INSTI-based Regimens Research Articles

Factors Associated with Virological Failure in First-Line Antiretroviral Therapy in Patients Diagnosed with HIV-1 between 2010 and 2018 in Israel.

Despite the progress in contemporary antiretroviral therapy (ART) and the continuous changes in treatment guidelines, virological failure (VF) is still an ongoing concern. The goal of this study was to assess factors related to VF after first-line ART. A longitudinal cohort retrospective study of individuals on first-line ART diagnosed with HIV-1 in 2010-2018 and followed-up for a median of two years was conducted. Demographics, baseline and longitudinal CD4 counts, treatment regimens, adherence and VF were recorded. The Cox proportional hazards regression and mixed models were used. A cohort of 1130 patients were included. Overall, 80% were males and 62% were Israeli-born individuals. Compared to individuals diagnosed in 2010-2014, when treatment was initiated according to CD4 levels, those diagnosed in 2015-2018 were older and had lower baseline CD4 counts. VF was recorded in 66 (5.8%) patients. Diagnosis with CD4 <200 cells/mmᶟ with AIDS-defining conditions (HR = 2.75, 95%CI:1.52-4.97, p < 0.001) and non-integrase strand transfer inhibitor regimens (non-INSTI, HR = 1.80, 95%CI:1.01-3.24, p = 0.047) increased VF risk. No impact of baseline resistance was observed. We concluded that the early detection of HIV-1 infection and usage of INSTI-based regimens are recommended to reduce VF.

1563. Incidence of Errors in an INSTI-Based Era: A Comparison of Error Rates Between Single Versus Multiple Tablet INSTI-Based Regimens in the Inpatient Setting

Abstract Background Errors related to antiretroviral therapy (ART) occur in up to 86% of hospitalized patients living with human immunodeficiency virus (HIV) and may contribute to treatment failure, increased drug resistance, adverse effects, and toxicity. ART can be administered as a single tablet regimen (STR) or multiple tablet regimen (MTR), with limited data on whether the number of tablets affects inpatient error rates. The purpose of this study is to evaluate the incidence of medication errors in adult patients admitted to an Ascension Seton hospital who are maintained on a bictegravir-based STR or a MTR with dolutegravir. Methods This is a multicenter, retrospective, observational study conducted in patients ≥18 years diagnosed with HIV and admitted to an Ascension Seton hospital between January 1, 2017 through September 1, 2022. Patients receiving the STR bictegravir-emtricitabine-tenofovir alafenamide fumarate or provided a dolutegravir(DTG)-based MTR (in place of the patient’s home DTG-based STR) while admitted will be included. DTG-based MTRs including lamivudine, or abacavir and lamivudine will be evaluated. The primary outcome is a composite ART-related error rate between groups. Statistical analysis of the primary outcome was evaluated using a chi-squared test with an α level of 0.05 for significance. Secondary outcomes include: each error type overall and between the two groups; time to error correction, defined as time between error occurrence and resolution of identified ART-related errors; and an acquisition cost-analysis of anticipated differences between dispensing DTG-based regimens as MTR versus commercially available STR. Results Overall, 726 patient encounters were screened and 514 patient encounters were included (257 encounters in each arm). Patients included in the study were 79.4% male and 48 years of age on average. The primary outcome occurred in 59/257 (23%) encounters in the STR bictegravir group compared to 81/257 (31.5%) encounters in the MTR dolutegravir group (p = 0.029). A total of 68 and 99 errors were identified in the bictegravir and dolutegravir groups, respectively. Conclusion Composite error occurrence was significantly higher in the MTR dolutegravir group compared to the STR bictegravir group. Disclosures All Authors: No reported disclosures

1566. Determinants associated with weight gain among persons with HIV who switch to integrase strand transfer inhibitors (INSTI)

