HIV Drug Resistance Profiles Among Individuals Failing Tenofovir/Lamivudine and Dolutegravir First Line Regimen in Brazil

SPECIFIC AIMS We are on the verge of the global rollout of the second-generation integrase strand-transfer inhibitor (INSTI) dolutegravir (DTG), as the World Health Organization (WHO) now recommends the combination of DTG + 2 nucleoside reverse transcriptase inhibitors (NRTIs) as first- and second-line therapy. As a result, millions of people living with HIV (PLWH) will soon receive DTG. In clinical trials, which mainly included people infected with HIV-1 subtype B, the combination of DTG + 2 NRTIs demonstrated very high efficacy and acquired drug resistance was absent (first-line treatment) or very rare (second-line treatment) in the event of virologic failure. It is not clear if this high efficacy and lack of acquired drug resistance can be extrapolated to clinical practice in low- and middle-income countries, where the majority of PLWH live and where most infections are due to non-B subtypes. Furthermore, in the pivotal studies for initial treatment with DTG, candidates harboring virus resistant to NRTIs met the exclusion criteria of these studies. Although DTG failure in first line regimens in clinical trials reveal the absence of integrase resistance, it is conceivable that mutations at other HIV genomic regions such as 5´PPT (nef) could contribute to DTG lack of efficacy.

Brazil was the first middle-income country to provide free and universal access to antiretroviral drugs to HIV infected individuals. Since 2014 local guidelines recommend that all HIV infected individuals be started on therapy regardless of CD4 count. Since January 2017, all patients are started on a DTG containing triple regimen. As of November 2018, 170,000 individuals were receiving DTG through the public health system. It is a public health priority to evaluate the risk of virologic failure and the subsequent development of INSTI resistance in these real-life settings. Our preliminary data from Brazil indicated a high virologic failure rate of 8% after 18 months of treatment TL+D. Moreover, acquired drug resistance was observed in first-line virologic failures (15 out of 84 investigated individuals). A relatively high rate of transmitted drug resistance (TDR) was also observed among those 84 individuals (15.6%) Our central hypothesis is that TDR may be associated and contribute to virologic failure with DTG in clinical practice. To test this central hypothesis, we will identify PLWH failing DTG containing regimens in Brazil, a model country for large-scale DTG implementation where various HIV subtypes co-circulate. The insights generated with these studies will contribute to a more effective use of second generation INSTI in the future.

The specific aims of this proposal are as follows:

1. Investigate the influence of Transmitted Drug resistance, HIV clade profile and immunological and virological features among individuals failing first line regimen with Tenofovir/3TC + Dolutegravir after 24 weeks of treatment in Brazil.
2. Determine the genotypic resistance profile among individuals failing first line regimen with Tenofovir/3TC + DTG after 24 weeks of treatment in Brazil.
3. Determine which changes in the 3'-PPT are observed in viruses from patients experiencing TL+D failure and assess if this novel resistance pathway contributes to acquired drug resistance in clinical practice.

The results from the proposed study can be used to optimize care of PLWH by improving treatment guidelines and drug resistance interpretation algorithms.