Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of ...RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC).
Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up.
Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS.
RZF was safe and efficacious in the treatment of candidemia and/or IC.
NCT02734862.
Glecaprevir/pibrentasvir is approved to treat hepatitis C virus genotype 1-6 infection. Patients coinfected with human immunodeficiency virus type 1 achieved high cure rates after 8- (without ...cirrhosis) and 12- (compensated cirrhosis) week treatment, without adjustments to antiretroviral therapy regimens.
NCT02738138.
Abstract
Background
Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis.
Methods
EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate.
Results
In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment.
Conclusions
Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir.
Clinical trial registration
NCT02738138.
Glecaprevir (GLE) and pibrentasvir (PIB) are direct-acting antivirals coformulated as a combination tablet for once-daily treatment of chronic hepatitis C virus infection. The objective of this study ...was to evaluate the effect of different methods of tablet manipulations-cutting in half, grinding into powder, or crushing-on the bioavailability of GLE and PIB relative to whole film-coated bilayer tablets. This was a phase 1, single-dose, open-label, randomized, 5-period, nonfasting crossover study in 25 healthy adult male and female subjects. Intensive pharmacokinetic measurements were carried out up to 48 h after dosing on day 1 of each period. Safety and tolerability was assessed throughout the study. Compared with the reference whole tablets, cutting into half had minimal impact on GLE and PIB exposures (≤15% difference), whereas grinding or crushing the tablets resulted in lower exposures (27% to 61%) for GLE and higher exposures (21% to 83%) for PIB. These results provide guidance on appropriate administration of GLE/PIB in patients who have difficulty swallowing whole tablets.
OBJECTIVE:To assess the pharmacokinetics (PK), safety and efficacy of dolutegravir plus optimized background regimen in HIV-infected treatment-experienced adolescents.
METHODS:Children older than 12 ...to younger than 18 years received dolutegravir weight-based fixed doses at approximately 1.0 mg/kg once daily in a phase I/II multicenter open label 48-week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through week 48.
RESULTS:Twenty-three adolescents were enrolled and 22 (96%) completed the 48-week study visit. Median age and weight were 15 years and 52 kg, respectively. Median interquartile range (IQR) baseline CD4+ cell count was 466 cells/μL (297, 771). Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 copies/mL (3.9, 4.6). Dolutegravir geometric mean of the area under the plasma concentration–time curve from time of administration to 24 hours after dosing (AUC0–24) and 24 hour postdose concentration (C24) were 46.0 μg hours/mL and 0.90 μg/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA <400 copies/mL was achieved in 74% 95% confidence interval (CI)52–90% at week 48. Additionally, 61% (95% CI39–80%) had an HIV RNA <50 copies/mL at week 48. Median (IQR) gain in CD4 cell count at week 48 was 84 cells/μL (−81, 238). Dolutegravir was well tolerated, with no grade 4 adverse events, serious adverse events or discontinuations because of serious adverse events.
CONCLUSIONS:Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through week 48.
Resistance to antiretroviral drugs is an increasingly prevalent challenge affecting both the adult and pediatric HIV-infected populations. Though data on the safety, pharmacokinetics, and efficacy of ...newer antiretroviral agents in children typically lags behind adult data, newer agents are becoming available for use in HIV-infected children who are failing to respond to or are experiencing toxicities with traditional antiretroviral regimens. Integrase strand transfer inhibitors are one such new class of antiretrovirals. Raltegravir has been US Food and Drug Administration (FDA) approved for use in patients over the age of 4 weeks. Elvitegravir is a second member of this class, and has the potential for use in children but does not yet have a Pediatric FDA indication. Dolutegravir, a second-generation integrase inhibitor, is approved for those older than 12 years. This review summarizes the use of integrase inhibitors in children and adolescents, and highlights the results of recent clinical trials.
Abstract
Background
Treatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV ...direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1–6 infection, including patients with HIV coinfection.
Methods
A series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure.
Results
Glecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents.
Conclusions
Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.
Concurrent treatment of chronic HCV infection with direct-acting antiviral agents and HIV infection with antiretroviral agents in coinfected patients requires careful consideration of potential drug-drug interactions. Results and implications of clinical studies for glecaprevir/pibrentasvir with 15 antiretroviral agents are summarized.
Background. Ombitasvir/paritaprevir/ritonavir with dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) is approved for hepatitis C virus (HCV) genotype 1 (GT1) treatment in HIV-1 coinfected patients. In ...healthy controls, coadministration of OBV/PTV/r + DSV + darunavir (DRV) lowered DRV trough concentration (Ctrough) levels. To assess the clinical significance of this change, TURQUOISE-I, Part 1b, evaluated the efficacy and safety of OBV/PTV/r + DSV + RBV in coinfected patients on stable, DRV-containing antiretroviral therapy (ART). Methods. Patients were HCV treatment-naive or interferon-experienced, had CD4⁺ lymphocyte count ≥200 cells/μL or ≥14%, and plasma HIV-1 RNA suppression on once-daily (QD) DRV-containing ART at screening. Patients were randomized to maintain DRV 800 mg QD or switch to twice-daily (BID) DRV 600 mg; all received OBV/PTV/r + DSV + RBV for 12 weeks. Results. Twenty-two patients were enrolled and achieved SVR12. No adverse events led to discontinuation. Coadministration had minimal impact on DRV maximum observed plasma concentration and area under the curve; DRV Ctrough levels were slightly lower with DRV QD and BID. No patient experienced plasma HIV-1 RNA >200 copies/mL during treatment. Conclusions. HCV GT1/HIV-1 coinfected patients on stable DRV-containing ART achieved 100% SVR12 while maintaining plasma HIV-1 RNA suppression. Despite DRV exposure changes, episodes of intermittent HIV-1 viremia were infrequent.
Introduction
We assessed effects of AZD7442 (tixagevimab/cilgavimab) on deaths from any cause or hospitalizations due to coronavirus disease 2019 (COVID-19) and symptom severity and longer-term ...safety in the TACKLE adult outpatient treatment study.
Methods
Participants received 600 mg AZD7442 (
n
= 452) or placebo (
n
= 451) ≤ 7 days of COVID-19 symptom onset.
Results
Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 (key secondary endpoint) occurred in 20/399 (5.0%) participants receiving AZD7442 versus 40/407 (9.8%) receiving placebo relative risk reduction (RRR) 49.1%; 95% confidence interval (CI) 14.5, 69.7;
p
= 0.009 or 50.7% (95% CI 17.5, 70.5;
p
= 0.006) after excluding participants unblinded before day 169 for consideration of vaccination). AZD7442 reduced progression of COVID-19 symptoms versus placebo through to day 29 (RRR 12.5%; 95% CI 0.5, 23.0) and improved most symptoms within 1–2 weeks. Over median safety follow-up of 170 days, adverse events occurred in 174 (38.5%) and 196 (43.5%) participants receiving AZD7442 or placebo, respectively. Cardiac serious adverse events occurred in two (0.4%) and three (0.7%) participants receiving AZD7442 or placebo, respectively.
Conclusions
AZD7442 was well tolerated and reduced hospitalization and mortality through 6 months, and symptom burden through 29 days, in outpatients with mild-to-moderate COVID-19.
Clinical Trial Registration
Clinicaltrials.gov, NCT04723394. (
https://beta.clinicaltrials.gov/study/NCT04723394
).
Graphical Abstract
Plain Language Summary
Antibodies are proteins produced by the body’s immune system to specifically combat foreign substances, such as viruses. Tixagevimab and cilgavimab are a pair of antibodies that bind to a specific part of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). When they bind to the virus, they reduce its ability to cause disease. These antibodies were tested in a clinical trial to see if they could prevent people with COVID-19 from being hospitalized or dying. Around 900 adults took part in this clinical trial. These people all had COVID-19 but were not sick enough to be in hospital. Half of this group were treated with a dose of tixagevimab and cilgavimab, given as two injections. The other half received a placebo (injections that look exactly like the tixagevimab and cilgavimab injections but contain no medicine). The study found that, over 6 months, people with COVID-19 who received tixagevimab and cilgavimab were less likely to need to go to hospital than people who received the placebo. They were also less likely to die of COVID-19. Tixagevimab and cilgavimab also helped to improve COVID-19 symptoms. People who received the antibodies saw their symptoms improve faster than people who received the placebo. They were also less likely to have symptoms that got worse. Most people felt better within 1–2 weeks of getting treatment. No safety issues were found with tixagevimab and cilgavimab compared with placebo.
Diagnosis of latent tuberculosis infection (LTBI) is facilitated by tuberculin skin testing (TST) or interferon-gamma release assays such as the QuantiFERON TB Gold In-Tube (QTF-GIT) assays. Limited ...data exist on the utility of interferon-gamma release assays in HIV-infected children, which may be falsely negative due to immunosuppression.
A cross-sectional study comparing TST to QTF-GIT for the diagnosis of suspected LTBI was performed in children in Tijuana, Mexico, and in San Diego, California. Concordance between TST (≥5 mm for HIV infected and ≥10 mm for HIV uninfected) and QTF-GIT was evaluated utilizing kappa coefficients. Multivariate logistic regression assessed factors influencing the results.
One hundred sixty-five children (70 HIV infected and 95 HIV uninfected) were evaluated (median age, 8.0 years). Among HIV-infected children, the median CD4 cell count was 913 cells/μL, with 92.9% of subjects on antiretroviral treatment and 80.0% with an HIV RNA load <400 copies/mL (76% <50 copies/mL). Among HIV-infected children with no history of tuberculosis, 12 HIV had either a positive QTF-GIT or TST ≥ 5 mm or both, giving a suspected LTBI prevalence of 20.3% (compared with 61.3% among HIV-uninfected children). Moderate concordance was demonstrated in HIV-infected children (both tests positive, κ = 0.42; 95% confidence interval: 8.9%-75.4%) and HIV-uninfected children (both tests positive, κ = 0.59; 95% confidence interval: 43.0%-76.5%).
A moderate correlation exists between TST and QTF-GIT among HIV-infected and uninfected children with preserved immune function in an area of moderate tuberculosis endemicity.
The three-direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin (RBV) is approved for treatment of hepatitis C virus (HCV) ...genotype 1 (GT1)/human immunodeficiency virus type 1 (HIV-1) coinfection. Results of a pharmacokinetic substudy of 3D and darunavir are presented. HCV/HIV-1-coinfected subjects were randomized to maintain an antiretroviral regimen with darunavir at 800 mg once daily (QD) or switched to a regimen with darunavir at 600 mg twice daily (BID). On study day 1, subjects received 3D and RBV plus darunavir for 12 weeks. Pharmacokinetic parameters were compared for darunavir and ritonavir with and without 3D (week 4 and day -1). Pharmacokinetic parameters of 3D were compared to historical data. Ten subjects received darunavir QD, and 12 subjects received darunavir BID. The central value ratios (90% confidence interval CI) for maximum concentrations (C
), area under the plasma concentration-time curve between 0 and 24 h postdose (AUC
), and trough plasma concentration at 24 h postdose (C
) of darunavir administered QD with 3D versus administration of darunavir alone were 0.92 (0.72, 1.18), 0.83 (0.71, 0.98), and 0.64 (0.44, 0.93), respectively. The ratios (90% CI) for darunavir C
, AUC
, and C
administered BID with 3D were 0.92 (0.76, 1.12), 0.88 (0.73, 1.05), and 0.73 (0.58, 0.92), respectively. Exposures of 3D were similar to or slightly lower than those in historical data. All darunavir trough concentrations (C
) associated with an HIV-1 RNA level of >40 copies/ml were above the darunavir 50% effective concentration (EC
) of 550 ng/ml for resistant virus. In conclusion, the 3D regimen with darunavir QD or BID did not affect darunavir C
and AUC, whereas the darunavir C
decreased. Changes in pharmacokinetic parameters of 3D were not considered clinically significant. Episodes of intermittent HIV-1 viremia were infrequent and were not associated with darunavir C
values below 550 ng/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT01939197.).
PDF