Abstract Background Weight gain associated with integrase strand transfer inhibitors (INSTI) has been well documented among patients with HIV. However, recent reports suggest that the observed weight gain among patients who switch to INSTIs may be associated in part with their pre-switch regimen. Methods We conducted retrospective analyses of a 50% sample of all treatment-experienced patients who switched to second-generation INSTI containing regimen (bictegravir/dolutegravir) at the Duke Adult Infectious Diseases Clinic (Durham, NC, USA) between 1 January 2014 and 31 December 2021. Covariates included sex at birth, age, race, ethnicity, pre-switch regimen, body mass index (BMI), CD4 count and HIV-1 viral load. All weights documented within 24 months from regimen switch were included. Outcomes of interest were percent change in weight and absolute weight change. Ordinary least squares was used to obtain average percent weight change from baseline, adjusted for covariates. Results Overall, 339 persons were included in the analyses. Cohort demographics were: median age 51.2 (interquartile range 44.4, 57.6), 73% male sex at birth, 56% Black, 4% Hispanic ethnicity. At regimen switch, median CD4 count was 671 (IQR 460-935), and 78% had a viral load &amp;lt; 200 copies/cc. Mean weight at regimen switch was 87.8 kg (standard deviation [SD] 22.1kg), and mean total weight change over 24 months post-switch was +1.3 kg (SD 7.1 kg). Overall, 28% of cohort members gained &amp;gt;5% of baseline body weight within 24 months of switch. Hispanic ethnicity (5.9% [95% CI 1.0, 10.7]) and BMI &amp;lt; 20 (3.7% [95% CI -0.3, 7.7]) were associated with post-switch weight gain. Only efavirenz-containing pre-switch regimens were significantly associated with weight gain over 24 months post-switch; EFV/FTC/TDF (3.1% [95% CI 0.2, 6.1]), all other EFV-containing regimens (6.3% [95% 0.1-12.4]). Conclusion Pre-switch regimens containing efavirenz were significantly associated with weight gain after switch to second-generation INSTI-based regimens, consistent with findings from non-US based cohorts. Disclosures Nwora Lance Okeke, MD MPH, Gilead Sciences: Advisor/Consultant

Investigating rates and predictors of viral blips, low-level viraemia and virological failure in the Australian HIV observational database.

Australia has made significant progress towards achieving the UNAIDS's 95-95-95 cascade targets including HIV viral suppression. To investigate the burden of HIV viraemia, we assessed viral blips, low-level viraemia (LLV) and virologic failure (VF) in an Australian cohort. We studied the proportion of people with viral suppression, viral blips, LLV and VF in the Australian HIV observational database (AHOD) between 2010 and 2021. The association between blips or LLV, and VF was investigated using Cox regression, and predictors of viral blips and LLV were assessed using repeated-measured logistic regression. Among 2544 AHOD participants who were in follow-up and on antiretroviral therapy (ART) from 1 January 2010 (88.7% male), 444 had experienced VF (incidence rate: 2.45 [95% CI: 2.23-2.69] per 100 person-years [PY]) during 18,125 PY of follow-up (a median of 7.6 years). The proportion of people with VF decreased over time, whereas rates of blips and LLV remained stable. Participants with blips (hazard ratio, 2.89; 95% CI: 2.31-3.61) and LLV (4.46; 95% CI: 3.38-5.89) were at increased risk of VF. Hepatitis B co-infection, longer documented treatment interruption duration, younger age and lower CD4 at ART initiation, and protease inhibitors-based initial regimen were associated with an increased risk of VF. Common predictors of blips and LLV such as higher HIV-1 RNA and lower CD4 at ART initiation, longer treatment interruption, more VL testing and types of care settings (hospitals vs. sexual health services) were identified. Blips and LLV predict subsequent VF development. We identified important predictors of HIV viraemia including VF among individuals on INSTI-based regimens to help direct HIV management plans.

Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration

A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events. We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates. The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15-45) and 52 in non-initiators (39 months; 18-47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (-0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9-29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15-37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference -0·068% (-0·60 to 0·52). We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV. National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.

Hepatic steatosis after switching to integrase inhibitor-based regimens does not parallel short-term weight gain.

We studied hepatic steatosis in people with HIV (PWH) who switched to an integrase inhibitor (INSTI)-based regimen. One hundred and fifty-four PWH were included. After 48 weeks, median (Q1-Q3) weight gain was 1.2 (-0.6 to 3.8) kg and median (Q1-Q3) controlled attenuation parameter (CAP) change was -4 (-33 to 27) dB/m. Weight gain was weakly correlated with CAP change [R2 95% confidence interval (CI) = 0.144 (-0.014 to 0.296); P = 0.074)]. Changes in hepatic steatosis after switching to INSTI-based regimens do not seem to parallel weight gain after 1 year.

