Integrase Strand Transfer Inhibitors Class Research Articles

Transmitted Antiretroviral Drug Resistance to Integrase Strand Transfer Inhibitors Class in São Paulo Metropolitan Area, Brazil.

A newer integrase strand transfer inhibitor (INSTI) cabotegravir was recently approved for both therapy and prophylaxis and can play an essential role in the fight against AIDS. It shares similar resistance profile to dolutegravir, the cornerstone of Brazilian antiretroviral (ARV) treatment, with about 600 thousand people living with HIV in Brazil currently on regimens that contain this INSTI. Health services in the São Paulo metropolitan area are responsible for a large proportion of ARV dispensation in the country. Estimating transmitted drug resistance mutation (TDRM) in the area before cabotegravir introduction may provide a useful baseline information. Partial HIV-1 pol gene was sequenced (Sanger) from 192 newly diagnosed individuals from São Paulo and nearby cities (2020 to March 2023) at integrase, with 85 also at protease/reverse transcriptase regions. Retrotranscribed plasma RNA, amplified with nested PCR, was edited (Recall or Sequencher) and analyzed at Rega and Stanford db. Surveillance drug resistance mutations (SDRM) to INSTI class was detected in three cases (1.6%; 95% CI: 0.5%-5%), two E138K and one R263K, with 7.8% (95% CI: 5%-13%) with resistance mutations (major or accessory). SDRM for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and PI classes were identified in 7 (8.2% CI: 95% 4%-16%) cases. Subtype B predominated (69%), followed by subtype C (16%), now the second most prevalent infection in this area. Among 131 patients treated for over 6 months, 92% were virally suppressed below 200 copies/mL, with low TCD4 counts independently associated to failure. SDRM to INSTI class is rare in the area. Intermediate rates of transmitted resistance to other ARV classes are comparable to previous estimates. Viral suppression rates may depend on TCD4 counts, another negative impact of late diagnosis in care that deserves more attention.

HIV-1 diversity and pre-treatment drug resistance in the era of integrase inhibitor among newly diagnosed ART-naïve adult patients in Luanda, Angola

The surveillance of drug resistance in the HIV-1 naïve population remains critical to optimizing the effectiveness of antiretroviral therapy (ART), mainly in the era of integrase strand transfer inhibitor (INSTI) regimens. Currently, there is no data regarding resistance to INSTI in Angola since Dolutegravir-DTG was included in the first-line ART regimen. Herein, we investigated the HIV-1 genetic diversity and pretreatment drug resistance (PDR) profile against nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and INSTIs, using a next-generation sequencing (NGS) approach with MinION, established to track and survey DRMs in Angola. This was a cross-sectional study comprising 48 newly HIV-diagnosed patients from Luanda, Angola, screened between March 2022 and May 2023. PR, RT, and IN fragments were sequenced for drug resistance and molecular transmission cluster analysis. A total of 45 out of the 48 plasma samples were successfully sequenced. Of these, 10/45 (22.2%) presented PDR to PIs/NRTIs/NNRTIs. Major mutations for NRTIs (2.2%), NNRTIs (20%), PIs (2.2%), and accessory mutations against INSTIs (13.3%) were detected. No major mutations against INSTIs were detected. M41L (2%) and I85V (2%) mutations were detected for NRTI and PI, respectively. K103N (7%), Y181C (7%), and K101E (7%) mutations were frequently observed in NNRTI. The L74M (9%) accessory mutation was frequently observed in the INSTI class. HIV-1 pure subtypes C (33%), F1 (17%), G (15%), A1 (10%), H (6%), and D (4%), CRF01_AG (4%) were observed, while about 10% were recombinant strains. About 31% of detected HIV-1C sequences were in clusters, suggesting small-scale local transmission chains. No major mutations against integrase inhibitors were detected, supporting the continued use of INSTI in the country. Further studies assessing the HIV-1 epidemiology in the era of INSTI-based ART regimens are needed in Angola.

