In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

Preferences and feasibility of long-acting technologies for treatment of hepatitis C virus in low- and middle-income countries: A survey of providers and policymakers.

Long-acting technologies (LATs) for hepatitis C virus (HCV) are under development as a strategy to improve linkage to care, treatment adherence and outcomes. We conducted a survey of HCV treatment prescribers and HCV policymakers in low- and middle-income countries (LMICs) regarding acceptability and feasibility of HCV LATs. We included one-time intramuscular injection, subdermal implant and transdermal patch as potential LAT options. We surveyed participants regarding optimal health system and patient characteristics, concerns, potential barriers, overall feasibility and preferences for HCV LAT as compared to daily oral medication. Overall, 122 providers and 50 policymakers from 42 LMICs completed the survey. Among providers, 93% (113/122) expressed willingness to prescribe LAT and 72% (88/120) of providers preferred LAT if provided at comparable efficacy, safety and cost as current oral treatments. Of providers preferring HCV LAT to daily oral medication, 67% (59/88) preferred injection, 24% (21/88) preferred patch and 9% (8/88) preferred implant. Only 20% (24/122) would prescribe LAT if it were more costly than oral treatment. In regression analysis, no provider characteristics were associated with preference for LAT over oral treatment. Policymakers reported high likelihood that LAT would be included in treatment guidelines (42/50; 84%) and national drug formularies (39/50; 78%) if efficacy, safety and cost were similar to oral treatment. HCV LATs could advance progress to HCV elimination in LMICs by diversifying treatment options to improve treatment coverage and outcomes. Provider preferences from LMICs are a critical consideration in the development of HCV LATs to ensure its early and equitable availability in LMICs.

A randomized trial of double vs single-dose etonogestrel implant to overcome the interaction with efavirenz-based antiretroviral therapy.

BACKGROUND: Concomitant use of efavirenz-based antiretroviral therapy and a standard-dose etonogestrel contraceptive implant led to 82% lower etonogestrel exposure when compared with women who do not receive antiretroviral therapy. The clinical impact of this reduced exposure is supported by retrospective cohort evaluations that demonstrated higher rates of unintended pregnancies when contraceptive implants were combined with efavirenz. We hypothesized that placement of 2 etonogestrel implants in those taking efavirenz-based antiretroviral therapy could increase etonogestrel exposure and improve measures of contraceptive efficacy. OBJECTIVE: This study compared the rate of ovulation and etonogestrel pharmacokinetics among women on efavirenz-based antiretroviral therapy who received 2 etonogestrel implants (136 mg; double implant group) in comparison with those who received 1 etonogestrel implant (68 mg; control group). STUDY DESIGN: This randomized, open-label study enrolled Ugandan women with regular menstrual periods who were receiving efavirenz-based antiretroviral therapy for the treatment of HIV. Participants were randomized 1:1 to the double implant or control group, and the etonogestrel implant(s) were placed in the same arm at enrollment. All participants used a copper intrauterine device to prevent pregnancy. Ovulation was evaluated by weekly serum progesterone concentrations measured over 4 consecutive weeks at months 3 (weeks 9-12), 6 (weeks 21-24), and 12 (weeks 45-48). Progesterone concentrations >3 ng/mL were interpreted as ovulation. The ovulation rate in each group was compared using Fisher's exact tests for each month and generalized estimating equations over 48 weeks. Plasma was collected at day 3 and weeks 1, 4, 12, 24, 36, and 48 after implant placement and analyzed using a validated liquid chromatography-triple quadrupole mass spectrometry method for etonogestrel. Etonogestrel concentrations were summarized as median (interquartile range) and compared between groups by geometric mean ratio with 90% confidence intervals. RESULTS: All participants (n=72) were cisgender Ugandan women with a median age of 31 years (interquartile range, 29-36), and 36 participants were enrolled in each study group. Two participants in the control group discontinued the trial; 1 at week 1 because of undetected pregnancy at entry and another at week 45 because of clinically significant depression. There were 47 ovulations over 104 person-months (45%) in 25 of 34 participants in the control group, and 2 ovulations over 108 person-months (2%) in 2 of 36 participants in the double implant group (month 3: 11 [31%] vs 0 [0%]; month 6: 17 [49%] vs 0 [0%]; month 12: 19 [56%] vs 2 [6%], respectively; all P<.001). The odds of ovulation were reduced by 97.7% (95% confidence interval, 90.1-99.5) in the double implant group over 48 weeks. At each time point, etonogestrel concentration was more than 2-fold higher in the double implant group than in the controls (geometric mean ratio, 2.30-2.83) with a geometric mean ratio of 2.83 (90% confidence interval, 1.89-3.35) at week 48. There were no differences in the adverse events between groups and no participant discontinued because of adverse events. CONCLUSION: Over 48 weeks of combined use, placing 2 etonogestrel implants suppressed ovulation and increased plasma etonogestrel exposure when compared with 1 etonogestrel implant among women on efavirenz-based antiretroviral therapy. Doubling the dose of etonogestrel during efavirenz-based antiretroviral therapy could improve contraceptive effectiveness.

