raltegravir-potassium and bictegravir

Integrase strand transfer inhibitors (INSTIs), including raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB), are increasingly used, given excellent data on their efficacy, effectiveness, and tolerability profile in adults, while data in children are accumulating. To review the most recent evidence on the efficacy, effectiveness, safety, and resistance of INSTIs in children, a quick narrative review of the available literature data was performed using the MEDLINE/PubMed and Scopus databases, including only English-language studies, published between 2009 and 2022. Six studies (259 children) on RAL use, 17 studies (3,448 children) on DTG, 2 studies (73 children) on EVG, and 1 study (102 children) on BIC were retrieved. Results on efficacy and effectiveness were close to those reported in adult studies, suggesting similarities between children and adult population. Resistance to RAL was detected in four studies, ranging between 5.0% to 35.3% of participants. In four studies resistance to DTG occurred in 12.4% to 22% of children. Adverse events to RAL have been uncommon reported. In studies on EVG, 8% to 74% of children developed uveitis, nausea, or abdominal pain. In DTG studies, the proportion of weight gain ranged from 10% to 87%, and neuropsychiatric effects ranged 1% to 16% of participants. One BIC study reported adverse events >10% of participants. The evidence supports high efficacy and low toxicity of INSTIs in pediatric and adolescent populations.

Topics: Adolescent; Adult; Child; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Integrases; Oxazines; Raltegravir Potassium

Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.

Topics: Adult; Child; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Raltegravir Potassium

Antiretroviral therapy has been imperative in controlling the human immunodeficiency virus (HIV) epidemic. Most low- and middle-income countries have used nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors extensively in the treatment of HIV. However, integrase strand transfer inhibitors (INSTIs) are becoming more common. Since their identification as a promising therapeutic drug, significant progress has been made that has led to the approval of five INSTIs by the US Food and Drug Administration (FDA), i.e. dolutegravir (DTG), raltegravir (RAL), elvitegravir (EVG), bictegravir (BIC) and cabotegravir (CAB). INSTIs have been shown to effectively halt HIV-1 replication and are commended for having a higher genetic barrier to resistance compared with NRTIs and NNRTIs. More interestingly, DTG has shown a higher genetic barrier to resistance compared with RAL and EVG, and CAB is being used as the first long-acting agent in HIV-1 treatment. Considering the increasing interest in INSTIs for HIV-1 treatment, we focus our review on the retroviral integrase, development of INSTIs and their mode of action. We also discuss each of the INSTI drugs, including potential drug resistance and known side effects.

Topics: Amides; Anti-Retroviral Agents; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

Integrase strand transfer inhibitors (INSTIs) are the most recent class of antiretroviral drugs with potent and durable antiviral activity used to treat human immunodeficiency virus type 1 (HIV-1) infection. However, development of drug resistance increases the risk of treatment failure, disease progression and mortality. A better understanding of drug efficacy and resistance against INSTIs is crucial for their efficient use and the development of new antiretrovirals. A meta-analysis of studies reporting efficacy and resistance data on INSTI use in HIV-infected patients was performed. Odds ratios (ORs) of efficacy outcome data favouring INSTI use in different clinical settings demonstrated that INSTIs have higher efficacy compared with drugs of other classes. For combination antiretroviral therapy-naïve patients and virologically-suppressed patients who switched to INSTI-based therapy, the OR was 1.484 (95% CI 1.229-1.790) and 1.341 (95% CI 0.913-1.971), respectively. ORs of resistance data indicated decreased treatment-emergent resistance development to dolutegravir (DTG) upon virological failure than to non-INSTIs (OR = 0.081, 95% CI 0.004-1.849), whereas the opposite was observed for raltegravir (RAL) (OR = 3.137, 95% CI 1.827-5.385) and elvitegravir (EVG) (OR = 1.886, 95% CI 0.569-6.252). Pooled analysis of resistance data indicated that development of resistance to DTG and bictegravir was rare, whereas EVG and RAL had low genetic barriers to resistance and the intensive cross-resistance between them limits INSTI efficiency. Efficient means of monitoring the emergence of resistance to INSTIs and the development of drugs with high genetic barriers are clear paths for future research.

