not (1)) has greater power than the Cox model. We also find that the quality of the infection time estimator majorly impacts method performance, and thus, incorporating details of an optimized estimator is critical. The methods apply more generally for assessing a time‐dependent longitudinal marker as a correlate of risk when the marker trajectory is modeled pharmacokinetically.

show abstract

“…11–13,30 Building on these NHP results, the first efficacy studies of VRC01 – termed the Antibody Mediated Prevention (AMP) trials – for HIV prevention were launched in 2016, with an estimated total study duration of 5 years including enrollment and follow up. 14 Together, the two AMP trials were designed to enroll and randomize 4200 HIV-negative volunteers in 1:1:1 allocation to receive a total of ten intravenous infusions (8-weekly) of VRC01 at a dose of 10 mg/kg, 30 mg/kg, or placebo. The 4200 volunteers are enrolled into two cohorts in harmonized protocols: HVTN 704/HPTN 085 (ClinicalTrials.gov #NCT02716675) in the United States, Peru, Brazil, and Switzerland (2700 HIV-uninfected men and transgender persons who have sex with men); and HVTN 703/HPTN 081 (ClinicalTrials.gov #NCT02568215) in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe (1500 HIV-uninfected sexually active women).…”

Section: Introductionmentioning

confidence: 99%

“…The primary efficacy objective of the AMP trials is to assess whether intravenously-delivered VRC01 prevents HIV infection. 14 …”

Section: Introductionmentioning

confidence: 99%

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

Huang

Karuna

Carpp

et al. 2018

Human Vaccines & Immunotherapeutics

Self Cite

View full text Add to dashboard Cite

The Antibody Mediated Prevention trials are assessing whether intravenously-administered VRC01 (10 mg/kg or 30 mg/kg vs placebo) can prevent HIV infection. In a modeling exercise, we used two models to predict the overall prevention efficacy (PE) of each VRC01 dose in preventing HIV infection. For the first per-exposure PE model, parameters were estimated from studies where nonhuman primates (NHPs) were administered high-dose intra-rectal simian-human immunodeficiency virus challenge two days post-VRC01 infusion at various dosages (“NHP model”). To account for the fact that humans may require greater VRC01 concentration to achieve the same level of protection, we next assumed that a 5-fold greater VRC01 serum concentration would be needed to provide the same level of per-exposure PE as seen in the NHP data (“5-fold model”). For the 10 mg/kg regimen, the 5-fold and NHP models predict an overall PE of 37% and 64%, respectively; for the 30 mg/kg regimen, the two models predict an overall PE of 53% and 82%, respectively. Our results support that VRC01 may plausibly confer positive PE in the AMP trials. Given the lack of available knowledge and data to verify the assumptions undergirding our modeling framework, its quantitative predictions of overall PE are preliminary. Its current main applications are to supplement decisions to advance mAb regimens to efficacy trials, and to enable mAb regimen ranking by their potential for PE in humans.

show abstract

Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials

Cited by 76 publications

References 90 publications

HIV/AIDS Vaccines: 2018

HIV/AIDS Vaccines: 2018

Assessing pharmacokinetic marker correlates of outcome, with application to antibody prevention efficacy trials

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

Contact Info

Product

Resources

About