Long-Acting Cabotegravir/Rilpivirine Concentrations in Combination With Intravenous Rifampin: A Case Report.

As antiretroviral therapy advancements focus on long-acting medications, there is a need to assess the potential impact of drug-drug interactions. We present a real-world case of long-acting cabotegravir/rilpivirine co-administered with intravenous rifampin. The combination resulted in both cabotegravir and rilpivirine concentrations falling below 4 times the protein-adjusted IC90.

Oestradiol concentrations in trans women with HIV suppressed on unboosted integrase inhibitor regimens versus trans women without HIV taking oral oestradiol: a pilot study.

BACKGROUND: Feminizing hormone therapy (FHT) is essential to many trans women. Concern about negative drug interactions between FHT and ART can be an ART adherence barrier among trans women with HIV. OBJECTIVES: In this single-centre, parallel group, cross-sectional pilot study, we measured serum oestradiol concentrations in trans women with HIV taking FHT and unboosted integrase strand transfer inhibitor (INSTI)-based ART versus trans women without HIV taking FHT. METHODS: We included trans women with and without HIV, aged ≥18 years, taking ≥2 mg/day of oral oestradiol for at least 3 months plus an anti-androgen. Trans women with HIV were on suppressive ART ≥3 months. Serum oestradiol concentrations were measured prior to medication dosing and 2, 4, 6 and 8 h post-dose. Median oestradiol concentrations were compared between groups using Wilcoxon rank-sum tests. RESULTS: Participants (n = 8 with HIV, n = 7 without) had a median age of 32 (IQR: 28, 39) years. Among participants, the median oral oestradiol dose was 4 mg (range 2-6 mg). Participants had been taking FHT for a median of 4 years (IQR: 2, 8). Six trans women with HIV were taking bictegravir/emtricitabine/tenofovir alafenamide and two were taking dolutegravir/abacavir/lamivudine. All oestradiol concentrations were not significantly different between groups. Eleven (73%) participants had target oestradiol concentrations in the range 200-735 pmol/L at C4h (75% among women with HIV, 71% among those without HIV). CONCLUSIONS: Oestradiol concentrations were not statistically different in trans women with HIV compared with those without HIV, suggesting a low probability of clinically relevant drug-drug interactions between FHT and unboosted INSTI-based ART.

Preferences of Patients and Providers in High-Burden Malaria Settings for Long-Acting Malaria Chemoprevention.

Antimalarial medications are recommended for chemoprevention as part of malaria control programs to decrease the morbidity and mortality related to more than 200 million infections each year. We sought to evaluate patient and provider acceptability of malaria chemoprevention in a long-acting formulation. We administered questionnaires to patients and providers in malaria endemic districts in Kenya and Zambia. Questions explored preferences and concerns around long-acting antimalarial formulations compared with oral formulations. We recruited 202 patient respondents (Kenya, n = 102; Zambia, n = 100) and 215 provider respondents (Kenya, n = 105; Zambia, n = 110). Long-acting injection was preferred to oral pills, whereas oral pills were preferred to implant or transdermal administration by patient respondents. Of 202 patient respondents, 80% indicated that they 'definitely would try' malaria chemoprevention offered by injection instead of oral pills. Of parents or guardians, 84% of 113 responded that they 'definitely would' have their child age < 12 years and 90% of 88 'definitely would' have their child ≥12 years receive an injection for malaria prevention. Provider respondents indicated that they would be more likely to prescribe a long-acting injectable product compared with an oral product for malaria chemoprevention in adults (70%), adolescents ages 12 years and older (67%), and children <12 years (81%). Potential for prolonged adverse effects with long-acting products was the highest concern for patient respondents, while higher medication-related cost was cited as the most concerning barrier to implementation by providers. Overall, these findings indicate enthusiasm for the development of long-acting injectable antimalarials to provide individual delivery method options across age groups.

