Dolutegravir- Versus Efavirenz-Based Treatment in Pregnancy: Impact on Red Blood Cell Folate Concentrations in Pregnant Women and Their Infants.

In IMPAACT 2010/VESTED, pregnant women were randomized to initiate dolutegravir (DTG)+emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG+FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF. We assessed red blood cell folate concentrations (RBC-folate) at maternal study entry and delivery, and infant birth. RBC-folate outcomes were: 1) maternal change entry to delivery (trajectory), 2) infant, 3) ratio of infant-to-maternal delivery. Generalized estimating equation models for each log(folate) outcome were fit to estimate adjusted geometric mean ratio (Adj-GMR)/GMR trajectories (Adj-GMRT) of each arm comparison in 340 mothers and 310 infants. Overall, 90% of mothers received folic acid supplements and 78% lived in Africa. At entry, median maternal age was 25 years, gestational age was 22 weeks, CD4 count was 482 cells/mm3 and log10HIV RNA was 3 copies/mL. Entry RBC-folate was similar across arms. Adj-GMRT of maternal folate was 3% higher in the DTG+FTC/TAF versus EFV/FTC/TDF arm (1.03, 95%CI 1.00, 1.06). The DTG+FTC/TAF arm had an 8% lower infant-maternal folate ratio (0.92, 95%CI 0.78, 1.09) versus EFV/FTC/TDF. Results are consistent with no clinically meaningful differences between arms for all RBC-folate outcomes and they suggest that cellular uptake of folate and folate transport to the infant do not differ in pregnant women starting DTG- vs. EFV-based ART.

Efficacy and effect on lipid profiles of switching to ainuovirine-based regimen versus continuing efavirenz-based regimen in people with HIV-1: 24-week results from a real-world, retrospective, multi-center cohort study.

Ainuovirine (ANV), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), was approved in China in 2021. In a previous randomized phase 3 trial, ANV demonstrated non-inferior efficacy relative to efavirenz (EFV) and was associated with lower rates of dyslipidemia. In this study, we aimed to explore lipid changes in treatment-experienced people with human immunodeficiency virus (HIV)-1 (PWH) switching to ANV from EFV in real world. At week 24, 96.65% of patients in the ANV group and 93.25% in the EFV group had HIV-1 RNA levels below the limit of quantification (LOQ). Median changes from baseline in CD4 +T cell counts (37.0 vs 36.0 cells/µL, P = 0.886) and CD4+/CD8 +ratio (0.03 vs 0.10, P = 0.360) were similar between the two groups. The ANV group was superior to the EFV group in mean changes in total cholesterol (TC, -0.06 vs 0.26 mmol/L, P = 0.006), triglyceride (TG, -0.6 vs 0.14 mmol/L, P < 0.001), high-density lipoprotein cholesterol (HDL-C, 0.09 vs 0.08 mmol/L, P = 0.006), and low-density lipoprotein cholesterol (LDL-C, -0.18 vs 0.29 mmol/L, P < 0.001) at week 24. We also observed that a higher proportion of patients demonstrated improved TC (13.55% vs 4.45%, P = 0.015) or LDL-C (12.93% vs 6.89%, P = 0.017), and a lower proportion of patients showed worsened LDL-C (5.57% vs 13.52%, P = 0.017) with ANV than with EFV at week 24. In conclusion, we observed good efficacy and favorable changes in lipids in switching to ANV from EFV in treatment-experienced PWH in real world, indicating a promising switching option for PWH who may be more prone to metabolic or cardiovascular diseases.

Influence of efavirenz and 8-hydroxy-efavirenz plasma levels on cognition and central nervous system side effects.

