A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.

BACKGROUND: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally. METHODS: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420.

Extended Postexposure Protection Against Vaginal Simian/Human Immunodeficiency Virus Infection With Tenofovir Alafenamide Fumarate/Elvitegravir Inserts in Macaques.

Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20 mg) and elvitegravir (EVG, 16 mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women.

Effectiveness, safety, and patient-reported outcomes of emtricitabine/tenofovir alafenamide-based regimens for the treatment of HIV-1 infection: Final 24-month results from the prospective German TAFNES cohort study.

BACKGROUND: Tenofovir alafenamide (TAF) was introduced in the European Union in 2015 as a novel prodrug of tenofovir showing similar efficacy in clinical trials and a more favorable safety profile than tenofovir disoproxil fumarate (TDF). The German TAFNES cohort study (2016-2019) was conducted to generate real-world evidence. METHODS: Treatment-naïve (TN) and treatment-experienced (TE) people with HIV (PWH) receiving elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF), rilpivirine/F/TAF (R/F/TAF) or F/TAF + 3rd agent were included. Month (M) 24 outcomes included virologic effectiveness (HIV RNA <50 copies/mL), treatment persistence, adverse drug reactions (ADRs) and patient-reported outcomes, using the HIV Symptom Index (HIV-SI), 36-Item Short Form Health Survey (SF-36) and HIV Treatment Satisfaction (HIVTSQ) questionnaires. RESULTS: The study included 767 PWH (92% men, median age 46 years; 301 TN, 466 TE; E/C/F/TAF [n = 318], R/F/TAF [n = 192], F/TAF + 3rd agent [n = 257]). Among TN, 35% had late HIV diagnosis (CD4 < 350/µL and/or AIDS). Of TE, 95% were on suppressive antiretroviral therapy (ART) before switching. D:A:D (Data Collection on Adverse Effects of Anti-HIV Drugs) 5-year risks for chronic kidney disease were high for about 1 in 10 TN and 4 in 10 TE. Overall treatment persistence at M24 was 81% (E/C/F/TAF: 88%; R/F/TAF: 86%; F/TAF + 3rd agent: 70%, with ART simplification of multiple-tablet regimens in 13%). M24 viral suppression (missing = excluded) was 96% (479/501). Discontinuations due to virologic failure or ADRs were rare, 2% (12/767) and 4% (30/767), respectively. HIV-SI and SF-36 summary scores improved in TN; HIVTSQ change scores showed an improvement in treatment satisfaction in TE. CONCLUSION: Real-world data confirmed a favorable safety profile and high virologic effectiveness with high treatment satisfaction on F/TAF-based ART.

A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection.

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.

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.

Changes in neurocognitive assessment scores after initiating dolutegravir- versus elvitegravir-based antiretroviral therapy.

This prospective cohort study enrolled people living with HIV initiating antiretroviral therapy (ART) containing the integrase inhibitors, dolutegravir (DTG) or elvitegravir (EVG) and administered the Montreal Cognitive Assessment (MoCA) at baseline and again after approximately six months to compare changes in MoCA scores. The proportion of patients found to have cognitive impairment, as indicated by a MoCA score <26/30, on each agent were also compared and comparisons were made between changes in each domain assessed by the MoCA (visuospatial/executive, naming, attention, language, abstraction, delayed recall, and orientation). Thirty-five evaluable participants were enrolled, 18 on DTG and 17 on EVG. The median [interquartile range(IQR)] age was 44 (32 to 54) years, 63% were male, 57% were African American. The median (IQR) MoCA score at baseline was 25 (23 to 27) with no difference between groups (p=0.249). The median (IQR) change in MoCA score was 0 (-1 to 2) for DTG and 1 (0 to 3) for EVG (p = 0.183). Of those on DTG, 8 (44%) had MoCA scores <26 on follow-up compared to 11 (65%) on EVG (p = 0.229). There were no significant differences in changes in any of the individual MoCA domains.