IP-10 and MIG are sensitive markers of early virological response to HIV-1 integrase inhibitors.

Interferon-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) are chemokines recognized as inflammatory biomarkers during HIV-1 infection. We assessed their early and long-term dynamics after initiation of antiretroviral treatment (ART). Persons with HIV-1 (PWH) aged>18 years starting their first ART in 2015-2021 in a prospective cohort (n=73) were included. IP-10 and MIG plasma levels were quantified using a multiplexed bead-based assay. IP-10 and MIG plasma levels showed a significant and consistent reduction following ART (80% integrase inhibitor [INSTI]-based) initiation, starting at day 20 and maintained throughout the study period (48 months), paralleling the HIV-1 RNA decay and CD4+ count recovery (p<0·001). At baseline, PWH≥ 50 years, CDC stage C and CD4+ count<350cells/mm3 had higher levels of IP-10 (p=0·022, p=0·001 and p=0·002, respectively) and MIG (p<0·001, p=0·024 and p=0·069, respectively). All of them matched their counterparts several months following ART initiation. MIG levels showed a greater decrease at day 10 in those treated with INSTI (p=0·038). Low-level HIV-1 viremia did not impact MIG or IP-10 levels. Plasma IP-10 and MIG showed an early significant decline following ART initiation, with greater early declines in MIG levels in INSTI-based regimens. These findings suggest a strong impact of HIV-1 viremia on IP-10 and MIG levels.

Impact of very early antiretroviral therapy during acute HIV infection on long-term immunovirological outcomes

ObjectivesWe aimed to determine if starting antiretroviral therapy (ART) in the first 30 days after acquiring HIV infection has an impact on immunovirological response. MethodsObservational, ambispective study including 147 patients with confirmed acute HIV infection (January/1995-August/2022). ART was defined as very early (≤30 days after the estimated date of infection), early (31-180 days), and late (>180 days). We compared time to viral suppression (viral load [VL] <50 copies/ml) and immune recovery (IR) (CD4+/CD8+ ratio ≥1) according to the timing and type of ART using survival analysis. ResultsART was started in 140 (95.2%) patients. ART was very early in 24 (17.1%), early in 77 (55.0%), and late in 39 (27.9%) cases. Integrase strand transfer inhibitor (INSTI)-based regimens were the most used in both the overall population (65%) and the very early ART group (23/24, 95.8%). Median HIV VL and CD4+/CD8+ ratio pre-ART were higher in the very early ART group (P <0.05). Patients in the very early and early ART groups and treated with INSTI-based regimens achieved IR earlier (P <0.05). Factors associated with faster IR were the CD4+/CD8+ ratio pre-ART (hazard ratio: 9.3, 95% CI: 3.1-27.8, P <0.001) and INSTI-based regimens (hazard ratio: 2.4, 95% CI: 1.3-4.2, P = 0.003). ConclusionsThe strongest predictors of IR in patients who start ART during AHI are the CD4+/CD8+ ratio pre-ART and INSTI-based ART regimens.

ART-related medication errors in hospitalized people with HIV in the INSTI-era: analysis from 2 health systems in South Georgia, U.S.

ABSTRACT ART-related medication errors occur at high rates in hospitalized people with HIV (PWH), but few studies included modern regimens. As such, we evaluated ART-related medication errors in hospitalized PWH in an era where use of INSTI-based regimens dominate. This multi-center, retrospective cohort included PWH at least 18 years hospitalized in South Georgia, U.S. between March 2016 and March 2018. Of those eligible for inclusion, 400 were randomly selected and included. Three hundred sixty-three inpatient ART-related medication errors occurred in 203 patients during the study period due to incorrect scheduling (44%), an incorrect or incomplete regimen (27%), and drug–drug interactions (27%). Approximately 25% of errors persisted to discharge. Medication errors were more likely to occur in patients receiving NNRTI- or PI-containing multi-tablet regimens, whereas those receiving INSTI-containing multi-tablet regimens were less likely to experience a medication error. ART-related medication errors are less likely in patients receiving INSTI-containing multi-tablet regimens. Ensuring appropriate transition of ART throughout hospitalization remains an area in need of significant improvement.

Predicting Factors of Plasma HIV RNA Undetectability after Switching to Co-Formulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Experienced HIV-1 Patients: A Multicenter Study.

Switching to bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) from other antiretroviral regimens is safe and effective for virologically suppressed people living with HIV (PLWH). The term virological suppression includes both low but detectable HIV viremia and undetectable HIV viremia, and the latter is possibly associated with a lower immune activation state. Herein, we describe a 24-month follow-up of experienced PLWH with plasma HIV RNA undetectable or detectable < 50 copies/ml switching to BIC/FTC/TAF. A previous 12-month monitoring was available, and the factors correlated with treatment efficacy. This retrospective multicenter study included PLWH who switched to BIC/FTC/TAF in the period of 2019-2022, and who were HBsAg and HCV RNA negative. The follow-up study times were 6 (T6), 12 (T12), 18 (T18), and 24 (T24) months after the switch (T0). Survival analysis with multiple-failure-per-subject design, Kaplan-Meier survival estimates, multivariate analysis of variance, multilevel linear regression, and a hierarchical ordered logistic model were applied. A total of 329 PLWH had plasma HIV RNA which was either undetectable or detectable at <50 copies/mL at T0, and 197 responded to all inclusion criteria: M/F 140/57; the median CD4+ cell count was 677 cells/mm3; and HIV RNA at T0 was undetectable in 108 patients. Most of the 197 patients (122, 61.9%) were on a previous INSTI-based regimen. HIV RNA undetectability was more frequent at each follow-up point in patients with HIV RNA that was undetectable at T0, and it showed a higher frequency throughout the follow-up period in patients with always-undetectable HIV RNA in the 12 months before the switch. A higher nadir CD4 cell count had a predictive role, and HBcAb positivity had no influence. In conclusion, the switch could be programmed and possibly delayed on a case-by-case basis in order to achieve persistent plasma HIV RNA undetectability. Undiagnosed loss of HBcAb has no detrimental consequences on the response to BIC/FTC/TAF.

Endothelial Glycocalyx Integrity in Treatment-Naïve People Living with HIV before and One Year after Antiretroviral Treatment Initiation.

Endothelial glycocalyx (EG) derangement has been associated with cardiovascular disease (CVD). Studies on EG integrity among people living with HIV (PLWH), are lacking. We conducted a prospective cohort study among treatment-naïve PLWH who received emtricitabine/tenofovir alafenamide, combined with either an integrase strand transfer inhibitor (INSTI, dolutegravir, raltegravir or elvitegravir/cobicistat), or a protease inhibitor (PI, darunavir/cobicistat). We assessed EG at baseline, 24 (±4) and 48 (±4) weeks, by measuring the perfused boundary region (PBR, inversely proportional to EG thickness), in sublingual microvessels. In total, 66 consecutive PLWH (60 (90.9%) males) with a median age (interquartile range, IQR) of 37 (12) years, were enrolled. In total, 40(60.6%) received INSTI-based regimens. The mean (standard deviation) PBR decreased significantly from 2.17 (0.29) μm at baseline to 2.04 (0.26) μm (p = 0.019), and then to 1.93 (0.3) μm (p < 0.0001) at 24 (±4) and 48 (±4) weeks, respectively. PBR did not differ among treatment groups. PLWH on INSTIs had a significant PBR reduction at 48 (±4) weeks. Smokers and PLWH with low levels of viremia experienced the greatest PBR reduction. This study is the first to report the benefit of antiretroviral treatment on EG improvement in treatment-naïve PLWH and depicts a potential bedside biomarker and therapeutic target for CVD in PLWH.

Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study.

Second-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients. Real-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) ≥200 copies/mL at 24 weeks or as a single determination of VL ≥1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated. Virological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir <100 cells/μL were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerability were consistent with expected safety profiles. Whereas second-generation INSTIs are preferred treatment options worldwide, and DTG is one of the treatment of choices in resource-limited settings, first-generation INSTIs may still provide high virological and immunological effectiveness when DTG is not available.

Gut Bacterial Communities in HIV-Infected Individuals with Metabolic Syndrome: Effects of the Therapy with Integrase Strand Transfer Inhibitor-Based and Protease Inhibitor-Based Regimens.

