[show abstract][hide abstract] ABSTRACT: Each year, thousands of cases of uncomplicated malaria are imported into Europe by travellers. Atovaquone-proguanil (AP) has been one of the first-line regimens used in France for uncomplicated malaria for almost ten years. While AP's efficacy and tolerance were evaluated in several trials, its use in "real life" conditions has never been described. This study aimed to describe outcome and tolerance after AP treatment in a large cohort of travellers returning from endemic areas.
Between September 2002 and January 2007, uncomplicated malaria treated in nine French travel clinics with AP were followed for 30 days after AP initiation. Clinical and biological data were collected at admission and during the follow-up.
A total of 553 patients were included. Eighty-eight percent of them were born in Africa, and 61.8 % were infected in West Africa, whereas 0.5 % were infected in Asia. Migrants visiting friends and relatives (VFR) constituted 77.9 % of the patients, the remainder (32.1 %) were backpackers. Three-hundred and sixty-four patients (66 %) fulfilled follow-up at day 7 and 265 (48 %) completed the study at day 30. Three patients had treatment failure. One-hundred and seventy-seven adverse drug reactions (ADR) were reported during the follow-up; 115 (77 %) of them were digestive ADR. Backpackers were more likely to experiment digestive ADR compared to VFR (OR = 3.8; CI 95 % [1.8-8.2]). Twenty patients had to be switched to another regimen due to ADR.
This study seems to be the largest in terms of number of imported uncomplicated malaria cases treated by AP. The high rate of reported digestive ADR is striking and should be taken into account in the follow-up of patients since it could affect their adherence to the treatment. Beside AP, artemisinin combination therapy (ACT) is now recommended as first-line regimen. A comparison of AP and ACT, in terms of efficacy and tolerance, would be useful.
[show abstract][hide abstract] ABSTRACT: Impairment of the intestinal barrier and subsequent microbial translocation (MT) may be involved in chronic immune activation, which plays a central role in HIV pathogenesis. Th17 cells are critical to prevent MT. The aim of the study was to investigate, in patients with primary HIV infection (PHI), the early relationship between the Th17/Treg ratio, monocyte activation and MT and their impact on the T-cell activation set point, which is known to predict disease progression. 27 patients with early PHI were included in a prospective longitudinal study and followed-up for 6 months. At baseline, the Th17/Treg ratio strongly negatively correlated with the proportion of activated CD8 T cells expressing CD38/HLA-DR or Ki-67. Also, the Th17/Treg ratio was negatively related to viral load and plasma levels of sCD14 and IL-1RA, two markers of monocyte activation. In untreated patients, the Th17/Treg ratio at baseline negatively correlated with CD8 T-cell activation at month 6 defining the T-cell activation set point (% HLA-DR(+)CD38(+) and %Ki-67(+)). Soluble CD14 and IL-1RA plasma levels also predicted the T-cell activation set point. Levels of I-FABP, a marker of mucosal damages, were similar to healthy controls at baseline but increased at month 6. No decrease in anti-endotoxin core antibody (EndoCAb) and no peptidoglycan were detected during PHI. In addition, 16S rDNA was only detected at low levels in 2 out 27 patients at baseline and in one additional patient at M6. Altogether, data support the hypothesis that T-cell and monocyte activation in PHI are not primarily driven by systemic MT but rather by viral replication. Moreover, the "innate immune set point" defined by the early levels of sCD14 and IL-1RA might be powerful early surrogate markers for disease progression and should be considered for use in clinical practice.
