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

Award Number: R01AI147330
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Novel mechanisms contributing to failure of dolutegravir-containing cART in clinical practice - Millions of people living with HIV (PLWH) will soon receive the integrase strand-transfer inhibitor (INSTI) dolutegravir (DTG), as the World Health Organization (WHO) now recommends DTG combined with two nucleoside reverse transcriptase inhibitors (NRTIs) as first- and second-line therapy. This combination therapy demonstrated very high efficacy in clinical trials and acquired drug resistance was absent (first-line treatment) or very rare (second-line treatment). It remains to be determined whether this high efficacy and lack of resistance development can be extrapolated to treatment of non-B subtype viruses in low- and middle-income countries where most PLWH live. Our long-term goal is to provide a scientific basis for optimal large-scale and long-term treatment of PLWH with DTG. Our central hypothesis is that novel viral mutations in and outside the integrase gene (with an emphasis on 3’-polypurine tract changes) contribute to virologic failure with DTG in clinical practice. This hypothesis will be tested by identifying PLWH failing DTG containing regimens in Brazil which is a model country for large-scale DTG implementation where various HIV subtypes co-circulate. Subsequently we will perform in-depth in vitro characterizations of novel viral mutations in and outside integrase gene in an HIV subtype comparative manner. The specific aims of this proposal are: 1) To characterize the pattern of INSTI resistance mutations that emerge during failure of DTG-containing cART in individuals infected with subtypes C, F, and BF recombinant forms in Brazil. These are the most prevalent non-B subtypes on the South-American continent. 2) To determine which changes in the 3’-PPT are observed in viruses from DTG failing individuals. Results of this study will show if this novel resistance pathway contributes to acquired drug resistance in clinical practice. 3) To determine the phenotypic consequences of mutations identified in specific aims 1 and 2. These studies assess and compare the effect of novel viral mutations on INSTI susceptibility and viral fitness in HIV subtypes A, B, C, and F in vitro (representing 70% of all infections worldwide), and the molecular mechanism of 3’-PPT mediated INSTI resistance will be determined. The insights generated with these studies will contribute to a more effective use of second generation INSTIs in the future.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $689,703 )
2023	2023	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM (ERASMUS MC)	DR. MOLEWATERPLEIN 40	ROTTERDAM				NLD	Allergy and Infectious Diseases Research	002	5	9/7/2023	NON-COMPETING CONTINUATION	$59,423
2023	2023	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM (ERASMUS MC)	DR. MOLEWATERPLEIN 40	ROTTERDAM				NLD	Allergy and Infectious Diseases Research	001	5	7/20/2023	NON-COMPETING CONTINUATION	$616,892
2023	2023	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM (ERASMUS MC)	DR. MOLEWATERPLEIN 40	ROTTERDAM				NLD	Allergy and Infectious Diseases Research	000	4	6/15/2023	SUPPLEMENT FOR EXPANSION	$13,388
														Subtotal = $689,703

Issue Date FY: 2022 ( Subtotal = $606,316 )
2022	2022	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM (ERASMUS MC)	DR. MOLEWATERPLEIN 40	ROTTERDAM	ZUID-HOLLAND			NLD	Allergy and Infectious Diseases Research	000	4	8/31/2022	NON-COMPETING CONTINUATION	$606,316
														Subtotal = $606,316

Issue Date FY: 2021 ( Subtotal = $614,205 )
2021	2021	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM (ERASMUS MC)	DR. MOLEWATERPLEIN 40	ROTTERDAM	ZUID-HOLLAND			NLD	Allergy and Infectious Diseases Research	000	3	9/14/2021	NON-COMPETING CONTINUATION	$614,205
2021	2021	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM (ERASMUS MC)	DR. MOLEWATERPLEIN 40	ROTTERDAM	ZUID-HOLLAND			NLD	Allergy and Infectious Diseases Research	001	3	9/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $614,205

Issue Date FY: 2020 ( Subtotal = $613,626 )
2020	2020	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM	'S-GRAVENDIJKWAL 230	ROTTERDAM	ZUID-HOLLAND	3015 CE		NLD	Allergy and Infectious Diseases Research	000	2	7/23/2020	NON-COMPETING CONTINUATION	$613,626
														Subtotal = $613,626

Issue Date FY: 2019 ( Subtotal = $628,572 )
2019	2019	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM	'S-GRAVENDIJKWAL 230	ROTTERDAM	ZUID-HOLLAND	3015 CE		NLD	Allergy and Infectious Diseases Research	000	1	8/20/2019	NEW	$628,572
														Subtotal = $628,572

Grand Total All Awards = $3,152,422

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

Award Number: R01AI147330

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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