Novel mechanisms contributing to failure of dolutegravir-containing cART in clinical practice

Project summary

In this project we study people living with HIV failing regimens containing the integrase inhibitor dolutegravir in Brazil, a model country for large-scale dolutegravir implementation where various HIV subtypes co-circulate, and then perform in-depth in vitro characterizations of novel viral mutations within and outside the integrase gene in an HIV subtype comparative manner. Results of the proposed studies will help to optimize care of people living with HIV by improving treatment guidelines and drug resistance interpretation algorithms, and may lead to the development of novel diagnostic assays for detecting determinants of integrase inhibitor resistance that lie outside the integrase gene, and novel integrase inhibitors with a higher barrier to drug resistance.

This proposal brings together a unique and innovative combination of clinical, pharmacologic, virologic and biochemical approaches to study DTG resistance in a real-life setting in Brazil, a model country for large-scale implementation of DTG for other low- and middle-income countries. Innovative, in-depth analyses of acquired DTG resistance and a thorough dissection of the underlying molecular mechanisms will be performed in different HIV subtypes prevalent in the region, including subtypes B, C, and F.