 |
|
|
| |
High Level Resistance to Dolutegravir (DTG) after Emergence of T97A Mutation
|
| |
| |
Mark Mascolini
Two case reports establish emergence of high-level resistance to the integrase inhibitor (INSTI) dolutegravir (DTG) with only one new INSTI resistance mutation, T97A [1]. Both people had INSTI experience and genotypes containing at least two other INSTI resistance mutations, G140S and Q148H.
T97A is an HIV-1 polymorphism, sometimes called an accessory mutation, infrequently found in people who have never taken an INSTI. National Institutes of Health (NIH) researchers who conducted this study noted that T97A (1) occurs with emergence of INSTI resistance in people with virologic failure while taking elvitegravir or raltegravir, (2) emerges during DTG therapy in heavily pretreated people with preexisting elvitegravir or raltegravir resistance mutations, and (3) emerges with additional INSTI resistance mutations, including those at integrase positions G140 and Q148.
Because the impact of T97A alone on resistance to DTG remains poorly understood, the NIH team analyzed solitary emergence of that mutation in two people with heavy antiretroviral experience, including prior INSTI therapy. Both people participated in an NIH trial exploring antiretroviral failure [2]. The analysis relied on commercial viral phenotyping and genotyping assays, additional phenotyping analyses with other assays, next-generation sequencing to detect low-level resistance mutations, and analyses with the Stanford and ANRS HIV resistance algorithms.
Participant A was a 52-year-old man diagnosed with HIV in 1989. He had deep antiretroviral experience, including the INSTI raltegravir, and had accumulated many major resistance mutations, among them the INSTI mutations G140S and Q148H. He stopped a regimen containing two protease inhibitors plus tenofovir/emtricitabine (TDF/FTC) and started twice-daily DTG, darunavir/ritonavir, maraviroc, and TDF/FTC. Phenotyping showed partial sensitivity to DTG, with a 4.61-fold change in the 50% inhibitory concentration (IC50).
This man's viral load fell below 40 copies after 12 weeks of treatment with the DTG regimen. But 3 months later his load rebounded to 1638 copies, when testing showed adequate levels of DTG and darunavir. Now phenotyping confirmed emergence of resistance to DTG with an IC50 of 66-fold. T97A was the only new mutation that emerged with the rebound.
Participant B was a 53-year-old man diagnosed with HIV in 1993. Like Participant A, he had deep antiretroviral experience including raltegravir. This man had already acquired three INSTI mutations, G140S, Q148H, and E138T, but his virus remained at least partially sensitive to DTG with a 6.71-fold change in IC50. Highly sensitive next-generation sequencing showed no other INSTI mutations when the man was taking raltegravir.
This man had taken DTG/abacavir/lamivudine plus TDF intermittently for several months before enrolling in the NIH study, when a baseline genotype revealed T97A plus the previously reported INSTI mutations. But T97A was the only new INSTI mutation to emerge. Two other new mutations detected confer resistance to nonnucleosides (A98A/G) or protease inhibitors (M46I). Phenotyping showed high-level resistance to DTG indicated by a 119-fold change in IC50.
The NIH team concluded that "isolated emergence of the T97A mutation led to high-level DTG resistance" with more than a 10-fold jump in DTG IC50 in these two men, both of whom had a record of acquiring two other INSTI mutations, G140S and Q148H. In both men T97A emerged rapidly, between 8 and 24 weeks of starting DTG. In this scenario, they added, viral load may rebound even after initial suppression with a DTG regimen.
References
1. Kuriakose SS, George JM, Dee N, et al. High level resistance to dolutegravir (DTG) after emergence of T97A mutation. 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 543.
2. ClinicalTrials.gov. Study of people with HIV infection who have high viral loads despite combination antiretroviral therapy. ClinicalTrials.gov identifier NCT01976715.
High Level Resistance to Dolutegravir (DTG) after Emergence of T97A Mutation
Safia Kuriakose1, Jomy George2, Nicola Dee1, Pamela Stoll2, Brian K. Agan3, Robin L. Dewar1, Alice Pau4, Frank Maldarelli5
1Leidos Biomedical Research, Inc., Frederick, MD, USA 2National Institutes of Health (NIH) Clinical Center (CC), Bethesda, MD, USA 3Uniformed Services University of the Health Sciences, Bethesda, MD, USA 4National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA 5National Cancer Institute, Frederick, MD, USA
WEBCAST - Themed Discussion: ARE INTEGRASE STRAND TRANSFER INHIBITORS RESISTANCE PROOF? - http://www.croiwebcasts.org/console/player/37220?mediaType=slideVideo&&crd_fl=1&ssmsrq=1521988681596&ctms=5000&csmsrq=1024
|
| |
|
|
|
|
|