Topics: Amides; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Microbial Sensitivity Tests; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Virus Replication

Prevention of mother-to-child transmission of HIV and optimal maternal treatment are the most important goals of antiretroviral therapy in pregnant women with HIV. These goals may be at risk due to possible reduced exposure during pregnancy caused by physiological changes. Limited information is available on the impact of these physiological changes. This is especially true for HIV-integrase inhibitors, a relatively new class of drugs, recommended first-line agents and hence used by a large proportion of HIV-infected patients. Therefore, the objective of this review is to provide a detailed overview of the pharmacokinetics of HIV-integrase inhibitors in pregnancy. Second, this review defines potential causes for the change in pharmacokinetics of HIV-integrase inhibitors during pregnancy. Despite increased clearance, for raltegravir 400 mg twice daily and dolutegravir 50 mg once daily, exposure during pregnancy seems adequate; however, for elvitegravir, the proposed minimal effective concentration is not reached during pregnancy. Lower exposure to these drugs may be caused by increased hormone levels and, subsequently, enhanced drug metabolism during pregnancy. The pharmacokinetics of bictegravir and cabotegravir, which are under development, have not yet been evaluated in pregnant women. New studies need to prospectively assess whether adequate exposure is reached in pregnant women using these new HIV-integrase inhibitors. To further optimize antiretroviral treatment in pregnant women, studies need to unravel the underlying mechanisms behind the changes in the pharmacokinetics of HIV-integrase inhibitors during pregnancy. More knowledge on altered pharmacokinetics during pregnancy and the underlying mechanisms contribute to the development of effective and safe antiretroviral therapy for HIV-infected pregnant women.

Topics: Amides; Anti-Retroviral Agents; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Infectious Disease Transmission, Vertical; Knowledge; Oxazines; Piperazines; Pregnancy; Pyridones; Quinolones; Raltegravir Potassium

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.

Topics: 3T3-L1 Cells; Adenine; Adipocytes; Animals; Anti-HIV Agents; Cell Differentiation; HIV Infections; Humans; Integrases; Mice; Raltegravir Potassium; Tenofovir

In recent years, integrase strand transfer inhibitor (INSTI)-containing regimens have been increasingly adopted in treatment for HIV/AIDS and promoted as non-occupational post-exposure prophylaxis in China. This study aims to describe the prevalence of resistance to integrase and drug resistance mutations (DRMs) among ART-naive patients in Shenzhen, China.. Serum samples and demographic information were collected from newly reported ART-naive patients in Shenzhen in 2020. The study sequenced the coding sequence of the HIV-1 integrase gene and determined the DRMs.​.. In this study, 1682 newly reported cases were included and 1071 of them were successfully sequenced finally. The prevalence of primary drug resistance was 1.77%, with 19 samples showing varying degrees of resistance to INSTIs. The study detected six major DRMs in 16 individuals and eight accessory DRMs in 24 individuals. The prevalence of transmitted drug resistance (TDR) mutations was 1.21%, with five transmitted mutations detected in 13 individuals. The prevalence of drug resistance to raltegravir and elvitegravir was statistically higher than to bictegravir, cabotegravir and dolutegravir.. The prevalence of INSTI resistance in Shenzhen in 2020 was relatively high. ​Continued surveillance for resistance to INSTIs is recommended and treatment regimens should be adopted based on the pattern of resistance to INSTIs. ​Dolutegravir or bictegravir is first recommended when considering INSTIs as treatment regimens.

Topics: Anti-HIV Agents; China; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Humans; Integrases; Mutation; Prevalence; Pyridones; Raltegravir Potassium

Cohort studies suggest higher discontinuation rates with integrase strand transfer inhibitors (INSTIs) than are seen in clinical trials. We assessed discontinuations and adverse events (AEs) that were considered related to the initial INSTI in the first year following initiation among treatment-naïve people living with HIV (PLWH).. Newly diagnosed PLWH initiating raltegravir, elvitegravir/cobicistat, dolutegravir or bictegravir in combination with emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate between 10/2007 and 1/2020 at the Orlando Immunology Center were included. Unadjusted incidence rates (IRs) and incidence rate ratios (IRRs) were calculated for treatment-related discontinuations and AEs associated with the initial INSTI in the first year following initiation.. Of 331 enrolled, 26 (8%) initiated raltegravir, 151 (46%) initiated elvitegravir/cobicistat, 74 (22%) initiated dolutegravir and 80 (24%) initiated bictegravir. Within the first year, treatment-related discontinuations occurred in 3 on elvitegravir/cobicistat (IR 0.02 per person-years (PPY)) and 5 on dolutegravir (IR 0.08 PPY); no treatment-related discontinuations occurred among those initiating raltegravir or bictegravir. Eleven treatment-related AEs occurred in 7 on raltegravir (IR 0.46 PPY), 100 treatment-related AEs occurred in 63 on elvitegravir/cobicistat (IR 0.72 PPY), 66 treatment-related AEs occurred in 37 on dolutegravir (IR 0.97 PPY) and 65 treatment-related AEs occurred in 34 on bictegravir (IR 0.88 PPY). Unadjusted IRRs did not reveal any significant difference between INSTIs in terms of early treatment-related discontinuations or AEs.. In our cohort, treatment-related AEs occurred in 43% initiating INSTIs but were responsible for early discontinuation in only 2% with no treatment-related discontinuations observed among those initiating RAL or BIC.

