Heterogeneities of the impact of public health policies on HIV/AIDS indicators in Brazil according to sociodemographic factors: A real-life study.

INTRODUCTION: The impact of specific policies on HIV care has been scarcely investigated. In this study we aimed to analyze the impact of the Treatment For All policy (TFA-2013) and the adoption of integrase strand transfer inhibitors (INSTIs-2017) as first-line therapy on clinical indicators of people living with HIV (PLHIV) in Brazil. METHODS: We assessed the public database of Brazil's Ministry of Health and extracted data from 2009 to 2019. We investigated the impact of TFA and INSTIs with a time-series analysis of four health indicators in PLHIV: antiretroviral treatment (ART) initiation with a CD4+ count >500/mm3 ; ART initiation <1 month after the first CD4+ measurement; viral load suppression (VLS); and treatment adherence. We explored trends over time by gender, age, macroregion of residency and municipal-level social vulnerability index. RESULTS: We included 753 316 PLHIV in 2019. Most were males (64.81%) in the 30-49 years age category (50.86%). We observed an overall improvement in all HIV clinical indicators, with notable impact of TFA on timely ART initiation and VLS, and mild impact of INSTIs on treatment adherence. Such improvements were heterogeneous, with remarkable gaps in gender, age and socioeconomic groups that have persisted over time. Indicators point to inferior outcomes among children, older adults, women and people living in socially vulnerable locations. CONCLUSIONS: Recent Brazilian public policies have had positive impacts on key HIV clinical indicators. However, our results highlight the need for specific policies to improve HIV care for children, older adults, women and socially vulnerable groups.

Clinical significance and management of low-level HIV viremia in the era of integrase strand transfer inhibitors.

BACKGROUND: People living with HIV (PLWH) and receiving antiretroviral therapy (ART) have a goal of achieving and maintaining viral suppression; however, the existence of PLWH that show events of low-level viremia (LLV) between 50 and 1000 copies/mL and with different virological consequences have been observed. Moreover, some reports indicate that LLV status can lead to residual immune activation and inflammation, leading to a higher occurrence of non-AIDS-defining events (nADEs) and other adverse clinical outcomes. Until now, however, published data have shown controversial results that hinder understanding of this phenomenon's actual cause(s) and origin(s). Integrase strand transfer inhibitors (INSTIs)-based therapies could lead to lower LLV over time and, therefore, more effective virological control. OBJECTIVES: This review aims to assess recent findings to provide a view of the clinical significance and management of low-level HIV viremia in the era of INSTIs.

Increased incidence of diabetes in people living with HIV treated with first-line integrase strand transfer inhibitors: A French multicentre retrospective study.

INTRODUCTION: Prevention of cardiovascular disease is a major issue in the current management of people living with HIV. Concern is growing about the metabolic impact of integrase strand transfer inhibitors (INSTIs), which could lead to an increased risk of diabetes, but the data are conflicting. This is an updated version of our previous analysis, with longer follow-up and new molecules. METHODS: We retrospectively evaluated the incidence of new-onset diabetes in people living with HIV starting combined antiretroviral therapy with an INSTI compared with non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Data were collected from the Dat'AIDS cohort study, a collaboration of 30 HIV treatment centres in France. We used a propensity score-based inverse probability of treatment weighting approach to adjust for baseline characteristics between the two groups (INSTI and non-INSTI). RESULTS: Between 2009 and 2021, a total of 12 150 people living with HIV were included. The incidence of diabetes was higher in the INSTI group than in the non-INSTI group (hazard ratio 1.38; 95% confidence interval 1.07-1.77; p = 0.012). Regardless of the third drug, but to a greater extent for INSTIs, we observed a peak of new-onset diabetes in the year following initiation of combined antiretroviral therapy. CONCLUSIONS: The incidence of diabetes was higher in people treated with integrase inhibitors than in those receiving other third agents. This increased risk occurred both during the first year of treatment and in the longer term.

