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Introduction: Combination antiretroviral therapy (cART) has dramatically reduced morbidity and mortality of HIV-1-infected patients. Integrase strand transfer inhibitors (INSTIs) play an important role as a key drug in cART. The second-generation INSTIs are very potent, but due to the emergence of highly resistant viruses and the demand for more conveniently usable drugs, the development of 'third-generation' INSTIs and mechanistically different inhibitors is actively being pursued., Areas Covered: This article reviews the patents (from 2018 to the present) for two classes of HIV-1 integrase inhibitors of INSTIs and integrase-LEDGF/p75 allosteric inhibitors (INLAIs)., Expert Opinion: Since the approval of the second-generation INSTI dolutegravir, the design of new INSTIs has been mostly focused on its scaffold, carbamoylpyridone (CAP). This CAP scaffold is used not only for HIV-1 INSTIs but also for drug discoveries targeting other viral enzymes. With the approval of cabotegravir as a regimen of long-acting injection in combination with rilpivirine, there is a growing need for longer-acting agents. INLAIs have been intensely studied by many groups but have yet to reach the market. However, INLAIs have recently been reported to also function as a latency promoting agent (LPA), indicating further development possibilities.

Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, metabolism, distribution, and elimination (ADME) characteristics of BIC were determined through in vivo nonclinical and clinical studies (IND 121318).[ 14 C]BIC was rapidly absorbed orally in mice, rats, monkeys and human. The cumulative dose recovery was high in nonclinical species (>80%) and humans (95.3%), with most of the excreted dose recovered in faeces. Quantifiable radioactivity with declining concentration was observed in rat tissues suggesting reversible binding. Unchanged BIC was the most abundant circulating component in all species along with two notable metabolites M20 (a sulphate conjugate of hydroxylated BIC) and M15 (a glucuronide conjugate of BIC). BIC was primarily eliminated by hepatic metabolism followed by excretion of the biotransformed products into faeces. In vitro drug-drug interaction (DDI) studies with M15 and M20 demonstrated that no clinically relevant interactions were expected.Overall, BIC is a novel and potent INSTI with a favourable resistance, PK, and ADME profile that provides important improvements over other currently available INSTIs for the treatment of HIV-1.