META-INSTI: metabolic adverse events following integrase strand transfer inhibitor administration in spontaneous adverse event reports.

Metabolic effects of integrase strand transfer inhibitors (INSTIs) have been reported. The FDA Adverse Event Reporting System (FAERS) is a publicly available database that captures spontaneously reported adverse events. The objective of this study was to evaluate the relationship between INSTIs and metabolic adverse events using the FAERS database. FAERS data were queried from quarter 4 of 2007 through quarter 4 of 2019 and limited to adults. The Standardized MedDRA Query for 'hyperglycaemia/new-onset diabetes mellitus' (H/DM) was used to identify metabolic adverse events of interest. Weight gain was analysed as a separate event. Reporting odds ratios (RORs) and 95% CIs were calculated for the INSTI class and individual agents. Over 10.1 million FAERS reports were identified. Any INSTI was mentioned as a primary and/or secondary suspect agent in 18,400 (0.18%) reports (bictegravir: 1414 [0.01%]; dolutegravir: 7840 [0.08%]; elvitegravir: 4034 [0.04%]; raltegravir: 5551 [0.05%]). RORs (95% CI) for H/DM and weight gain for any INSTI were 1.20 (1.15-1.27) and 2.16 (1.96-2.38). For individual agents, RORs (95% CI) for H/DM and weight gain were as follows: bictegravir, 1.23 (1.10-1.37) and 6.82 (5.50-8.41); dolutegravir, 1.28 (1.19-1.39) and 1.86 (1.58-2.18); elvitegravir, 0.76 (0.56-1.02) and 1.63 (1.37-1.92); and raltegravir, 1.00 (0.90-1.11) and 3.29 (2.77-3.91). H/DM was noted in 159 bictegravir and 712 dolutegravir reports. Overall, H/DM was associated with bictegravir and dolutegravir and weight gain with all INSTIs. Clinicians should know the potential relationship between INSTIs and metabolic effects and institute appropriate monitoring. META-INSTI: Metabolic Adverse Events Following Integrase Strand Transfer Inhibitor Administration in Spontaneous Adverse Event Reports. Platform Presentation. ID Week. Virtual 2020.

Evaluation of integrase resistance in individuals who failed a regimen containing dolutegravir in French and Italian clinical settings.

This work aims to evaluate integrase resistance and its predictors in HIV-1 infected combined antiretroviral therapy (cART) experienced individuals failing a dolutegravir-based regimen. Major resistance mutations (MRM) and genotypic susceptibility score (GSS) of dolutegravir companion drugs were evaluated on plasma genotypic resistance test (GRT) performed at dolutegravir failure. Logistic regression was used to evaluate factors associated to the risk of integrase strand-transfer inhibitors (INSTI)-resistance at dolutegravir failure. We retrospectively analysed 467 individuals. At failure GRT, individuals had been under dolutegravir for a median (IQR) time of 11 (5-20) months; around half of them had never been exposed to INSTI (52%) and 10.7% were at first-line regimen. Fifty-eight (12.4%) individuals showed ≥1 INSTI MRM. Among them, people INSTI-exposed showed significantly higher prevalence of INSTI resistance compared to those who were INSTI naïve [46 (21.2%) versus 9 (3.9%), P < 0.001].N155H was the most prevalent MRM (5.4%), followed by G140S (4.5%) and Q148H (4.3%). These MRM were more probably present in INSTI-experienced individuals compared to those INSTI naïve. Despite failure, 89.5% of individuals harboured viral strains fully susceptible to dolutegravir and bictegravir and 85.0% to all INSTI. No INSTI exposure before receiving dolutegravir [OR: 0.35 (0.16-0.78), P < 0.010] and a GSS for companion drugs ≥2 (OR: 0.09 [0.04-0.23], P < 0.001) were negatively associated with INSTI resistance at failure. In a large set of individuals failing dolutegravir in real-life, INSTI resistance was low and mainly related to previous first-generation INSTI exposure. Surveillance of integrase resistance remains crucial to preserve efficacy of INSTI class in the future.