Therapeutic drug monitoring and virological response at week 48 in a cohort of HIV-1-infected patients switching to dolutegravir/rilpivirine dual maintenance therapy (ANRS-MIE-BIRIDER study).

AIMS: Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV-1 RNA viral load (VL) during maintenance dual therapy. METHODS: We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study. RESULTS: At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow-up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P = .015). CONCLUSION: A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin.

Molecular design and evaluation of aza-polycyclic carbamoyl pyridones as HIV-1 integrase strand transfer inhibitors.

Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure-activity studies using these scaffolds resulted in several leads with promising properties.

Efficacy, safety, and tolerability of dolutegravir-based ART regimen in Durban, South Africa: a cohort study.

BACKGROUND: Dolutegravir is an integrase strand transfer inhibitor that has been recommended for use in first-line antiretroviral regimens by the World Health Organisation and is currently being rolled out globally. There has been safety concerns with dolutegravir which has caused concern about its use in the general population. Dolutegravir first-line regimens have been used in South Africa since early 2020. Therefore, the aim of the present study was to assess the efficacy, safety, and tolerability of first-line dolutegravir-based antiretrovirals amongst adults living with HIV in Durban, South Africa. METHODS: This was a mixed-methods study, which comprised a cross-sectional survey and longitudinal retrospective follow-up of medical records. The study was conducted between October 2020 and January 2022. Data were described using descriptive and summary statistics. Bivariate logistic regression was applied to socio-demographic and clinical variables and crude odds ratios with a 95% confidence interval was calculated. Pearson chi-square tests, paired sample T-tests, and cross-tabulations were performed on selected variables. RESULTS: A total of 461 participants were enrolled in the study. There was a significant change in immunological outcomes (p < 0.001) after dolutegravir initiation. Furthermore, an assessment of laboratory parameters showed that there was a significant decrease in cholesterol (p < 0.001) and increase in creatinine (p < 0.001) levels. Increased weight was shown by 60.7% of the participants but was not associated with age, gender, CD4 counts, and previous antiretroviral usage. The study found that 43.6% of the participants experienced at least one side-effect. A total of 21.6% and 23.2% of the participants experienced neuropsychiatric and central nervous system side-effects, respectively. In the bivariate analyses, only gender was shown to be associated with side-effects, and only 1.7% of the participants discontinued the study due to side-effects. CONCLUSION: Our results suggest that dolutegravir is effective, safe, and well tolerated in the study population.

Safety and adherence of bictegravir/emtricitabine/tenofovir alafenamide for HIV post-exposure prophylaxis among adults in Guiyang China: a prospective cohort study.

BACKGROUND: The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens. METHODS: In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG). RESULTS: The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events. CONCLUSIONS: BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes. TRIAL REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 ).

Incidence of low-level viremia and its impact on virologic failure among people living with HIV who started an integrase strand transfer inhibitors: a longitudinal cohort study.

BACKGROUND: Low-level viremia (LLV) has been identified as a potential precursor to virologic failure (VF), yet its clinical implications, particularly within the context of Integrase Strand Transfer Inhibitors (INSTIs)-based regimens, remain insufficiently explored. The study aimed to investigate the relationship between LLV and VF within ART-naïve patients on INSTIs-based regimens in China. METHODS: A longitudinal cohort study was conducted with ART-naïve patients aged ≥ 18 years at Beijing Ditan Hospital, under the Chinese National Free Antiretroviral Treatment Program (NFATP). The LLV was defined as a viral load (VL) ranging from 50 to 199 copies/mL after six months of ART initiation, and VF as a VL ≥ 200 copies/mL. Sensitive analyses were also performed, defining LLV as 50-999 copies/mL and VF as exceeding 1000 copies/mL. Multivariate logistic regression, Kaplan-Meier (KM) curve, and Generalized Estimating Equation (GEE) models were used to evaluate the risk factors associated with LLV and VF events. RESULTS: The study involved 830 ART-naïve patients, comprising 600 in the INSTIs group and 230 in the protease inhibitors (PIs) group. LLV events were observed in 10.4% of patients on PIs-based regimens and and 3.2% on INSTIs-based regimens (P < 0.001). INSTIs-based regimens demonstrated a protective effect against LLV events (aHR = 0.27, 95% CI 0.137-0.532). VF events occurred in 10.9% of patients on PIs-based regimens and 2.0% on INSTIs-based regimens, respectively (P < 0.001). The occurrence of LLV events significantly increased the risk of VF by 123.5% (95% CI 7.5%-364.4%), while the integrase inhibitors were associated with a 76.9% (95% CI 59.1%-86.9%) reduction in VF risk. CONCLUSION: Our findings indicate that INSTIs-based regimens are critical protective factors against LLV and subsequent VF. These results underscore the importance of HIV viral load monitoring to ensuring effective treatment outcomes, highlighting the necessity for prompt and precise monitoring to refine HIV treatment methodologies.

Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 µM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

Effect of the L74I Polymorphism on Fitness of Cabotegravir-Resistant Variants of Human Immunodeficiency Virus 1 Subtype A6.

The presence of human immunodeficiency virus (HIV) 1 subtype A6, characterized by the L74I integrase (IN) polymorphism, is associated with confirmed virologic failure in clinical trials of long-acting cabotegravir and rilpivirine. We investigated the effect of L74I on replication capacity (RC) of recombinant viruses carrying this polymorphism in combination with various IN stand-transfer inhibitor resistance mutations. The presence of L74I conferred greater RC to recombinant viruses expressing HIV-1 A6 IN when present together with G118R, G140R, Q148H, and R263K; no significant difference in RC was observed for the Q148K or R mutants. These findings may explain, in part, the association of HIV-1 subtype A6 with virologic failure.

Changes in Body Mass Index with Longer-term Integrase Inhibitor Use: A Longitudinal Analysis of Data from the Randomized Trial to Prevent Vascular Events in Human Immunodeficiency Virus (REPRIEVE).

Over 2-years of follow-up, integrase strand transfer inhibitor (INSTI)-use was associated with weight gain among those on an INSTI <2 years at entry (+0.27 kg/m2/year; 95% confidence interval [CI], .22 to .33 vs +0.17 kg/m2/year; 95% CI, .12 to .23; P = .01), but not those on an entry INSTI >2 years.

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.

Integrated analysis of viral blips, residual viremia, and associated factors in people with HIV: Results from a retrospective cohort study.

The etiology of viral blips is not yet fully elucidated. One of the hypotheses is that blips reflect variations in residual viremia (RV) near the detectability threshold. In this study, we evaluated whether RV is associated with viral blips and which factors are associated with RV. All treatment regimens in 2010-2020 consisting of two nucleos(-t)ide reverse transcriptase inhibitors and one anchor (integrase strand transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor [NNRTI], or protease inhibitor [PI]) in people with HIV (PWH) were evaluated for RV (detectable viremia <50 cp/mL) and blips (isolated viral loads [VLs] 50-499 cp/mL between measurements <50 cp/mL). All medical records were reviewed and regimens in which a VL ≥ 50 cp/mL was deemed to result from non-adherence (based on the documented conclusion by the treating physician) were excluded. Factors associated with blips and RV were identified using generalized linear mixed models. In total, 24 518 VLs from 1658 PWH were analyzed. VLs were measured during INSTI- (n = 5119; 20.9%), PI- (n = 8935; 36.4%), and NNRTI-use (n = 10 464; 42.7%). VLs were categorized as blips in 1.4% (n = 332). The 24,186 non-blip VLs were RNAneg (no RV) (n = 15 326; 63.4%), 1-19 cp/mL (n = 6318; 26.1%), 20-49 cp/mL (n = 1620; 6.7%), or <50 cp/mL with an unknown RV level (n = 922; 3.8%). In 193/1658 PWH (11.6%), the RV level was RNAneg in all VLs assessed. RV 1-19 cp/mL and 20-49 cp/mL (vs. RNAneg ) were significantly associated with subsequent viral blips (respective odds ratio 2.66 and 4.90 [95% confidence intervals: 1.98-3.58 and 3.41-7.04]). Zenith VL and use of PIs (vs. INSTIs/NNRTIs) were associated with higher RV and blip odds. This large cohort study showed that blips were associated with higher preceding RV. Both the anchor type and factors previously linked to the latent viral reservoir were associated with RV, suggesting blips having a multifactorial origin.