Clinically Significant Lower Elvitegravir Exposure During the Third Trimester of Pregnant Patients Living With Human Immunodeficiency Virus: Data From the Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) Network.

This phase 4 study investigated the influence of pregnancy on the pharmacokinetics of elvitegravir/cobicistat in 14 women with human immunodeficiency virus type 1. The results support the recommendation against elvitegravir/cobicistat use during pregnancy, as the elvitegravir concentration at the end of the dosing interval (Ctrough) was reduced by 77%, with 85% of pregnant women having a Ctrough below the effective concentration (EC90). Clinical Trials Registration. NCT00825929.

Switching to Tenofovir Alafenamide in Elvitegravir-Based Regimens: Pharmacokinetics and Antiviral Activity in Cerebrospinal Fluid.

BACKGROUND: Tenofovir alafenamide fumarate (TAF) co-formulated with elvitegravir (EVG; E), cobicistat (C), and emtricitabine (F), a recommended antiretroviral regimen, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF) as well as neurocognitive (NC) performance change in participants switching from E/C/F/tenofovir disoproxil fumarate (TDF) to E/C/F/TAF. METHODS: This was a 24-week, single-arm, open-label study in treatment-experienced adults living with human immunodeficiency virus (HIV). Nine participants switched from E/C/F/TDF (150/150/200/300 mg once daily) to E/C/F/TAF (150/150/200/10 mg once daily) at week 12. CSF and total plasma concentrations of EVG, TDF, TAF, tenofovir (TFV), and HIV RNA levels were measured at baseline and week 24. NC performance was estimated by the Montreal Cognitive Assessment. RESULTS: EVG concentrations in CSF and the CSF:plasma ratio remained stable (P = .203) over time. Following the switch, TFV concentrations in CSF and plasma declined (P = .004), although the TFV CSF:plasma ratio increased (P = .004). At week 24, median TAF plasma concentration was 11.05 ng/mL (range, 2.84-147.1 ng/mL) 2 hours postdose but was below assay sensitivity 6 hours after dosing. TAF was below assay sensitivity in all CSF specimens. HIV RNA was ≤40 copies/mL in all CSF and plasma specimens. Three participants (33%) had NC impairment at baseline and 2 (22%) remained impaired at week 24. CONCLUSIONS: Switch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF but stable EVG concentrations that exceeded the 50% inhibitory concentration for wild-type HIV, suggesting that EVG achieves therapeutic concentrations in the central nervous system. No virologic failure or significant NC changes were detected following the switch. CLINICAL TRIALS REGISTRATION: NCT02251236.

Weight gain in antiretroviral therapy-naive HIV-1-infected patients starting a regimen including an integrase strand transfer inhibitor or darunavir/ritonavir.

BACKGROUND: Weight gain after initiation of combination antiretroviral therapy (cART) is a possible side effect of all antiretroviral regimens, but it seems to be more evident in association with integrase strand transfer inhibitors (INSTIs). So, we aimed to evaluate weight change associated with an initial cART including one INSTI or darunavir-ritonavir (DRV/r). METHODS: A retrospective, observational, cohort study of antiretroviral therapy-naive adult HIV-positive patients starting an initial cART including raltegravir (RAL), dolutegravir (DTG), elvitegravir-cobicistat (EVG), or DRV/r. We compared changes in weight and body mass index (BMI) across the four groups during a 12-month follow-up. RESULTS: As a whole, 680 patients (470 males, mean age 42.1 years) were enrolled: 196 starting RAL, 174 DTG, 158 EVG/c, and 152 DRV/r. Baseline mean CD4 lymphocyte count was 455 cells/mm3 and 7.3% had an AIDS diagnosis. After 12 months, mean increase in body weight was 1.93 kg in the RAL group, 2.38 kg in the DTG group, 2.14 kg in the EVG group, and 1.85 in the DRV/r group. Mean increase in BMI was 0.71, 0.84, 0.77 and 0.63 kg/m2, respectively (p > 0.05 for each comparison). Therefore, no significant increases in weight and BMI were reported in each group, and no significant differences in weight and BMI changes were described across the four treatment groups. CONCLUSIONS: In our study, patients starting an initial cART including one INSTI or DRV/r after 12 months showed a small and comparable, but not significant, increase in body weight, whose long-term clinical consequences are unknown.

Discontinuation of dolutegravir, elvitegravir/cobicistat and raltegravir because of toxicity in a prospective cohort.

OBJECTIVES: The aim of the study was to assess the rates of discontinuation of integrase inhibitor regimens because of any neuropsychiatric adverse event (NPAE) and the factors associated with discontinuation. METHODS: A population-based, prospective, multicentre cohort study was carried out. Treatment-naïve subjects starting therapy with a regimen containing integrase inhibitors, or those switching to such a regimen, with plasma HIV-1 RNA < 50 HIV-1 RNA copies/mL in 14 hospitals in Catalonia or the Balearic Islands (Spain) were included in the study. Every discontinuation because of adverse events (AEs) was double-checked directly with treating physicians. Multivariable Cox models identified factors correlated with discontinuation. RESULTS: A total of 4165 subjects (37% treatment-naïve) started regimens containing dolutegravir (n = 1650; 91% with abacavir), raltegravir (n = 930) or elvitegravir/cobicistat (n = 1585). There were no significant differences among regimens in the rate of discontinuation because of any AE. Rates of discontinuation because of NPAEs were low but higher for dolutegravir/abacavir/lamivudine [2.1%; 2.9 (95% confidence interval (CI) 2.0, 4.2) discontinuations/100 patients/year] versus elvitegravir/cobicistat (0.5%; 0.8 (95% CI 0.3, 1.5) discontinuations/100 patients/year], with significant differences among centres for dolutegravir/abacavir/lamivudine and NPAEs (P = 0.003). We identified an association of female gender and lower CD4 count with increased risk of discontinuation because of any AE [Incidence ratio (IR) 2.3 (95% CI 1.4, 4.0) and 1.8 (95% CI 1.1, 2.8), respectively]. Female gender, age > 60 years and abacavir use were not associated with NPAE discontinuations. NPAEs were commonly grade 1-2, and had been present before and improved after drug withdrawal. CONCLUSIONS: In this large prospective cohort study, patients receiving dolutegravir, raltegravir or elvitegravir/cobicistat did not show significant differences in the rate of discontinuation because of any toxicity. The rate of discontinuations because of NPAEs was low, but was significantly higher for dolutegravir than for elvitegravir/cobicistat, with significant differences among centres, suggesting that greater predisposition to believe that a given adverse event is caused by a given drug of some treating physicians might play a role in the discordance seen between cohorts.

Efficacy and safety of switching to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (TDF) or elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed HIV-infected patients in clinical practice: results from a multicentre, observational study.

OBJECTIVES: The aim of the study was to compare the efficacy and tolerability of switching antiretroviral therapy to dolutegravir + emtricitabine/tenofovir disoproxil fumarate (TDF) with those of switching to elvitegravir/cobicistat/emtricitabine/TDF in clinical practice. METHODS: In a multicentre real-life observational study, we analysed data for HIV-infected patients on antiretroviral treatment with viral load < 50 HIV-1 RNA copies/mL switching to dolutegravir + emtricitabine/TDF (dolutegravir group) or elvitegravir/cobicistat/emtricitabine/TDF (elvitegravir group). Follow-up was censored at 48 weeks. RESULTS: The 48-week estimated proportion maintaining virological efficacy was 96.1% with dolutegravir (n = 123) and 95.4% with elvitegravir (n = 186; P = 0.941). Patients in the dolutegravir group showed more treatment discontinuations, but these were mainly as a result of simplification. The elvitegravir group showed more discontinuations because of renal adverse events (2.7% versus 0% with dolutegravir). Interestingly, no difference was observed between the two regimens in central nervous system toxicity-related discontinuations. Switching to dolutegravir was associated with a better blood lipid profile. CONCLUSIONS: Switching to dolutegravir + emtricitabine/TDF was associated with similar efficacy and tolerability to switching to elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed patients in clinical practice, although reasons for discontinuation showed differences between regimens. These results should be interpreted with caution, as this is a nonrandomized comparison.