Increasing trend of transmitted integrase inhibitor resistance in a cohort of antiretroviral therapy-naive people living with HIV.

Drug regimens containing integrase strand transfer inhibitors (INSTIs) are widely recommended by international guidelines for ART-naive people living with HIV (PLWH).1,2 However, INSTI resistance mutations are uncommon and therefore their surveillance is not suggested before starting ART. The aim of the study was to evaluate the prevalence trend of transmitted INSTI drug resistance (DR) and to assess factors associated with transmitted INSTI resistance among ART-naive PLWH over the past decade. We conducted a time-trend, single-centre study over the period 2009–19 on adult naive PLWH with a genotypic resistance test (GRT) performed before the ART initiation. GRT was determined by Sanger sequencing using an ABI PRISM 3130xl Genetic Analyzer (Applied Biosystems, Foster City, CA, USA); we included in the analysis the immediate pre-ART GRT available in people newly diagnosed with HIV infection. The degree of resistance to each INSTI drug was calculated using the Genotypic Resistance Interpretation Algorithm of the Stanford HIV Drug Resistance Database Program (version 9.1.1) (https://hivdb.stanford.edu/hivdb/by-patterns/). The obtained scores were used to classify the presence of low-level, intermediate or high-level resistance to each INSTI drug and to the INSTI drug class. DR within the INSTI class was defined by the presence of at least low-level resistance to ≥1 drug of the INSTI class.

Drug-drug interactions of Integrase Strand Transfer Inhibitors among older people living with HIV: Interazioni farmacologiche degli inibitori delle integrase tra le persone anziane che vivono con HIV.

The advancement of Human Immunodeficiency Virus (HIV) treatment improves the life expectancy of HIV-positive individuals. People living with HIV have more polypharmacy and drug-drug interactions than those without HIV. Integrase strand transfer inhibitors (INSTIs) are the newest class commonly used for HIV treatment. There are five INSTIs currently approved by the Food and Drug Administration, including raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. INSTIs class contributes to better safety and efficacy profile, making them the preferred or recommended antiretroviral regimens in HIV treatment guidelines worldwide. Despite the shared mechanism of action, INSTIs differ in pharmacokinetics, contributing to different drug-drug interactions. This review summarized the potential drug interactions of INSTIs and the management of the drug interactions in clinical practice.

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

To describe weight changes with integrase strand transfer inhibitor (INSTI) therapy. 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." 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. 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. 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. 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.

894. Trend of Transmitted Resistance Associated Mutations in People Living with HIV (PLWH) in a Large Southeastern U.S. Ryan White Clinic

