Eur. J. Immunol. 2014Immunol. . 44: 2802Immunol. -2810 Clinical immunology 2803 IntroductionTo date, no effective therapeutic or prophylactic HIV vaccines are yet available. Recent encouraging results from the RV 144 trial showed a modest but statistically significant 31% reduction in the rate of HIV infection in vaccinated healthy volunteers receiving a prophylactic vaccine [1]. However, immune responses that would eradicate or control HIV are likely to be different from those needed to prevent primary infection. Indeed, eradication of HIV infection is likely to depend on the establishment of strong cytotoxic T lymphocytes, while prevention of infection will likely depend on the establishment of antibodies neutralizing the virus [2,3]. In both cases, CD4 + T helper cells are necessary for the establishment of robust and long-lasting immunity. Several candidate vaccines are under evaluation including peptides, inactivated virus, viral vectors, and ex vivo-generated DCs [4]. The latter represents an approach to optimize the induction of immune responses [5]. To date, only two studies, in which DCs have been loaded with chemically inactivated autologous virus, have reported a decrease in viral load [6,7]. Another approach using DCs transfected with RNA isolated from autologous virus yielded immune responses without control of viral replication [8]. However, these very promising data with inactivated autologous virus still need to be reproduced. For large scale use of DC vaccination, it would be advantageous to identify an antigenic cargo that could be used without having to isolate and expand the autologous virus which necessitates antiretroviral treatment interruption. We report here the safety and immunogenicity of a new DC platform loaded with five HIV-1-derived lipopeptides (LP) [9] in HIV-1-infected patients treated with highly active antiretroviral treatment (HAART). The study design included a 6-month analytical treatment interruption (ATI), a period which allowed us to evaluate the effects of vaccine-elicited immune responses on viral replication (Fig. 1). Results Patients and study outcomesTwenty patients were screened and 19 were enrolled within 17 months. Baseline characteristics of patients are reported in Table 1. All patients received the four vaccinations with no changes in vaccine dose. All patients but one completed the trial at 48 weeks.The vaccination was well tolerated. Two patients reached a safety endpoint (CD4 + T-cell counts below 500 cells/μL) during the vaccination phase while no safety endpoints were observed during the ATI phase. Systemic or local adverse events were mild or moderate (grade 1 or 2) and resolved in less than 2 days in the majority of cases. All patients stopped HAART at 24 weeks post inclusion except two of them who stopped at 25 and 26 weeks.Through 48 weeks, eight patients reached the immunology endpoint defining a failure of the strategy: at 28 (two patients), 32 (three patients), 36, 40, and 44 weeks. Three of these patients resumed HAART. No clinical events or pro...

ObjectiveThis study was conducted to investigate the pharmacokinetics of emtricitabine (FTC), didanosine (ddI), and efavirenz (EFV) when administered in a once-daily combination. MethodsNine antiretroviral-naïve HIV-infected adults who received FTC [200 mg once a day (qd)], ddI (400 mg qd if !60 kg; 250 mg qd if o60 kg) and EFV (600 mg qd) were studied. The following pharmacokinetic (PK) parameters were determined over 24 h at steady-state after 4 weeks of treatment: area under the plasma concentration vs. time curve (AUC 0-24 h ), maximum (C max ) and minimum (C min ) plasma concentrations, time to reach C max (T max ), and the elimination half-life (t 1/2 ). EFV plasma concentrations were also measured during follow-up. ResultsMedian PK parameters for FTC, ddI and EFV, respectively, were as follows. AUC 0-24 h : 7.2, 7.0 and 36.4 hÂmg/L; C max : 1.8, 2.6 and 2.5 mg/L; C min : 0.04, o 0.01 and 1.0 mg/L; T max : 1.8, 1.1 and 2.5 h; t 1/2 : 7.4, 2.3, and 23.7 h. EFV plasma concentrations measured 10-13 h postdosing were higher during follow-up than during the PK study (2.57 vs. 1.19 mg/L, Po0.01). ConclusionThe simultaneous administration of FTC, ddI and EFV did not affect the PK parameters of FTC when compared to historical controls. EFV C max and C min were lower than expected, but the data may have been slightly underestimated in this study. High ddI AUC and C max were measured in these patients, and further studies are warranted to confirm this finding.Keywords: didanosine, efavirenz, emtricitabine, pharmacokinetics IntroductionThe once-daily administration of antiretroviral agents has become the focus of increasing interest, as it has been suggested that this less frequent treatment strategy may improve convenience and optimize adherence to therapy, both of which are of critical importance for the long-term success of the treatment of HIV infection [1][2][3]. Only a few clinical trials, however, have yet assessed the efficacy and safety of truly once-daily antiretroviral combinations. We previously conducted a pilot study (the Montana ANRS 091 trial) on 40 antiretroviral-naïve HIV-infected patients who received a once-daily combination of emtricitabine (FTC), didanosine (ddI) and efavirenz (EFV) [4]. The results of this study have demonstrated the long-term antiviral efficacy and good tolerance of this combination [5]. Large comparative trials using this same convenient once-daily 99 regimen have been recently completed and support the use of this treatment strategy [6,7]. We report here the results of a pharmacokinetic (PK) substudy of the Montana ANRS 091 trial, which was performed to study potential PK interactions between these three drugs when they are coadministered in a once-daily regimen. Methods Study design and patientsThis study was a PK substudy of the Montana trial (ANRS 091 study), the details of which have been published elsewhere [4]. Briefly, the Montana study was a prospective, noncomparative, multicentre, open-label trial that assessed the antiviral efficacy and safety of the once-daily c...