[show abstract][hide abstract] ABSTRACT: BACKGROUND AND AIMS: The systematic use of rapid tests performed at points-of-care may facilitate hepatitis B virus (HBV) screening and substantially increase HBV infection awareness. The objective of this study was to evaluate the effectiveness of such tests for HBsAg and anti-HBsAb detection among individuals visiting a variety of healthcare centers located in a low HBV-prevalent area. METHODS: Three rapid tests for hepatitis B surface antigen (HBsAg) detection (VIKIA®, Determine(TM) and Quick Profile(TM)) and one test for anti-hepatitis B surface antibody (anti-HBsAb) detection (Quick Profile(TM)) were evaluated in comparison with ELISA serology. Sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV and NPV, respectively) and area under the ROC curve were used to estimate test performance. Non-inferiority criteria of the joint (Se, Sp) were set at (0.80, 0.95). RESULTS: Among the 3956 persons screened, 85 (2.1%) were HBsAg-positive and 2225 (56.5%) had a protective anti-HBsAb titer. Test Se and Sp (lower bound of 97.5%CI) were as follows: 96.5% (89.0%), 99.9% (99.8%) for Vikia®; 93.6% (80.7%), 100.0% (99.8%) for Determine(TM); and 90.5% (80.8%), 99.7% (99.5%) for Quick Profile(TM), with all three tests achieving minimal non-inferiority criteria. False negative tests were typically observed in inactive HBsAg carriers. The anti-HBsAb Quick Profile(TM) test had excellent specificity (97.8%) and PPV (97.8%) albeit low sensitivity (58.3%), thus failing to establish non-inferiority. CONCLUSION: All three HBsAg rapid tests could be considered ideal for HBV screening in low HBV-prevalent countries, given the ease of use, rapidity, and high classification probabilities. The anti-HBsAb Quick Profile(TM) could be considered reliable only for positive tests.
Journal of Hepatology 11/2012; · 9.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: In HIV-infected patients, data on immunogenicity of Yellow fever immunization are scarce, and there is conflicting evidence of the influence of CD4 T-cell count and plasma HIV RNA on neutralizing antibody titer (NT) after vaccine injection.
In this prospective cohort study, NT was measured in all consecutive HIV outpatients who had previously received at least 1 injection of Yellow fever vaccine. Risk factors for vaccine failure (NT < 1:10) and magnitude of NT according to dates of HIV diagnosis and immunization were assessed by logistic regression and general linear models.
Among 364 included patients, 24 (7%) had NT <1:10 after a mean delay of 8.4 years after immunization. Among patients immunized after HIV diagnosis (n = 240), NT <1:10 was associated only with detectable plasma HIV RNA at immunization. Among 79 patients with primary vaccination after diagnosis of HIV infection, higher HIV RNA at immunization was the unique independent risk factor for NT <1:10 [adjusted odds ratio (OR) = 3.73 per log10, 95% confidence interval (CI): 1.14 to 12.28]. Lower values of NT were independently associated with a shorter duration of undetectable plasma HIV RNA (OR = 1.05 per year, 95% CI: 1.005 to 1.09) and higher plasma HIV RNA (OR = 0.91 per log10, 95% CI: 0.84 to 0.99) at immunization.
The key determinant of antibody response was the HIV replication status at immunization. No association was found between antibody response and CD4 T-cell count.
[show abstract][hide abstract] ABSTRACT: Objective: Persistent immune activation plays a central role in the pathogenesis of HIV disease. Besides natural regulatory T cells (nTregs), ‘double negative’ T cells shown to exhibit regulatory properties could be involved in the control of harmful immune activation. The aim of this study was to analyze, in patients with primary HIV infection (PHI), the relationship between CD4+CD25+CD127lowFoxP3+ nTregs or CD3+CD4−CD8− double negative T cells and systemic immune activation.
Design: A prospective longitudinal study of patients with early PHI.
Methods: Twenty-five patients were included. Relationships between frequency of Treg subsets and T-cell activation, assessed on fresh peripheral blood mononuclear cells, were analyzed using nonparametric tests. Cytokine production by double negative T cells was assessed following anti-CD3/anti-CD28 stimulation.