OBJECTIVES: To investigate whether efavirenz (EFV) or 8-hydroxy-EFV (8-OH-EFV) plasma levels are associated with neurocognitive impairment and central nervous system (CNS) side effects. METHODS: We conducted a cross-sectional analysis to explore the potential links between EFV/8-OH-EFV levels and cognitive performance or CNS-related side effects in patients screened within a randomized trial involving a switch from EFV to rilpivirine. The Mann-Whitney test was employed to compare drug levels in patients with or without cognitive impairment, depression, anxiety, sleep disorder or CNS symptoms. Additionally, Spearman's test was used to assess correlations between drug levels and test scores. RESULTS: Among 104 patients, neither EFV nor 8-OH-EFV levels were linked to cognitive impairment, although trends towards higher EFV levels were observed in those with impaired executive function (p = 0.055) and language performances (p = 0.021). On the other hand, elevated 8-OH-EFV levels, but not EFV levels, were associated with more CNS side effects (222 vs. 151 ng/mL, p = 0.027), depressive symptoms (247 vs. 164 ng/mL, p = 0.067) and sleep impairment (247 vs. 164 ng/mL, p = 0.078). Consistently, a trend towards a correlation between EFV levels and lower z-scores in executive function and motor function was observed, while 8-OH-EFV levels, but not EFV levels, were directly correlated with symptom scores. CONCLUSIONS: Higher levels of 8-OH-EFV were associated with CNS side effects, while EFV levels were only marginally associated with cognitive performance, thus suggesting that EFV and its metabolite may act differently in determining detrimental neurological effects.

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.

The normalizing effects of the CYP46A1 activator efavirenz on retinal sterol levels and risk factors for glaucoma in Apoj-/- mice.

Apolipoprotein J (APOJ) is a multifunctional protein with genetic evidence suggesting an association between APOJ polymorphisms and Alzheimer's disease as well as exfoliation glaucoma. Herein we conducted ocular characterizations of Apoj-/- mice and found that their retinal cholesterol levels were decreased and that this genotype had several risk factors for glaucoma: increased intraocular pressure and cup-to-disk ratio and impaired retinal ganglion cell (RGC) function. The latter was not due to RGC degeneration or activation of retinal Muller cells and microglia/macrophages. There was also a decrease in retinal levels of 24-hydroxycholesterol, a suggested neuroprotectant under glaucomatous conditions and a positive allosteric modulator of N-methyl-D-aspartate receptors mediating the light-evoked response of the RGC. Therefore, Apoj-/- mice were treated with low-dose efavirenz, an allosteric activator of CYP46A1 which converts cholesterol into 24-hydroxycholesterol. Efavirenz treatment increased retinal cholesterol and 24-hydroxycholesterol levels, normalized intraocular pressure and cup-to-disk ratio, and rescued in part RGC function. Retinal expression of Abcg1 (a cholesterol efflux transporter), Apoa1 (a constituent of lipoprotein particles), and Scarb1 (a lipoprotein particle receptor) was increased in EVF-treated Apoj-/- mice, indicating increased retinal cholesterol transport on lipoprotein particles. Ocular characterizations of Cyp46a1-/- mice supported the beneficial efavirenz treatment effects via CYP46A1 activation. The data obtained demonstrate an important APOJ role in retinal cholesterol homeostasis and link this apolipoprotein to the glaucoma risk factors and retinal 24-hydroxycholesterol production by CYP46A1. As the CYP46A1 activator efavirenz is an FDA-approved anti-HIV drug, our studies suggest a new therapeutic approach for treatment of glaucomatous conditions.

Angiolipoma associated with antiretroviral switch therapy: a case report.