Quantification of nine antiretroviral drugs in cerebrospinal fluid: An approach to overcome sample collection tube adsorption.

A highly sensitive LC-MS/MS methods were developed and validated to quantify nine antiretrovirals (atazanavir [ATV], tenofovir [TFV], emtricitabine [FTC], darunavir [DRV], dolutegravir [DTG], efavirenz [EFV], lamivudine [3TC], raltegravir [RAL], and ritonavir [RTV]) in human cerebral spinal fluid (CSF). The approach remedies adsorption issues caused by polypropylene based sample collection tubes. 1% ammonium hydroxide in methanol was added in an amount equal to the volume of each quality control (QC) or patient sample. Protein precipitation was utilized with a CSF sample volume of 100 µL and a 100 µL of methanol:ACN and vortexed. Chromatographic separation was achieved with a 3 × 100 ACE® C18 column for ATV, DRV, DTG, EFV, RTV and RAL, and a 2 × 100 Polar RP column for TFV/FTC/3TC. Mobile phase was methanol:water:formic acid (70:30:0.1, v/v/v) for ATV, DRV, DTG, EFV and RTV (10 uL injection, flow rate: 1.00 mL/min), ACN:water:formic acid (35:65:0.1, v/v/v) for RAL (50 uL injection, flow rate: 1.00 mL/min), ACN:water:formic acid (2:98:0.1, v/v/v) for TFV, FTC and 3TC (50 uL injection, flow rate: 0.35 mL/min). Column temperature was 40° C across all assays. The mass spectrometer was operated in positive, multiple-reaction-monitoring (MRM) mode with electrospray ionization (ESI) for all analytes with the exception of EFV, which was operated in negative, MRM mode with ESI. The assay was linear over the calibration range of 1 to 250 ng/mL for all analytes. The addition of 1% ammonium hydroxide in sample tubes overcame up to 44% negative bias in QC samples and allowed the methods to meet full validation criteria.

Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

OBJECTIVE: In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. METHODS: Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. RESULTS: Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CONCLUSION: CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Long-acting antiretrovirals and HIV treatment adherence.

Intramuscular injection of long-acting cabotegravir and rilpivirine is a novel, long-acting antiretroviral therapy (ART) combination approved for use as a fully suppressive regimen for people living with HIV. Long-acting cabotegravir with rilpivirine ART has reduced required dosing frequency from once daily to once every month or every 2 months injections. This new era of long-acting ART, which includes other antiretrovirals and formulations in various stages of clinical development, holds tremendous promise to change the standard of HIV treatment. Although long-acting ART has high potential to be revolutionary in the landscape of HIV care, prevention, and treatment cascade, more data are needed to substantiate its efficacy and cost-effectiveness among patients at risk of non-adherence and across age groups, pregnancy, and post partum. Advocacy efforts and policy changes to optimise a sustained, high-quality, equitable reach of long-acting ART, especially in low-income and middle-income countries where most people living with HIV reside, are needed to realise the full benefits of long-acting ART.

A novel 4-cell in-vitro blood-brain barrier model and its characterization by confocal microscopy and TEER measurement.