Results: No relationship was found between T-cell activation and frequencies of nTregs. In contrast, a strong negative relationship was found at baseline between the proportion of double negative T cells and the proportion of activated CD8 T cells coexpressing CD38 and HLA-DR (P = 0.005) or expressing Ki-67 (P = 0.002). In addition, the frequency of double negative T cells at baseline negatively correlated with the frequency of HLA-DR+CD38+CD8+ T cells at month 6, defining the immune activation set point (P = 0.031). High proportions of stimulated double negative T cells were found to produce the immunosuppressive cytokines transforming growth factor-β1 and/or IL-10.
Conclusion: The proportion of double negative T cells at baseline was found to be predictive of the immune activation set point. Our data strongly suggest that double negative T cells may control immune activation in PHI. This effect might be mediated through the production of TGF-β1/IL-10 known to downmodulate immune activation.
[show abstract][hide abstract] ABSTRACT: Little is known in HIV-2 infection about the kinetics of disappearance of raltegravir (RAL)-resistant virus after RAL withdrawal.
RAL was interrupted in four highly antiretroviral-experienced HIV-2-infected patients exhibiting a virological failure when receiving RAL. Integrase gene was sequenced from plasma samples collected at the time of RAL failure and at further time points following RAL withdrawal.
At the time of RAL withdrawal, virus exhibited different integrase resistance pathways: G140S/Q148R, E92Q/N155H, T97A/N155H and T97A/Y143C. In patient 1, the G140S/Q148R double-mutant was still detected at month (M)7 and at M11 after stopping RAL, but was no longer detected at M15. Regarding patient 2, the double-mutant E92Q/N155H was still present at M2 and M8 after stopping RAL, and was no longer detected at M12. In patient 3, RAL-resistant virus with T97A/N155H mutations were still present 1 month after stopping RAL, and were no longer detected at M14. Regarding patient 4, the mutant T97A/Y143C was still detected at M1 and M3 following RAL withdrawal. At M18 after RAL stop, integrase genotypic pattern evolved to T97A/Y143G.
Persistence of HIV-2 RAL-resistant mutants was observed in all the key genetic RAL resistance pathways. These findings have clinical implications especially in HIV-2-infected patients for whom therapeutic arsenal is limited compared to HIV-1, since the persistence of resistant mutants might compromise the possible efficacy of upcoming second-generation integrase inhibitors.
[show abstract][hide abstract] ABSTRACT: The emergence of non-AIDS-related events in the HIV-infected population experiencing a longer life expectancy implies the implementation of a comprehensive approach of HIV clinical management through better access to care, prevention, and early diagnosis of co-morbidities.
The Orchestra program is a computer-assisted HIV care and support tool implemented since December 2004 in the outpatient clinic of a University Hospital set in Paris, France. The intervention aims at improving access to HIV information care and support specifically targeted five areas of actions: cardiovascular risk factors; gynecological follow-up; anti-hepatitis B virus (HBV) vaccine coverage; sexuality and prevention of sexually transmitted infections; and compliance to antiretrovirals. The impact of this program was examined prospectively on a "before-after" basis after a two-year implementation.
In the two-year period, 1717 patients were regularly followed. The level of the database information significantly increased in time (low density lipoprotein (LDL) cholesterol and glycemia were informed in 74% of patients at inclusion versus 95% at two years, and 83% versus 97%, p < 0.001, respectively). The number of targeted interventions was also higher. For eligible women, papanicolaou smears and mammography were prescribed in 52% of cases after intervention, versus 44% at inclusion, p0.04 and 83% versus 50%, p < 0.001, respectively. Indicators of care eventually improved significantly. Initially 72% non-adherent patients declared to be adherent after the intervention ( p < 0.001) and 67% of patients with initial LDL-hypercholesterolemia normalized their LDL level within two years ( p < 0.001).
The Orchestra program has provided a unique opportunity to assess and improve prevention and management of co-morbidities in HIV patients.
AIDS Care 05/2010; 22(5):588-96. · 1.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: In 29 antiretroviral-naive HIV-2-infected patients starting lopinavir/ritonavir-containing regimen, the median CD4 cell count change from baseline (142 cells/microl) was +71 cells/microl at week 24 and +132 cells/microl at week 96. Seventeen (59%) patients had a CD4 cell count increase of at least 50 cells/microl and undetectable HIV-2 RNA at week 24 and were considered as responders to treatment. This sustained elevation of CD4 cell count in the first 2 years of combination antiretroviral therapy shows the potential for lopinavir/ritonavir regimens as first-line therapy in HIV-2 infection.
