Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study

Background. Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1–infected subjects with genotypic evidence of RAL resistance.Methods. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log10 copies/mL from baseline or was <400 copies/mL.Results. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen.Conclusion. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL

Lower ribavirin biodisponibility in patients with HIV-HCV coinfection in comparison with HCV monoinfected patients.

International audienceBACKGROUND: In HIV infected patients, the impact of ribavirin (RBV) pharmacology on sustained virologic response (SVR) to hepatitis C virus (HCV) treatment has not been fully investigated. The objective of this study was to compare the early RBV plasma exposure between a population of HIV-HCV coinfected patients and an HCV monoinfected group. METHODS: Early RBV plasma exposure (expressed as Area Under the Curve (AUC) from 0 to 4 h) after a 600 mg first dose of RBV was measured in a population of HIV-HCV coinfected patients in comparison with an HCV monoinfected group. Peripheral blood samples were collected before the 600 mg RBV first dose (T0) to ensure no detectable baseline plasma RBV, and then 30 mn, 1, 2 and 4 hours after RBV intake (T0.5, T1, T2 and T4). RESULTS: Eighty-six patients with chronic hepatitis C entered the study among whom 23 (27%) were HIV-HCV coinfected. Coinfected patients had a significantly lower RBV-AUC(0-4h) (median: 1469 μg*h/L [range 936-3677]) compared with monoinfected patients (2030 μg*h/L [851-7700]; p = 0.018). This RBV under exposure in coinfected patients persisted after normalization of AUC to RBV dose per kilogram of body weight (182 μg*h/L [110-425] versus 271 μg*h/L [82-1091], p = 0.001). CONCLUSIONS: These results suggest that lower early bioavailability of RBV could be one of the reasons for lower SVR in HIV-HCV coinfected patients treated with pegylated interferon/RBV combination therapy. RBV plasma underexposure seems to be associated with the immunological status of the patients with lower AUC(0-4h) values observed in the more immunosuppressed coinfected patients

Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study

Background. Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1–infected subjects with genotypic evidence of RAL resistance. Methods. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log(10) copies/mL from baseline or was <400 copies/mL. Results. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen. Conclusion. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL

Decreased darunavir concentrations during once-daily co-administration with maraviroc and raltegravir: OPTIPRIM-ANRS 147 trial

International audienceBackgroundThe OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values <50 copies/mL was lower in the pentatherapy arm than in the tritherapy arm. Here we compared antiretroviral drug concentrations between the two arms.MethodsPlasma samples were collected from 50 patients at various times after drug administration. A Bayesian approach based on published population pharmacokinetic models was used to estimate residual drug concentrations (Ctrough) and exposures (AUC) in each patient. A mixed linear regression model was then used to compare the AUC and Ctrough values of each drug used in both groups.ResultsPublished models adequately described our data and could be used to predict Ctrough and AUC. No significant difference in tenofovir disoproxil fumarate, emtricitabine and ritonavir parameters was found between the two arms. However, darunavir Ctrough and AUC were significantly lower in the pentatherapy arm than in the tritherapy arm (P = 0.03 and P = 0.04, respectively).ConclusionsAdding maraviroc and raltegravir to darunavir-based tritherapy decreased darunavir concentrations. Compliance issues, maraviroc–darunavir interaction and raltegravir–darunavir interaction were suspected and may affect the kinetics of viral decay during pentatherapy. A specific pharmacokinetic interaction study is needed to explore the interactions between darunavir and maraviroc and raltegravir

A highly virulent variant of HIV-1 circulating in the Netherlands

We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence

Doravirine plus lamivudine two-drug regimen as maintenance antiretroviral therapy in people living with HIV: a French observational study

International audienceBackground: Two-drug regimens based on integrase strand transfer inhibitors (INSTIs) and boosted PIs have entered recommended ART. However, INSTIs and boosted PIs may not be suitable for all patients. We aimed to report our experience with doravirine/lamivudine as maintenance therapy in people living with HIV (PLWH) followed in French HIV settings.Methods: This observational study enrolled all adults who initiated doravirine/lamivudine between 1 September 2019 and 31 October 2021, in French HIV centres participating in the Dat'AIDS cohort. The primary outcome was the rate of virological success (plasma HIV-RNA < 50 copies/mL) at Week (W)48. Secondary outcomes included: rate of treatment discontinuation for non-virological reasons, evolution of CD4 count and CD4/CD8 ratio over follow-up.Results: Fifty patients were included, with 34 (68%) men; median age: 58 years (IQR 51-62), ART duration: 20 years (13-23), duration of virological suppression: 14 years (8-19), CD4 count: 784 cells/mm3 (636-889). Prior to switching, all had plasma HIV-RNA < 50 copies/mL. All but three were naive to doravirine, and 36 (72%) came from a three-drug regimen. Median follow-up was 79 weeks (IQR 60-96). Virological success rate at W48 was 98.0% (95% CI 89.4-99.9). One virological failure occurred at W18 (HIV-RNA = 101 copies/mL) in a patient who briefly discontinued doravirine/lamivudine due to intense nightmares; there was no resistance at baseline and no resistance emergence. There were three strategy discontinuations for adverse events (digestive disorders: n = 2; insomnia: n = 1). There was no significant change in CD4/CD8 ratio, while CD4 T cell count significantly increased.Conclusions: These preliminary findings suggest that doravirine/lamivudine regimens can maintain high levels of viral suppression in highly ART-experienced PLWH with long-term viral suppression, and good CD4+ T cell count

Trastuzumab resistance: Bringing tailored therapy to the clinic

SCOPUS: re.jinfo:eu-repo/semantics/publishe

Long-term neurological symptoms after acute COVID-19 illness requiring hospitalization in adult patients: insights from the ISARIC-COVID-19 follow-up study

in this study we aimed to characterize the type and prevalence of neurological symptoms related to neurological long-COVID-19 from a large international multicenter cohort of adults after discharge from hospital for acute COVID-19