Pauline Campa

High Rate of Acquisition but Short Duration of Carriage of Multidrug-Resistant Enterobacteriaceae After Travel to the Tropics

BACKGROUND Multidrug-resistant Enterobacteriaceae (MRE) are widespread in the community, especially in tropical regions. Travelers are at risk of acquiring MRE in these regions, but the precise extent of the problem is not known. METHODS From February 2012 to April 2013, travelers attending 6 international vaccination centers in the Paris area prior to traveling to tropical regions were asked to provide a fecal sample before and after their trip. Those found to have acquired MRE were asked to send fecal samples 1, 2, 3, 6, and 12 months after their return, or until MRE was no longer detected. The fecal relative abundance of MRE among all Enterobacteriaceae was determined in each carrier. RESULTS Among 824 participating travelers, 574 provided fecal samples before and after travel and were not MRE carriers before departure. Of these, 292 (50.9%) acquired an average of 1.8 MRE. Three travelers (0.5%) acquired carbapenemase-producing Enterobacteriaceae. The acquisition rate was higher in Asia (142/196 [72.4%]) than in sub-Saharan Africa (93/195 [47.7%]) or Latin America (57/183 [31.1%]). MRE acquisition was associated with the type of travel, diarrhea, and exposure to β-lactams during the travel. Three months after return, 4.7% of the travelers carried MRE. Carriage lasted longer in travelers returning from Asia and in travelers with a high relative abundance of MRE at return. CONCLUSIONS MRE acquisition is very frequent among travelers to tropical regions. Travel to these regions should be considered a risk factor of MRE carriage during the first 3 months after return, but not beyond. CLINICAL TRIALS REGISTRATION NCT01526187.

In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors

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.

Plasma RNA Viral Load in Human Immunodeficiency Virus Type 2 Subtype A and Subtype B Infections

ABSTRACT Human immunodeficiency virus type 2 (HIV-2) is much less pathogenic than HIV-1, and HIV-2 infection is associated with plasma viral loads significantly lower than those found in HIV-1 infection. We have developed a real-time quantitative PCR method for measuring the HIV-2 RNA load that covers the range of genetic diversity of HIV-2 isolates and that detects extremely low viral loads. Samples from 49 patients were studied. Proviral DNA was first detected and quantified. The strains that were detected were then genotyped: 21 patients were infected with HIV-2 subtype A and 15 patients were infected with HIV-2 subtype B; 1 patient was infected with a highly divergent strain. Env PCR failed for the remaining 12 patients, so subtypes could not be determined. For viral RNA quantification, a stock of HIV-2 strain NIHZ, which was counted by electron microscopy, was used as the standard. Several primer sets targeting the highly conserved gag region were evaluated. Various primer combinations failed to amplify subtype B strains. With the final primer pair selected, which detected both subtype A and subtype B strains, the sensitivity of the assay was 100% at a viral load of 250 copies/ml and 66% at a viral load of 125 copies/ml. We found a correlation between the CD4+-cell count, the clinical stage, and the plasma HIV-2 RNA level. The median plasma HIV-2 RNA value for the 33 asymptomatic patients was 2.14 log10, whereas it was 3.1 log10 for the 16 patients with AIDS (P < 0.01). Proviral DNA was detectable in 18 symptom-free patients with high CD4+-cell counts, in whom viral RNA was undetectable.

Quantification of Proviral Load of Human Immunodeficiency Virus Type 2 Subtypes A and B Using Real-Time PCR

ABSTRACT We have developed and evaluated a new method to quantify human immunodeficiency virus type 2 (HIV-2) proviral DNA based on LightCycler real-time PCR. The assay has a detection limit of 5 copies/105 peripheral blood mononuclear cells (PBMC) and is insensitive to HIV-2 strain variability: HIV-2 subtypes A and B are both recognized and quantified. The intra- and interassay coefficients of variation range from 16 to 40% for high provirus concentrations (5 × 105 copies) and from 41 to 39% for low concentrations (5 copies). We used this method to compare the proviral DNA load and viral RNA load in plasma with clinical and immunological status for 29 patients infected by HIV-2 (subtype A in 17 and subtype B in 12). The proviral load (median, 201 copies/105PBMC) was similar to that reported for HIV-1 infection. The median proviral loads did not correlate with the CD4+ cell count categories and were as follows for CD4+ cell counts of >400, 200 to 400, and <200 cells/mm3, respectively: 121 copies/105 PBMC (n = 8; range, <5 to 712 copies/105 PBMC); 114 copies/105 PBMC (n = 9; range, <5 to 1,907 copies/105PBMC); and 285 copies/105 PBMC (n = 12; range, 53 to 2,524 copies/105 PBMC). Proviral load did not correlate with plasma HIV-2 RNA positivity. As HIV-2 is considered to replicate less efficiently than HIV-1, these high proviral loads might be explained by the proliferation of infected cells.

Polymorphism of the human immunodeficiency virus type 2 (HIV-2) protease gene and selection of drug resistance mutations in HIV-2-infected patients treated with protease inhibitors.

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.

CD4 cell recovery in treated HIV-2-infected adults is lower than expected: results from the French ANRS CO5 HIV-2 cohort.

In 61 antiretroviral-naive HIV-2-infected patients starting triple therapy at a median CD4 cell count of 136 cells/μl, the median increase was 41 cells/μl 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.

Improved Sensitivity of Human Immunodeficiency Virus Type 2 Subtype B Plasma Viral Load Assay

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.

Plasma HIV-RNA is the key determinant of long-term antibody persistence after Yellow fever immunization in a cohort of 364 HIV-infected patients.

BackgroundIn 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. MethodsIn 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. ResultsAmong 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. ConclusionsThe key determinant of antibody response was the HIV replication status at immunization. No association was found between antibody response and CD4 T-cell count.

Level of double negative T cells, which produce TGF-β and IL-10, predicts CD8 T-cell activation in primary HIV-1 infection.

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-&bgr;1 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-&bgr;1/IL-10 known to downmodulate immune activation.

Good response to lopinavir/ritonavir-containing antiretroviral regimens in antiretroviral-naive HIV-2-infected patients

In 29 antiretroviral-naive HIV-2-infected patients starting lopinavir/ritonavir-containing regimen, the median CD4 cell count change from baseline (142 cells/μl) was +71 cells/μl at week 24 and +132 cells/μl at week 96. Seventeen (59%) patients had a CD4 cell count increase of at least 50 cells/μl 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.