BACKGROUND: Angiolipomas have been well described in patients with HIV exposed to protease inhibitors with possible resolution after switching to non-nucleoside reverse transcriptase inhibitor-based regimens. Resolution of symptoms have occurred with switches to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens; however, little is known regarding the development of angiolipomas when switching from NNRTI- to modern, integrase strand transfer inhibitor-based regimens. We describe a patient who underwent switch therapy from tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) to tenofovir alafenamide/FTC/bictegravir (TAF/FTC/BIC) who later developed angiolipomas. CASE PRESENTATION: A 55-year-old male had been on TDF/FTC/EFV for 8 years before switching to TAF/FTC/BIC. Nineteen months after antiretroviral switch, the patient presented with multiple lesions in the upper extremities and abdomen. Diagnostic biopsies revealed non-encapsulated angiolipomas and HHV-8 and non-alcoholic fatty liver disease was ruled out. New lesions continued to appear 29 months after ART switch, after which now lesions appeared and prior lesions remained stable with no increase in size noted. No surgical intervention or change in antiretroviral therapy was needed. CONCLUSIONS: Angiogenesis may have been suppressed with TDF/FTC/EFV treatment, however when switched to TAF/FTC/BIC, promoted the growth of angiolipomas. Clinicians should be aware of the impact of switching to modern ART therapies resulting in possible adipogenesis.

Effect of dolutegravir-based versus efavirenz-based antiretroviral therapy on excessive weight gain in adult treatment-naïve HIV patients at Matsanjeni health center, Eswatini: a retrospective cohort study.

BACKGROUND: There is limited data on dolutegravir (DTG)-associated weight gain from settings with a dual burden of HIV and overnutrition. METHODS: In Eswatini (at Matsanjeni), among 156 and 160 adult patients on DTG-based and EFV-based antiretroviral therapy (ART), respectively, we studied excessive weight gain (BMI at 24 months ART greater than baseline and ≥25 kg/m2). RESULTS: The median BMI increase in DTG-based patients was 1.09 (IQR:-0.28,3.28) kg/m2 compared to 0.20 (IQR:-0.85,2.18) kg/m2 in EFV-based patients (p value = 0.001). DTG-based ART predicted excessive weight gain (aOR 2.61;95% CI:1.39-4.93). CONCLUSION: Practitioners should consider DTG-based regimens as one of the risk factors for overweight/obesity.

7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite.

High dose (S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer's disease. Simultaneously, we evaluate EFV dihydroxymetabolites for in vivo brain effects to compare with those of (S)-EFV. We have already tested (rac)-8,14dihydroxy EFV on 5XFAD mice, a model of Alzheimer's disease. Herein, we treated 5XFAD mice with (rac)-7,8dihydroxy EFV. In both sexes, the treatment modestly activated CYP46A1 in the brain and increased brain content of acetyl-CoA and acetylcholine. Male mice also showed a decrease in the brain levels of insoluble amyloid ß40 peptides. However, the treatment had no effect on animal performance in different memory tasks. Thus, the overall brain effects of (rac)-7,8dihydroxy EFV were weaker than those of EFV and (rac)-8,14dihydroxy EFV and did not lead to cognitive improvements as were seen in treatments with EFV and (rac)-8,14dihydroxy EFV. An in vitro study assessing CYP46A1 activation in co-incubations with EFV and (rac)-7,8dihydroxy EFV or (rac)-8,14dihydroxy EFV was carried out and provided insight into the compound doses and ratios that could be used for in vivo co-treatments with EFV and its dihydroxymetabolite.

Metabolic, Mitochondrial, and Inflammatory Effects of Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate in Asymptomatic Antiretroviral-Naïve People with HIV.

This study aimed to comprehensively assess the metabolic, mitochondrial, and inflammatory effects of first-line efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) single-tablet regimen (STR) relative to untreated asymptomatic HIV infection. To this end, we analyzed 29 people with HIV (PWH) treated for at least one year with this regimen vs. 33 antiretroviral-naïve PWH. Excellent therapeutic activity was accompanied by significant alterations in metabolic parameters. The treatment group showed increased plasmatic levels of glucose, total cholesterol and its fractions (LDL and HDL), triglycerides, and hepatic enzymes (GGT, ALP); conversely, bilirubin levels (total and indirect fraction) decreased in the treated cohort. Mitochondrial performance was preserved overall and treatment administration even promoted the recovery of mitochondrial DNA (mtDNA) content depleted by the virus, although this was not accompanied by the recovery in some of their encoded proteins (since cytochrome c oxidase II was significantly decreased). Inflammatory profile (TNFα, IL-6), ameliorated after treatment in accordance with viral reduction and the recovery of TNFα levels correlated to mtDNA cell restoration. Thus, although this regimen causes subclinical metabolic alterations, its antiviral and anti-inflammatory properties may be associated with partial improvement in mitochondrial function.

