A four-drug combination oral tablet of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide for the treatment of HIV-1 infection in adults.

INTRODUCTION: Darunavir (DRV)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir alafenamide (TAF) is the only protease inhibitor-based single-tablet regimen (STR) approved for the treatment of HIV infection of adults and pediatric patients weighing at least 40 kg. DRV/COBI/FTC/TAF has demonstrated to be an effective regimen, to have a high genetic barrier to resistance, and to be well tolerated. AREAS COVERED: The authors summarize the chemistry and pharmacology of DRV, COBI, FTC, and TAF and discuss trials conducted on antiretroviral therapy (ART)-naïve and -experienced people living with HIV designed to evaluate safety, tolerability, and efficacy of the STR. This work also reports studies comparing DRV/COBI/FTC/TAF with competitive agents in real-world settings. EXPERT OPINION: Despite the availability of newer antiretroviral drugs and strategies in the management of HIV infection, including long-acting therapies, DRV/COBI/FTC/TAF is still considered an alternative regimen for the treatment of ART-naïve adults. DRV/COBI/FTC/TAF is an effective, well-tolerated, and safe antiretroviral regimen and represents a valid option for people who need to switch therapy due to tolerability issues, such as the onset of neuropsychiatric effects related to integrase strand transfer inhibitors, or virological failure.

Long-term outcomes of highly experienced people with HIV undergoing salvage therapy with raltegravir.

Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan-Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.

Drug-induced liver injury secondary to increased levonorgestrel exposure in a patient taking ritonavir.

We report the first published case of a drug induced liver injury (DILI) presumed secondary to a drug-drug interaction between ritonavir and levonorgestrel progestogen-only emergency contraception (POEC). Our patient is a 25-year-old female living with human immunodeficiency virus (HIV), taking antiretroviral therapy (ART) containing tenofovir alafenamide/emtricitabine and darunavir/ritonavir. She was found to have elevated transaminases at a routine clinic appointment consistent with hepatocellular DILI. Further investigation found the most likely cause of this was a drug-drug interaction (DDI) between the ritonavir component of her ART and recent use of levonorgestrel POEC 3 days earlier. Evidence suggests that ritonavir increases levonorgestrel exposure, yet our patient received double the usual dose as per dispensing guidance at the time. We review the pharmacokinetics of ritonavir-levonorgestrel DDIs and highlight the need for consistent guidelines on this topic.

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.

Dolutegravir in Pregnancy as Compared with Current HIV Regimens in the United States.

BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Analysis of virological response to therapy and resistance profile in treatment-experienced and naive HIV-1 infected Romanian patients receiving regimens containing darunavir boosted with ritonavir or cobicistat.

77% of Romanians infected with HIV receive antiretroviral therapy, with the challenge of maintaining long-term therapeutic success (the viral load becoming/remaining undetectable). The main purpose of this study was to provide comparative analysis of the long-term virological response to therapeutic regimens containing pharmacokinetically enhanced darunavir (DRV) with ritonavir (RTV) or cobicistat (COBI). The second aim was to evaluate the viral resistance profile to therapy, by number/type/frequency of viral mutations. This retrospective study was conducted on 462 patients infected with subtype F HIV-1, registered at the "Matei Bals" National Institute of Infectious Diseases, between 2018 and 2021: 384 patients received (among other ARV) DRV 600 mg, enhanced with RTV 100 mg (twice daily) and 78 patients received DRV 800 mg boosted with COBI 150 mg (once daily). The virological response was measured by determining the viral load (HIV-1 RNA copies/mL), while the incidence of viral resistance to therapy was assessed by genotyping tests. Comparing the patients with undetectable viremia, from the 1st visit to the 3rd one, the outcomes showed that at the last visit, 84.6% subjects in the DRV/c group achieved virological efficiency over those from DRV/r group (76.8%). The differences observed between this time points are statistically significant p < 0.05. DRV/c administered in combination with other ARV, in subtype F HIV-1 infected patients, proved to be more virologically effective, maintaining a favorable long-time result. When comparing the outcomes of the two groups, a statistically significant difference of p < 0.05 was obtained. 32 patients (27 from DRV/r group and 5 from DRV/c group) were evaluated with persistent HIV-1 ARN plasma load > 1000 copies/mL, during all 3 clinical visits. They formed a research sub-group evaluated in terms of resistance to therapy and were reported as virological failures. 28.12% of the sub-group with persistent HIV-1 RNA > 1000 copies/mL were from the DRV/r group and only 3.12% from the DRV/c group. Drug mutations (DRM) involved in antiretroviral resistance/sensitivity occurred both in the protease gene, and in the reverse transcriptase gene, with the involved ARV classes being protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors. 16 different types of mutations were evaluated in the PR gene and 20 mutations were evaluated in RT gene.