Identification of integrase inhibitor-related drug resistance mutations in newly diagnosed ART-naïve HIV patients.

BACKGROUND: In China, the recommended treatment regimens for HIV-infected individuals were tenofovir in combination with lamivudine or emtricitabine as NRTIs, efavirenz or rilpivirine as NNRTIs, lopinavir/ritonavir as protease inhibitors, and raltegravir or dolutegravir as INSTIs. The development of drug resistance increases the risk of viral rebound, opportunistic infections, and ultimately treatment failure such that the early detection of resistance is ideal. This study was developed to explore primary drug resistance characteristics and genotypic distributions in newly diagnosed antiretroviral therapy (ART)-naïve HIV-1 patients in Nanjing with the goal of establishing a basis for their individualized treatment in the clinic. METHODS: Samples of serum were collected from newly diagnosed ART-naïve HIV patients from the Second Hospital of Nanjing between May 2021 and May 2022. The HIV-1 integrase (IN), protease (PR), and reverse transcriptase (RT) gene coding sequences were amplified from these samples, sequenced, and assessed for drug resistance-related mutations. RESULTS: Major integrase resistance-related mutations were detected in 4/360 amplified samples, with 5 other patient samples exhibiting accessory resistance mutations. The overall prevalence of PR and RT inhibitor-related transmitted drug resistance mutations (TDRMs) in this patient population was 16.99% (61/359). The most common mutations were non-nucleoside reverse transcriptase inhibitor-related mutations (51/359; 14.21%), followed by those associated with nucleoside reverse transcriptase inhibitors (7/359; 1.95%) and protease inhibitors (7/359; 1.95%). Dual-resistant strains were also observed in a subset of patients. CONCLUSIONS: In summary, this study is the first to have surveyed the prevalence of integrase inhibitor resistance-related mutations and other drug resistance-related mutations among newly diagnosed ART-naïve HIV-positive patients in Nanjing, China. These results highlight the need for further molecular surveillance-based monitoring of the HIV epidemic in Nanjing.

A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants.

AIDS (Acquired immunodeficiency syndrome) is one of the chronic and potentially life-threatening epidemics across the world. Hitherto, the non-existence of definitive drugs that could completely cure the Human immunodeficiency virus (HIV) implies an urgent necessity for the discovery of novel anti-HIV agents. Since integration is the most crucial stage in retroviral replication, hindering it can inhibit overall viral transmission. The 5 FDA-approved integrase inhibitors were computationally investigated, especially owing to the rising multiple mutations against their susceptibility. This comparative study will open new possibilities to guide the rational design of novel lead compounds for antiretroviral therapies (ARTs), more specifically the structure-based design of novel Integrase strand transfer inhibitors (INSTIs) that may possess a better resistance profile than present drugs. Further, we have discussed potent anti-HIV natural compounds and their interactions as an alternative approach, recommending the urgent need to tap into the rich vein of indigenous knowledge for reverse pharmacology. Moreover, herein, we discuss existing evidence that might change in the near future.

The impact of integrase inhibitors on steatosis and fibrosis biomarkers in persons with HIV naïve to antiretroviral therapy.

BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD) has a high prevalence among persons with HIV infection. Since Integrase Strand Transfer Inhibitors (INSTIs) are used worldwide and have been associated with weight gain, we must determine their effect in the development of NAFLD and Non-alcoholic Steatohepatitis (NASH) in these patients. The aim of this study was to explore the impact of INSTIs on variation of liver steatosis and fibrosis in the ART-naïve person with HIV, using Hepatic Steatosis Index (HSI), Fibrosis-4 Index (FIB-4), BARD score and NAFLD Fibrosis Score (NFS). METHODS: We performed a monocentric, retrospective cohort study in ART-naïve persons with HIV that initiated INSTI based regimens between December 2019 and January 2022. Data was collected at baseline, 6 and 12 months after initiation. Demographic, clinical and laboratory characteristics, hepatic steatosis, and fibrosis scores were compared between baseline and last visit at 12 months. Linear regression models were performed to analyse the associations between analytical data at baseline and hepatic scores variation during the 12 months of treatment. Models were performed unadjusted and adjusted for age and sex. RESULTS: 99 patients were included in our study. 82% were male and median age was 36 years. We observed a significant increase in body mass index (BMI), HDL, platelet count, albumin, and creatinine and a significant decrease in AST levels. HSI showed no statistically significant differences during follow-up (p = 0.114). We observed a significant decrease in FIB-4 (p = 0.007) and NFS (p = 0.002). BARD score showed a significant increase (p = 0.006). The linear regression model demonstrated a significant negative association between baseline HIV RNA and FIB-4 change (ß= -0.08, 95% CI [-0.16 to -0.00], p = 0.045), suggesting that higher HIV RNA loads at baseline were associated with a greater decrease in FIB-4. CONCLUSION: INSTIs seem to have no impact on hepatic steatosis, even though they were associated with a significant increase in BMI. This might be explained by the direct effect of a dolutegravir-containing regimen and/or by the "return-to-health effect" observed with ART initiation. Furthermore, INSTIs were associated with a reduction in risk of liver fibrosis in ART-naïve persons with HIV, possibly due to their effect on viral suppression.

Integrase Strand Transfer Inhibitors Are Associated With Incident Diabetes Mellitus in People With Human Immunodeficiency Virus.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH). Less is known about the risk of other metabolic outcomes such as diabetes mellitus and hyperglycemia. METHODS: IBM® MarketScan® databases for commercially and Medicaid-insured adults were used to identify PWH newly initiating antiretroviral therapy (ART). The primary outcome was a composite of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation and was identified using International Classification of Disease, Ninth revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis and procedure codes and Current Procedural Terminology, 4th Edition (CPT-4) codes. To examine the relationship between INSTI use and the composite outcome, we estimated the risk using Cox proportional hazards models with calendar time-specific standardized mortality ratio weights. RESULTS: Of 42 382 PWH who initiated ART between 1 July 2007 and 30 June 2018, 22 762 (54%) were treated with INSTI-based regimens. Mean age was 38 years, 74% were male, and 19% were Medicaid insured. PWH on INSTIs were 31% more likely to develop new-onset diabetes mellitus/hyperglycemia (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.48]) compared with those who initiated non-INSTI-based regimens. When examined individually, the highest risk was associated with elvitegravir (HR, 1.54; 95% CI, 1.32-1.97; P < .001) and the lowest risk with raltegravir (HR, 1.19; 95% CI, 1.03-1.37; P = .02). CONCLUSIONS: INSTI use was associated with increased risk of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation.

Effectiveness of integrase strand transfer inhibitors in HIV-infected treatment-experienced individuals across Europe.

