Might dolutegravir be part of a functional cure for HIV?

Abstract

Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a secondgeneration integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.Key words: dolutegravir, drug resistance, HIV, cure. Résumé :Les traitements antirétroviraux (TAR) ont considérablement réduit la morbidité et la mortalité associées au VIH. Or, le VIH peut établir des réservoirs viraux pour se soustraire au système immunitaire et aux TAR. Le dolutégravir (DTG) est un inhibiteur du transfert de brin par l'intégrase (integrase strand transfer inhibitor, INSTI) de deuxième génération qui s'apparente au raltégravir (RAL) et à l'elvitégravir (EVG), des INSTI de première génération. Comparativement au RAL et à l'EVG, le DTG présente une plus grande barrière génétique au dével-oppement de la résistance chez le VIH. On remarque avec intérêt que des mutations menant à la résistance clinique au DTG chez des patients jamais traités auparavant n'ont pas encore été observées. La présente revue fait la synthèse des études récentes abordant des stratégies visant à éliminer le VIH, explore les profils de résistance au DTG et discute de la possibilité de mettre au point un remède contre le VIH à l'aide du DTG. [Traduit par la Rédaction]

Creation of a long-acting nanoformulated dolutegravir

“…In vitro, the most common mutation against DTG is the R263K that severely reduces viral replication fitness, reducing the impact and rendering it insignificant for HIV/AIDS treatments 48 . Prevention of renewed viral infection emerging from tissue reservoirs experiencing suboptimal drug levels may allow infected cells to die off through normal cell turnover without spreading virus to other cells that may act as viral reservoirs 49 . Thus, the changes in antiretroviral drug treatment made here could limit viral replication in its native reservoirs, allowing antiretroviral drugs alone to keep the virus in check and attenuate new infections.…”

HIV drug resistance against strand transfer integrase inhibitors

“…What is notable about this substitution is that, unlike those discussed for RAL and EVG, the R263K substitution only results in low levels of resistance to DTG. It also has a significant impact on the fitness of the virus, and has yet to be compensated by secondary resistance mutations in tissue culture selections [33, 83]. It has been reported that patients with non-B subtype viruses selected for N155 pathway mutations in response to DTG (Table 3; see also [35]).…”

HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: a systematic review and meta-analysis protocol

“…Several findings support that early treatment with DTG may reduce the emergence of HIV-1 drug resistance (HIVDR) in resource-limited settings (RLS) [15]. These evidences are in line with the WHO recommendations on transitioning to DTG-based regimens for initial option or alternative ART in case of multi-resistance [10,11]. Up-to-date, few African countries carried out studies on INSTI-resistance.…”

“…These INSTIs are highly effective in both treatment-naïve as well as in treatment-experienced individuals who may harbor multidrug resistance to other drug classes, with a superior efficacy of DTG, CAB, and BIC both in vitro and in vivo [2,4,7]. These latter molecules are known as second generation while RAL and EVG are first-generation INSTI [1,3,[7][8][9][10][11]. In the group of second-generation INSTI, BIC has been recently approved by the US Food and Drug Administration (FDA) and exist only as part of the fixed dose combination bictegravir/emtricitabine/tenofovir alafenamide (BIC/3TC/TAF) [12,13].…”