Antiretroviral therapies (ART) are strongly associated with weight gain and metabolic syndrome (MetS) development in HIV-infected patients. Few studies have evaluated the association between gut microbiota and integrase strand transfer inhibitor (INSTI)-based and protease inhibitor (PI)-based regimens in HIV-infected patients with MetS. To assess this, fecal samples were obtained from HIV-infected patients treated with different regimens (16 PI + MetS or 30 INSTI + MetS) and 18 healthy controls (HCs). The microbial composition was characterized using 16S rRNA amplicon sequencing. The INSTI-based and PI-based regimens were associated with a significant decrease in α-diversity compared to HCs. The INSTI + MetS group showed the lowest α-diversity between both regimens. A significant increase in the abundance of short-chain fatty acid (SCFA)-producing genera (Roseburia, Dorea, Ruminococcus torques, and Coprococcus) was observed in the PI + MetS group, while Prevotella, Fusobacterium, and Succinivibrio were significantly increased in the INSTI + MetS group. Moreover, the Proteobacteria/Firmicutes ratio was overrepresented, and functional pathways related to the biosynthesis of LPS components were increased in the INSTI + MetS group. The gut microbiota of patients receiving INSTIs showed a more pronounced dysbiosis orchestrated by decreased bacterial richness and diversity, with an almost complete absence of SCFA-producing bacteria and alterations in gut microbiota functional pathways. These findings have not been previously observed.

Real-world effectiveness of WHO recommended first-line antiretroviral therapies: a cohort study from a middle-income country

ABSTRACT We estimate the effectiveness of antiretroviral therapy (ART) among individuals receiving HIV care in Rio de Janeiro, Brazil. Adults (18y+) initiating ART between Jan/2008 and Dec/2018 (follow-up through Dec/2020) were included. First-line ART (two nucleoside reverse transcriptase inhibitors plus one antiretroviral from another class) was categorized into four categories: non-nucleoside reverse transcriptase inhibitor/NNRTI-based, protease inhibitor/PI-based, integrase strand transfer inhibitor/INSTI-based, and single-tablet regimen (STR, Tenofovir 300mg + Lamivudine 300mg + Efavirenz 600mg). Effectiveness (viral load ≤50 copies/µL) was evaluated at 6(3–9) and 12(9–15) months from ART initiation. Bayesian logistic regression models were used to quantify the association between exposure and outcomes while accounting for missing data. Overall, 1863(57%), 652(19.9%), 412(12.6%), and 342(10.5%) individuals used, respectively, NNRTI-based, PI-based, INSTI-based regimens, and STR. Compared to NNRTIs, the odds of viral suppression with INSTI-based regimens was 76% higher (adjusted OR:1.76, 95%CI:1.23–2.51) at six months but no higher at 12 months. Older age, higher education, CD4 count ≥500 cells/mm3 and viral load <100,000 copies/µL at ART initiation increased the odds of viral suppression. Viral suppression at six months was the strongest predictor of viral suppression at 12 months. These results highlight population groups that could benefit from close monitoring during the first year of ART.

Optimizing Treatment for Human Immunodeficiency Virus to Improve Clinical Outcomes Using Precision Medicine.

In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz-based regimen than an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009-2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of acquired immune deficiency syndrome (AIDS)-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an efavirenz- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval (CI): 8.6, 11.3), corresponding to an absolute risk reduction of 2.3% (95% CI: 0.9, 3.8) when compared with recommending an efavirenz-based regimen for all patients and 2.6% (95% CI: 1.0, 4.2) when compared with recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome compared with assigning all patients the same drug regimen.

Type and timing of antiretroviral therapy during pregnancy: Impact on risk of preterm delivery and small-for-gestational age births in Canada, a retrospective cohort study.