BackgroundDepartment of Health and Human Services (DHHS) guidelines recommend integrase strand transfer inhibitors (INSTIs) as the backbone of preferred initial antiretroviral (ART) regimens (1). Baseline mutation rates for the INSTI class is 0.8% compared with an overall rate of 19% for all ART classes, based on Centers for Disease Control and Prevention (CDC) U.S. data from 2013-16 (2). First-generation INSTIs (raltegravir and elvitegravir) have a lower genetic barrier to resistance compared with newer, second generation INSTIs (bictegravir and dolutegravir) (3, 4). DHHS guidelines do not currently recommend routine HIV genotypic resistance testing to INSTIs prior to ART initiation (1). Our study seeks to determine the current prevalence of transmitted INSTI and overall resistance in a large southeastern U.S. Ryan White clinic.MethodsThis was a single-center, retrospective analysis of treatment naïve PLWH presenting for care from January 1, 2017 to December 31, 2020. Of these, 164 had a baseline genotype performed by one of two commercially available assays – Vela Genomics or ViroSeq. Subsequent interpretations were based on Stanford HIV Drug Resistance Database. Results65 patients (39.6%) had at least one transmitted resistance associated mutation (RAMs). Of these, 24 (36.9%) had an INSTI RAM. Baseline PI, NRTI, and NNRTI RAMs declined during the four-year interval (2017-2020), while the rate of INSTI RAMs increased from 11.1% to 19%; all conferred resistance to the first generation INSTIs with one also conferring resistance to second generation INSTIs.INSTI Resistance Associated Mutation Prevalence 2017-2020 Frequency of Antiretroviral Therapy Class Mutations Per Year Trend of INSTI Mutations and Resistance Associated Mutations 2017-2020 ConclusionUnlike the CDC data which showed the overall prevalence of INSTI RAM transmission rates during 2013-2016 to be 0.8%, our data suggests a higher rate of INSTI RAMs (14.6%) with overall ART RAM transmission of 39.6%. This increase in baseline resistance to the INSTI class, which occurred over time, mimics the historical development of RAMs seen in the earlier ART classes. Though suboptimal adherence in the population promotes development of RAMs, increased frequency of INSTI RAMs may be due to a lower barrier to resistance of first generation INSTIs. Should our observed trend continue, routine baseline INSTI resistance testing may need to be considered prior to ART initiation.Disclosures Cheryl Newman, MD, Gilead (Scientific Research Study Investigator)GSK/ViiV (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Janssen (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)

Weighing in on the Role of Integrase Strand Transfer Inhibitors (INSTIs) on Weight Gain: Fact or Fiction?

The goal of this manuscript was to review the growing body of evidence examining the relationship between integrase strand inhibitors (INSTIs) and weight gain in treatment-naive and treatment-experienced populations of people living with HIV. INSTIs have proven to be efficacious in virologic suppression in combination with other antiretrovirals (ARVs); however, recent data has demonstrated a potential link between weight gain and INSTIs, causing concern for risk of developing further metabolic complications. The intent of this review was to understand the magnitude of the weight gain and whether INSTIs were the sole cause. Of 71 studies conducted on this topic, 25 trials were evaluated and organized into treatment-naive and treatment-experienced studies. While these studies were not designed homogeneously, clear patterns emerged while assessing the data. Among treatment-naive populations, dolutegravir (DTG) generally exhibited greater levels of weight gain when compared with elvitegravir (EVG) and raltegravir (RAL). Furthermore, some studies demonstrated greater weight gain with DTG-containing groups when combined with tenofovir alafenamide (TAF). Studies in treatment-experienced patients switching to an INSTI-based regimen exhibited similar patterns. DTG was once again associated with the most weight gain in this population, with weight gain also exhibited with RAL and EVG. Due to bictegravir (BIC) being a newer agent, there was limited data in both populations. This compilation of data suggests a link between the INSTI class and weight gain. However, it remains unclear whether weight gain occurs with INSTI initiation or long-term treatment. As more data supports the INSTI class causing weight gain, the cardiovascular and metabolic ramifications have yet to be investigated. Future research should study populations at greater risk for gaining weight, the occurrence of comorbidities associated with weight gain, and data on emerging integrase inhibitors.

Integrase Inhibitor-Based Antiretroviral Therapy Among Women Living with HIV: Data from the OPERA Cohort