Associations of modern initial antiretroviral drug regimens with all-cause mortality in adults with HIV in Europe and North America: a cohort study.

BACKGROUND: Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. METHODS: This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. FINDINGS: 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs. INTERPRETATION: This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. FUNDING: US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.

Low Incidence and Brief Duration of Gastrointestinal Adverse Events with Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Over 96 Weeks: Post hoc Analyses of AMBER and EMERALD.

Gastrointestinal intolerance has been associated with ritonavir-boosted protease inhibitors. This post hoc analysis evaluated gastrointestinal adverse events of interest (AEOIs; diarrhea, nausea, abdominal discomfort, flatulence [MedDRAv21]) through Wk96 among patients enrolled in the phase 3 AMBER (treatment-naïve) and EMERALD (virologically suppressed) studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg. 362 and 763 patients initiated D/C/F/TAF in AMBER and EMERALD, respectively. All D/C/F/TAF-related gastrointestinal AEOIs were grade 1/2 in severity; none were serious. Across studies, incidence of D/C/F/TAF-related diarrhea and nausea were each ≤5% in Wk1 (≤1% post-Wk2); prevalence of each decreased to <5% post-Wk2. In each study, there was 1 case of D/C/F/TAF-related abdominal discomfort during Wk1 and none thereafter. Incidence of D/C/F/TAF-related flatulence was <1% throughout. Median duration of D/C/F/TAF-related gastrointestinal AEOIs was 16.5 (AMBER) and 8.5 (EMERALD) days. In conclusion, in treatment-naïve and virologically suppressed patients, incidences and prevalences of D/C/F/TAF-related gastrointestinal AEOIs were low and tended to present early.

Observational study to evaluate discontinuation of monotherapy with cobicistat-boosted darunavir in patients with human immunodeficiency virus.

To evaluate the reasons for changing to monotherapy with protease inhibitors, together with the proportion and reasons for the interruption to treatment, in patients who have been treated at some point with cobicistat-boosted darunavir (DRV/c). Outpatients in a tertiary hospital. Observational retrospective study to evaluate monotherapy with DRV/c (800 mg/150 mg) in adult patients with human immunodeficiency virus infection, from December 2014 to July 2022. Demographic variables, viral load, cluster of differentiation 4 lymphocyte lymphocyte count, and antiretroviral therapy were assessed. 42 patients were included. 36% of the patients were undergoing monotherapy at the time of the analysis. The main reason for discontinuation was poor adherence. At time of analysis, 80% of the patients in monotherapy had an undetectable viral load. Antiretroviral therapy recommendations advise against exposing the patient to functional monotherapy with a single drug due to the high risk of virological failure and the onset of resistance to a single drug. Following the analysis of the results, DRV/c in monotherapy is not an effective strategy in the medium and long term due to factors such as lack of adherence or virological failure, although it can be maintained in specific circumstances. Therefore, patients undergoing monotherapy require close monitoring.

Body mass index increase and weight gain among people living with HIV-1 initiated on single-tablet darunavir/cobicistat/emtricitabine/tenofovir alafenamide or bictegravir/emtricitabine/tenofovir alafenamide in the United States.

OBJECTIVE: This study evaluated body mass index (BMI) and weight changes in people living with human immunodeficiency virus (HIV-1; PLWH) initiated on single-tablet darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/FTC/TAF) or bictegravir/FTC/TAF (BIC/FTC/TAF). METHODS: Electronic medical record (EMR) data for treatment-naïve or virologically suppressed adults with HIV-1 who initiated treatment with DRV/c/FTC/TAF or BIC/FTC/TAF (index date) were obtained from Decision Resources Group's EMRs (17 July 2017-1 March 2020). Inverse probability of treatment weighting was used to account for differences in baseline characteristics between the two cohorts. BMI and weight changes from pre-index to 3, 6, 9 and 12 months following the index date were compared using weighted mean differences (MDs). The time until an increase in BMI or weight ≥5% or ≥10% was compared using weighted hazard ratios (HRs). RESULTS: The weighted DRV/c/FTC/TAF and BIC/FTC/TAF cohorts comprised 1116 and 1134 PLWH, respectively (mean age = ∼49 years, females: ∼28%). Larger increases in BMI and weight from pre-index to each post-index time point were observed in PLWH initiating BIC/FTC/TAF vs DRV/c/FTC/TAF (12 months: MD in BMI = 1.23 kg/m2, p < .001; MD in weight = 2.84 kg [6.26 lbs], p = .008). PLWH receiving BIC/FTC/TAF were significantly more likely to experience weight gain ≥5% (HR = 1.76, p = .004) and ≥10% (HR = 2.01, p = .020), and BMI increase ≥5% (HR = 1.77, p = .004) and ≥10% (HR = 1.76, p = .044) than those receiving DRV/c/FTC/TAF. CONCLUSIONS: BIC/FTC/TAF was associated with greater BMI and weight increases compared to DRV/c/FTC/TAF. Weight gain and its sequelae may add to the clinical burden of PLWH and should be considered among other factors when selecting antiretroviral single-tablet regimens.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

ABSTRACT: High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV.

BACKGROUND: The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine. METHODS: In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points). RESULTS: We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison. CONCLUSIONS: Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).

Systematic analysis of safety profile for darunavir and its boosted agents using data mining in the FDA Adverse Event Reporting System database.

This current investigation was aimed to generate signals for adverse events (AEs) of darunavir-containing agents by data mining using the US Food and Drug Administration Adverse Event Reporting System (FAERS). All AE reports for darunavir, darunavir/ritonavir, or darunavir/cobicistat between July 2006 and December 2019 were identified. The reporting Odds Ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) were used to detect the risk signals. A suspicious signal was generated only if the results of the three algorithms were all positive. A total of 10,756 reports were identified commonly observed in hepatobiliary, endocrine, cardiovascular, musculoskeletal, gastrointestinal, metabolic, and nutrition system. 40 suspicious signals were generated, and therein 20 signals were not included in the label. Severe high signals (i.e. progressive extraocular muscle paralysis, acute pancreatitis, exfoliative dermatitis, acquired lipodystrophy and mitochondrial toxicity) were identified. In pregnant women, umbilical cord abnormality, fetal growth restriction, low birth weight, stillbirth, premature rupture of membranes, premature birth and spontaneous abortion showed positive signals. Darunavir and its boosted agents induced AEs in various organs/tissues, and were shown to be possibly associated with multiple adverse pregnant conditions. This study highlighted some novel and severe AEs of darunavir which need to be monitored prospectively.

Population Pharmacokinetic Analysis of Darunavir and Tenofovir Alafenamide in HIV-1-Infected Patients on the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen (AMBER and EMERALD Studies).

The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data. Individual exposure metrics for DRV and TAF in patients receiving D/C/F/TAF were derived (AMBER, n=356; EMERALD, n=750). The DRV PopPK model is a two-compartment model with sequential zero-order, first-order input. TAF PK is described by a one-compartment model with dual parallel input for absorption (slow and fast pathway). DRV covariates were α1-acid-glycoprotein and body weight. TAF covariates were lean body weight and α1-acid-glycoprotein. DRV and TAF PK were unaffected by age, race, or gender. Estimated DRV mean (SD) C0h and AUC24h, respectively, were 1899 (759) ng/mL and 87,909 (20,232) ng*h/mL in AMBER; 1813 (859) ng/mL and 85,972 (22,413) ng*h/mL in EMERALD. Estimated TAF mean (SD) AUC24h was 132 (41) ng*h/mL. These PK parameters were in line with historical data. No apparent relationships of DRV or TAF exposure with efficacy (virologic response) or safety (metabolic, cardiac, liver, gastrointestinal, skin, bone, renal, pancreas, lipid events) parameters were seen. Additionally, our findings demonstrate that in patients with low plasma concentrations, there is no risk of decreased virologic response or virologic rebound. This supports the use of a once-daily, single-tablet regimen of D/C/F/TAF 800/150/200/10 mg for the treatment of HIV-1-infected subjects.

Cardiovascular risks associated with protease inhibitors for the treatment of HIV.

Introduction: Cumulative use of some first-generation protease inhibitors has been associated with higher rates of dyslipidemia and increased risk of cardiovascular disease. The protease inhibitors most commonly in use are atazanavir and darunavir, which have fewer detrimental lipid effects and greater tolerability. This paper aims to review the evidence of a potential association of these contemporary protease inhibitors with the risk of ischemic CVD and atherosclerotic markers.Areas covered: We searched for publications of randomized trials and observational studies on PubMed from 1 January 2000 onwards, using search terms including: protease inhibitors; darunavir; atazanavir; cardiovascular disease; cardiovascular events; dyslipidemia; mortality; carotid intima media thickness; arterial elasticity; arterial stiffness and drug discontinuation. Ongoing studies registered on clinicaltrials.gov as well as conference abstracts from major HIV conferences from 2015-2020 were also searched.Expert opinion: Atazanavir and darunavir are no longer part of first-line HIV treatment, but continue to be recommended as alternative first line, second- and third-line regimens, as part of two drug regimens, and darunavir is used as salvage therapy. Although these drugs will likely remain in use globally for several years to come, baseline CVD risk should be considered when considering their use, especially as the population with HIV ages.

Iatrogenic Cushing syndrome following lumbar medial branch block in a patient with HIV on ritonavir and darunavir.

We present a case report of a 62-year old female with HIV and chronic facetogenic back pain who underwent bilateral L3-L4 and L4-L5 medial branch nerve blocks using triamcinolone acetonide 80 mg. 2 weeks later she presented to the emergency department with acute anxiety/depression and was discharged with psychiatric follow-up. 2 weeks after this she presented to the outpatient HIV clinic with persistent uncontrolled depression alongside classic cushingoid features (e.g., buffalo hump, moon facies). She was diagnosed with iatrogenic Cushing syndrome caused by a drug-drug interaction between triamcinolone and ritonavir, a protease inhibitor and a CYP3A4 enzyme inhibitor. While the literature describes the interaction of ritonavir with intra-articular/intranasal/epidural triamcinolone, this is the first documented occurrence following a nerve block procedure. Symptoms resolved within 6 months alongside discontinuation of protease inhibitor therapy.

Lay abstract We report a 62-year old woman with history of HIV and depression who developed Cushing syndrome, which is a state of steroid excess in the body, after a nerve block procedure for treatment of back pain. Her first symptoms were worsening anxiety and depression, causing her to go to the emergency department. Unfortunately, the relationship to the steroids was not identified at the time. Later, she developed increased fat deposition in her face and upper neck, which is characteristic of Cushing syndrome. The HIV medications responsible for this adverse event were determined to be ritonavir and darunavir, which are classified as protease inhibitors. Her symptoms improved within 6 months in association with discontinuation of ritonavir and darunavir. This is the first known case of Cushing syndrome following a nerve block procedure for back pain, although previous cases have documented this occurrence following other forms of steroid treatments.

Darunavir/Cobicistat Is Associated with Negative Outcomes in HIV-Negative Patients with Severe COVID-19 Pneumonia.

The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p > .05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c, p = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.

Higher plasma drug levels in elderly people living with HIV treated with darunavir.

BACKGROUND: The proportion of elderly people living with HIV-1 (PLHIV) is rising. In older patients, comorbidities and concomitant medications are more frequent, increasing the risk of potential drug-drug interactions (PDDIs). Data on the pharmacokinetics of ART in individuals aged ≥ 65 years of age are scarce. We compared plasma drug levels of ART, PDDIs, and side-effects in PLHIV aged ≥ 65 years of age, with controls ≤ 49 years of age. METHODS: Patients ≥ 65 years of age and controls ≤ 49 years of age, all of whom were on stable treatment with atazanavir (ATV), darunavir (DRV), or efavirenz (EFV) were included cross-sectionally. Plasma drug levels of ART were analyzed, comorbidities, concomitant medication, adherence, and side-effects recorded, and PDDIs analyzed using drug interactions databases. RESULTS: Between 2013 and 2015, we included 100 individuals ≥ 65 years of age (study group) and 99 controls (≤ 49 years of age). Steady-state DRV concentrations were significantly higher in the study group than in the control group (p = 0.047). In the ATV group there was a trend towards a significant difference (p = 0.056). No significant differences were found in the EFV arm. The DRV arm had a higher frequency of reported side-effects than the ATV and EFV arms in the study group (36.7% vs. 0% and 23.8% respectively (p = 0.014), with significant differences between DRV vs. ATV, and EFV vs. ATV). CONCLUSIONS: Higher steady-state plasma levels of DRV and ATV (but not EFV) were found in PLHIV aged ≥ 65 years of age, compared to controls ≤ 49 years of age.

Unveiling the basis of antiretroviral therapy-induced osteopenia: the effects of Dolutegravir, Darunavir and Atazanavir on osteogenesis.

OBJECTIVES: Osteopenia is frequent in HIV-infected patients treated with antiretroviral therapy (ART) and has been linked to increased osteoclastogenesis. Little is known about the effects of ART on osteogenesis. DESIGN: We investigated the effect on human mesenchymal stem cells (hMSC) and osteoblasts of Darunavir and Dolutegravir, the most highly used as anchor drugs within a three-drug regimen, and Atazanavir, which was widely utilized in the past. RESULTS: We found that Atazanavir and Dolutegravir delay the osteogenic differentiation of hMSC, impair the activity of osteoblasts and inhibit their conversion into osteocytes, whereas Darunavir exerts no effect. CONCLUSION: Atazanavir and Dolutegravir impair osteogenesis. It is essential to diagnose impaired osteogenesis early and to devise effective therapeutic interventions to preserve bone health in ART-treated HIV patients, putting it in the context of a correct antiretroviral combination.

Effects on QT interval of hydroxychloroquine associated with ritonavir/darunavir or azithromycin in patients with SARS-CoV-2 infection.

INTRODUCTION: Most of the drugs associations that have been used to treat patients with SARS-CoV-2 infection increase the risk of prolongation of the corrected QT interval (QTc). OBJECTIVE: To evaluate the effects of an association therapy of hydroxychloroquine (HY) plus ritonavir/darunavir (RD) or azithromycin (AZ) on QTc intervals. METHODS: At the beginning of COVID-19 pandemic patients admitted to our hospital were treated with the empiric association of HY/RD; one week later the therapeutic protocol was modified with the combination of HY/AZ. Patients underwent an ECG at baseline, then 3 and 7 days after starting therapy. We prospectively enrolled 113 patients (61 in the HY/RD group-52 in the HY/AZ group). RESULTS: A significant increase in median QTc was reported after seven days of therapy in both groups: from 438 to 452 ms in HY/RD patients; from 433 to 440 ms in HY/AZ patients (p = 0.001 for both). 23 patients (21.2%) had a QTc > 500 ms at 7 days. The risk of developing a QTc > 500 ms was greater in patients with prolonged baseline QTc values (≥ 440 ms for female and ≥ 460 ms for male patients) (OR 7.10 (95% IC 1.88-26.81); p = 0.004) and in patients with an increase in the QTc > 40 ms 3 days after onset of treatment (OR 30.15 (95% IC 6.96-130.55); p = 0.001). One patient per group suffered a malignant ventricular arrhythmia. CONCLUSION: Hydroxychloroquine with both ritonavir/darunavir or azithromycin therapy significantly increased the QTc-interval at 7 days. The risk of developing malignant arrhythmias remained relatively low when these drugs were administered for a limited period of time.