Vacc-4s

Sodium-glucose co-transporter 2 inhibitors were first approved in the US in 2013; therefore, real-world (RW) studies describing outcomes are limited. This retrospective study evaluated adherence and persistence among patients initiating canagliflozin (CANA), dapagliflozin (DAPA), GLP-1 agonists (GLP-1s), and DPP-4 inhibitors (DPP-4s) over a 12-month follow-up from a US managed care perspective.

Patients newly initiating CANA, DAPA, GLP-1s, or DPP-4s from February 1, 2014-June 30, 2014 were identified from the QuintilesIMS PharMetrics Plus Database. The first fill defined the index date/drug. Patients were required to have a T2DM diagnosis (ICD-9-CM 250.x[0,2]) and ≥12 months of continuous enrollment pre- and post-index (follow-up). Main outcome measures were adherence (proportion of days covered, PDC; medication possession ratio, MPR) and persistence on index therapy. PDC or MPR ≥0.80 was considered adherent. Patients were considered persistent until evidence of discontinuation (gap ≥90 days between two subsequent index therapy prescriptions). Kaplan-Meier (KM) analysis assessed time to discontinuation, while a Cox proportional hazards model (PHM) evaluated risk of discontinuation. Logistic regression models evaluated the likelihood of non-adherence.

The final sample consisted of 23,702 patients (6,546 CANA, 3,087 DAPA, 6,273 GLP-1s, and 7,796 DPP-4s; 56% male, and mean [SD] age = 55 [9.1] years). Mean PDC ranged from 0.56 (GLP-1), to 0.71 (CANA), with 33-56% adherent, respectively; MPR results were similar. Fifty-two per cent (GLP-1) to 68% (CANA) were persistent over the follow-up. CANA patients had the longest time to discontinuation. In regression analyses, compared to CANA 100 mg, DAPA, DPP-4, and GLP-1 patients had a significantly higher likelihood of non-adherence and a significantly higher risk of discontinuation. CANA 300 mg patients had a significantly lower likelihood of non-adherence and a significantly lower risk of discontinuation compared to CANA 100 mg.

Adherence and persistence were significantly better with CANA (100 mg and 300 mg) compared to DAPA, GLP-1s, and DPP-4s in the RW setting.

Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1.

Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789.

174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations.

The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies.

Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.