Antiviral activity of HIV-1 integrase strand-transfer inhibitors against mutants with integrase resistance-associated mutations and their frequency in treatment-naïve individuals.

The development of resistance to human immunodeficiency virus 1 (HIV-1) integrase strand-transfer inhibitors (INSTI) has been documented; however, knowledge of the impact of pre-existing integrase (IN) mutations on INSTI resistance (INSTI-R) is still evolving. The frequency of HIV-1 IN mutations in 2177 treatment-naïve subjects was investigated, along with the INSTI susceptibility of site-directed mutant viruses containing major and minor INSTI-R mutations. Total 6 of 39 minor INSTI-R mutations (M50I, S119P/G/T/R, and E157Q) were found in >1% of IN-treatment-naïve subjects with no impact on INSTI susceptibility. When each combined with major INSTI-R mutation, M50I, S119P, and E157Q led to decreased susceptibility to elvitegravir but remained sensitive to dolutegravir and bictegravir.

Overdose of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in an HIV-1-infected subject with attempted suicide.

INTRODUCTION: Data are lacking regarding overdose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF). MATERIAL AND METHODS: We present the first report of suicidal attempt with E/C/F/TAF in a Human Immunodeficiency Virus-infected subject. RESULTS: A reversible acute renal failure with no proximal tubulopathy and neuropsychiatric issues are discussed. E/C/F/TAF withdrawal resulted in favourable renal and neuropsychiatric outcomes. The suicide attempt seemed unrelated to the integrase strand transfer inhibitor, being evenly explained within the context of stressful personal conflicts. CONCLUSION: A suicidal attempt with an E/C/F/TAF overdose in an HIV-infected patient, resulted in a favourable outcome from a renal and neuropsychiatric standpoint.

Pharmacokinetics and Safety of the Integrase Inhibitors Elvitegravir and Dolutegravir in Pregnant Women With HIV.

Objective: To synthesize data on the pharmacokinetics and safety of dolutegravir and elvitegravir in pregnant women living with HIV. Data Sources: A PubMed, EMBASE, Web of Science, and Google Scholar literature search (January 2010 to December 2018) was performed using the search terms dolutegravir, elvitegravir, women, pregnant*, and HIV. Additional reports were identified from conference abstracts and review of reference lists. Study Selection and Data Extraction: English-language studies reporting pharmacokinetic and/or safety data in pregnant women receiving dolutegravir or elvitegravir/cobicistat were included. Data Synthesis: A total of 17 studies were selected. Studies demonstrated a modest decrease in dolutegravir concentrations in pregnancy. Preliminary data suggest an increased risk of neural tube defects when dolutegravir is used at the time of conception. Available pharmacokinetic data in pregnant women showed significantly reduced plasma concentrations of elvitegravir/cobicistat which may increase the risk of virological failure. Current guidelines recommend that dolutegravir should not be initiated in women who have the potential to become pregnant or women in their first trimester of pregnancy and elvitegravir/cobicistat should be avoided during pregnancy. Relevance to Patient Care and Clinical Practice: This review highlights pharmacokinetic and safety data for dolutegravir and elvitegravir/cobicistat in pregnant women. Clinicians need to be aware of these data to convey the risks and benefits of using these agents in women of child-bearing potential. Conclusions: Changes in guideline recommendations reflect emerging data regarding the use of dolutegravir and elvitegravir/cobicistat in pregnancy. Until further information is available, raltegravir or other first-line agents are recommended for women with HIV planning to become pregnant.

