Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance

Abstract

This manuscript reviews the reasons why Integrase inhibitors should now routinely constitute a part of first line antiretroviral therapy for the treatment of HIV disease. The use of these drugs that are generally well tolerated has resulted in far less drug resistance than was the case with most other categories of antiviral compounds. In addition, the integrase inhibitor family of drugs has been less prone to the problem of transmitted drug resistance which is due to a wide variety of substitutions in the HIV genome that can be sexually transmitted from one person to another. However, the use of integrase inhibitors in first line therapy may unfortunately not soon happen in developing country settings where non-nucleoside reverse transcriptase inhibitors continue to be a mainstay of initial therapy, primarily for reasons of cost. As long as this situation continues, problems of drug resistance and transmitted drug resistance will be common in such settings. Current evidence also suggests that the use of dolutegravir as a first line integrase inhibitor may limit development of drug resistance to an extent that exceeds the use of other members of this family of drugs. This may be due to particular patterns of resistance involving dolutegravir, whereby the mutations that are associated with resistance against this compound may actually diminish both HIV replication capacity as well as integrase enzymatic activity in a far-reaching and unique manner. This gives potential hope that the use of dolutegravir in first line therapy could actually form part of the long-sought goal of attainment of a functional cure for HIV disease.

Keywords: Dolutegravir; Fitness; Inhibitors; Integrase; Replication; Resistance mutations.