AIDS (London, England) 05/2009; 23(9):1171-3. · 4.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: We investigated the in vitro phenotypic susceptibility of HIV-2 isolates from integrase inhibitor (INI)-naive patients to INIs and its relation to HIV-2 integrase gene polymorphism.
We determined the phenotypic susceptibility to raltegravir and elvitegravir of co-cultured isolates obtained from the HIV-2 ROD reference strain and from 14 clinical isolates. IC(50) values were compared with those for HIV-1 reference strains. HIV-2 integrase gene polymorphism was assessed in isolates from 52 INI-naive patients enrolled in the French HIV-2 cohort.
Median raltegravir and elvitegravir IC(50) values for the 14 clinical HIV-2 isolates were 2.4 and 0.7 nM, respectively, and were similar to those observed for HIV-2 ROD and HIV-1 reference strains. Overall, 38% of HIV-2 integrase amino acids were polymorphic. The catalytic triad DDE and the HHCC and RKK motifs were fully conserved, at the same genomic positions as described in HIV-1. In subtype B isolates, the total length of the integrase gene varied, owing to the presence of stop codons at positions 288, 294, 297 and 302. Fourteen of the positions associated with substitutions conferring INI resistance in HIV-1 were polymorphic in HIV-2.
Despite 40% heterogeneity between the HIV-1 and HIV-2 integrase genes, the phenotypic susceptibility of clinical HIV-2 isolates to INIs was similar to that of HIV-1. This new class of antiretroviral drugs thus represents a novel therapeutic possibility for HIV-2-infected patients who otherwise have few treatment options.
Journal of Antimicrobial Chemotherapy 09/2008; 62(5):914-20. · 5.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
Antimicrobial Agents and Chemotherapy 05/2008; 52(4):1545-8. · 4.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Saint-Antoine Orchestra Program aims at improving the clinical management of HIV-infected patients through access to care, prevention and early diagnosis of comorbidities.
The program was initiated in December 2004 on the whole database. The following topics were concerned: cardiovascular risk factors, gynecological follow-up, anti-HBV vaccinal coverage, sexuality and prevention of STIs, therapeutic adherence and counsels to travelers. The program included several actions: diffusion of information to patients, development of a computerized chart (alert pop-ups), individualized prescription advice and recommendations for specialist referral.
The program was applied to 1959 patients whose initial characteristics were: mean age: 43+/-10 years; ratio M/W: 1466/493; European origin: 69%; sub-Saharan: 19%; mean duration of HIV infection: 9.3+/-6 years; naïve of antiretrovirals: 14%; mean CD4+count: 494+/-277/mm(3); HIV viral load inferior to 50 cp/ml: 62%. Among 1347 patients for whom cardiovascular risk factors were completely informed, 42% had two or more factors. In particular, 31% of them were smokers, 7% had an arterial pressure superior to 140/90 mmHg and 11% had LDL-cholesterolemia superior to 4.1 mmol/l. Among 1448 untreated patients, 70% were initially considered as adherent. Half of the concerned women had neither cervical smear nor mammography up to date. Among 67% patients with an informed complete HBV serology, 27% were seronegative among which 310 (86%) were eligible for the vaccine. Problems of sexual difficulties or prevention were initially discussed for 11% of patients. Among them, 14% had a problem of prevention and 148 (66%) recognized sexual difficulties.
The initiation of the Saint-Antoine Orchestra program has provided a unique opportunity to assess and improve the prevention and management of comorbidities in HIV patients. Also, this program aimed to improve professional practices.
