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1 INSTI alone was not significantly associated with excess
2 INSTI DRMs were detected in 86 (14%) individuals; 20 (3%
3 INSTI resistance prevalence among successfully genotyped
4 INSTI use nearly doubled from pre- to peri-HCV treatment
5 INSTI use was associated with increased risk of new-onse
6 INSTI-CRR was 2.33% (0.15% dolutegravir/bictegravir, 2.2
7 INSTIs were prescribed to 22% of White patients and only
8 INSTIs work by blocking retroviral integration; an essen
9 nd rilpivirine coverage, compared with 14.0% INSTI PDR and 6.9% INSTI TDR with continued oral doluteg
11 09 non-INSTI, 818 PWOH) compared to men (223 INSTI, 412 non-INSTI, 891 PWOH) were younger (47.2 vs 54
12 iduals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and
13 iduals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and
14 tance levels, with 30.6% INSTI PDR and 11.3% INSTI TDR at 30% LAI cabotegravir and rilpivirine covera
15 ong pharmacokinetic tail, resulting in 22.3% INSTI PDR and 26.0% rilpivirine PDR when using LAI cabot
18 Of 3464 participants included, women (411 INSTI, 709 non-INSTI, 818 PWOH) compared to men (223 INS
20 10 antiretroviral-experienced patients, to 5 INSTIs (bictegravir, cabotegravir, dolutegravir, elviteg
21 o higher INSTI resistance levels, with 30.6% INSTI PDR and 11.3% INSTI TDR at 30% LAI cabotegravir an
23 rage, compared with 14.0% INSTI PDR and 6.9% INSTI TDR with continued oral dolutegravir-based ART.
24 genotype; 12-week suppression rates are 90% (INSTI-susceptible [INSTI-S] virus) and 35% (INSTI-R viru
27 visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resol
28 characterization of metabolic changes after INSTI initiation and potential therapeutic interventions
29 red 6-12 months before and 6-18 months after INSTI switch/add in SWAD with comparable time points in
30 ng ART in earlier time periods but not after INSTIs became guideline-recommended initial therapy for
33 ) from 2006-2017 who switched to or added an INSTI to ART (SWAD group) were compared to women on non-
34 ) from 2006-2017 who switched to or added an INSTI to ART (SWAD) were compared to women on non-INSTI
35 hydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and
38 ssociated with weight gain among those on an INSTI <2 years at entry (+0.27 kg/m2/year; 95% confidenc
39 afenamide (IRR 1.70, 95% CI 1.54-1.88) or an INSTI without tenofovir alafenamide (1.41, 1.30-1.53) co
40 attenuated risk in participants receiving an INSTI with (IRR 1.48, 1.31-1.68) or without (1.25, 1.13-
41 was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1.70, 95% CI 1.54-
44 ants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1.21, 1.07-1.37), whereas the risk i
46 % confidence interval {CI}: -.29 to .32] and INSTI-: 0.22 cm per 6 months [95% CI: -.01 to .44]) that
49 .4% (34.6-42.1) on tenofovir alafenamide and INSTI-based regimens had gained more than 10% of their b
53 the reduced risk of HAND found with dual and INSTI-based regimens along with a more recent ART initia
55 vement in survival between the pre-INSTI and INSTI recipients with HIV (adjusted hazard ratio [aHR],
56 ontrast to other mutations such as M184V and INSTI RAMs, NNRTI RAMs tended to persist within the HIV-
58 ore potential interactions between NNRTI and INSTI resistance mutations, we investigated the combined
59 e depiction of interactions of intasomes and INSTIs to be leveraged for structure-based drug design.
