ritonavir and etravirine

This review focuses on the use of tipranavir/ritonavir, darunavir/ritonavir and etravirine for the treatment of HIV infection that has become resistant to protease inhibitors and/or nonnucleoside reverse transcriptase inhibitors.. Tipranavir/ritonavir and darunavir/ritonavir are boosted protease inhibitors highly active against HIV that has developed mutations that confer resistance to other protease inhibitors. For both drugs, there are scores to predict activity based on a combination of mutations. Best results are obtained when each drug is combined with one and preferably two other completely active antiretrovirals. The interaction profile and toxicity profile is better for darunavir/ritonavir, which in addition has shown positive outcomes in clinical trials of patients with early failure.Etravirine is a nonnucleoside reverse transcriptase inhibitor highly active against HIV that has developed mutations that confer resistance to nevirapine or efavirenz. Clinical trials results suggest that etravirine should be used with other active antiretrovirals. Best results for etravirine have been obtained in combination with darunavir/ritonavir in patients with extensive protease inhibitor and nonnucleoside reverse transcriptase inhibitor resistance. The role of etravirine for the treatment of early failure of efavirenz-based or nevirapine-based regimens remains to be elucidated. Resistance to etravirine requires the accumulation of multiple reverse transcriptase mutations different from K103N, which has no impact on activity.. Tipranavir/ritonavir, darunavir/ritonavir and etravirine are very important additions to the therapeutic armamentarium against HIV that has become resistant to protease inhibitors and nonnucleoside reverse transcriptase inhibitors.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Viral; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Nitriles; Pyridazines; Pyridines; Pyrimidines; Pyrones; Ritonavir; Sulfonamides

Darunavir is a new protease inhibitor. This drug is highly active against wild-type and multiresistant HIV strains, binds strongly to the HIV-1 protease, has extremely high affinity for the protease and, when enhanced by subtherapeutic doses of ritonavir, has a favorable resistance profile differing from that of current protease inhibitors (PIs). After determining the optimal dose, phase IIb clinical trials (POWER studies 1 and 2) observed much higher virological and immunological efficacy with darunavir than with the comparator PIs. The results of a phase III clinical trial (POWER 3) provide further support for the safety and efficacy of darunavir, and the three POWER studies demonstrate the high genetic barrier of this drug against mutations conferring resistance to other PIs, although the baseline sensitivity of darunavir and the specific mutations to this PI influence the virological response. Better therapeutic responses have been obtained when there are two or more antiretroviral drugs active against multiresistant HIV strains. The phase III trials (DUET 1 and 2), in which darunavir was administered with the new nonnucleoside reverse transcriptase inhibitor, etravirine, found that if these two drugs were administered in highly treatment-experienced patients, a large percentage showed suppression of plasma viremia and immunological recovery. These data have been supported by the results of the BENCHMARK studies, in which darunavir was included in an optimized regimen in a substantial number of patients. In these trials, when darunavir was administered with the integrase inhibitor, raltegravir, undetectable viral loads both in the raltegravir arm and in the control group were substantially improved with respect to the overall results obtained in the control group.

Topics: Adult; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Darunavir; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Integrase Inhibitors; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Multicenter Studies as Topic; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viremia

Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure.. A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367.. From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60-68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]).. Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance.. National Institutes of Health.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Darunavir; Developing Countries; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nitriles; Prospective Studies; Pyridazines; Pyrimidines; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load

Data on the combination of darunavir/ritonavir and etravirine both given twice daily in adolescents/young adults are lacking. In this study, we assessed the pharmacokinetics of darunavir/ritonavir 600/100 mg with etravirine 200 mg twice daily in 36 treatment-experienced human immunodeficiency virus-infected adolescents and young adults and found that exposures were comparable to those reported in adults.

Topics: Adolescent; Darunavir; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Nitriles; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Ritonavir; Viral Load; Young Adult

Following antiretroviral therapy failure, patients are often treated with a three-drug regimen that includes two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. An alternative two-drug nucleoside-sparing regimen may decrease the pill burden and drug toxicities associated with the use of N(t)RTIs. The Intelence aNd pRezista Once A Day Study (INROADS; NCT01199939) evaluated the nucleoside-sparing regimen of etravirine 400 mg with darunavir/ritonavir 800/100 mg once-daily in HIV-1-infected treatment-experienced subjects or treatment-naïve subjects with transmitted resistance.. In this exploratory phase 2b, single-arm, open-label, multicentre, 48-week study, the primary endpoint was the proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at week 48 [confirmed virological response (CVR), non-virological failure (VF) censored]. Key secondary endpoints included assessments of changes from baseline to week 48 in viral load, immunological response, pharmacokinetics/pharmacodynamics, safety, tolerability, metabolic and bone markers and body fat.. Forty-one of the 54 enrolled subjects completed the study. Adverse events (7%) and VF (7%) were the most common reasons for discontinuation. The week 48 CVR rate in the intent-to-treat (ITT) non-VF censored population was 89% (primary endpoint). Seven subjects experienced VF. Common adverse events were diarrhoea (15%), rash (15%) and upper respiratory tract infection (11%). Mild/moderate lipid elevations, minimal changes in limb fat distribution and bone mineral density and no clinically relevant changes in glucose metabolism were observed.. Etravirine 400 mg and darunavir/ritonavir 800/100 mg as a two-drug once-daily regimen in treatment-experienced subjects or treatment-naïve subjects with transmitted resistance was virologically efficacious and well tolerated.

Topics: Adult; Aged; Anti-HIV Agents; Body Fat Distribution; Bone Density; CD4 Lymphocyte Count; Darunavir; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lipids; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

This observational study in antiretroviral treatment-experienced, HIV-1-infected adults explored the efficacy of etravirine plus darunavir/ritonavir (DRV group; n = 999) vs. etravirine plus an alternative boosted protease inhibitor (other PI group; n = 116) using pooled European cohort data.. Two international (EuroSIDA; EUResist Network) and five national (France, Italy, Spain, Switzerland and UK) cohorts provided data (collected in 2007-2012). Stratum-adjusted (for confounding factors) Mantel-Haenszel differences in virological responses (viral load < 50 HIV-1 RNA copies/mL) and odds ratios (ORs) with 95% confidence intervals (CIs) were derived.. Baseline characteristics were balanced between groups except for previous use of antiretrovirals (≥ 10: 63% in the DRV group vs. 49% in the other PI group), including previous use of at least three PIs (64% vs. 53%, respectively) and mean number of PI resistance mutations (2.3 vs. 1.9, respectively). Week 24 responses were 73% vs. 75% (observed) and 49% vs. 43% (missing = failure), respectively. Week 48 responses were 75% vs. 73% and 32% vs. 30%, respectively. All 95% CIs around unadjusted and adjusted differences encompassed 0 (difference in responses) or 1 (ORs). While ORs by cohort indicated heterogeneity in response, for pooled data the difference between unadjusted and adjusted for cohort ORs was small.. These data do not indicate a difference in response between the DRV and other PI groups, although caution should be applied given the small size of the other PI group and the lack of randomization. This suggests that the efficacy and virology results from DUET can be extrapolated to a regimen of etravirine with a boosted PI other than darunavir/ritonavir.

Topics: CD4 Lymphocyte Count; Darunavir; Drug Therapy, Combination; Female; France; HIV Infections; HIV Protease Inhibitors; Humans; Italy; Male; Meta-Analysis as Topic; Middle Aged; Nitriles; Odds Ratio; Pyridazines; Pyrimidines; Ritonavir; Spain; Sulfonamides; Switzerland; United Kingdom; Viral Load

Regimen selection for highly treatment-experienced patients is complicated.. Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3-4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression.. A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR] = 2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR = 6.2) or boosted protease inhibitor (PI, OR = 6.6), prior use of integrase strand transfer inhibitor (INSTI, OR = 25), and race-ethnicity (all P ≤ 0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR = 0.5) and Hispanic participants from the continental US (OR = 0.2) were less likely to start a complex regimen, compared to white non-Hispanics.. In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race-ethnicity were key factors in decisions to select a more complex regimen.

Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Drug Resistance, Viral; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Infections; Humans; Male; Middle Aged; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy

A previous study investigating coadministration of etravirine, a nonnucleoside reverse transcriptase inhibitor, and lopinavir/ritonavir soft-gel formulation resulted in nonclinically relevant changes in etravirine and lopinavir exposure. The current study evaluated the pharmacokinetic interaction between etravirine and the lopinavir/ritonavir melt extrusion formulation.. Sixteen human immunodeficiency virus (HIV)-negative volunteers were randomized to either treatment sequence A/B or B/A, with 14 days- washout between treatments (treatment A: etravirine 200 mg bid for 8 days; treatment B: lopinavir/ritonavir 400/100 mg bid for 16 days with etravirine 200 mg bid on days 9-16). Steady-state pharmacokinetics were assessed for all antiretrovirals alone and coadministered; pharmacokinetic parameters were obtained by noncompartmental analysis. Safety and tolerability were assessed.. Coadministration of etravirine and lopinavir/ritonavir resulted in a 35% decrease in etravirine exposure. Smaller decreases (<13%) were observed in lopinavir and ritonavir exposure. Six volunteers reported headache; 1 grade 3 triglyceride increase was reported.. Lopinavir/ritonavir induced etravirine metabolism to a similar extent as most other boosted HIV protease inhibitors. The short-term coadministration of etravirine and lopinavir/ritonavir was well tolerated and did not lead to increased incidences of adverse events.

Topics: Adult; Anti-HIV Agents; Cross-Over Studies; Drug Interactions; Drug Therapy, Combination; Female; Gels; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Young Adult

Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine.. This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given.. Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co-administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study.. Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution.

Topics: Adult; Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; Cross-Over Studies; Darunavir; Drug Interactions; Ethanolamines; Fluorenes; Healthy Volunteers; HIV; HIV Infections; Humans; Lumefantrine; Malaria; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides

Abstract The influence of efavirenz, etravirine, raltegravir, and nevirapine administration on the pharmacokinetics of ritonavir-boosted darunavir was investigated using population pharmacokinetics analysis. The population was composed of 142 patients infected with HIV: darunavir plus nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), 54 patients (group A); darunavir plus efavirenz±NRTI, 4 patients (group B); darunavir plus etravirine±NRTI, 5 patients (group C); darunavir plus nevirapine±NRTI, 21 patients (group D); darunavir plus raltegravir±NRTI, 38 patients (group E); and darunavir plus raltegravir and etravirine±NRTI, 20 patients (group F). A significant increase in darunavir clearance in combination with nevirapine (+66%) and efavirenz (+235%) was observed. A significant decrease (p<0.05) in trough plasma concentration was observed in groups B and D compared with the other groups. Our study indicates that the combination of ritonavir-boosted darunavir and etravirine or raltegravir has no significant influence on the pharmacokinetics of darunavir in contrast to the combination of ritonavir-boosted darunavir and nevirapine or efavirenz, which involves an increase in darunavir clearance and a decrease in the plasma concentration of darunavir.

Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Darunavir; Drug Synergism; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Nevirapine; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

To assess the cost-effectiveness of etravirine (INTELENCE), a novel nonnucleoside reverse transcriptase inhibitor, used in combination with a background regimen that included darunavir/ritonavir, from a Canadian Provincial Ministry of Health perspective.. A Markov model with a 3-month cycle time and six health states based on CD4 cell count ranges was developed to follow a hypothetical cohort of treatment-experienced adults with HIV-1 infection through initial and subsequent treatment regimens.. Costs (in 2009 Canadian dollars), utilities, and HIV-related mortality data for each health state as well as non-HIV-related mortality data were estimated from Canadian sources and published literature. Transition probabilities between health states and first-year hospitalization and mortality rates were derived from clinical trial data. Incremental 1-year costs per additional adult with viral load less than 50 copies/ml at 48 weeks and incremental lifetime costs per quality-adjusted life-year (QALY) gained were estimated using a 5% discount rate. Sensitivity and variability analyses and model validation were performed.. Etravirine was associated with an increased probability of achieving less than 50 copies/ml at 48 weeks of 0.205 and an estimated gain of 0.66 discounted (1.48 undiscounted) QALYs over a lifetime. The incremental 1-year cost per additional person with viral load less than 50 copies/ml was $23,862. The lifetime incremental cost per QALY gained was $49,120. For the uncertainty ranges and variability scenarios tested for the lifetime horizon, the cost-effectiveness ratio was between $28,859 and 66,249.. When compared with optimized standard of care including darunavir/ritonavir, adding etravirine represents a cost-effective option for treatment-experienced adults in Canada.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Canada; CD4 Lymphocyte Count; Cost-Benefit Analysis; Darunavir; Double-Blind Method; Drug Therapy, Combination; Female; HIV-1; Humans; Male; Markov Chains; Middle Aged; Models, Economic; Nitriles; Pyridazines; Pyrimidines; Quality-Adjusted Life Years; Ritonavir; Sulfonamides; Viral Load; Young Adult

To evaluate the pharmacokinetics, weight-based dose selection and short-term safety and tolerability of etravirine in HIV-1-infected children and adolescents.. Phase I, nonrandomized, open-label study in two stages.. Children and adolescents aged at least 6 years to 17 years or less on a stable lopinavir/ritonavir-based antiretroviral regimen with HIV-1 RNA plasma viral load less than 50 copies/ml were enrolled. In both stages, etravirine (4 mg/kg twice daily in stage I, 5.2 mg/kg twice daily in stage II), added to the existing antiretroviral regimen, was administered for 7 days followed by a morning dose and 12-h pharmacokinetic assessment on day 8. Pharmacokinetic parameters were determined using noncompartmental analysis. Data were compared with those previously established in HIV-1-infected adults on a similar etravirine (200 mg twice daily) combination antiretroviral regimen.. Twenty-one patients were recruited to each stage; 19 and 20 had evaluable pharmacokinetics in stages I and II, respectively. Mean (SD) maximum plasma concentrations in stages I and II were 495 (453) and 757 ng/ml (680), respectively; area under the plasma concentration-time curve over 12 h was 4050 (3602) and 6141 ng h/ml (5586), respectively. Statistical/qualitative comparisons showed comparable exposures with adults in stage II; however, the upper 90% confidence interval fell outside the predefined range. Plasma viral load remained undetectable on day 8 in all patients, and etravirine was well tolerated at both doses.. Etravirine 5.2 mg/kg was well tolerated in this study and this dose was selected for further investigation in clinical trials.

Topics: Adolescent; Anti-HIV Agents; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Seropositivity; Humans; Lopinavir; Male; Nitriles; Pyridazines; Pyrimidines; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

The GRACE (Gender, Race and Clinical Experience) trial enrolled treatment-experienced, HIV-1-infected patients, mainly women, in North America, to assess outcomes with a darunavir/ritonavir-based regimen, which could include etravirine (ETR). We present outcomes at week 48 for men and women receiving ETR. Virologic response (HIV-1 RNA <50 copies/ml) and safety were assessed; descriptive statistics are reported. To evaluate the independent contribution of ETR treatment, a post hoc analysis including a multivariate model assessed factors predictive of virologic response for the entire GRACE population (429 patients). Of 207 patients who received ETR (women, 57.5%; black or Hispanic, 81.7%), 71.4% of women and 79.5% of men completed the study. Week 48 virologic response rates in women and men (intent-to-treat population) were 58.0% and 61.4%, respectively. After censoring patients who discontinued treatment for reasons other than virologic failure, response rates were 79.3% and 73.0%, respectively. Overall, ETR was well tolerated. Women experienced more nausea (24.4% vs. 11.4%) and rash-related events (21.0% vs. 15.9%), but less diarrhea (15.1% vs. 21.6%), compared with men. Grade 3-4 hypertriglyceridemia was more common in men (9.3%) than women (1.1%). In total, 11 (9.2%) women and 7 (8.0%) men discontinued ETR due to adverse events. In the multivariate model of the entire GRACE population, ETR use was independently associated with improved virologic response. ETR is effective and well tolerated in treatment-experienced patients with HIV-1, with similar outcomes among women and men.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; Female; HIV Protease Inhibitors; HIV-1; Humans; Male; Nitriles; North America; Pyridazines; Pyrimidines; Ritonavir; RNA, Viral; Sex Distribution; Sex Factors; Sulfonamides; Treatment Outcome; Viral Load

We report darunavir, ritonavir, and etravirine pharmacokinetics in cervicovaginal fluid and blood plasma for women from the Gender, Race and Clinical Experience (GRACE) study. Eight women received darunavir-ritonavir (600/100 mg) twice daily (b.i.d.); two also received etravirine (200 mg) b.i.d. Week 4 paired blood plasma and cervicovaginal fluid samples were collected over 12 h. Darunavir and etravirine cervicovaginal fluid exposures were higher than blood plasma exposures; ritonavir cervicovaginal fluid exposure was lower than blood plasma exposure. The high exposures of darunavir and etravirine in cervicovaginal fluid warrant further evaluation of these drugs for use in HIV-1 prevention.

Topics: Adult; Darunavir; Female; HIV Infections; Humans; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides

The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.

Topics: Adolescent; Adult; Cyclohexanes; Darunavir; Drug Interactions; Female; Humans; Male; Maraviroc; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides; Triazoles; Young Adult

Dolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC(0-τ)), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration (C(max)), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval (C(τ)). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC(0-τ) and C(max), whereas the C(τ) increased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC(0-τ), C(max), and C(τ) by 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered.

Topics: Adult; Drug Interactions; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Young Adult

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Darunavir; Drug Administration Schedule; Female; HIV; HIV Infections; Humans; Immunosuppression Therapy; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome

Etravirine, a nonnucleoside reverse transcriptase inhibitor, was provided through an international early access program (EAP) prior to regulatory approval.. The Phase III, nonrandomized, open-label EAP investigated etravirine 200 mg twice daily plus a background regimen (BR) in patients who had failed multiple antiretroviral regimens. Efficacy and safety are reported for HIV-infected adults from the United States through week 48, including subgroups receiving etravirine +/- darunavir/ritonavir and/or raltegravir.. The intent-to-treat population included 2578 patients; 62.4% and 56.7% of patients received darunavir/ritonavir and raltegravir, respectively, in their BR. At week 48, 62.3% of patients achieved viral loads <75 copies per milliliter; responses across subgroups were similar. Median CD4 count increase from baseline was >100 cells per cubic millimeter. No unexpected safety concerns emerged; serious AEs and deaths due to AEs, considered possibly related to etravirine, occurred in 2.0% and 0.3% of patients, respectively. Discontinuations due to AEs were low overall (4.4%) and comparable across subgroups.. Etravirine combined with a BR, often including other new antiretrovirals, such as darunavir/ritonavir and/or raltegravir, provided an effective treatment option in treatment-experienced patients with HIV-1.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; United States; Viral Load

A pharmacokinetic trial was conducted to evaluate the potential for once-daily etravirine in antiretroviral regimens without and with darunavir/ritonavir.. During this multicentre, open-label, Phase IIa trial, treatment-naive patients aged > or =18 years with HIV type-1 (HIV-1) received etravirine 400 mg once daily with tenofovir disoproxil fumarate/emtricitabine 300/200 mg once daily from days 1-14; on days 15-28, darunavir/ritonavir 800/100 mg once daily was added. On day 29, etravirine was discontinued and patients continued with the other medications to day 42. Serial blood sampling for etravirine pharmacokinetics was performed over 24 h on day 14 and 28; patients fasted for > or =10 h prior to these visits.. Of 23 enrolled patients (male 87%, Caucasian 39%), pharmacokinetic profiles for etravirine were available for 21 and 20 patients on day 14 and 28, respectively. The plasma concentration-time profile and pharmacokinetics for etravirine were unchanged with or without darunavir/ritonavir. The mean maximum plasma concentration (C(max)) was reached 4 h after administration and was 790 and 801 ng/ml on day 14 and 28, respectively; mean area under the plasma concentration-time curve (AUC) from before administration to 24 h after administration was 10,410 ng*h/ml on day 14 and 10,720 ng*h/ml on day 28. In a post-hoc analysis, etravirine C(max) was higher, minimum plasma concentration was lower and AUC was similar when compared with etravirine 200 mg twice daily.. Addition of darunavir/ritonavir to etravirine, all dosed once daily, did not have a clinically significant effect on the pharmacokinetics of etravirine. Findings support further investigation of etravirine 400 mg once daily in HIV-1-infected patients. (Trial registration number NCT00534352.).

Topics: Adenine; Adult; Anti-HIV Agents; Darunavir; Deoxycytidine; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; Humans; Male; Nitriles; Organophosphonates; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Tenofovir; Treatment Outcome

ANRS 139 TRIO trial was a phase II noncomparative trial that evaluated in highly experienced patients, a combination of raltegravir, etravirine and darunavir boosted with ritonavir. We analyzed emergence of resistant viruses at the time of virological failure and investigated the impact of baseline integrase polymorphisms on virological failure occurrence.. Bulk sequencing of protease, reverse transcriptase and integrase genes was performed for 103 patients at baseline and 14 patients at the time of virological failure. Additionally, integrase clonal analyses were performed at baseline and at virological failure in patients with successful integrase gene amplification. Impact of baseline integrase polymorphisms on virological failure occurrence was analyzed using Fisher exact and Wilcoxon tests.. In the 14 failing patients median viral load at virological failure was 90 copies/ml (interquartile range = 60-783). Emergence of darunavir and etravirine resistance mutations was observed at virological failure in only one and three patients, respectively. Raltegravir resistance mutations were found neither at baseline nor at the time of virologic failure. Integrase clonal analyses showed neither the presence nor the selection of minority variants carrying raltegravir resistance mutations at baseline or at virological failure. No impact of baseline integrase polymorphisms was observed on virological failure either at week 24 or at week 48.. Virological failure occurred in a small proportion of patients with low viral load. No raltegravir resistance mutations were observed using bulk sequencing or clonal analyses, and darunavir and etravirine resistance-associated mutations were detected in only one and three patients, respectively at virological failure. No impact of baseline integrase polymorphism was observed on virological failure occurrence.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Male; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Topics: Adenine; Administration, Oral; Adolescent; Adult; Aged; Darunavir; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Nitriles; Organophosphonates; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Tenofovir; Treatment Outcome; Viral Load; Young Adult