The blood-brain barrier (BBB) is a protective cellular anatomical layer with a dynamic micro-environment, tightly regulating the transport of materials across it. To achieve in-vivo characteristics, an in-vitro BBB model requires the constituent cell types to be layered in an appropriate order. A cost-effective in-vitro BBB model is desired to facilitate central nervous system (CNS) drug penetration studies. Enhanced integrity of tight junctions observed during the in-vitro BBB establishment and post-experiment is essential in these models. We successfully developed an in-vitro BBB model mimicking the in-vivo cell composition and a distinct order of seeding primary human brain cells. Unlike other in-vitro BBB models, our work avoids the need for pre-coated plates for cell adhesion and provides better cell visualization during the procedure. We found that using bovine collagen-I coating, followed by bovine fibronectin coating and poly-L-lysine coating, yields better adhesion and layering of cells on the transwell membrane compared to earlier reported use of collagen and poly-L-lysine only. Our results indicated better cell visibility and imaging with the polyester transwell membrane as well as point to a higher and more stable Trans Endothelial Electrical Resistance values in this plate. In addition, we found that the addition of zinc induced higher claudin 5 expressions in neuronal cells. Dolutegravir, a drug used in the treatment of HIV, is known to appear in moderate concentrations in the CNS. Thus, dolutegravir was used to assess the functionality of the final model and cells. Using primary cells and an in-house coating strategy substantially reduces costs and provides superior imaging of cells and their tight junction protein expression. Our 4-cell-based BBB model is a suitable experimental model for the drug screening process.

Effectiveness and Safety of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Patients With HIV-1 Infection and Ongoing Substance Use Disorder: The BASE Study.

Background: People with human immunodeficiency virus (HIV) and substance use disorder (PWH/SUD) are at higher risk of nonadherence to antiretroviral therapy. Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) exhibits high rates of efficacy with a favorable adverse event profile. The BASE study (NCT03998176) is a phase 4, single-arm study evaluating the effectiveness and safety of B/F/TAF among PWH/SUD. Methods: Viremic (HIV RNA >1000 copies/mL) PWH/SUD initiated B/F/TAF once daily for 48 weeks (W). The primary endpoint was proportion of participants with HIV RNA <50 copies/mL at W24. Secondary endpoints were proportion of participants with HIV-1 RNA <50 copies/mL at W48, safety, B/F/TAF adherence (dried blood spot [DBS] concentrations of emtricitabine triphosphate and tenofovir diphosphate [TFV-DP]), substance use (NIDA-ASSIST), and quality of life (SF-12). Results: Forty-three participants were enrolled; 95% reported methamphetamine use. Median age was 38 (range, 21-62) years; 21% were female, 81% White, 14% Black, and 16% Hispanic. Thirty-two (74%) and 21 (49%) participants had HIV RNA <50 copies/mL (intention-to-treat) at W24 and W48, respectively. Seven participants (16%) experienced confirmed virologic failure through W48; 1 developed emergent drug resistance (M184V). Fifteen participants (35%) experienced grade ≥3 adverse events. Five participants (12%) reported suicidal ideation; none resulted in discontinuation. Median DBS concentrations were representative of 5-6 doses/week (TFV-DP, 1603 fmol/punches). NIDA-ASSIST scores declined from baseline to W48 with methamphetamine use decreasing most (-7.9 points; -29%), and SF-12 physical/mental scores increased 1.2 and 7.6 points, respectively. Conclusions: B/F/TAF among a high-risk population of PWH/SUD resulted in an initial 72% viral suppression rate at W24 before dropping to 49% at W48 as retention declined. One participant developed emergent drug resistance (M184V).

Effect of double-dose levonorgestrel subdermal implant in women taking efavirenz-based antiretroviral therapy: The DoubLNG pharmacokinetic study.