Women face unique complexities in HIV treatment yet are underrepresented in antiretroviral therapy (ART) studies. This analysis assessed the one-year durability of the first integrase strand transfer inhibitor (INSTI)-based regimens prescribed to women in a large cohort of patients living with HIV in care. Women with HIV who initiated their first INSTI-containing regimen between 08/12/2013 and 11/30/2015 were identified in the OPERA cohort, a collaboration of 79 US outpatient clinics. Discontinuation within the first year of treatment with an INSTI was compared between dolutegravir (DTG), raltegravir (RAL) and elvitegravir (EVG), using multivariable Cox regression and Kaplan- Meier estimates. Virologic response and regimen modifications were described and compared across INSTIs. A total of 537 treatment-naïve (DTG: 39%, EVG: 48%, RAL: 13%) and 878 treatmentexperienced (DTG: 57%, EVG: 29%, RAL: 13%) women were analyzed. In the first twelve months after initiation, women taking EVG or RAL were more likely to discontinue their initial INSTI than those taking DTG among both treatment-naïve (adjusted hazard ratio EVG vs. DTG: 1.59 (95% CI: 1.09, 2.39); RAL vs. DTG: 2.46 (1.49, 4.05)) and treatment-experienced women (EVG vs. DTG: 1.39 (1.02, 1.88); RAL vs. DTG: 2.17 (1.51, 3.12)). Following discontinuation of the initial INSTI, women commonly switched to a regimen containing a different drug from the INSTI class (treatment-naïve DTG: 34%, RAL: 33% EVG: 41%; treatment-experienced DTG: 23%, RAL: 19% EVG: 41%). In treatment-naïve and treatment-experienced women living with HIV, women taking DTG had the lowest risk for early (≤1 year) discontinuation.

Integrase Inhibitors: After 10 Years of Experience, Is the Best Yet to Come?

The era of the integrase strand transfer inhibitors (INSTIs) for the treatment of human immunodeficiency virus (HIV) infection began with raltegravir in 2007. Since that time, several other INSTIs have been introduced including elvitegravir, dolutegravir, and, most recently, bictegravir, that have shown great utility as part of antiretroviral regimens in both treatment-naive and treatment-experienced patients. At present, antiretroviral guidelines fully endorse the INSTI class as part of all first-line treatment regimens. After 10years of experience with INSTIs, newer agents are on the horizon such as cabotegravir and MK-2048 for potential use as either HIV pre-exposure prophylaxis or maintenance therapy. This review provides a brief overview of the INSTI class including agents currently available and those still in development, reviews available data from both completed and ongoing clinical trials, and outlines simplification strategies using INSTIs.

Surveillance of transmitted drug resistance to integrase inhibitors in Spain: implications for clinical practice.

Integrase strand-transfer inhibitors (INSTIs) constitute at present one of the pillars of first-line ART. To study the prevalence of and the trend in transmitted drug resistance (TDR) to INSTIs in ART-naive patients in Spain. During the period 2012-17, 1109 patients from CoRIS were analysed. The Stanford algorithm v8.7 was used to evaluate TDR and transmission of clinically relevant resistance. To describe individual mutations/polymorphisms, the most recent IAS list (for INSTIs) and the 2009 WHO list update (for the backbone NRTIs used in combination with INSTIs in first-line treatment) were used. Clinically relevant resistance to the INSTI class was 0.2%: T66I, 0.1%, resistance to elvitegravir and intermediate resistance to raltegravir; and G163K, 0.1%, intermediate resistance to raltegravir and elvitegravir. No clinical resistance to dolutegravir or bictegravir was observed. The prevalence of INSTI TDR following the IAS-USA INSTI mutation list was 2.6%, with no trend towards changes in the prevalence throughout the study period. The overall prevalence of NRTI WHO mutations was 4.3%, whereas clinically relevant resistance to tenofovir, abacavir and emtricitabine/lamivudine was 1.7%, 1.9% and 0.7%, respectively. Given the low prevalence of clinically relevant resistance to INSTIs and first-line NRTIs in Spain, it is very unlikely that a newly diagnosed patient will present with clinical resistance to a first-line INSTI-based regimen. These patients may not benefit from INSTI and NRTI baseline resistance testing.

Dolutegravir, the Second-Generation of Integrase Strand Transfer Inhibitors (INSTIs) for the Treatment of HIV.