Durable efficacy and long-term safety of antiretroviral therapy are important goals in the management of treatment-experienced patients. The 96-week efficacy and safety of the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine were evaluated in the Phase III DUET trials.. HIV type-1-infected treatment-experienced adults with viral loads >5,000 copies/ml and NNRTI and protease inhibitor resistance were randomized to receive etravirine 200 mg or placebo, each twice daily and in combination with a background regimen of darunavir/ritonavir twice daily, nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. The primary end point was the proportion of patients with viral load <50 copies/ml (intent-to-treat analysis, time-to-loss of virological response algorithm) at week 24. Results from both trials were combined in the pre-specified pooled 96-week analysis.. In total, 599 patients received etravirine and 604 received placebo. At week 96, 57% of patients in the etravirine group versus 36% in the placebo group had a viral load <50 copies/ml (P<0.0001); 91% and 88% of patients, respectively, had maintained this response from week 48. Mean increases in CD4(+) T-cell count from baseline at week 96 were 128 cells/mm(3) with etravirine versus 86 cells/mm(3) with placebo (P<0.0001). With the exception of rash, which was reported more frequently with etravirine than placebo (21% versus 12%, respectively; P<0.0001), the safety and tolerability profile of etravirine was similar to placebo over the treatment period.. Etravirine, in combination with an antiretroviral background regimen, provided durable virological and immunological responses with no new safety concerns in treatment-experienced patients over 96 weeks in the DUET trials.

Topics: Adult; Anti-HIV Agents; Darunavir; Double-Blind Method; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

Treatment options for HIV-infected patients can be limited due to viral drug resistance to antiretroviral agents. Enfuvirtide (ENF) is an injectable entry/fusion inhibitor that is effective in achieving viral suppression when used in combination with protease inhibitors (PIs) in patients with pre-existing resistance. However, ENF treatment is associated with injection site reactions and dosing fatigue. This multicenter, open-label, Phase IIIb, 48-week pilot study assessed safety, tolerability, and effectiveness of the PI darunavir (DRV), boosted with ritonavir (DRV/r), and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETR), when substituted for ENF/PI (±NNRTI)-based therapy. Ten virologically suppressed (HIV RNA less than 50 copies/ml) men who were intolerant to ENF were enrolled. Median (range) CD4+ count was 301 (187-663) cells/mm(3). Two patients discontinued the study; all remaining patients maintained a viral load of less than 50 copies/ml at Week 48. Viral load increased to greater than 50 copies/ml in two patients, but was eventually re-suppressed without the need for changes in treatment. Median (range) increase (last observation carried forward) in CD4+ count from baseline to Week 48 was 64 (-53-100) cells/mm(3). Two grade 3 adverse events (AEs), nausea and weight loss, and one serious AE, acute cholecystitis, were reported; each AE resolved without treatment interruption. Most common AEs related to study drug were fatigue, rash, headache, and diarrhea. Decreases in triglycerides, low-density lipoprotein, and high-density lipoprotein, were observed. This study suggests that a DRV/r- and ETR-based regimen can be substituted for an ENF-based regimen while maintaining virologic suppression.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Darunavir; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Protease; HIV Reverse Transcriptase; Humans; Male; Middle Aged; Nitriles; Peptide Fragments; Pilot Projects; Pyridazines; Pyrimidines; Ritonavir; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load

The introduction of 2 or 3 fully active drugs in human immunodeficiency virus (HIV)-infected patients receiving failing antiretroviral therapy is a key determinant of subsequent treatment efficacy. The aim of this study was to assess the safety and efficacy of a regimen containing raltegravir, etravirine, and darunavir/ritonavir for treatment-experienced patients infected with multidrug-resistant HIV.. Patients enrolled in this phase II, noncomparative, multicenter trial were naive to the investigational drugs and had plasma HIV RNA levels >1000 copies/mL, a history of virologic failure while receiving nonnucleoside reverse-transcriptase inhibitors (NNRTI), > or =3 primary protease inhibitor and nucleoside reverse transcriptase inhibitor (NRTI) mutations, and < or =3 darunavir and NNRTI mutations. The primary end point was the proportion of patients with plasma HIV RNA levels <50 copies/mL at 24 weeks.. A total of 103 patients enrolled in the study. At baseline, genotypic resistance profiles showed a median of 4 primary protease inhibitor mutations, 1 NNRTI mutation, and 6 NRTI mutations. In addition to the investigational drugs, 90 patients (87%) received optimized background therapy that included NRTIs (86 patients) or enfuvirtide (12 patients). At week 24, 90% of patients (95% confidence interval, 85%-96%) had an HIV RNA level <50 copies/mL. At week 48, 86% (95% confidence interval, 80%-93%) had an HIV RNA level <50 copies/mL. The median CD4 cell count increase was 108 cells/mm(3). Grade 3 or 4 clinical adverse events were reported in 15 patients (14.6%). Only 1 patient discontinued the investigational antiretroviral regimen, because of an adverse event.. In patients infected with multidrug-resistant virus who have few remaining treatment options, the combination of raltegravir, etravirine, and darunavir/ritonavir is well tolerated and is associated with a rate of virologic suppression similar to that expected in treatment-naive patients.

Topics: Adult; Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; Female; HIV Infections; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Treatment Outcome

This crossover, open-label clinical study evaluated the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (elvitegravir/r), an HIV integrase inhibitor, and etravirine, a non-nucleoside reverse transcriptase inhibitor.. Healthy volunteers were randomized into one of two groups, each with two arms. Group 1 (n = 20) followed a sequence of 10-day dosing of elvitegravir/r (150/100 mg once daily) and elvitegravir/r plus etravirine (200 mg twice daily) or the reverse (n = 10 per sequence). Group 2 (n = 14) followed a sequence of 10-day dosing of etravirine and etravirine plus elvitegravir/r or the reverse (n = 7 per sequence), all under fed conditions. Elvitegravir, ritonavir and etravirine pharmacokinetics were determined on days 10 and 20 using non-compartmental analyses. Lack of pharmacokinetic alteration bounds for 90% confidence intervals (CI) about the geometric mean ratio (GMR; coadministration versus alone) were 70-143% for elvitegravir and ritonavir pharmacokinetics (maximum concentration [C(max)], concentration at the end of the dosing interval [C(tau)] and area under the plasma concentration-time curve [AUC(tau); 0-24 h] and 80-125% for etravirine pharmacokinetics (AUC(tau) 0-12 h).. Of the 34 enrolled participants, 31 completed the study. There were three discontinuations, but none were caused by adverse events (AEs). The most common treatment-emergent AE was headache. Elvitegravir pharmacokinetic GMR was 6-7% higher following elvitegravir/r plus etravirine dosing versus elvitegravir/r. The GMR for etravirine and ritonavir AUC(tau) were 2.4% and 12.3% lower, respectively. Importantly, the 90% CI for elvitegravir and etravirine pharmacokinetics and AUC(tau) and C(max) for ritonavir were within the lack of alteration bounds.. Elvitegravir/r and etravirine do not undergo clinically relevant drug interactions and can be coadministered without dose adjustment.