60 ions, 3' processing and strand transfer, and INSTIs tightly bind the divalent metal ions and viral DN
63 studies have suggested associations between INSTIs and weight gain, women living with HIV (WLHIV) ar
64 studies have suggested associations between INSTIs and weight gain, women living with HIV (WLHIV) ha
68 inhibition of the 3'-processing reaction by INSTIs and how INSTIs can be modified to overcome drug r
69 tutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination
71 of bictegravir, a novel, potent, once-daily INSTI designed to improve on existing INSTI options with
72 rate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined b
75 d channelling bias cannot fully be excluded, INSTIs initiation was associated with an early onset, ex
76 -daily INSTI designed to improve on existing INSTI options with the backbone of emtricitabine and ten
77 V care from October 12, 2007, when the first INSTI was approved by the US Food and Drug Administratio
81 y, adjusted mean cognitive domain scores for INSTI-exposed infants were close to the expected populat
86 a third had been exposed to first-generation INSTIs (n=193, 32%), 70 (12%) were on dolutegravir dual
90 sistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to G
91 T initiation was estimated to lead to higher INSTI resistance levels, with 30.6% INSTI PDR and 11.3%
95 the 3'-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, nota
99 Neural tube defects were observed only in INSTI groups, with litter prevalence rates of 0.66% for
100 almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positiv
105 rary of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffold
106 to the integrase strand transfer inhibitor (INSTI) class; 1 patient discontinued DTG/ABC/3TC due to
110 LA), an integrase strand transfer inhibitor (INSTI), reduces dosing frequency to bimonthly injections
111 eration integrase strand transfer inhibitor (INSTI), was recently approved for use in the treatment o
115 itiated integrase strand transfer inhibitor (INSTI)-based ART regimens, 1809 (31.7%) initiated protea
116 receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART
122 ual and integrase strand transfer inhibitor (INSTI)-based therapies was associated with a decreased r
124 smitted integrase strand transfer inhibitor (INSTI)-resistant (INSTI-R) virus is estimated at 0.1%.
125 ence of integrase strand transfer inhibitor (INSTI)-transmitted drug resistance (TDR) may increase wi
126 low-up, integrase strand transfer inhibitor (INSTI)-use was associated with weight gain among those o
127 th non-integrase strand transfer inhibitor (-INSTI) or tenofovir alafenamide fumarate (TAF)-exposed p
129 d integrase (IN) strand transfer inhibitors (INSTI) are key components of antiretroviral regimens.
130 RTANCE Integrase Strand Transfer Inhibitors (INSTI) are recommended by national and international gui
131 (HIV) integrase strand transfer inhibitors (INSTI) increases and formulations are being developed fo
133 ns that include integrase strand inhibitors (INSTIs) have become the most commonly used for people wi
137 1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS.
143 on HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechani
144 Integrase (IN) strand transfer inhibitors (INSTIs) are recent compounds in the antiretroviral arsen
148 aining integrase strand transfer inhibitors (INSTIs) combined with a tenofovir and lamivudine or emtr
149 n with integrase strand transfer inhibitors (INSTIs) has been associated with excess weight gain.
150 aining integrase strand transfer inhibitors (INSTIs) has been associated with weight gain in both ART
152 h some integrase strand transfer inhibitors (INSTIs) promote peripheral and central adipose tissue/we
153 s were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonucleas
156 ion of integrase strand transfer inhibitors (INSTIs), but few studies have evaluated the safety of IN
157 ked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely u
159 which act as IN strand transfer inhibitors (INSTIs), were the first anti-IN drugs to be approved by
160 mechanism of IN strand transfer inhibitors (INSTIs), which are front-line drugs for the treatment of
164 nts, 306 were exposed in utero to an initial INSTI-based maternal ART regimen, 473 to a PI-based regi
165 Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir
166 Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)-, and nonnucleoside reve
167 cART-naive adults (>=18 years) initiating INSTI-, PI-, or NNRTI-based regimens from 01/2007-12/201
168 y-suppressed WWH (419 who switched to INSTI [INSTI+]; 712 who did not switch [INSTI-]) and 887 women
169 tter efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previ
170 tion was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infe
171 vide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-
172 findings, virological benefits of first-line INSTIs-based ART might not translate to differences in m
173 Although VF rates with CAB/RPV were low, INSTI resistance emerged in approximately 40%-70% of ind
177 NA testing identified infection before major INSTI RAMs emerged in 4 cases and before additional majo
179 ter linear increases in WC and in menopause, INSTI+ was associated with faster increases, peaking at
185 18 PWOH) compared to men (223 INSTI, 412 non-INSTI, 891 PWOH) were younger (47.2 vs 54.5 years), were
