Sunday, November 24, 2024
11/24/2024
HIV Drug Resistance in the New ART Era in Kenya Rami Kantor, MD SUMMARY Since the emergence of resistance to zidovudine in the late 1980’s, we have been in a race: an HIV drug is developed and used, followed by the inevitable emergence of viral resistance to it, another drug is developed and used, and so on. This largely resistance-driven process has informed antiretroviral drug development since its inception. However, treatment monitoring, including drug resistance testing and at times viral load testing, are limited in resource limited settings, where HIV burden is greatest, creating the global paradox: we test for and know less about HIV drug resistance in locations where our understanding of it is most crucial. Such settings may be more prone for resistance due to restricted monitoring in clinical care, higher treatment failure thresholds, limited availability of advanced medications and formulations, circulating diverse HIV-1 subtypes, and special circumstances like HIV-TB coinfection. Such situations might further enhance the risk to develop resistance and exacerbate the complexity of addressing it. This paradox is even greater now that we are in the new global antiretroviral therapy (ART) era. Remarkable progress in antiretrovirals like dolutegravir (DTG), with enhanced efficacy, reduced toxicity, high barrier to resistance, and importantly, global accessibility, all instill a profound confidence, suggesting that we may have achieved a pivotal milestone in the ongoing race against HIV. However, the widespread utilization of DTG in all lines of ART, especially in settings with imperfect monitoring and limited medication availability, raises concerns about continuing the drug resistance race. Emerging data confirm these concerns and highlight research gaps related to resistance development to current era drugs and their magnitude and consequences. This proposal is designed to address these gaps. Leveraging our long-standing North- South collaboration, we propose to comprehensively and prospectively investigate the extent and impact of transmitted and acquired resistance in a large HIV care program in Kenya, one of the earlier countries to enter the new ART era in 2017. We hypothesize that the scale-up of DTG-based regimens across all lines of treatment in resource limited settings is leading to a gradual escalation of drug resistance over time, impacting care. To address this hypothesis, we will enroll and prospectively follow 1,840 Kenyan persons with HIV across the HIV, ART and resistance timelines. We will characterize transmitted resistance (Aim 1) and investigate acquired resistance (Aim 2) of 1st-line DTG-based ART (Aim 2a), 2nd-line ART (Aim 2b), beyond 2nd-line ART (Aim 2c), and special populations (Aim 3). Our understanding of resistance development in the new ART era is limited, yet crucial to ensure its sustainable success. This timely Proposal will generate hypothesis-driven data to address existing gaps and inform patient care towards ending the HIV epidemic. We expect to have a high and direct impact on guiding future ART strategies to minimize resistance. The new ART era has been rolled out for ~5 years, providing a unique opportunity to conduct this research. The right time to comprehensively investigate resistance in the new ART era is now, to ensure that we don’t lose the race, in Kenya and beyond.
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