Comparison of 48-week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor-sparing regimens: a systematic review and network meta-analysis.

OBJECTIVES: To compare nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens with tenofovir alafenamide (TAF)-based combinations in HIV-1-infected adults, we performed a network meta-analysis (NMA) to provide estimates of relative efficacy for these two regimens. METHODS: A systematic literature review (SLR) was performed to identify phase 3/4 randomized controlled clinical trials evaluating the efficacy of commonly used combination antiretroviral therapy (cART) including an NRTI backbone or that of commonly used NRTI-sparing regimens. A Bayesian random-effect model was used to compare virological suppression rates at 48 weeks for NRTI-sparing regimens and elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF). RESULTS: Twenty-three studies in treatment-naïve patients identified by the SLR were included in the NMA, including four studies assessing NRTI-sparing regimens. In treatment-naïve patients, the probability of achieving virological suppression at 48 weeks was between 40% and 60% higher with E/C/F/TAF than with NRTI-sparing strategies. The credible interval vs. darunavir/ritonavir (DVR/r) + raltegravir (RAL) and LPV/r monotherapy did not include 1. In the subgroup of naïve patients with viral load < 100 000 HIV-1 RNA copies/mL, a credible difference was found between NRTI-sparing treatments and E/C/F/TAF. Studies in treatment-experienced patients were too heterogeneous to allow for an NMA. CONCLUSIONS: The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI-sparing regimens in terms of 48-week efficacy in treatment-naïve patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI-sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI-sparing regimens for initiation of antiretroviral therapy in treatment-naïve HIV-infected patients.

Development and validation of an HPLC-UV method for quantification of elvitegravir and two other new antiretrovirals, dolutegravir and rilpivirine, in the plasma of HIV-positive patients.

Therapeutic drug monitoring may be crucial in selected clinical conditions for the management of HIV infection. In recent years, new antiretrovirals have been introduced and in particular elvitegravir (EVG) is now recommended for first-line and simplification treatment as well as dolutegravir (DTG) and rilpivirine (RPV). The aim of this study was to develop and validate a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining EVG and new antiretrovirals DTG and RPV in human plasma. Solid-phase extraction was applied to a 600 µL plasma sample. Chromatographic separation of the three drugs and internal standard was achieved with a gradient of acetonitrile and phosphate buffer on a C18 reverse-phase analytical column with a 20 min analytical run time. EVG and DTG were detected at 265 nm and RPV at 290 nm. Mean intra- and inter-day precisions were < 10%; the mean accuracy was <15%. Extraction recovery ranged between 105 and 82% for the drugs analyzed. Calibration curves were optimized according to the expected ranges of drug concentrations in patients; the coefficient of determination was >0.997 for all drugs. This method allows for monitoring EVG, DTG and RPV in the plasma of HIV-positive patients using HPLC-UV.

HIV drug resistance against strand transfer integrase inhibitors.

Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell's chromatin. Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance. Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second-generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants. In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual. This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold-changes in resistance of resistant variants in in vitro assays. While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the "second-generation" drugs of this class. This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development.

Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy.