OBJECTIVE: We evaluated the pharmacokinetics of double-dose levonorgestrel (LNG) implants to overcome the drug-drug interaction with efavirenz-based antiretroviral therapy (ART). STUDY DESIGN: We conducted a nonrandomized, open-label, parallel-group, longitudinal pharmacokinetic study among Ugandan women ages 18-45 years. Participants with HIV on ART containing efavirenz 600 mg received 300 mg of LNG implants (Jadelle®, Bayer, New Zealand): 300LNG+ART group. We compared our outcomes with women without HIV using standard dose, 150 mg of LNG implants: 150LNG group. The implant was placed on day zero in both groups, and we quantified plasma LNG concentrations over 48 weeks post implant insertion. LNG pharmacokinetic parameters were estimated using noncompartmental techniques. Our primary outcome was the geometric mean ratio with 90% confidence intervals of LNG area under the concentration-time curve over 24 weeks (AUC0-24w) between groups. Demographic data were described as median (interquartile range). A secondary outcome compared between-group percent of LNG concentrations ≥300 pg/mL, a minimum threshold selected a priori based on observed pregnancies in Ugandan women on standard-dose LNG implants plus efavirenz. RESULTS: We enrolled 27 women in the 300LNG+ART group (34 [28.0 to 40.5] years and 61.0 [49.8-66.0] kg) and 19 women in the 150LNG group (33 [30.0 to 34.5] years and 64.9 [59.0 to 74.5] kg). LNG AUC0-24w was 34% lower for 300LNG+ART versus 150LNG (geometric mean 9998 vs. 15,231 pg*week/mL, respectively [geometric mean ratio 0.66 (90% confidence intervals, 0.54 to 0.80)]). The percentage of participants with LNG concentrations ≥300 pg/mL was not statistically different between groups at week 24 (300LNG+ART: 74.1%; 150LNG: 89.5%; p = 0.27). CONCLUSION: Double-dose LNG implant did not completely overcome the drug-drug interaction with efavirenz. IMPLICATION: In women using ART containing efavirenz, placing two implant systems (300 mg) did not normalize LNG pharmacokinetics compared with the standard-dose implant (150 mg), and some women had evidence of ovulatory activity. Alternative ART without drug-drug interactions, such as dolutegravir, is recommended with contraceptive implants.

Antiretrovirals for Human Immunodeficiency Virus Treatment and Prevention in Pregnancy.

Safe and effective antiretroviral medications are needed during pregnancy to reduce maternal morbidity and mortality associated with untreated human immunodeficiency virus (HIV) infection and to prevent viral transmission to the infant. Pharmacokinetic studies have helped inform the appropriate dosing of antiretroviral medications during pregnancy. However, data from these studies consistently become available years after initial regulatory approvals in nonpregnant adults. In this article, the authors provide an overview of considerations in use of antiretroviral medications in pregnant people with or at risk for HIV, pharmacokinetic studies that helped support recommended options, and therapies either under active investigation or in need of prospective study.

Pharmacokinetics of dose-adjusted levonorgestrel emergency contraception combined with efavirenz-based antiretroviral therapy or rifampicin-containing tuberculosis regimens.

OBJECTIVES: To determine if double-dose levonorgestrel emergency contraception (EC) in combination with efavirenz or rifampicin, 2 drugs known to decrease levonorgestrel exposure, resulted in similar pharmacokinetics compared to standard-dose levonorgestrel EC without drug-drug interactions. STUDY DESIGN: We conducted a phase 2, open-label, multicenter, partially randomized, 4 parallel group trial in pre-menopausal females ≥16 years old without an indication for EC and not on hormonal contraception. Participants on dolutegravir-based antiretroviral therapy (ART) received levonorgestrel 1.5 mg (control group); those on rifampicin-containing tuberculosis therapy received levonorgestrel 3 mg; those on efavirenz-based ART were randomized 1:2 to levonorgestrel 1.5 mg or 3 mg. Plasma was collected through 48 hours post-dose to assess levonorgestrel pharmacokinetics. Area under the concentration-time curve (AUC) over 8 hours was the primary outcome. Levonorgestrel pharmacokinetic parameters were compared between groups using geometric mean ratios (GMR) with 90% confidence intervals. RESULTS: The median (Q1, Q3) age for all participants (n = 118) was 34 (27, 41) years and BMI was 23.2 (20, 26.3) kg/m2. Participants receiving levonorgestrel 1.5mg plus efavirenz (n = 17) had 50% lower AUC0-8h compared to the control group (n = 32) [0.50 (0.40, 0.62)]. Participants receiving levonorgestrel 3 mg had a similar AUC0-8h when receiving either efavirenz (n = 35) [0.99 (0.81, 1.20)] or rifampicin (n = 34) [1.16 (0.99, 1.36)] compared to control. Levonorgestrel 3 mg resulted in similar or higher maximum concentration with either efavirenz [1.17 (0.96, 1.41)] or rifampicin [1.27 (1.09, 1.49)] compared to the control group. CONCLUSIONS: Doubling the dose of levonorgestrel EC successfully increased levonorgestrel exposure over the first 8 hours in participants receiving either efavirenz-based ART or rifampicin-containing tuberculosis therapy. IMPLICATIONS: Adjusting levonorgestrel emergency contraception from 1.5 mg to 3 mg improves levonorgestrel pharmacokinetic exposure in participants receiving either efavirenz-based antiretroviral regimens or rifampicin-containing tuberculosis therapy. These data support guideline recommendations to double the dose of levonorgestrel emergency contraception in persons on medications that decrease levonorgestrel exposure by inducing levonorgestrel metabolism.