Topics: Adolescent; Adult; Cross-Over Studies; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Quinolones; Reverse Transcriptase Inhibitors; Ritonavir

To evaluate the pharmacokinetics of TMC125 (etravirine) and darunavir (DRV) with low-dose ritonavir (DRV/r).. Open-label, randomized, two-way crossover Phase I trial.. Thirty-two HIV-negative volunteers were randomized 1:1 to two panels. All received TMC125 100 mg twice daily for 8 days and, after 14 days washout, DRV/r 600/100 mg twice daily for 16 days. During days 9-16, TMC125 100 or 200 mg twice daily was coadministered (Panel I or II, respectively).. Twenty-three volunteers completed the trial. With DRV/r coadministration, mean exposure (area under the plasma concentration-time curve from 0 to 12 h [AUC12h) to TMC125 given as 100 mg twice daily was decreased by 37%; maximum and minimum plasma concentrations (Cmax and Cmin) were decreased by 32% and 49%, respectively. For TMC125 200 mg twice daily coadministered with DRV/r, AUC12h, Cmax and Cmin of TMC125 were 80%, 81% and 67% greater, respectively, versus TMC125 100 mg twice daily alone. DRV pharmacokinetics were unchanged except a 15% increase in AUC12h when given with TMC125 200 mg twice daily.. No clinically relevant changes in DRV pharmacokinetics were observed when combined with TMC125; therefore DRV dose adjustment is not required. Coadministration of TMC125 100 mg twice daily with DRV/r decreased TMC125 exposure by 37%. The increase of TMC125 exposure by 80% when given as 200 mg twice daily reflects the higher dose and the interaction with DRV/r. The magnitude of this interaction is comparable to TMC125 interactions with other boosted PIs observed in Phase IIb trials in HIV-1-infected patients. As these trials demonstrated TMC125 efficacy, no dose adjustment of TMC125 is needed when combined with DRV/r.

Topics: Adult; Cross-Over Studies; Darunavir; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Reference Values; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

To assess the efficacy of raltegravir, etravirine and darunavir/ritonavir (TRIO regimen) in treatment-experienced patients with human immunodeficiency virus-1 (HIV-1) infection by describing the proportion of patients who experienced virological failure (VF) at Week 24. The secondary objectives were to assess the HIV-1 plasma viral load (pVL) after Week 24, the proportion of patients who were receiving dual therapy or monotherapy at the last visit, and the number of deaths.. Patients from the ANRS CO3 Aquitaine Cohort who were prescribed the TRIO regimen between February 2007 and September 2018 were classified into two groups based on their pVL at study inclusion: the virological failure group (VFG; pVL >50 copies/mL) and the virologically suppressed group (VSG; pVL <50 copies/mL). The impact of baseline pVL and genotypic susceptibility score (GSS) on VF was analysed.. In total, 184 patients were enrolled in this study, with 123 (66.8%) in the VFG and 61 (33.2%) in the VSG. The median length of follow-up was 7.5 (interquartile range 4.1-9.6) years, and 29 (15.8%) patients died. Thirty-seven (25.5%) patients experienced VF at Week 24, including 32/145 (32.7%) in the VFG and 5/47 (10.6%) in the VSG (P<0.01). Resistance-associated mutations were detected in integrase, reverse transcriptase and protease for 7/37 (18.9%), 3/37 (8.1%) and 1/37 (2.7%) patients, respectively. High pVL and GSS at baseline were independently associated with VF. At the last visit, 76/184 (41.3%) patients were still receiving the TRIO regimen, while 55/184 (29.9%) were receiving dual therapy and 1/184 (0.5%) was receiving protease inhibitor monotherapy. Among the 56 patients receiving dual therapy or monotherapy, 51 (96.2%) had pVL <50 copies/mL.. Despite a high level of mutation resistance at baseline, long-term virological follow-up was favourable and one-third of patients were eligible for drug-reducing strategies.

Topics: Anti-HIV Agents; Darunavir; Drug Resistance, Viral; Follow-Up Studies; HIV Infections; HIV-1; Humans; Raltegravir Potassium; Ritonavir; Treatment Outcome; Viral Load

To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age.. Phase I/II, open-label, multicenter, dose-finding study.. Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants with ETR AUC12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics.. Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC12  h less than 2350 ng h/ml and underwent a dose increase. ETR AUC12  h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued.. ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.

Topics: Adult; Anti-HIV Agents; Child; Child, Preschool; HIV Infections; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Treatment Outcome

Solid dosage forms of amorphous solid dispersions (ASDs) have rarely been assessed for their crushability, although it might possibly be a more frequent practice than thought to facilitate oral administration in several clinical conditions (e.g. dysphagia) when no oral liquids of the same drug are available. Nevertheless, there are concerns that contraindicate these formulations' modification by grinding. For example, amorphous-amorphous phase separation, induction of crystallization, decreasing particle sizes, etc. might occur during grinding without knowing the implications on bioavailability. Hence, in this study, Sporanox® (itraconazole), Intelence® (etravirine), Noxafil® (posaconazole) and Norvir® (ritonavir), were selected as "model" enabling formulations (based on ASD) to evaluate if this concern was justified. Their assessment in simple and biorelevant media by two-stage in-vitro drug-release testing was performed which resulted in strong suspicion that pulverization is contradicted for some of these formulations. Despite differences were observed, uncertainty remains on the clinical relevance of these data as by golden standard it should still be confirmed by bioequivalence trials.

Topics: Administration, Oral; Antifungal Agents; Antiviral Agents; Biological Availability; Chemistry, Pharmaceutical; Crystallization; Drug Compounding; Drug Liberation; Equivalence Trials as Topic; Itraconazole; Nitriles; Particle Size; Pyridazines; Pyrimidines; Research Design; Ritonavir; Solubility; Therapeutic Equivalency; Triazoles; X-Ray Diffraction

Data are limited on the selection and sequencing of second-line and third-line pediatric antiretroviral treatment (ART) in resource-limited settings. This study aimed to evaluate characteristics of African pediatric patients initiated on darunavir (DRV) and/or etravirine (ETR) through a specific drug donation program.. This was a cross-sectional study of baseline immunologic, virologic and demographic characteristics of children and adolescents initiating DRV-based and/or ETR-based ART. Descriptive statistics were used.. Study enrolled 48 patients (45.8% women; median age = 15 years [interquartile range 17.7-10.3]) at 9 clinical sites in Zambia, Swaziland, Kenya and Lesotho. The majority (87.5%; n = 42) had received ≥2 prior ART regimens; most (81.2%) had received lopinavir/ritonavir-based ART before switch. All patients had detectable HIV RNA (median = 56,653 copies/mL). Forty seven patients (98.9%) had HIV genotype results: 41 (87.2%) had ≥1 nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistance mutation (RM), predominantly M184V (76.6%; n = 36); 31 (65.9%) had ≥1 non-NRTI-RM, including 27 (57.4%) with ≥1 ETR-RM; 30 (63.8%) had ≥3 protease inhibitor RM, including 20 (42.6%) with ≥1 DRV-RM. For new ART regimens, DRV and raltegravir were most frequently prescribed (83.3%; n = 40 on DRV and raltegravir, each). Eighteen patients (37.5%) were initiated on the NRTI-sparing ART.. In our study, a significant proportion of treatment-experienced African children and adolescents had one or more DRV-RM and ETR-RM. For the new regimen, more than a third of pediatric patients failing second-line ART were prescribed NRTI-sparing regimens. Better understanding of the current approaches to pediatric ART sequencing in resource-limited settings is needed.