Topics: Anti-HIV Agents; Cobicistat; Emtricitabine; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Integrase Inhibitors; Pyridones; Raltegravir Potassium

Topics: Amides; Chromatography, Liquid; Heterocyclic Compounds, 3-Ring; HIV Integrase Inhibitors; Humans; Piperazines; Pyridones; Raltegravir Potassium; Reproducibility of Results; Reverse Transcriptase Inhibitors; Tandem Mass Spectrometry; Triazoles

To assess the potential direct effects of the integrase strand-transfer inhibitors (INsTIs) dolutegravir, bictegravir, and raltegravir, drugs used as treatment for people living with human immunodeficiency virus (PLWH), on human adipose cells.. Drugs were added to the differentiation medium of human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells and morphological adipogenesis was monitored for 10 days. Also, adipocytes were exposed to drugs following differentiation (day 14). The gene expression levels of selected adipogenesis markers, adipocyte metabolism markers, adipokines, and cytokines were determined by quantitative-reverse transcription polymerase-chain reaction. The release of adiponectin and leptin into the culture medium was measured using specific enzyme-linked immunosorbent assay, and release of interleukin-6 and chemokine (CC motif) ligand-2 using Multiplex assays.. Overall morphological adipogenesis was unaltered by INsTIs. The expression of adipogenesis marker genes (peroxisome proliferator-activated receptor-Ɣ and lipoprotein lipase) was slightly reduced in dolutegravir-treated differentiating adipocytes. Bictegravir repressed gene expression and the release of pro-inflammatory cytokines in differentiating adipocytes. Dolutegravir and raltegravir increased interleukin-6 gene expression, but only dolutegravir increased interleukin-6 release. Dolutegravir repressed adiponectin expression and release in differentiating adipocytes and had a similar but milder effect on leptin. Drug treatment of mature adipocytes reduced adiponectin gene expression in response to dolutegravir.. The INsTIs studied do not have a significant effect on human adipose cell differentiation but exert distinct effects on gene expression and secretion of adipokines and cytokines. These findings will help understand and manage the effects of INsTI-containing treatments on body weight and metabolic dysregulation in PLWH.

Topics: Adipocytes; Adipokines; Adiponectin; Amides; Cytokines; Heterocyclic Compounds, 3-Ring; Humans; Inflammation; Integrases; Interleukin-6; Leptin; Ligands; Lipoprotein Lipase; Oxazines; Peroxisome Proliferator-Activated Receptors; Piperazines; Pyridones; Raltegravir Potassium

Each year, approximately 1.1 million children are exposed in utero to human immunodeficiency virus antiretrovirals, yet their safety is often not well characterized during pregnancy. The Tsepamo study reported a neural tube defect signal in infants exposed to the integrase strand transfer inhibitor (InSTI) dolutegravir from conception, suggesting that exposure during early fetal development may be detrimental.. The effects of InSTIs on 2 human embryonic stem cell (hESC) lines were characterized with respect to markers of pluripotency, early differentiation, and cellular health. In addition, fetal resorptions after exposure to InSTIs from conception were analyzed in pregnant mice.. At subtherapeutic concentrations, second-generation InSTIs bictegravir, cabotegravir, and dolutegravir decreased hESC counts and pluripotency and induced dysregulation of genes involved in early differentiation. At therapeutic concentrations, bictegravir induced substantial hESC death and fetal resorptions. It is notable that first-generation InSTI raltegravir did not induce any hESC toxicity or differentiation, at any concentration tested.. Exposure to some InSTIs, even at subtherapeutic concentrations, can induce adverse effects in hESCs and pregnant mice. Given the increasingly prevalent use of second-generation InSTIs, including in women of reproductive age, it is imperative to further elucidate the effect of InSTIs on embryonic development, as well as their long-term safety after in utero exposure.

