Challenges for Novel Antiretroviral Development in an Era of Widespread tenofovir-disoproxil/lamivudine (or emtricitabine)/dolutegravir availability (TLD) Availability.

More than 80% of people with human immunodeficiency virus (HIV) in low- and middle-income countries (LMICs) take first-line tenofovir-disoproxil/lamivudine (or emtricitabine)/dolutegravir (TLD). Due to hard-fought activism, TLD now costs <$45 per person per year in more than 100 LMICs under Voluntary License. With final dolutegravir (DTG) patents expiring by 2029, generic TLD will soon be available globally. Here, we identify seven critical benchmarks that underpin TLDs' success which novel antiretroviral therapy (ART) should now meet, and an eighth benchmark for which novel ART should aim. These benchmarks are superior efficacy; high genetic barrier to resistance; safety in hepatitis B coinfection; favourable drug interaction profiles; HIV2 efficacy; safety in pregnancy, long-acting formulation availability and affordable pricing. We compare the generic TLD availability timeline with development timelines for two case-study novel ART combinations: islatravir/doravirine and cabotegravir/rilpivirine. We demonstrate that currently these regimens and trial programs will not meet key benchmarks required to compete with TLD.