Topics: Adolescent; Anti-Retroviral Agents; Child; Child, Preschool; Cross-Sectional Studies; Darunavir; Eswatini; Female; HIV Infections; HIV-1; Humans; Kenya; Lesotho; Lopinavir; Male; Nitriles; Pyridazines; Pyrimidines; Raltegravir Potassium; Ritonavir; RNA, Viral; Viral Load; Young Adult; Zambia

Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor (NNRTI) available in France since 2006, is indicated for antiretroviral-experienced HIV-infected adults, in combination with a ritonavir-boosted protease inhibitor (PI). To assess its clinical impact in routine care, we compared hospitalization rates according to ETR + PI prescription or not, among heavily treated HIV-1 infected individuals on failing regimens between 2005 and 2011.. From the French Hospital Database on HIV (ANRS CO4), we selected heavily treated individuals (prior exposure to at least 2 nucleoside reverse transcriptase inhibitor (NRTI), 2PI and 1 NNRTI) with viral load (VL) > 50 copies/mL who started a new antiretroviral (ARV) regimen between 2005 and 2011. Using an intention-to-continue-treatment approach, hospitalization rates were calculated for the individuals who received ETR + PI, during the months after initiating ETR + PI (ETR + PI) or for the individuals who received ETR + PI, in the months before ETR + PI initiation and for the individuals who never received ETR + PI (no ETR + PI). hospitalization from an AIDS-defining cause and hospitalization from a non-AIDS defining cause rates were also calculated. Poisson regression models were used to compare the incidences between the two groups, with adjustment for potential confounders.. Of 3884 patients who met the inclusion criteria, 838 (21.6%) received ETR + PI. During 13,986 person-years (P-Y) of follow-up, there were 2484 hospitalizations in 956 individuals. The hospitalization rates per 1000 P-Y were 169.0 among individuals exposed to ETR + PI and 179.3 among those not exposed to ETR + PI. After adjustment, the respective hospitalization rates were 148.8 and 186.7 per 1000 P-Y, with an estimated relative risk of 0.80 (95%CI: 0.71-0.90), AIDS hospitalization rates were 11.5 and 22.7 per 1000 P-Y, with an estimated relative risk of 0.51(95%CI: 0.39-0.66) and non-AIDS hospitalization rates were 139.5 and 152.2 per 1000 P-Y, with an estimated relative risk of 0.92 (95%CI: 0.80-1.05).. Between 2005 and 2011, access to ETR + PI was associated with a 20% reduction in the hospitalization rate among heavily treated HIV-1-infected individuals. This reduction was mainly due to a reduction in the AIDS hospitalization rate.

Topics: Adolescent; Adult; Drug Therapy, Combination; Female; France; HIV Infections; HIV-1; Hospitalization; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Risk; Ritonavir; RNA, Viral; Viral Load; Young Adult

Drug therapy has been instrumental in prolonging the lives of patients infected by human immunodeficiency virus (HIV). In order to combat development of resistance, therapies involving three or more drugs in combination are recommended by the World Health Organization (WHO) to suppress HIV and prevent development of acquired immune deficiency syndrome (AIDS). It is desirable for multidrug combinations to be coformulated into single dosage forms where possible, to promote patient convenience and adherence to dosage regimens, for which amorphous solid dispersion (ASD) is particularly well-suited. We investigated multidrug ASDs of three model anti-HIV drugs, ritonavir (Rit), etravirine (Etra), and efavirenz (Efa), in cellulosic polymer matrices. We hypothesized that the presence of multiple drugs would reduce crystallization tendency, thereby providing stable, supersaturating formulations for bioavailability enhancement. We explored new ASD polymers including cellulose acetate suberate (DS

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cellulose; Crystallization; Cyclopropanes; Drug Stability; Humans; Hydrophobic and Hydrophilic Interactions; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Solubility

Genotyping tests were developed to attenuate the impact of viral resistance. Information about the efficacy in genotype base antiretroviral therapy in children is rare and even more in low- and middle-income countries.. Sixteen children with antiretroviral therapy (ART) failure and triple-class drug-resistant viruses were included in this study. Protease and retrotranscriptase genotypes were available for all patients. Switch of ART regimen was guided by genotyping data. The primary end point was virological suppression (<50 copies/ml) and immunological improvement after 48 wk of treatment with the new ART regimen.. The median age of the patients was 14.5 y (interquartile range (IQR) 11-16.5). Median HIV-1 RNA viral load was 4.2 log10 (IQR: 3.4-4.8). The primary end point was found in 11 children (69%), and 13 children (81%) had an HIV-1 RNA viral load <200 copies/ml. Median (IQR) for the baseline CD4(+) cell count was 382 cells/μl (281-686 cells/μl), whereas after 48 wk of treatment with the new ART regimen, it was 640 cells/μl (361-936 cells/μl) (P < 0.001).. Darunavir/ritonavir, raltegravir, and etravirine were well tolerated in the present pediatric population. These drugs provide good options for children exposed to extensive ART. Regimens guided by genotyping data were effective for children who had ART failure and multidrug-resistant HIV-1 infection.

Topics: Adolescent; Anti-Retroviral Agents; CD4 Lymphocyte Count; Child; Darunavir; Drug Resistance, Multiple, Viral; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Nitriles; Poverty; Pyridazines; Pyrimidines; Raltegravir Potassium; Retrospective Studies; Ritonavir; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

Topics: Anti-HIV Agents; Antiviral Agents; Area Under Curve; Carbamates; Coinfection; Darunavir; Diuretics; Drug Interactions; Hepatitis C, Chronic; HIV Infections; Humans; Imidazoles; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidines; Renal Insufficiency; Ritonavir; Treatment Outcome; Valine

Limited data are available for once-daily (QD) darunavir (DRV)/ritonavir (r) in the pediatric population. Coadministration of etravirine (ETR) may alter the pharmacokinetics (PK) of DRV. We evaluated the PK interactions between DRV/r (QD) and ETR QD or twice-daily (BID) in children, adolescents, and young adults.. Human immunodeficiency virus-infected subjects 9 to < 24 years old on optimized background therapy including DRV/r 800/100 mg QD alone or combined with ETR 200 mg BID or ETR 400 mg QD were enrolled. Protocol-defined target drug exposure ranges based on adult data were used to assess the adequacy of each regimen. Intensive 24-hour blood sampling was performed, and PK parameters were determined using noncompartmental analysis.. Thirty-one subjects (14 males) completed the study; 16 received DRV/r QD alone (group 1), 6 received DRV/r plus ETR BID (group 2A), and 9 received DRV/r plus ETR QD (group 2B). The geometric mean (90% confidence interval [CI] geometric mean) for DRV area under the curve at 24 hours (AUC24) was 57.9 (49.6-67.6), 74.9 (44.4-126.5), and 66.4 (50.8-86.9) mg × h/L for patients in groups 1, 2A, and 2B, respectively. The increased DRV exposure when coadministered with ETR was not statistically significant. The geometric mean (90% CI geometric mean) of ETR AUC24 was 8.6 (4.4-16.8) and 11.9 (7.5-18.9) mg × h/L for groups 2A and 2B, respectively, with comparable C24.. The results suggest that DRV/r QD with ETR 400 mg QD or 200 mg BID is appropriate and support further evaluation of the safety and efficacy of the once-daily regimen in older children, adolescents, and young adults.

Topics: Adolescent; Adult; Anti-HIV Agents; Child; Darunavir; Female; HIV Infections; Humans; Male; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides; Young Adult

The development of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with baseline human immunodeficiency virus (HIV)-1 RNA level (VL), CD4 cell counts (CD4), subtype, and treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in individuals from Thailand, South Africa, India, Malawi, Tanzania.. CD4 and VL were captured at AIDs Clinical Trial Group (ACTG) A5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on an NNRTI regimen. HIV drug-resistance mutation associations with subtype, site, study entry VL, and CD4 were evaluated using Fisher exact and Kruskall-Wallis tests.. Of the 207 individuals who were screened for A5230, sequence data were available for 148 individuals. Subtypes observed: subtype C (n = 97, 66%) AE (n = 27, 18%), A1 (n = 12, 8%), and D (n = 10, 7%). Of the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (P < .001). Differences in drug-resistance patterns in both NRTI and NNRTI were observed by site.. The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry. Thirty-two percent of individuals remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Resistance, Viral; Female; Health Resources; HIV Infections; HIV-1; Humans; India; Lopinavir; Malawi; Male; Middle Aged; Mutation Rate; Nitriles; Pilot Projects; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Ritonavir; South Africa; Tanzania; Thailand; Treatment Failure; Young Adult

Topics: Adult; Anti-HIV Agents; Brain Edema; Darunavir; Diagnosis, Differential; Dideoxynucleosides; Emergencies; Female; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Nitriles; Posterior Leukoencephalopathy Syndrome; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

Among 103 patients with multidrug-resistant HIV who initiated raltegravir, etravirine, and darunavir/ritonavir-containing regimen in the ANRS 139 TRIO trial, 100 participated in extended follow-up and continued study treatment until week 96. Among them, 87 (87%) received an optimized background therapy including either nucleoside reverse transcriptase inhibitors or enfuvirtide, they were 78 (78%) at week 96. At week 96, 88% achieved durable virologic response (<50 copies/mL). CD4 response was maintained (median change of +150 cells/mm(3)). No major toxicity was reported. This triple drug combination showed sustained efficacy and thus should be strongly considered for patients with multiclass-resistant virus.