Topics: Animals; Drug Resistance, Viral; Female; Fetal Resorption; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; Human Embryonic Stem Cells; Humans; Infant, Newborn; Maternal Exposure; Mice; Pregnancy; Pyridones; Raltegravir Potassium

Previous clinical data have shown that raltegravir-based antiretroviral therapy (ART) with fewer drug-drug interactions (DDIs) and adverse events (AEs) is a good regimen in patients with HIV infection who need cancer chemotherapy. There are currently few data on ART regimens that include Integrase inhibitors (INSTIs) other than RAL among this patient subgroup.. We evaluated the safety and efficacy of different kinds of INSTI-based regimens among patients with HIV and concomitant colorectal cancer (CRC) who received antineoplastic agents.. From January 2020 to November 2021, 66 patients were enrolled. The patients were divided into three groups: 20 patients treated with dolutegravir (DTG)/lamivudine (3TC)/tenofovir (TDF) (group I), 24 patients treated with DTG/albuvirtide (ABT) (group II), and 22 patients treated with bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (group III). The majority of AEs during treatment were of grade 1-2. Treatment-related AEs of grade 3-4 occurred in 6 patients (9.09%), and no grade 5 AEs occurred. The most common AEs were nausea (100%) and neutrophils (84.85%) attributed to anticancer agents, and there was no significant difference in the incidence of these AEs among the three groups (P > 0.05). Viral load rebound was not observed among pretreated patients during chemotherapy. The viral load of untreated patients who started their ART concomitant with chemotherapy almost decreased to the lower limit of detection 6 months after ART initiation (only one patient in group III had a viral load of 102 copies/ml). At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05). However, the change in CD4 count was not significant in group II (P = 0.457) or group III (P = 0.748).. DTG- or BIC-containing regimens are good options for patients with HIV and concomitant CRC.

Topics: Amides; Anti-HIV Agents; Colorectal Neoplasms; Emtricitabine; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Integrase Inhibitors; Lamivudine; Piperazines; Pyridones; Raltegravir Potassium; Tenofovir

In 2018, Switzerland changed its guidelines to support women living with HIV wishing to breastfeed. The exposure of antiretroviral drugs (ARVs) in breastmilk and the ingested daily dose by the breastfed infant are understudied, notably for newer ARVs. This study aimed to quantify ARV concentrations in maternal plasma and breastmilk to determine the milk/plasma ratio, to estimate daily infant ARV dose from breastfeeding and to measure ARV concentrations in infants.. All women wishing to breastfeed were included, regardless of their ARV treatment. Breastmilk and maternal plasma samples were mostly collected at mid-dosing interval.. Twenty-one mother/child pairs were enrolled; of those several were on newer ARVs including 10 raltegravir, 1 bictegravir, 2 rilpivirine, 2 darunavir/ritonavir and 3 tenofovir alafenamide. No vertical HIV transmission was detected (one infant still breastfed). The median milk/plasma ratios were 0.96/0.39 for raltegravir once/twice daily, 0.01 for bictegravir, 1.08 for rilpivirine, 0.12 for darunavir/ritonavir and 4.09 for tenofovir alafenamide. The median estimated infant daily dose (mg/kg) from breastfeeding was 0.02/0.25 for raltegravir once/twice daily, 0.01 for bictegravir, 0.02 for rilpivirine, 0.05 for darunavir/ritonavir and 0.007 for tenofovir alafenamide, resulting in relative infant dose <10% exposure index for all ARVs.. ARVs were transferred to a variable extent in breastmilk. Nevertheless, the estimated daily ARV dose from breastfeeding remained low. Differential ARV exposure was observed in breastfed infants with some ARVs being below/above their effective concentrations raising the concern of resistance development if HIV infection occurs. More data on this potential risk are warranted to better support breastfeeding.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Cohort Studies; Darunavir; Female; HIV Infections; Humans; Infant; Milk, Human; Mothers; Prospective Studies; Raltegravir Potassium; Rilpivirine; Ritonavir; Switzerland

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.