Long-acting reversible contraception with etonogestrel implants in female macaques (Macaca mulatta and Macaca fascicularis).

Introduction: Contraception is often required for management and population control purposes in group-housed and free-roaming non-human primates. Long-acting reversible contraceptives, including subdermal progestin-releasing implants, are preferred as they eliminate challenges associated with frequent administration. Etonogestrel (ENG)-releasing subdermal implants are reversible and long-acting for a minimum of 3 years, and are commercially available for human use as Implanon® or Nexplanon®. Methods: A retrospective analysis was performed detailing the contraceptive effectiveness and reversibility of subdermal placement of one-fourth or one-third of an ENG implant (68 mg/implant) in 129 female rhesus macaques (Macaca mulatta) and 67 cynomolgus macaques (Macaca fascicularis) at the Biomedical Primate Research Centre (Rijswijk, Netherlands). Furthermore, single cross-sectional ENG serum concentrations were measured for 16 rhesus and 10 cynomolgus macaques, and hemoglobin and blood chemistry pre-ENG and at timepoints >0.5, >1.5, and > 2.5 years post-ENG insertion were evaluated for 24 rhesus macaques. Finally, data were obtained using trans-abdominal ultrasound regarding the influence of ENG on uterine volume and endometrial thickness in 14 rhesus and 11 cynomolgus macaques. Results: As a contraceptive ENG was in 99.80% (CI 93.50-99.99) and 99.95% (CI 99.95-100) effective in rhesus and cynomolgus macaques, respectively. Prolonged ENG durations of implant use in 14 rhesus macaques (range 3.1-5.0 years) and eight cynomolgus macaques (range 3.2-4.0 years) resulted in no unintended pregnancies. A total of 17 female macaques were allowed to breed after ENG removal, and among them, 14 female macaques (82%) had an uneventful delivery. Serum ENG concentrations with a median ENG duration of 1.2 years (range 0.1-6.0 years) and 1.9 years (range 0.6-4.7 years) resulted in median concentrations of 112 pg./mL (range 0-305 pg./mL) and 310 pg./mL (range 183-382 pg./mL) for rhesus and cynomolgus macaques, respectively. ENG had no clinical effect on hemoglobin and blood chemistry parameters nor on the thickness of the endometrial lining or uterus volume. Conclusion: This study indicates that both one-fourth and one-third of the ENG implants are effective, long-acting, reversible, and safe contraceptive to use in macaques.

Pharmacokinetics of levonorgestrel and etonogestrel contraceptive implants over 48†weeks with rilpivirine- or darunavir-based antiretroviral therapy.

BACKGROUND: Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART. OBJECTIVES: To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48 weeks. PATIENTS AND METHODS: Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6 weeks or darunavir-based ART with a run-in of 2 weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48 weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI. RESULTS: At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99-1.37); levonorgestrel: 1.16 (0.97-1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69-3.28); levonorgestrel: 1.89 (1.38-2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel. CONCLUSIONS: Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART.

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV.

PURPOSE OF REVIEW: Cabotegravir (CAB) and rilpivirine (RPV) is the first long-acting injectable antiretroviral therapy (ART) option approved for virologically suppressed adults with HIV-1. In addition, long-acting CAB is a promising agent for HIV preexposure prophylaxis (PrEP). This review focuses on phase 3 clinical trial results and implementation considerations for these long-acting ART and PrEP strategies. RECENT FINDINGS: Long-acting CAB and RPV administered every 4 weeks demonstrated noninferiority to oral ART through week 96 in both the ATLAS and FLAIR studies, whereas ATLAS-2M found similar efficacy through 96 weeks when the long-acting injectable ART was administered every 8 weeks instead of every 4 weeks. For prevention, two phase 3 trials were stopped early due to fewer incident HIV infections in participants receiving long-acting CAB every 8 weeks compared with daily oral tenofovir disoproxil fumarate-emtricitabine for PrEP. The long-acting therapies were well tolerated across all clinical trials. SUMMARY: Clinical trial results support the use of long-acting CAB for HIV PrEP and long-acting CAB and RPV as a switch strategy for adults with HIV-1 who are first virologically suppressed with oral ART. Implementation challenges persist, and data are urgently needed in populations who may benefit most from long-acting therapy, including adolescents, pregnant individuals, and those with barriers to medication adherence.