Topics: Adult; Darunavir; Drug Resistance, Multiple, Viral; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides

Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal tissues is paramount to designing future prevention interventions.. A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One rectal tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days.. Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine.. Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.

Topics: Adult; Anti-HIV Agents; Darunavir; Human Experimentation; Humans; Male; Nitriles; Plasma; Pyridazines; Pyrimidines; Rectum; Ritonavir; Semen; Sulfonamides; Young Adult

Thirty-nine HIV-1-infected patients treated for 156 weeks with a new nucleoside analogue-sparing regimen [raltegravir, etravirine and maraviroc (REM) or raltegravir, etravirine and darunavir/ritonavir (RED)] showed a uniform increase in fasting glucose levels and a uniform decrease in insulin secretory capacity. Diabetes mellitus occurred in one RED-treated and four REM-treated patients. A worsening glucose tolerance was observed in highly treatment-experienced HIV-infected patients receiving effective antiretroviral therapy after virological failure.

Topics: Anti-HIV Agents; Blood Glucose; Cyclohexanes; Darunavir; Fasting; Glucose Tolerance Test; HIV Protease Inhibitors; HIV Seropositivity; HIV-1; Humans; Insulin; Insulin Resistance; Maraviroc; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Treatment Outcome; Triazoles; Viral Load

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cyclohexanes; Drug Interactions; Female; HIV Infections; Humans; Male; Maraviroc; Middle Aged; Multicenter Studies as Topic; Nitriles; Plasma; Pyridazines; Pyrimidines; Ritonavir; Triazoles

The effectiveness of etravirine has not been thoroughly investigated in routine clinical practice, where adherence rates and the heterogeneous nature of patients differ from the clinical trial setting. We evaluated the effectiveness of rescue regimens containing etravirine and the factors associated with treatment response. Multicenter retrospective cohort of all consecutive patients was recruited in a routine clinical practice setting. Patients were taking rescue regimens containing etravirine plus an optimized background regimen. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/ml at week 48. The secondary endpoints were those factors associated with treatment response to etravirine. Endpoints were evaluated using univariate and multivariate analysis. A total of 122 patients were included with a median viral load of 11,938 (1055-55,500) copies/ml at baseline. The most frequent drugs in the backbone were darunavir/ritonavir in 98 (80.3%) patients and raltegravir in 76 (62.3%). In the full dataset analysis, 73% (89/122; 95% CI, 64-81%) of patients responded to treatment at week 48; in the on-treatment analysis, 82% (89/109; 95% CI, 71-87%) responded. The factors associated with treatment failure to etravirine [HR (95% CI)] were baseline CD4(+) T cell count <200 cells/mm(3) [2.45 (1.17-5.16)] and use of raltegravir [0.47 (0.22-0.99)] and darunavir [0.45 (0.21-0.98)] as backbone drugs. Skin rash was the only adverse event directly related to etravirine and led to withdrawal in three patients (2.5%). In routine clinical practice, rescue ETR-containing regimens are well tolerated and achieve rates of virological suppression higher than those observed in its pivotal clinical trials, especially when combined with darunavir and raltegravir.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cohort Studies; Darunavir; Exanthema; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Retrospective Studies; Ritonavir; RNA, Viral; Sulfonamides; Treatment Failure; Treatment Outcome; Viral Load

It was the purpose of this study to investigate excipient-mediated precipitation inhibition upon induction of supersaturation of poorly water-soluble drugs in aspirated human intestinal fluids (HIF) representing both the fasted and fed state. Etravirine, ritonavir, loviride, danazol and fenofibrate were selected as model compounds. For comparative purposes, precipitation inhibition was also evaluated in simple aqueous buffer, and in intestinal simulation media representative for the fasted and fed state (FaSSIF and FeSSIF, respectively). Supersaturation was induced in the test media containing predissolved excipient (HPMC-AS, HPMC-E5, HPMC-E50, HPMC-E4M, HPMC-P and PVP) at a defined degree of supersaturation (DS = 20) using the solvent shift method. The results illustrate that cellulosic polymers can reduce the precipitation rate and stabilize supersaturation in HIF. The extent of stabilization was compound and excipient dependent but independent of the nutritional state. Whenever excipient effects were observed, the predictive value of simple buffer or FaSSIF/FeSSIF was rather limited. In general, excipient-mediated precipitation inhibition was less pronounced in HIF compared to simple aqueous buffer or FaSSIF/FeSSIF. However, excipients showing no effect in simple aqueous buffer or FaSSIF/FeSSIF also proved to be ineffective in HIF, indicating the value of these simulation media in the elimination of excipients during formulation development.

Topics: Acetamides; Acetophenones; Adult; Body Fluids; Danazol; Excipients; Female; Fenofibrate; Humans; Intestines; Male; Nitriles; Pharmaceutical Preparations; Polymers; Pyridazines; Pyrimidines; Ritonavir; Solubility; Young Adult

Topics: Anti-Retroviral Agents; Aspergillosis; Aspergillus; Drug Interactions; Female; HIV Infections; HIV-1; Humans; Male; Nitriles; Pneumonia, Aspiration; Pyridazines; Pyrimidines; Ritonavir; Triazoles; Voriconazole

Topics: Darunavir; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Measurement of drug levels in plasma is currently the gold standard for pharmacological studies. However, venous sampling is not feasible in some populations (e.g., neonates) or may be difficult in certain situations, such as nonhospital-based settings. Dried blood spots (DBS) can be obtained by a simple fingerprick and the subsequent collection of blood on a filter card, allowing patient-friendly sample collection in non-hospital-based settings. Despite these advantages, thus far no clinical evaluation has been performed for the use of DBS concentrations as surrogates for plasma levels. Our purpose was to clinically evaluate DBS sampling for the determination of plasma concentrations for the novel antiretroviral drugs etravirine, darunavir/ritonavir and raltegravir.. DBS concentrations were measured in 11 HIV-infected patients using LC-MS/MS. DBS concentrations were proportional to plasma concentrations. All drug concentrations were higher in DBS than in plasma samples. The plasma:DBS ratio and the respective relative standard error of estimate (RSE) of darunavir, etravirine, raltegravir and ritonavir were 0.632 (4.97% RSE), 0.523 (4.84% RSE), 0.617 (14.9% RSE) and 0.592 (2.99% RSE), respectively. Hematocrit did not explain variability in our study.. DBS are reproducibly correlated to plasma levels and can be used for monitoring antiretroviral drug exposure in HIV-infected patients.

