The 2015 WHO guidelines recommend anti-retroviral therapy (ART) for all HIV-infected people, and massive efforts to expand ART access will result in >30M adults and >1.7M children on ART by 2020, at a cost of almost US$53B. Consequently, the number of patients prescribed alternative, protease-inhibitor (PI)-based ART following failure of first-line regimens will also increase. Studies of patients on PI-based ART in resource-limited countries have shown high rates of virologic failure at 12 and 24 months on treatment, and patients maintained on failing PI-based regimens accumulate drug resistance mutations (DRMs) that hamper current and future treatment options. Resource constraints often limit the ability to collect genotype information, and genotype-blind drug switching has been shown to be cost-ineffective when compared to stratifying patients based on resistance genotype. Thus, there is an urgent unmet need for an affordable HIV genotyping option for patients failing PI- based ART. Focused genotyping could significantly enhance patient care by: 1) optimizing the NRTI backbone in patients failing a PI-based regimen with only NRTI resistance; or 2) preventing ART switches in patients failing without resistance until adherence issues are rectified. Aldatu?s Pan-Degenerate Amplification and Adaptation (PANDAA?) technology is a novel point mutation assay that enables inexpensive and high-throughput focused genotypic resistance testing, and such an approach could be cost-saving for national ART programs. PANDAA compensates for high intra- and inter-patient HIV genomic variability by removing secondary polymorphisms, minimizing their impact on qPCR sensitivity/specificity, and enabling qPCR for HIV genotyping for the first time. Feasibility studies have demonstrated that PANDAA: 1) detects NNRTI and NRTI-resistant HIV variants with >99% sensitivity; 2) is HIV subtype-independent; and 3) can be multiplexed to simultaneously quantify resistance at multiple genomic positions. Aldatu has pioneered the commercial development of PANDAA and established a reagent formulation that allows for the production of PANDAA-based diagnostics in a thermostable, sample- ready format. In this Phase II project, Aldatu will apply the PANDAA technology to the development of PANDAA PIDR+, a rapid, low-cost, thermostable test for detection of drug resistance in patients failing a PI-based ART regimen, which can radically improve clinical decision-making in low- and middle-income countries. Through the aims proposed here, we will 1) experimentally validate the design of PANDAA reagents to quantify mutations associated with protease inhibitor resistance comprising 10% of the viral quasispecies; 2) establish an extensive, collaborative proficiency panel of drug resistant and drug sensitive HIV-1 isolates for PANDAA PIDR+ validation; 3) assess PANDAA PIDR+ using established performance criteria for HIV drug resistance genotyping and produce PANDAA PIDR+ under GMP conditions; and 4) verify that end-user, multi-site implementation of PANDAA PIDR+ is highly reproducible. The first of its kind, a validated, GMP-produced PANDAA PIDR+ test kit from Aldatu will be poised to capture a significant share of this rapidly growing diagnostic market opportunity.

Public Health Relevance

The 2015 WHO guidelines recommend anti-retroviral therapy (ART) for all HIV-infected people, and massive efforts to expand ART access will result in >30M adults and >1.7M children on ART by 2020, including an increased number of patients receiving protease-inhibitor (PI)-based ART following failure of first-line regimens. High rates of virologic failure observed in patients on PI-based ART in resource-limited countries, together with the high drug cost of a genotype-blind approach to therapeutic decision-making, necessitate an affordable HIV genotyping option for these patients in these settings. This SBIR project aims to develop a rapid, low-cost, thermostable test for detection of drug resistance in patients failing a PI-based ART regimen, which can radically improve clinical decision-making in low- and middle-income countries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AI128974-03
Application #
9613777
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fitzgibbon, Joseph E
Project Start
2017-01-17
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Aldatu Biosciences, Inc.
Department
Type
DUNS #
079348936
City
Boston
State
MA
Country
United States
Zip Code
02134
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