In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel.

OBJECTIVES: The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug-drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CLint.app. ) and CYP gene expression. METHODS: In vitro CYP-mediated CLint.app. of levonorgestrel was quantified using a recombinant human CYP (rhCYP) enzyme system. A primary human hepatocyte model of drug metabolism was used to assess the effects of dolutegravir on (1) levonorgestrel CLint.app. , using liquid chromatography-tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real-time polymerase chain reaction. RESULTS: Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CLint.app. was 22.4 ± 5.0 µL/min/106  hepatocytes. Incubation with 43.1 nM of unbound dolutegravir elevated levonorgestrel CLint.app. to 31.4 ± 7.8 µL/min/106  hepatocytes (P = 0.168), while 142.23 nM increased levonorgestrel CLint.app. to 37.0 ± 2.9 µL/min/106  hepatocytes (P = 0.012). Unbound dolutegravir ≥ 431 nM induced expression of CYP3A4 (≥ two-fold) in a dose-dependent manner, while 1.44 µM of unbound dolutegravir induced CYP2B6 expression 2.2 ± 0.3-fold (P = 0.0004). CONCLUSIONS: In summary, this in vitro study suggests that dolutegravir has the potential to increase hepatic clearance of levonorgestrel by inducing both CYP3A and non-CYP3A enzymes. The observed in vitro dolutegravir-levonorgestrel drug-drug interaction should be further examined in clinical studies.

The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

As with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers. Unfortunately, high levels of adherence to antiretroviral therapy are required to maintain virologic suppression. Alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products. Phase 3 data support the efficacy of nanoformulated injectable cabotegravir and rilpivirine for HIV treatment in patients with undetectable viremia, but we have yet to learn how this strategy may benefit those with medication adherence challenges. Despite this, the affected community and HIV providers are very interested in exploring the role of long-acting therapies to address some types of barriers to medication adherence. This review summarizes available information about the potential for long-acting therapy to improve adherence for some patients and outlines associated opportunities and challenges with the implementation of long-acting therapy for the treatment and prevention of HIV.

Predictors of vaccination rates in people living with HIV followed at a specialty care clinic.

People Living with HIV (PLWH) remain disproportionately susceptible to vaccine-preventable illnesses due to increased morbidity and mortality from common pathogens, increased transmission related to epidemiologic factors, and decreased vaccination rates. We aimed to describe patient-specific predictive factors that may impact adherence to the CDC's recommended vaccination schedules in PLWH. We retrospectively evaluated adult PLWH in care at the University of Nebraska Medical Center's HIV clinic and collected information related to demographics, clinic visits, vaccination status, and measures of HIV disease control. Patients were categorized as "Adherent" if they had received all vaccinations for which they were eligible and were categorized as "Non-Adherent" if they were deficient or delayed in receiving one or more vaccinations. Participant characteristics were compared between groups by multivariable logistic regression to identify predictors associated with vaccine schedule non-adherence. We evaluated 502 PLWH who met our inclusion criteria; 206 of these (41%) had received all eligible vaccinations, while 296 (59%) were missing one or more vaccinations. The mean age of participants was 48 years old, 76% were male, and 53% were white. Our participants had a median of 2.83 clinic visits per year and missed 8.3% of scheduled clinic visits. Factors associated with non-adherence to vaccination schedules included a high frequency of missed clinic appointments (>10%), men who have sex with men, and a CD4 count <200 cells/mm3. Knowledge of variables associated with vaccination rates may be beneficial in identifying patients at-risk for under-vaccination and designing targeted education programs for providers and patients.