Topics: Blood Specimen Collection; Chromatography, High Pressure Liquid; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Male; Mass Spectrometry; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Therapeutic options for treatment-experienced HIV-infected patients have been limited. The DUET trial evaluated the use of etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), or placebo, in 1203 treatment-experienced, HIV-infected patients. Eligible patients had to have evidence of NNRTI and protease inhibitor resistance-associated mutations, and evidence of virologic failure, as defined as a plasma viral load > 5000 copies/ml on antiretroviral therapy at the time of screening. Patients in both arms received an optimized background regimen including darunavir/ritonavir. DUET demonstrated superior outcomes in virologic suppression (plasma viral load < 50 copies/ml) and clinical end points including new AIDS-defining illnesses and death, in those randomized to receive etravirine. These results were maintained at 48 weeks of follow-up. Furthermore, etravirine was shown to be safe and well-tolerated over this period. In exploratory analyses, patients in the DUET study with greater number of active agents within the background regimen were more likely to have a fully suppressive response. Taken together, the DUET results highlight the high rates of virological success that can be achieved using new active agents, such as ritonavir-boosted darunavir and etravirine, in treatment-experienced patients with underlying drug-resistant HIV infection.

Topics: Antiretroviral Therapy, Highly Active; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Nitriles; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Ritonavir; Sulfonamides; Viral Load

Topics: Drug Approval; Drug Labeling; HIV Protease Inhibitors; Humans; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Tablets; United States; United States Food and Drug Administration

To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients.. Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling.. Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l(-1) in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%.. The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK-PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance.

Topics: Anti-HIV Agents; Darunavir; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Intestinal Absorption; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Salvage Therapy; Sulfonamides

The randomized, placebo-controlled Phase III DUET studies enrolled treatment-experienced, HIV-1-infected patients. We examined the genotypic and phenotypic changes at endpoint relative to baseline, including the emergence of individual reverse transcriptase (RT) mutations, in patients who received the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine and experienced virologic failure by rebound by the time of the Week 96 analysis. Patients received etravirine 200 mg twice-daily in combination with a background regimen containing darunavir/ritonavir, investigator-selected nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. Virologic failure by rebound occurred in 93 (15.5%) etravirine-treated patients (compared with 170 [28.1%] placebo-treated patients). Patients experiencing virologic failure had more baseline antiretroviral resistance and lower activity of the background regimen relative to those not experiencing failure. Emergence of NNRTI resistance-associated mutations was observed in 55 of 93 patients. The most frequently emerging RT mutations were V179F, V179I, and Y181C, with positions K101 and E138 also showing frequent changes. Mutations usually emerged in a background of multiple other NNRTI mutations and were, in most cases, associated with a decrease in phenotypic sensitivity to etravirine at endpoint. Further analysis is needed to clarify the role of mutations at position 138 as determinants of etravirine resistance.

Topics: Amino Acid Substitution; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials, Phase III as Topic; Darunavir; Drug Resistance, Viral; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Mutation, Missense; Nitriles; Peptide Fragments; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Ritonavir; Sequence Analysis, DNA; Sulfonamides; Treatment Failure; Viral Load

Etravirine is an enzyme inducer and could lower the concentration of combined drugs. Ten HIV-1-infected patients with multiple treatment failure received raltegravir (400 mg, twice daily) and darunavir/ritonavir (600/100 mg, twice daily). Addition of etravirine (200 mg, twice daily) leads to a significant increase in raltegravir and darunavir trough concentrations (405 vs. 118 and 3837 vs. 2241 ng/ml) and darunavir area under the curve (AUC(12h)) (50 083 vs. 36 277 ng h/ml). All pharmacokinetic parameters appeared to be highly variable regardless to the addition of etravirine.

Topics: Adolescent; Adult; Darunavir; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides; Young Adult

Multiclass-drug resistance, often caused by poor treatment compliance, is a challenging problem in all categories of HIV-infected patients. Selective pressure is higher in youth for both biological and behavioral reasons. We report the case of a 15-year-old Caucasian male, with vertically acquired HIV-1 infection, who failed several lines of antiretroviral therapy and was successfully treated with darunavir/ritonavir and etravirine.

Topics: Adolescent; Darunavir; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Infectious Disease Transmission, Vertical; Male; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides; Treatment Outcome

The new potent combination of antiretrovirals etravirine, darunavir, and ritonavir requires a new bioanalytical method for clinical pharmacology investigations and potential therapeutic drug monitoring. The development and validation of a novel LC-MS method for the simultaneous quantification of the most recently FDA-approved protease inhibitor and non-nucleoside reverse transcriptase inhibitor is described. This novel method was developed and validated using a sub-2 microm particle column, and provides excellent chromatographic separation and peak shape for all three analytes and internal standard. The method was validated over the range of 0.002-2.0 microg/mL. Intra- and inter-day accuracy of all analytes ranged from 88 to 106%, and intra- and inter-day precision was <7%. Dilution of samples 2-, 5-, and 10-fold maintained accuracy and precision, using a sample volume as low as 10 microL. Finally, the applicability of the method was investigated with clinical samples and external quality assurance proficiency testing samples.

Topics: Chromatography, High Pressure Liquid; Darunavir; HIV Protease Inhibitors; Humans; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Spectrometry, Mass, Electrospray Ionization; Sulfonamides; Tandem Mass Spectrometry

An increasing prevalence of antiretroviral therapy (ART) resistance in ART-experienced and ART-naive pregnant women has been reported. Some studies suggest that antiretroviral drug-resistant viruses might have decreased replication capacity and transmissibility. However, cases of perinatal transmission of multidrug-resistant HIV type-1 (HIV-1) have been described. Here, we report the case of one child with vertically-acquired multidrug-resistant HIV-1 and the outcome of a rescue therapy with a darunavir/ritonavir- and etravirine-containing antiretroviral regimen. During the 15 months of therapy, the child showed clinical improvement, including no side effects, persistent suppression of viral replication and a great increase in CD4+ T-cell count. Paediatric HIV specialists should be prepared to manage a small, but increasing, number of babies with a 'nightmare' multidrug-resistant virus with no available treatment options. The use of experimental agents might become a compelling issue in vertically HIV-infected children born in the era of highly active ART.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Darunavir; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Nitriles; Pregnancy; Pregnancy Complications, Infectious; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

Cumulative antiretroviral exposure can result in multiclass HIV drug resistance. Experimental antiretroviral agents offer limited therapeutic benefit as resistance quickly develops after their introduction as a sole new agent.. To assess the pharmacokinetic profile, safety and virological response of two novel investigational antiretroviral agents when used in combination in HIV-1-infected subjects with multidrug-resistant virus.. HIV-1-infected subjects, with current virological failure on a stable antiretroviral regimen with no viable treatment options were assigned to a regimen comprising two new investigational agents, etravirine, a novel nonnucleoside reverse transcriptase inhibitor, and darunavir, a novel protease inhibitor, plus nucleoside reverse transcriptase inhibitors (and enfuvirtide in selected patients) for 24 weeks. Virological, immunological and safety parameters were collected. Detailed pharmacokinetic assessments of darunavir and etravirine were determined on days 7 and 28.. Follow up of 24 weeks was achieved by 10/12 patients. Median reduction in HIV RNA was 2.7 log10 copies/ml (range, 2.3-3.9) and increase in CD4 lymphocytes was 113 cells/microl (range, 41-268). HIV RNA was < 40 copies/ml in nine. No serious adverse events were recorded. Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor.. This first study to assess the use of etravirine and darunavir in HIV-1-infected subjects with no treatment options showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions.

Topics: Adult; Anti-Retroviral Agents; Area Under Curve; CD4 Lymphocyte Count; Darunavir; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; RNA, Viral; Sulfonamides; Viral Load