A 35-Year Review of Pre-Clinical HIV Therapeutics Research Reported by NIH ChemDB: Influences of Target Discoveries, Drug Approvals and Research Funding

Abstract

We present a retrospective analysis of trends in human immunodeficiency virus (HIV) small molecule drug development over the last thirty-five years based on data captured by ChemDB, a United States (US) National Institutes of Health (NIH) database of chemical and biological HIV testing data. These data are analyzed alongside NIH funding levels, US Food and Drug Administration (FDA) drug approvals, and new target identifications to explore the influences of these factors on anti-HIV drug discovery research. The NIH's ChemDB database collects chemical and biological testing data describing published and patented pre-clinical compounds in development as potential HIV therapeutics. These data were used as a proxy for estimating overall levels of HIV therapeutics research activities in order to assess research trends. Data extracted from ChemDB were compared with records of drug approvals from the FDA, NIH funding levels, and drug target discoveries to elucidate the influences that these factors have on levels of HIV therapeutics research activities. Despite the increasingly wide suite of HIV therapeutic options that have accumulated during decades of research, interest in HIV therapeutics research activities remains strong. While decreases in research activity levels have followed cuts in research funding, FDA-approved HIV therapeutics have continued to accumulate. The comparisons presented here indicate that HIV drug research activity levels have historically been more responsive to changes in funding levels and the identification of new drug targets, than they have been to drug approvals. Continued interest in HIV therapeutics research may reflect that fact that of the 55 drugs approved for HIV treatment as of 2018, only seven inhibitory targets are represented. Moreover, drug resistance presents substantial clinical challenges. Sustained research interest despite drug approvals and fluctuations in available funding likely reflects the clinical need for safer, more palatable and more efficacious therapeutics; robust attention to both novel therapeutics and inhibitory targets is necessary given the speed of development of drug-resistant HIV strains. Only with such continued interest will we reduce the burden of acquired immunodeficiency syndrome (AIDS) disease and control the AIDS epidemic.

Keywords: AIDS; Drug development; HIV; Historical trends; Research funding; Therapeutics.

Figure 1.

Timeline of HIV therapeutics target discoveries, first-in-class drug approvals, and major advances in treatment approaches. Note: Only those therapeutics for which an FDA approved drug(s) exists are included. Major shifts in clinical approaches to treatment and prevention are noted as HAART (highly active antiretroviral therapy) and PrEP (pre-exposure prophylaxis).

Figure 2.

Comparison of Chem-DB-based metrics for research activities with yearly NIH HIV/AIDS therapeutics funding and FDA drug approvals. Note: The gray bars indicate the percentage of maximum NIH therapeutics funding per year in 2017 dollars. The black boxes indicate the percentage of the cumulative maximum of FDA-approved drugs reached per year. The yearly statistics from ChemDB (number of publications, number of targets, number of target references, and number of compounds, overlaid lines) are graphed as a percentage of the maximum value for each metric (see Methods). Underlying data are available in Table A1. Note that a change in programmatic funding reporting led to a substantial reduction in funds reported for HIV therapeutics development from 2017 onward [12,13].

Figure 3.

Relative levels of interest in potential therapeutic targets: percentages of target-specific compounds tested in 5-year increments and for all 35 years (1984–2018). Note: For each 5-year interval investigated (upper bars) and for the 35-year history of the field (lower bar), the percentages of compounds tested for activity against the top 10 targets for inhibition entered in ChemDB are presented. “Other” indicates the sum of all compounds tested for activity against all targets (viral and host) other than the top 10. Underlying data are available in Tables A2 and A4.

Figure 4.

Accumulation of target-specific compounds tested and hiv drug approvals over 35 years (1984–2018). Note: The cumulative number of drugs approved by the FDA for all seven targets for which a drug has been approved (symbols) is plotted along with the cumulative number of compounds tested for inhibitory activity against those seven targets, as entered in ChemDB (lines). “Other” indicates the cumulative sum for all targets (viral and host) other than the seven for which HIV drugs have been approved by the FDA. Combination drugs with two or more targets each (RT and integrase, RT and protease, some including cytochrome P450) are depicted by open or black diamonds. Underlying data provided in Tables A2 and A3; research activity data for CD4 provided in Table A6.