Plasma Concentrations of Rosmarinic Acid in Patients on Antiretroviral Therapy: In Silico Exploration Based on Clinical Data.

Rosmarinic acid (RA) is a phenolic compound with antiviral properties, often encountered in dietary supplements and herbal drugs. Data on the pharmacokinetics of RA are lacking in cases of the chronic use of supplements containing this compound, and only limited data on the metabolism and distribution of RA are available. The aim of the study was to investigate the plasma levels of RA after 12 weeks of use and determine potential interactions of RA and selected antiretroviral drugs. Patients infected with human immunodeficiency virus took a supplement containing RA for 12 weeks, after which the RA concentrations in the plasma samples were analyzed. A detailed in silico analysis was conducted in order to elucidate the potential interactions between RA and the drugs efavirenz, darunavir and raltegravir. It was found that RA can be detected in patients' plasma samples, mainly in the form of sulphoglucuronide. The potential interactions are suggested on the level of liver metabolizing enzymes and efflux P-glycoprotein, with RA competing with antiretroviral drugs as a substrate in metabolism and distribution systems. The present study suggests that the simultaneous use of RA and antiretroviral therapy (containing efavirenz, darunavir or raltegravir) may affect the plasma levels of RA after prolonged supplementation.

Mannosylated PAMAM G2 dendrimers mediated rate programmed delivery of efavirenz target HIV viral latency at reservoirs.

In this current research, we conceptualized a novel nanotechnology-enabled synthesis approach of targeting HIV-harboring tissues via second-generation (G2) polyamidoamine (PAMAM) mannosylated (MPG2) dendrimers for programmed delivery of anti-HIV drugs efavirenz (EFV) and ritonavir (RTV). Briefly, here mannose served purpose of ligand in this EFV and RTV-loaded PAMAM G2 dendrimers, synthesized by divergent techniques, denoted as MPG2ER. The developed nanocarriers were characterized by different analytical tools FTIR, NMR, zeta potential, particle size, and surface morphology. The results of confocal microscopy showed substantial alterations in the morphology of H9 cells, favored by relatively higher drug uptake through the MPG2ER. Interestingly, the drug uptake study and cytotoxicity assay of MPG2ER demonstrated that it showed no significant toxicity up to 12.5 µM. A typical flow cytometry histogram also revealed that MPG2ER efficiently internalized both drugs, with an increase in drug uptake of up to 81.2 %. It also enhanced the plasma pharmacokinetics of EFV, with Cmax7.68 µg/ml, AUC of 149.19 (µg/ml) * hr, and MRT of 26.87 hrs. Subsequently, tissue pharmacokinetics further evidence that MPG2ER accumulated more in distant Human immunodeficiency virus (HIV) reservoir tissues, such as the lymph nodes and spleen, but without exhibiting significant toxicity. Abovementioned compelling evidences strongly favored translational roles of MPG2 as a potential therapeutic strategy in the clinical eradication of HIV from viral reservoir tissue.

Initial Supplementary Dose of Dolutegravir in Second-Line Antiretroviral Therapy: A Noncomparative, Double-Blind, Randomized Placebo-Controlled Trial.

BACKGROUND: Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms. RESULTS: One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and 2 were lost to follow-up. At week 24, 55 of 64 (86% [95% confidence interval {CI}: 75%-93%]) in the supplementary dolutegravir arm and 53 of 65 (82% [95% CI: 70%-90%]) in the placebo arm had HIV-1 RNA <50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of 6 participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. CONCLUSIONS: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. CLINICAL TRIALS REGISTRATION: NCT03991013.

Weight and Metabolic Changes After Switching From Tenofovir Alafenamide/Emtricitabine (FTC)+Dolutegravir (DTG), Tenofovir Disoproxil Fumarate (TDF)/FTC + DTG, and TDF/FTC/Efavirenz to TDF/Lamivudine/DTG.

Participants randomized to first-line tenofovir alafenamide (TAF)/emtricitabine (FTC)+dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)/FTC + DTG, or TDF/FTC/efavirenz (EFV) for 192 weeks were then switched to TDF/lamivudine (3TC)/DTG for 52 weeks. Participants switching either TAF/FTC + DTG or TDF/FTC/EFV to TDF/3TC/DTG showed statistically significant reductions in weight, low-density lipoprotein, triglycerides, glucose and glycated hemoglobin.

Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin.

BACKGROUND: Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug-drug interactions with antiretroviral therapy (ART) and safety in people with human immunodeficiency virus (HIV) have not been evaluated. METHODS: This was a randomized, open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily-dose rifampicin. ART treatment-naive patients were randomized to dolutegravir- or efavirenz-based ART. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. HIV viral load was measured at week 24. RESULTS: Among 128 patients randomized, the median CD4 count was 191 cells/mm3. The geometric mean ratio (GMR) for trough dolutegravir concentrations on higher- vs standard-dose rifampicin was 0.57 (95% confidence interval [CI], .34-.97; P = .039) and the GMR for mid-dose efavirenz was 0.63 (95% CI, .38-1.07; P = .083). There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs 14.0%, P = .901), as was the incidence of drug-related grade 3-4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higher-dose rifampicin (18.6% vs 37.0%, P = .063). CONCLUSIONS: Compared with standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures, but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion. CLINICAL TRIALS REGISTRATION: NCT03982277.

Optimizing Treatment for Human Immunodeficiency Virus to Improve Clinical Outcomes Using Precision Medicine.

In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz-based regimen than an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009-2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of acquired immune deficiency syndrome (AIDS)-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an efavirenz- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval (CI): 8.6, 11.3), corresponding to an absolute risk reduction of 2.3% (95% CI: 0.9, 3.8) when compared with recommending an efavirenz-based regimen for all patients and 2.6% (95% CI: 1.0, 4.2) when compared with recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome compared with assigning all patients the same drug regimen.

Optimizing Moxifloxacin Dose in MDR-TB Participants with or without Efavirenz Coadministration Using Population Pharmacokinetic Modeling.

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic and MIC distribution in participants with MDR-TB. Participants enrolled at two TB hospitals in South Africa underwent intensive pharmacokinetic sampling approximately 1 to 6 weeks after treatment initiation. Plasma drug concentrations and clinical data were analyzed using nonlinear mixed-effects modeling with simulations to evaluate doses for different scenarios. We enrolled 131 participants (54 females), with median age of 35.7 (interquartile range, 28.5 to 43.5) years, median weight of 47 (42.0 to 54.0) kg, and median fat-free mass of 40.1 (32.3 to 44.7) kg; 79 were HIV positive, 29 of whom were on efavirenz-based antiretroviral therapy. Moxifloxacin pharmacokinetics were described with a 2-compartment model, transit absorption, and elimination via a liver compartment. We included allometry based on fat-free mass to estimate disposition parameters. We estimated an oral clearance for a typical patient to be 17.6 L/h. Participants treated with efavirenz had increased clearance, resulting in a 44% reduction in moxifloxacin exposure. Simulations predicted that, even at a median MIC of 0.25 (0.06 to 16) mg/L, the standard daily dose of 400 mg has a low probability of attaining the ratio of the area under the unbound concentration-time curve from 0 to 24 h to the MIC (fAUC0-24)/MIC target of >53, particularly in heavier participants. The high-dose WHO regimen (600 to 800 mg) yielded higher, more balanced exposures across the weight ranges, with better target attainment. When coadministered with efavirenz, moxifloxacin doses of up to 1,000 mg are needed to match these exposures. The safety of higher moxifloxacin doses in clinical settings should be confirmed.

Efavirenz-Based Antiretroviral Therapy but Not Pregnancy Increased Unbound Piperaquine Exposure in Women during Malaria Chemoprevention.

Dihydroartemisinin-piperaquine (DP) is highly effective for malaria chemoprevention during pregnancy, but the standard dosing of DP that is used for nonpregnant adults may not be optimal for pregnant women. We previously reported that the pharmacokinetic exposure of total piperaquine (PQ; both bound and unbound to plasma proteins) is reduced significantly in the context of pregnancy or efavirenz (EFV)-based antiretroviral therapy (ART). However, as PQ is >99% protein-bound, reduced protein binding during pregnancy may lead to an increase in the pharmacologically active unbound drug fraction (fu), relative to the total PQ. We investigated the impact of pregnancy and EFV use on the fu of PQ to inform the interpretation of pharmacokinetics. Plasma samples from 0 to 24 h after the third (final) DP dose were collected from pregnant women at 28 weeks gestation who were receiving or not receiving EFV-based ART as well as from women 34 to 54 weeks postpartum who were not receiving EFV-based ART, who served as controls. Unbound PQ was quantified via ultrafiltration and liquid chromatography-tandem mass spectrometry, with fu being calculated as PQunbound/PQtotal. The geometric mean fu did not differ between pregnant and postpartum women (P = 0.66), but it was 23% (P < 0.01) greater in pregnant women receiving EFV-based ART, compared to that in postpartum women who were not receiving EFV-based ART. The altered drug-protein binding, potentially due to the displacement of PQ from plasma proteins by EFV, resulted in only a 14% lower unbound PQ exposure (P = 0.13) in the presence of a 31% lower total PQ exposure (P < 0.01), as estimated by the area under the concentration time curve from 0 to 24 h post-last dose in pregnant women who were receiving EFV-based ART. The results suggest that the impact of pregnancy and EFV-based ART on the exposure and, in turn, the efficacy of PQ for malaria prevention may not be as significant as was suggested by the changes in the total PQ exposure. Further study during the terminal elimination phase (e.g., on day 28 post-dose) would help better characterize the unbound PQ exposure during the full dosing interval and, thus, the overall efficacy of PQ for malaria chemoprevention in this special population.

Effect of a moderate CYP3A inducer efavirenz on the pharmacokinetics of fuzuloparib: An open-label, fixed sequence study in Chinese healthy male subjects.

To evaluate the potential drug-drug interaction (DDI), safety and tolerability of fuzuloparib co-administered with a moderate CYP3A inducer efavirenz in healthy male subjects. Eighteen healthy male subjects were enrolled in a single-center, single-arm, open-label, fixed-sequence study. Fuzuloparib was administered as a single oral 50 mg under a fasting state on day 1, efavirenz (600 mg once daily) was given on days 4-17 before bed time, concomitantly with fuzuloparib on day 18, and for the follow-up 3 additional days (days 19-20). Pharmacokinetic sampling was performed following each fuzuloparib dose. Safety and tolerability were assessed during the whole process via clinical laboratory tests. Ratios of least-squares means (GMRs) and 90% geometric confidence interval (90% CI) of maximum plasma concentration (Cmax), the area under the curve of plasma concentration-time from zero to the last measurable concentration (AUC0 - t) and the area under the curve of blood concentration from zero to infinity (AUC0-∞) for fuzuloparib combined with efavirenz to fuzuloparib alone were 0.473 (0.394, 0.568), 0.220 (0.185, 0.263) and 0.221 (0.185, 0.263), respectively. Co-administration with efavirenz led to 53% and 78% decreases in fuzuloparib Cmax and AUC0-∞. All 18 subjects enrolled in this study were included in the safety analysis set. A total of 16 subjects had 62 AEs during the study period. No serious adverse events (SAE) were reported. Most treatment-emergent adverse events were grade 1 or 2 based on CTCAE. Only one grade 3 adverse event was observed. Concomitant intake of fuzuloparib with the moderate CYP3A inhibitor efavirenz resulted in a decrease in fuzuloparib AUC0-∞ and Cmax of 78% and 53% respectively. The results suggested that concomitant moderate CYP3A inducers should be avoided during the administration of fuzuloparib, or else the dosage adjustments should be required. (This trial was registered at http://www.chinadrugtrials.org.cn . The registration No. is CTR20211022, and the date of registration is 2021-05-13).

Intramuscular cabotegravir and rilpivirine concentrations after switching from efavirenz-containing regimen.

AIMS: Intramuscular cabotegravir/rilpivirine (IM CAB/RPV) are metabolized by UGT1A1/CYP3A4. Efavirenz induces both enzymes; therefore, switching from an efavirenz-containing regimen to IM CAB/RPV could possibly result in suboptimal levels. Due to their long dosing interval, clinical studies with IM CAB/RPV are challenging. We used physiologically based pharmacokinetics (PBPK) modelling to simulate the switch from efavirenz to IM CAB/RPV. METHODS: First, we developed the drug models and verified the performance of the PBPK model to predict the pharmacokinetics of IM cabotegravir, IM rilpivirine and efavirenz by comparing the simulations against observed clinical data. Second, we verified the ability of the model to predict the effect of residual induction with observed data for the switch from efavirenz to dolutegravir or rilpivirine. Finally, we generated a cohort of 100 virtual individuals (20-50 years, 50% female, 18.5-30 kg/m2 ) to simulate IM CAB/RPV concentrations after discontinuing efavirenz in extensive and slow metabolizers of efavirenz. RESULTS: IM CAB concentrations were predicted to decrease by 11% (95% confidence interval 7-15%), 13% (6-21%) and 8% (0-18%) at day 1, 7 and 14 after efavirenz discontinuation. CAB concentrations were predicted to remain above the minimal efficacy threshold (i.e., 664 ng/mL) throughout the switch period both in extensive and slow metabolizers of efavirenz. Similarly, IM RPV concentrations were modestly decreased with the lowest reduction being 10% (6-14%) on day 7 post last efavirenz dose. CONCLUSION: Our simulations indicate that switching from an efavirenz-containing regimen to IM CAB/RPV does not put at risk of having a time window with suboptimal drug levels.

Levels of adherence to contemporary antiretroviral regimens and the likelihood of viral suppression: a cohort study in a Brazilian metropolis.

Levels of adherence to antiretroviral therapy (ART) can affect the likelihood of viral suppression differentially among ART regimens. In this prospective cohort conducted in Belo Horizonte, Brazil, we included 354 individuals who initiated ART containing tenofovir disoproxil fumarate/lamivudine/efavirenz in fixed-dose combination (TDF/3TC/EFV) or tenofovir disoproxil fumarate/lamivudine associated with dolutegravir (TDF/3TC + DTG). Viral suppression (viral load <50 copies/mL) was evaluated within six months of follow-up at different adherence levels and by therapeutic regimen. Adherence was measured by the Proportion of Days Covered (PDC) and classified into low (≤84%), intermediate (85-89%) or high (≥90%). The association between viral suppression, adherence levels, and other explanatory variables was analyzed using chi-square and multivariable logistic regression. Viral suppression was achieved by 76.0% of individuals and was more frequent among those who achieved higher levels of adherence (high adherence: 79.3%, intermediate: 71.4% and low: 45.2%), those on TDF/3TC + DTG, and those who had viral load ≤100,000 copies/mL at the onset of treatment (p < 0.05). Moreover, individuals on TDF/3TC + DTG had an approximately 90% probability of achieving viral suppression at intermediate adherence levels. These results add new insights on the possibility of lower adherence levels for contemporary antiretroviral regimens currently used as first-line therapy worldwide.