The integrase strand transfer inhibitors (INSTIs) are the newest antiretroviral class in the HIV treatment armamentarium. Dolutegravir (DTG) is the only second-generation INSTI with FDA approval (2013). It has potential advantages in comparison to first-generation INSTI’s, including unboosted daily dosing, limited cross resistance with raltegravir and elvitegravir, and a high barrier to resistance. Clinical trials have evaluated DTG as a 50-mg daily dose in both treatment-naïve and treatment-experienced, INSTI-naïve participants. In those treatment-naïve participants with baseline viral load <100,000 copies/mL, DTG combined with abacavir and lamivudine was non-inferior and superior to fixed-dose combination emtricitabine/tenofovir/efavirenz. DTG was also superior to the protease inhibitor regimen darunavir/ritonavir in treatment-naïve participants regardless of baseline viral load. Among treatment-experienced patients naïve to INSTI, DTG (50 mg daily) demonstrated both non-inferiority and superiority when compared to the first-generation INSTI raltegravir (400 mg twice daily) regardless of the background regimen. No phenotypically significant DTG resistance has been demonstrated in INSTI-naïve participant trials. The VIKING trials evaluated DTG’s ability to treat persons with HIV with prior INSTI exposure. VIKING demonstrated twice-daily DTG was more efficacious than daily dosing when treating participants receiving and failing first-generation INSTI regimens. DTG maintained potency against single mutations from any of the three major INSTI pathways (Y143, H155, Q148); however, the Q148 mutation with two or more additional mutations significantly reduced its potency. The long-acting formulation of DTG, GSK1265744LA, is the next innovation in this second-generation INSTI class, holding promise for the future of HIV prevention and treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0029-7) contains supplementary material, which is available to authorized users.

Integrating Integrase Inhibitors Into an Antiretroviral Regimen

Integrase strand transfer inhibitors (INSTI) are the newest drug class for treating HIV-1 infections and arguably the most important class available to clinicians. The INSTIs raltegravir, elvitegravir and dolutegravir block strand transfer, the final step catalyzed by integrase, thus preventing incorporation of the viral cDNA into the host genome and subsequent replication. INSTIs are potent, safe and extremely well tolerated. They are the only class of antiretroviral medications in which all members are now recommended by the United States Department of Health and Human Services (DHHS) as preferred first line therapy for treatment-naive HIV-infected patients. They provide a potent component in treatment-experienced patients who have failed prior therapy. INSTIs have minimal effect on serum lipids or glucose. Raltegravir and dolutegravir have few drug interactions, but elvitegravir is co-formulated with the CYP3A4 inhibitor cobicistat, which has significant drug interactions. Stewardship of the INSTI class is a prominent consideration for clinicians as resistance can develop even at low viral loads and mutations can confer cross-resistance within the class. Patients with virologic failure will continue to accumulate integrase resistance mutations over-time, therefore INSTIs should be stopped if virologic failure occurs to conserve sensitivity to other drugs in the class. Dolutegravir has a somewhat unique resistance pattern and appears to have a higher barrier to resistance, which may make it an option for patients who have failed prior raltegravir or elvitegravir-containing regimens. Treatment failure rates are more common in virologically suppressed patients with archived resistance. In patients with a history of virologic failure, switching from a boosted protease inhibitor to raltegravir is not recommended. Clinical trials are evaluating the compound GSK744, an analogue of dolutegravir with a long half-life, which may provide the option of administering INSTI-based antiretroviral therapy with long lasting depot injections rather than daily pills.

Dolutegravir: First Global Approval

Dolutegravir, an orally administered HIV-1 integrase strand transfer inhibitor (INSTI), is under development by ViiV Healthcare. Like other drugs belonging in the INSTI class of antiretroviral agents, dolutegravir binds to the integrase site of HIV-1 and blocks the strand transfer integration step, thereby preventing the replication of HIV-1. Dolutegravir is being developed as an unboosted once-daily therapy for use in combination with other antiretroviral agents for the treatment of both treatment-naïve and treatment-experienced patients with HIV-1 infection. Dolutegravir has been approved in the USA for the treatment of HIV-1 infection in combination with other antiretroviral agents and has been filed for approval in the EU and Canada. Phase III development is underway in North America, Europe, South Africa, South America, Australia and Taiwan. This article summarizes the milestones in the development of dolutegravir leading to this first approval for the treatment of HIV-1 infection in both therapy-naïve and -experienced patients.