Topics: Anti-HIV Agents; beta-Lactams; Drug Resistance, Viral; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; HIV-1; HIV-2; Humans; Raltegravir Potassium

To investigate the durability of the first integrase inhibitor-based regimen in a HIV geriatric multicentric prospective cohort and to explore the reasons of regimen discontinuation.. This is an analysis conducted on the Geriatric Patients Living with HIV/AIDS (GEPPO) cohort, an Italian prospective observational multicentre cohort of people living with HIV with 65 years of age or more.. The analysis was performed using R (version 4.0.2). The tests performed were two sided assuming a 5% significance level (Kruskal-Wallis test, Chi-squared test, log-rank test and a Cox Proportional Hazard model). The proportion of participants discontinuing the three regimens was displayed using cumulative curves.. Among 1531 patients enrolled between 2017 and 2019 in the GEPPO cohort, we included 822 participants in this analysis. At baseline, median age was 69.8, the immunovirological profile good, multimorbidity was present in 42.3% of participants, while 27.4% were on polypharmacy. Overall, 483, 243 and 96 participants received DTG, RAL and EVG/c respectively as first InSTI. At the end of the follow up 6.4%, 21.1% and 22.9% participants discontinued DTG, RAL and EVG/c respectively. Using a log-rank test, EVG showed a significantly lower durability than DTG (p<0.001) or RAL (p 0.05) or both, DTG and RAL (p<0.001). Among participants who discontinued their regimen we found 0 virological failure and 56.7% simplification/deprescription.. The three integrase inhibitors considered showed a good durability and no virological failures in geriatric patients such as those enrolled in the GEPPO cohort when used in a two or three drug regimen.

Topics: Aged; Amides; Anti-Retroviral Agents; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Longitudinal Studies; Male; Medication Adherence; Oxazines; Piperazines; Polypharmacy; Proportional Hazards Models; Prospective Studies; Pyridones; Quinolones; Raltegravir Potassium; Treatment Outcome

The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs.. HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells.. HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug.. Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.

Topics: Amides; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Piperazines; Pyridones; Raltegravir Potassium

The aim of this study was to characterize the genotypic and phenotypic resistance profile to the integrase strand transfer inhibitor (INSTI) bictegravir (BIC) and other INSTIs in patients who previously failed twice-daily raltegravir (RAL)-based or twice-daily dolutegravir (DTG)-based regimens. Twenty-two samples were collected after failure on an INSTI-based regimen in 17 highly treatment-experienced patients with HIV-1 with multi-drug-resistant virus, recorded in the Italian PRESTIGIO registry. Genotypic resistance mutations and phenotypic susceptibility to INSTIs were detected by GeneSeqIN and PhenoSenseIN assays, respectively (Monogram Biosciences, San Francisco, CA, USA). The primary INSTI resistance substitutions E138A/K, G140S, Y143C/H/R, Q148H and N155H were detected in 14 of 22 samples and were associated with resistance to one or more INSTIs, with G140S+Q148H present in 11 of 22 samples. Of these 14 samples, all showed high levels of resistance to elvitegravir (EVG) and RAL. Two isolates contained L74M, E138K, G140S and Q148H, or L74M, T97A, S119T, E138K, G140S, Y143R and Q148H, and had high-level resistance to all INSTIs, including BIC and DTG. Intermediate resistance was reported for eight of 14 isolates for BIC and nine of 14 isolates for DTG. Overall, for the 14 INSTI-resistant isolates, the median fold-change values in phenotypic susceptibility were: BIC 3.2 [interquartile range (IQR) 0.6-66], DTG 6.3 (IQR 0.8->186), EVG >164 (IQR 2.6->164) and RAL >188 (IQR 2.7->197). In conclusion, the study findings supported the in-vitro activity of BIC and DTG against most isolates derived from highly treatment-experienced patients who failed INSTI regimens.

Topics: Amides; Drug Resistance, Multiple, Viral; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Treatment Outcome

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.

Topics: Amides; Binding Sites; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Linear Models; Models, Molecular; Molecular Docking Simulation; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Sequence Alignment

Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC, and CAB demonstrated a comparable activity on a panel of INSTI-resistant strains isolated from patients exposed to RAL, EVG, and/or DTG, with a significantly reduced susceptibility only with the pathway Q148H/K/R plus one to two additional INSTI mutations.

Topics: Amides; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

Topics: Amides; Anti-HIV Agents; Cell Line; Drug Resistance, Viral; Drug Synergism; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Oxazines; Piperazines; Pyridones; Raltegravir Potassium