[show abstract][hide abstract] ABSTRACT: Out of 183 HIV-2-infected patients tested in the ANRS CO8 HIV-2 cohort, 69 were exposed to GB virus C (GBV-C), yielding a prevalence of 38% (95% CI 30.7, 45.2). There was no significant difference between the CD4 cell count and HIV-2-RNA plasma viral load in patients exposed and not exposed to GBV-C. After adjusting for age and CD4 cell count, co-infection with GBV-C was not associated with clinical progression (hazard ratio 0.78; 95% CI 0.24-2.56, 16 clinical events).
[show abstract][hide abstract] ABSTRACT: In 61 antiretroviral-naive HIV-2-infected patients starting triple therapy at a median CD4 cell count of 136 cells/microl, the median increase was 41 cells/microl at month 12, which was no different among those on protease inhibitors or triple nucleoside analogues. Despite virological response, as the median plasma load was under the detectable threshold from month 3, CD4 cell recovery remained poor in treated HIV-2 infection. Our results raise the question of the optimal regimen to recommend in HIV-2-infected patients.
[show abstract][hide abstract] ABSTRACT: To evaluate HIV-2-specific proliferative, interferon (IFN)gamma- and interleukin (IL)-2-producing T-cell responses in HIV-2 infection and their relationship with plasma HIV-2 RNA.
HIV-2-Gag-p26 and cytomegalovirus (CMV)-specific CD4 T-cell responses from 19 untreated HIV-2-infected subjects (median CD4 cell counts, 561 x 10/l) were compared by lymphoproliferation assay, IFNgamma secretion in culture supernatants by ELISA, and intracellular staining (ICS) of IFNgamma and IL-2. CD8 responses were assessed by IFNgamma-ELISpot using pools of SIVmac239-Gag peptides (87% of homology with HIV-2).
HIV-2-specific IFNgamma production was detected in 53% and 92% patients by ELISA and ICS, respectively, while HIV-2-specific IL-2 production was detected in only 33% by ICS and lymphoproliferation in 21% patients. All IL-2-producing CD4 T cells co-produced IFNgamma. Overall, frequencies of Th1 responses to HIV-2 were similar to CMV in subjects with undetectable plasma HIV-2 RNA, while significantly lower than CMV in HIV-2 RNA-positive subjects, despite similar CD4 cell counts in both groups. In addition, proliferative responses to HIV-2 were correlated to IFNgamma secretion (r > 0.68, P < 0.01), and were significantly higher in HIV-2 RNA-negative (P < 0.05) than in HIV-2 RNA-positive subjects. Frequencies of SIV-Gag-specific CD8 cells, detected in 93% of patients, were also higher in HIV-2 RNA-negative subjects, though not significantly. Overall, HIV-2-specific T-cell responses were not correlated to CD4 cell counts.
Proliferative, IFNgamma- and IL-2-producing T-cell responses to HIV-2 are as robust as CMV-specific responses in untreated HIV-2 subjects with undetectable plasma HIV-2 levels, independently of CD4 cell depletion and despite lower frequencies of IL-2-producing T cells compared to IFNgamma. In addition, lymphoproliferative responses to HIV-2 were associated with lack of viral replication.
[show abstract][hide abstract] ABSTRACT: We developed a new assay for human immunodeficiency virus type 2 plasma RNA quantification based on a previous format. The new version performed significantly better than the original regarding the detection of subtype B, allowing the detection of 14 out of 36 plasma RNAs in the subtype B-infected patients not detected with the original version.
Journal of Clinical Microbiology 09/2005; 43(8):4234-6. · 4.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: We described the baseline polymorphism of the human immunodeficiency virus type 2 (HIV-2) protease gene from 94 treatment-naive patients and the longitudinal follow-up of 17 protease inhibitor-treated patients. Compared to the HIV-2 consensus sequences, baseline polymorphism involved 47 positions. Substitutions selected under treatment were observed at positions corresponding to HIV-1 resistance mutations as well as at positions of currently unknown impact on HIV-1.
Journal of Clinical Microbiology 02/2005; 43(1):484-7. · 4.07 Impact Factor