The integrase inhibitors elvitegravir (EVG) and dolutegravir (DTG) rapidly decrease the plasma HIV-1 viral load, a key factor in the prevention of maternal-to-fetal transmission of HIV-1. No data have been reported on the concentrations of these drugs in cord blood, maternal peripheral blood mononuclear cells (PBMCs), or placental tissue in pregnant women. We present in vivo pharmacokinetic data on antiretrovirals (ARV) within maternal and cord blood and within placentae from HIV-1-infected pregnant women. Maternal blood and cord blood were obtained from women receiving EVG, cobicistat, tenofovir disoproxil fumarate, and emtricitabine as a single fixed-dose combination formulation or DTG as part of a combination regimen. Plasma and PBMCs from maternal and cord blood were obtained along with villous placental samples. Drug concentrations were simultaneously determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Utilizing medians and ranges to interpret our data, we compared the drug concentration ratios between different matrices (maternal and cord blood plasma, PBMCs, and placenta). All five agents transferred from maternal into fetal circulation via the placenta. Concentration ratios for EVG, cobicistat, tenofovir, and emtricitabine (n = 10) and DTG (n = 3) were determined between cord plasma and placenta, cord and maternal plasma, and cord PBMCs and maternal PBMCs. TFV moves from maternal plasma through the placenta to the cord blood and then into cord PBMCs, where it is phosphorylated into its active forms (TFV diphosphate). These five ARVs were detected in each of the compartments, highlighting transfer of these agents from the maternal into the fetal circulation.

The inhibition process of HIV-1 integrase by diketoacids molecules: Understanding the factors governing the better efficiency of dolutegravir.

The Human Immunodeficiency Virus-1 integrase is responsible for the covalent insertion of a newly synthesized double-stranded viral DNA into the host cells, and is an emerging target for antivirus drug design. Raltegravir (RAL) and elvitegravir (EVG) are the first two integrase strand transfer inhibitors used in therapy. However, treated patients eventually develop detrimental resistance mutations. By contrast, a recently approved drug, dolutegravir (DTG), presents a high barrier to resistance. This study aims to understand the increased efficiency of DTG upon focusing on its interaction properties with viral DNA. The results showed DTG to be involved in more extended interactions with viral DNA than EVG. Such interactions involve the halobenzene and scaffold of DTG and EVG and bases 5'G-43', 3'A35'and 3'C45'.

Elvitegravir concentrations in seminal plasma in HIV-1-infected men.

OBJECTIVES: The aim of the study was to quantify elvitegravir (EVG) concentrations in the semen of HIV-1-infected men receiving antiretroviral therapy (ART) consisting of an elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) single-tablet regimen. METHODS: A phase IV, cross-sectional study was carried out including HIV-1-infected male adults with suppressed plasma HIV-1 RNA who switched ART to EVG/COBI/FTC/TDF. Total EVG concentrations at the end of the dosing interval (C24 h ) and HIV-1 RNA were measured in paired seminal plasma (SP) and blood plasma (BP) samples 4 weeks after switching to EVG/COBI/FTC/TDF. Validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify EVG concentrations, and HIV-1 RNA was determined by real-time polymerase chain reaction (PCR). RESULTS: Ten men were included. Their median age was 40 years (range 24-47 years), the median time on ART was 50 months (range 10-186 months), the median time with plasma HIV-1 RNA < 40 copies/mL was 37 months (range 7-113 months), and the median CD4 count was 737 cells/µL (range 190-1122 cells/µL). Four weeks after switching to EVG/COBI/FTC/TDF, all subjects had HIV-1 RNA < 40 copies/mL in both BP and SP. Median EVG C24 h was 277 ng/mL (range 64.8-1790 ng/mL) in BP and 169 ng/mL (range 12.8-792 ng/mL) in SP. A significant correlation was observed between BP and SP EVG concentrations (Spearman rho 0.952; P < 0.001). The median SP:BP EVG concentration ratio was 0.39 (range 0.20-0.92). EVG C24 h in SP was at least 23-fold the in vitro protein-unbound 50% effective response (EC50 ) of HIV-1 clinical isolates (0.04-0.55 ng/mL). In all but one individual, EVG C24 h in SP was also higher than the blood plasma protein binding-adjusted 95% inhibitory concentration (IC95 ) of wild-type HIV-1 (45 ng/mL). CONCLUSIONS: Seminal EVG concentrations in HIV-infected men treated with EVG/COBI/FTC/TDF sufficed to contribute to maintaining HIV-1 RNA suppression in this compartment.