To evaluate the impact of type and timing of antiretroviral therapy (ART) on the risk of preterm delivery (PTD) and small-for-gestational age (SGA) birth among pregnant women and people living with HIV in Canada. Data for this retrospective cohort study were analyzed from the Canadian Perinatal HIV Surveillance Program from 1990 to 2020. The association between ART and risk of PTD (<37 weeks) and SGA birth(<10th percentile)was explored using mixed effects logistic regression and time-dependent Cox proportional hazards models. Overall, there were 14.9% (654 of 4379) PTD and 18.5% (732 of 3947) SGA cases. A higher risk of PTD was observed with nonnucleoside reverse transcriptase inhibitor-(adjusted hazard ratio [aHR], 1.73; P=0.019) and boosted protease inhibitor-(aHR,186;P=0.007)based regimenscompared with integrase strand transfer inhibitor (INSTI)-based regimens. ART initiation prior to conception was associated with a lower risk of SGA birthcompared with ART initiation after conception at 1 to 14 weeks (adjusted odds ratio [aOR], 0.69; P=0.024) and > 14 weeks (aOR, 0.70; P=0.005). INSTI-based ART regimens were associated with lower risk of PTD compared with other regimens, and ART initiation before conception was associated with a lower risk of SGAbirth. These findings, with overall safety data, should be considered when providing pregnancy counseling to people living with HIV.

Molecular Epidemiology of HIV-1 in Ghana: Subtype Distribution, Drug Resistance and Coreceptor Usage.

The greatest HIV-1 genetic diversity is found in West/Central Africa due to the pandemic’s origins in this region, but this diversity remains understudied. We characterized HIV-1 subtype diversity (from both sub-genomic and full-genome viral sequences), drug resistance and coreceptor usage in 103 predominantly (90%) antiretroviral-naive individuals living with HIV-1 in Ghana. Full-genome HIV-1 subtyping confirmed the circulating recombinant form CRF02_AG as the dominant (53.9%) subtype in the region, with the complex recombinant 06_cpx (4%) present as well. Unique recombinants, most of which were mosaics containing CRF02_AG and/or 06_cpx, made up 37% of sequences, while “pure” subtypes were rare (<6%). Pretreatment resistance to at least one drug class was observed in 17% of the cohort, with NNRTI resistance being the most common (12%) and INSTI resistance being relatively rare (2%). CXCR4-using HIV-1 sequences were identified in 23% of participants. Overall, our findings advance our understanding of HIV-1 molecular epidemiology in Ghana. Extensive HIV-1 genetic diversity in the region appears to be fueling the ongoing creation of novel recombinants, the majority CRF02_AG-containing, in the region. The relatively high prevalence of pretreatment NNRTI resistance but low prevalence of INSTI resistance supports the use of INSTI-based first-line regimens in Ghana.

1271. HIV-1 Drug Resistance in Patients Failing Integrase Strand Transfer Inhibitor-Based Regimens in Rhode Island, USA

Abstract Background Integrase Strand Transfer Inhibitors (INSTIs) are the most common antiretroviral therapy (ART) anchor drugs. Despite reassuring clinical trial data, real-life extent and characteristics of resistance at failure of INSTI-based regimens are unclear and can inform care. Methods We investigated drug resistance upon failure of INSTI-based regimens at the largest HIV program in Rhode Island (RI), caring for &amp;gt; 80% of the state’s people with HIV. Eligible patients had full ART history, were on INSTI-based regimens, and had available protease-reverse transcriptase-integrase sequences from clinical care. Resistance interpretation was done with Stanford Database tools. Results Of 1,169 eligible patients (55% of clinic population), 102 (9%) were failing INSTI-based regimens; mean age at genotyping 39 years, CD4 377 cells/µL, and 11 years on ART; 67% male; 53% white, 44% Black, 63% non-Hispanic; 58% US born; with prior exposure to 8 drugs and 4 regimens. Of these 102, 55% were on 1st-generation INSTI (41% elvitegravir (EVG); 14% raltegravir (RAL)), and 45% on 2nd-generation INSTI (23% bictegravir (BIC); 22% dolutegravir (DTG)); most (73%) with only 2 NRTIs. Overall, 57% had any intermediate-high level predicted resistance (55% on 1st-, 45% on 2nd-generation INSTI); NRTI 37%; NNRTI 40%; PI 3%; INSTI 22% (EVG 22%, RAL 21%, DTG/BIC/cabotegravir 8% each). Common INSTI mutations were N155H (n=7); E92Q, Q148H/R, S147G (5 each); T66I/K, E138A/K/T (4 each); G140A/S (3), R263K (2), Y143R (1). Multi (≥ 3) class resistance occurred in 12%, a third of whom had intermediate-high resistance to all five INSTIs (50% on 1st-, 50% on 2nd-generation). Resistance trends were stable over 2014-2021, and 2nd-generation INSTI resistance was only seen in those with prior exposure to 1st-generation INSTI. Conclusion At the largest RI HIV clinic, 9% of eligible patients were failing INSTI-based regimens, most with clinically relevant resistance that was stable over time, and 1% had multi-class resistance including some to all available INSTIs. Though low resistance levels to 2nd-generation INSTIs are encouraging, they exist; and continued ADR monitoring is important, particularly with increasing incorporation of INSTIs in HIV treatment and prevention and use of 2-drug regimens. Disclosures All Authors: No reported disclosures.