Combinational therapies for HIV: a focus on EVG/COBI/FTC/TDF

Introduction: The co-formulation of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) is a new, investigational, once-daily (q.d.) drug, currently undergoing Phase II and III clinical trials. Next to the nucleotide/nucleoside reverse transcriptase inhibitors FTC and TDF, it contains EVG, the second member of the HIV-1 integrase strand transfer inhibitor class, together with its pharmacokinetic booster COBI.Areas covered: In this article, the authors review EVG/COBI/FTC/TDF, in addition to discussing the single-tablet regimens (STRs) containing EFV/FTC/TDF or RPV/FTC/TDF, and the investigational combination pill containing dolutegravir, lamivudine and abacavir (DTG/3TC/ABC, 572-Trii pill). A Medline review was conducted of Phase II and III trials, as well as a review of abstracts from major HIV and infectious disease conferences from 2010 to 2012, involving EVG/COBI/FTC/TDF.Expert opinion: Next to the combination of EFV/FTC/TDF or RPV/FTC/TDF, the co-formulation of EVG/COBI/FTC/TDF offers a new, q.d., single-tablet alternative in treatment-naïve HIV patients. EVG/COBI/FTC/TDF combines a high efficacy with a good tolerability profile. The effect on the renal function and virologic failure with the development of resistance to two or more compounds present in EVG/COBI/FTC/TDF, requires further monitoring. STRs certainly bring the standard for HIV treatment and drug development to a higher level.

Update on Raltegravir and the Development of New Integrase Strand Transfer Inhibitors

Raltegravir (RAL) is the first antiretroviral in the integrase strand transfer inhibitors (INSTI) class. The use of RAL has expanded since its approval in October 2007 for multidrug-resistant human immunodeficiency virus type 1 infection in adults. RAL is now a guideline-preferred treatment option for antiretroviral-naïve patients, indicated for treatment in adolescents, and is being studied as an integral part of nucleoside sparing regimens. The development of resistance and the need for a once-daily dosing option has led to the development of new INSTIs, including elvitegravir and dolutegravir. Elvitegravir is being studied in a promising once-daily single-tablet regimen with tenofovir, emtricitabine, and the investigational pharmacoenhancer cobicistat. The development of cobicistat and the new once-daily INSTIs may revolutionize the treatment of human immunodeficiency virus type 1 infection. This article reviews the current literature on raltegravir and new developments in the INSTI class.

Elvitegravir: a once-daily, boosted, HIV-1 integrase inhibitor

The development of HIV-1 integrase strand transfer inhibitors (INSTIs) has been a major therapeutic breakthrough in the management of HIV-1 infection. The first HIV-1 integrase inhibitor, raltegravir, was licensed in 2007 and was subsequently approved for use in treatment-naive patients. Since then, newer members of the INSTI class have been developed, including elvitegravir (EVG), which is in advanced clinical development and is being developed for use in both treatment-naive and treatment-experienced patients. EVG utilizes pharmacokinetic boosting to achieve adequate serum levels with once-daily dosing. Boosting agents with which it is being studied include ritonavir and cobicistat. In addition, EVG is being studied as a once-daily INSTI in a coformulated fixed-dose combination pill with the agents tenofovir disoproxil fumarate, emtricitabine and cobicistat (QUAD pill), which has the additional potential benefit of convenient once-daily dosing. The in vitro activity, pharmacokinetic and pharmacodynamic properties, results of Phase I–III clinical trials, resistance profile and drug–drug interactions of EVG will be reviewed in this article.