187 icipants included, women (411 INSTI, 709 non-INSTI, 818 PWOH) compared to men (223 INSTI, 412 non-INS
188 rget trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same exce
191 viduals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (<=50
194 n-obese women, those in the INSTI versus non-INSTI group had a greater increase in NFS (but not FIB4
196 ial HIV-1 treatment with bictegravir-a novel INSTI with a high in-vitro barrier to resistance and low
199 necessary to fully understand the impact of INSTI-based regimens on the health of the individual dur
200 Continued population-level monitoring of INSTI and NRTI mutations, especially M184V and K65R, is
201 ease was increased in the first 24 months of INSTI exposure and thereafter decreased to levels simila
205 e fumarate (TAF)-exposed persons, receipt of INSTI+TAF showed a 1.7-fold increased RR of excess gesta
207 inically preferred unless DTG suppression of INSTI-R virus was <20% or 96-week DRV/r suppression was
209 Our findings suggest a direct effect of INSTIs and tenofovir alafenamide on bodyweight gain, rat
213 examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) t
215 ddress some critical questions on the use of INSTIs in settings with a high tuberculosis burden, incl
216 ND, compared with non-INSTIs, current use of INSTIs was associated with an increased DM risk, which p
217 ding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and th
219 .5-24.9 kg/m(2), 31.3% (95% CI 29.5-33.1) on INSTI-based regimens, 25.3% (23.0-27.7) on protease inhi
220 studies have compared virological failure on INSTI-based with other regimens, few data are available
221 d adults with HIV-1 and >=10% weight gain on INSTI + tenofovir alafenamide (TAF)/emtricitabine (FTC;
226 ow-level resistance of HIV-1 to DTG or other INSTI were detected, and these were sometimes followed b
227 Bictegravir had a lower IC50 than the other INSTIs on those HIV-2 isolates bearing major, resistance
229 Compared to INSTI-, in late perimenopause, INSTI+ had 0.26 cm per 6 months (95% CI: .02-.50) faster
231 tion that mutant viruses carrying NNRTI plus INSTI resistance mutations had reduced amounts of virion
234 nce to antiretrovirals, including the potent INSTIs, in the absence of drug-target gene mutations.
235 cant improvement in survival between the pre-INSTI and INSTI recipients with HIV (adjusted hazard rat
236 cipients had higher mortality during the pre-INSTI era, but survival was comparable between groups du
237 y less likely than White patients to receive INSTI-containing ART in earlier time periods but not aft
240 orized according to their first ART regimen (INSTI vs other ART) and were followed from ART start unt
242 intain ART success, particularly with rising INSTI use in all lines of therapy and 2-drug and long-ac
243 ing, all patients are diagnosed with INSTI-S/INSTI-R virus prior to ART initiation and start DTG- or
244 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART.
246 differences between individuals who started INSTIs and those who started other ART were -0.17% (95%
247 differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens.
250 d to INSTI [INSTI+]; 712 who did not switch [INSTI-]) and 887 women without HIV (WWOH) from the Women
252 6-12 months before and 6-18 months after the INSTI switch/add in SWAD participants, with comparable m
253 iency virus (SIV) and HIV have clarified the INSTI binding modes within the intasome active sites and
256 ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to en
261 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virolog
263 ong patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with
267 virally-suppressed WWH (419 who switched to INSTI [INSTI+]; 712 who did not switch [INSTI-]) and 887
269 is cohort study, infants exposed in utero to INSTI-based ART regimens had mean neurodevelopmental sco
270 d December 31, 2023, and exposed in utero to INSTI-based, PI-based, or NNRTI-based combination ART re
274 ether similar gains are seen after switch to INSTIs among virologically suppressed persons is less cl
275 ly weight gain increased following switch to INSTIs, particularly for women, blacks, and persons aged
282 ll effector functions in the presence of two INSTIs, dolutegravir and elvitegravir, which may contrib
283 Bictegravir, a novel, once-daily, unboosted INSTI, showed potent activity in a 10 day monotherapy st
284 ophylaxis, assessing virus suppression under INSTI-based regimens in prevention-relevant biologic com
286 D/C/F/TAF, 0.63% [95% CI, -.44% to 1.70%] vs INSTI + TAF/FTC, -0.24% [95% CI, -1.35% to .87%]; P = .2
287 uring premenopause, WWH had increases in WC (INSTI+: 0.01 cm per 6 months [95% confidence interval {C
288 % [95% CI, -7% to -3%]) from 2009-2014, when INSTIs were approved as initial therapy but were not yet
289 .37 cm per 6 months [95% CI: .15-.60]) while INSTI- had smaller increases (0.14 cm per 6 months [95%
290 , peaking at 43 months then declining, while INSTI- had smaller increases (0.14 cm per 6 months [95%
291 in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characteri
293 weeks undergo IR testing; if diagnosed with INSTI-R virus, they change to ritonavir-boosted darunavi
294 IR testing, all patients are diagnosed with INSTI-S/INSTI-R virus prior to ART initiation and start
297 However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk o