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

Immunovirological status in people with perinatal and adult-acquired HIV-1 infection: a multi-cohort analysis from FranceResearch in context

Summary: Background: No study has compared the virological and immunological status of young people with perinatally-acquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. Methods: 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA ≥ 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. Findings: 310 P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4–25.5] and 45.9 [IQR:37.9–53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p ≤ 0.0001. The risk of VF was particularly high among the youngest children (2–5 years), adolescents (13–17 years) and young adults (18–24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6–12 and 13–17 were more likely than A-HIV to have a CD4:CD8 ratio ≥ 1: 84.1% vs. 58.8% (aOR = 3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR = 1.9 [0.9; 4.2]) respectively. Interpretation: P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Funding: Inserm - ANRS MIE

Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries

Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis. Methods: We identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, hadCD4+ cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4+ cell count and HIV-RNA via inverse probability weighting. Results: Out of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90-1.63) for tuberculosis, 2.61 (1.05-6.49) for MAC, 1.17 (0.34-4.08) for CMV retinitis, 1.18 (0.62-2.26) for PML, 1.21 (0.83-1.75) for HSV, 1.18 (0.87-1.58) for Kaposi sarcoma, 1.56 (0.82-2.95) for NHL, 1.11 (0.56-2.18) for cryptococcosis and 0.77 (0.40-1.49) for candidiasis. Conclusion: With the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries