Increasing rates of acquired and transmitted HIV drug resistance threaten to cripple large-scale antiretroviral therapy (ART) rollout and undermine HIV treatment programs in resource-limited settings. Existing drug resistance genotyping approaches are costly and complex, and their use in low- and middle-income nations prior to two consecutive ART regimen failures is precluded on account of high costs and limited resources. A simple and inexpensive ART drug resistance monitoring option stands to improve the treatment paradigm in these areas, facilitating better clinical decision-making regarding ART treatment and resulting in improved patient outcomes, reduced HIV transmission rates, and healthcare system cost savings. To this end, Aldatu Biosciences has pioneered the development of Pan-Degenerate Amplification and Adaption (or PANDAA(tm)), a simple, low-cost, highly sensitive method for HIV drug resistance detection with multi-parameter superiority to currently available commercial genotyping options. PANDAA(tm) enables for the first time an already low-cost and sensitive genotyping technology, quantitative real-time PCR (qPCR), for HIV genotyping by overcoming previously insurmountable challenges associated with the biology of HIV. Specifically, PANDAA(tm) reagents compensate for secondary sequence variation in the HIV genome without sacrificing specificity, allowing rapid and sensitive detection of drug resistant variants. Feasibility studies performed at the Harvard School of Public Health have rigorously demonstrated that PANDAA(tm) 1) detects drug-resistant HIV variants with >99% sensitivity; 2) is HIV subtype-independent; 3) is multiplexed to simultaneously quantify resistance at multiple genomic positions; and 4) quantitative detection using a calibrator probe measures total HIV RNA and serves as a confirmatory viral load test. In this Phase II project, Aldatu will translate our validated lab-based assay into a clinical diagnostic product - PANDAA(tm) HIV6 - a thermostable, sample-in/answer-out kit that identifies six clinically actionable HIV mutations found in >95% of patients failing a WHO-recommended first-line regimen. This will facilitate Aldatu's long-term goal of radically improving HIV treatment program efficacy and cost- efficiency by empowering clinicians to make informed therapeutic decisions and assign the most effective ART regimens at the lowest achievable cost. Through the aims proposed here, we will 1) confirm that an optimized thermostable PANDAA(tm) HIV6 prototype can sensitively and specifically quantify drug resistance from HIV-1 infected whole blood, plasma, and dried blood spots using existing RNA extraction methods; 2) demonstrate that PANDAA(tm) HIV6 performance metrics fulfill established criteria for both in vitro HIV drug resistance genotyping and quantitative assays; and 3) verify that PANDAA(tm) HIV6 intended end-user, multi-site implementation is highly reproducible. Successful commercialization of PANDAA(tm) HIV6 will result in the first- time availability of an HIV genotyping option that is cos-effective to implement at first-line ART failure in low- and middle-income countries, creating an annual market of $120M USD for HIV drug resistance testing.

Public Health Relevance

HIV drug resistance genotyping allows HIV-infected patients to be matched with effective antiretroviral drugs and is an essential component of HIV patient management, but currently available testing options are insufficiently sensitive and cost-prohibitive for low- and middle-income countries. To address this clinical and market need, this project aims to translate our novel low-cost HIV genotyping assay into a clinical diagnostic product (PANDAA(tm) HIV6) designed to address the specific clinical and economic needs of resource-limited settings. Optimization and end-user testing of our product prototype in this Phase II project will position us to launch PANDAA(tm) HIV6 in Phase III as the first HIV genotyping option to make drug resistance testing affordable at an earlier stage in the HIV treatment paradigm, with healthcare system-wide impacts in the form of improved patient outcomes and substantial HIV patient care cost savings.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Fitzgibbon, Joseph E
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Aldatu Biosciences, Inc.
United States
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Duarte, Horacio A; Panpradist, Nuttada; Beck, Ingrid A et al. (2017) Current Status of Point-of-Care Testing for Human Immunodeficiency Virus Drug Resistance. J Infect Dis 216:S824-S828