2060. Evaluation of the real world incidence of integrase inhibitor resistance since adoption as guideline preferred therapy

Abstract Background There are limited data reporting real-world incidence of integrase inhibitor resistance (INSTI-R) since the approval and first-line treatment recommendation of INSTIs in the US. A recent analysis of the national surveillance data estimated INSTI-R to be 6.3%. The purpose of this study was to describe real-world incidence of INSTI-R in patients who used an INSTI-based single tablet regimen (STR) in a major metropolitan area and identify risk factors for resistance. Methods This was a retrospective study of adult patients living with human immunodeficiency virus (HIV) who were prescribed an INSTI-STR between September 2017 and September 2020 and followed for &amp;gt; 12 months at the University of Illinois Chicago Community Clinic Network (UCCN). The primary endpoint was the difference in INSTI-R in UCCN patients compared to the national prevalence of 6.3%. Other outcomes included development of virologic failure (VF), defined as 2 consecutive HIV-1 viral loads (VL) &amp;gt; 200 copies/mL after week 24, and documented INSTI-R mutations. Patient specific factors associated with medication nonadherence were also collected. All endpoints were analyzed using chi-square and Fisher’s exact tests. Results Of 948 patients screened, 248 patients were included. Baseline characteristics are summarized in Table 1. VF occurred in 17 subjects (6.8%). Two of the 17 (11.8%) received subsequent INSTI-R testing and nine eventually virally suppressed without regimen changes (52.9%). Patients without VF were assumed to have no INSTI-R. No subjects developed INSTI-R, which was significantly less than the national prevalence of 6.3% (p=0.0029). Patients with a high VL at baseline were more likely to experience VF (p=0.001). The most common factors associated with nonadherence in patients with VF are summarized in Table 2. Conclusion The true rate of INSTI-R in UCCN patients is still unknown and factors associated with developing INSTI-R were unable to be assessed. Among patients at UCCN on INSTI-based STRs, INSTI-R rates were lower than the national average. Future analyses should also include patients on INSTI-based non-STR regimens as increased pill burden is a known risk factor for nonadherence leading to VF and drug resistance. Disclosures All Authors: No reported disclosures.

Adipocyte differentiation of 3T3-L1 cells under tenofovir alafenamide, tenofovir disoproxil fumarate, and integrase strand transfer inhibitors selective challenge: an in-vitro model.

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral therapy (ART) medications with a good tolerability profile and a high genetic barrier to HIV drug resistance. However, several studies report significant weight gain among persons receiving INSTI-based ART regimens compared with other regimens. In-vitro model of adipogenesis. We used 3T3-L1 cells to investigate the effects of the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), alone or in combination with INSTIs: raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG), and bictegravir (BIC) on adipose differentiation. To monitor adipocyte differentiation, expression levels of PPARɣ and C/EBPα and the intracellular lipid accumulation by Red Oil staining were used. Furthermore, we evaluated the immunohistochemical expression of ER-TR7, a fibroblastic marker, after INSTIs treatment. Compared with control, INSTIs were able to increase adipogenesis, especially RAL and ELV. TAF and TDF inhibited adipogenesis alone and in combination with INSTIs. This ability was more evident when TAF was used in combination with DTG and BIC. Finally, INSTIs increased the expression of ER-TR7 compared with control and cells treated with TAF or TDF. Our data support the evidence that in-vitro challenge of 3T3-L1 cells with INSTIs is able to increase adipocytic differentiation and to drive a number of these cells toward the expression of fibroblastic features, with a different degree according to the various drugs used whereas TAF and TDF have an antagonistic role on this phenomenon.