OBJECTIVES: To explore the effectiveness and durability of integrase strand transfer inhibitor (INSTI)-based regimens in pre-treated subjects. METHODS: Treatment-experienced individuals starting an INSTI-based regimen during 2012-2019 were selected from the INTEGRATE collaborative study. The time to virological failure [VF: one measurement of viral load (VL) ≥ 1000 copies/mL or two ≥ 50 copies/ml or one VL measurement ≥ 50 copies/mL followed by treatment change] and to INSTI discontinuation were evaluated. RESULTS: Of 13 560 treatments analysed, 4284 were from INSTI-naïve, non-viraemic (IN-NV) individuals, 1465 were from INSTI-naïve, viraemic (IN-V) individuals, 6016 were from INSTI-experienced, non-viraemic (IE-NV) individuals and 1795 were from INSTI-experienced, viraemic (IE-V) individuals. Major INSTI drug resistance mutations (DRMs) were previously detected in 4/519 (0.8%) IN-NV, 3/394 (0.8%) IN-V, 7/1510 (0.5%) IE-NV and 25/935 (2.7%) IE-V individuals. The 1-year estimated probabilities of VF were 3.1% [95% confidence interval (CI): 2.5-3.8] in IN-NV, 18.4% (95% CI: 15.8-21.2) in IN-V, 4.2% (95% CI: 3.6-4.9) in IE-NV and 23.9% (95% CI: 20.9-26.9) in IE-V subjects. The 1-year estimated probabilities of INSTI discontinuation were 12.1% (95% CI: 11.1-13.0) in IN-NV, 19.6% (95% CI: 17.5-21.6) in IN-V, 10.8% (95% CI: 10.0-11.6) in IE-NV and 21.7% (95% CI: 19.7-23.5) in IE-V subjects. CONCLUSIONS: Both VF and INSTI discontinuation occur at substantial rates in viraemic subjects. Detection of DRMs in a proportion of INSTI-experienced individuals makes INSTI resistance testing mandatory after failure.

Long-Acting Injectable Cabotegravir for HIV Prevention: What Do We Know and Need to Know about the Risks and Consequences of Cabotegravir Resistance?

PURPOSE OF REVIEW: Cabotegravir is a potent integrase strand transfer inhibitor (INSTI) recently approved as a long-acting injectable formulation for HIV prevention (CAB-LA). We summarize what is known about cabotegravir pharmacokinetics, activity, and emergence of resistance from in vitro, macaque and clinical studies, and we evaluate the risk of resistance from CAB-LA with on-time injections and after CAB-LA discontinuation. RECENT FINDINGS: The accumulation of multiple INSTI mutations is required for high-level cabotegravir resistance, and the same mutation combinations may cause cross-resistance to dolutegravir, which is widely used for first-line antiretroviral therapy in low- and middle-income countries. Though CAB-LA was highly effective in preventing HIV, breakthrough infections did occur in trials of CAB-LA despite on-time injections, resulting in selection of single and combinations of INSTI resistance mutations. As CAB-LA is scaled-up, prompt HIV diagnosis to prevent resistance, and resistance monitoring could help preserve the effectiveness of INSTIs for both HIV treatment and prevention.

Weight Changes With Integrase Strand Transfer Inhibitor Therapy in the Management of HIV Infection: A Systematic Review.

OBJECTIVE: To describe weight changes with integrase strand transfer inhibitor (INSTI) therapy. DATA SOURCES: A literature search was performed (through December 15, 2021) using the PubMed and CINAHL databases using the search terms: "integrase inhibitors," "integrase strand transfer inhibitors," and "weight." STUDY SELECTION AND DATA EXTRACTION: Studies were included that provided relevant information on weight or body mass index (BMI) changes on INSTI therapy. Controlled or observational studies comparing different INSTI therapies or compared INSTI therapy to another class of antiretroviral therapy were included. DATA SYNTHESIS: Forty-three articles met criteria for inclusion, and data are presented. Although some trials have observed similar weight gains between INSTI, protease inhibitor, and non-nucleoside inhibitor therapies, the increase appears to be greater with INSTI therapy, particularly during initiation of therapy. Risk factors for weight gain with INSTI therapy include female gender, lower CD4 count, and combined use of tenofovir alafenamide. Within the INSTI class, dolutegravir and bictegravir appear to have the greatest propensity for weight gain. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: INSTI-based therapies are the preferred initial management of HIV infection. Discerning the factors contributing to weight changes on INSTI therapy and risks of associated health-related outcomes is important to both the management of weight gain and HIV medical management. CONCLUSIONS: Within the INSTI class, dolutegravir and bictegravir may be associated with the greatest risk for weight gain particularly when combined with tenofovir alafenamide. Further research is needed to determine mechanisms for observed weight changes and any contributions to clinically significant metabolic and cardiovascular adverse outcomes associated with INSTI therapy.