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1.  Viral-bacterial coinfection affects the presentation and alters the prognosis of severe community-acquired pneumonia 
Critical Care  2016;20:375.
Background
Multiplex polymerase chain reaction (mPCR) enables recovery of viruses from airways of patients with community-acquired pneumonia (CAP), although their clinical impact remains uncertain.
Methods
Among consecutive adult patients who had undergone a mPCR within 72 hours following their admission to one intensive care unit (ICU), we retrospectively included those with a final diagnosis of CAP. Four etiology groups were clustered: bacterial, viral, mixed (viral-bacterial) and no etiology. A composite criterion of complicated course (hospital death or mechanical ventilation > 7 days) was used. A subgroup analysis compared patients with bacterial and viral-bacterial CAP matched on the bacterial pathogens.
Results
Among 174 patients (132 men [76 %], age 63 [53–75] years, SAPSII 38 [27;55], median PSI score 106 [78;130]), bacterial, viral, mixed and no etiology groups gathered 46 (26 %), 53 (31 %), 45 (26 %) and 30 (17 %) patients, respectively. Virus-infected patients displayed a high creatine kinase serum level, a low platelet count, and a trend toward more frequent alveolar-interstitial infiltrates. A complicated course was more frequent in the mixed group (31/45, 69 %), as compared to bacterial (18/46, 39 %), viral (15/53, 28 %) and no etiology (12/30, 40 %) groups (p < 0.01). In multivariate analysis, the mixed (viral-bacterial) infection was independently associated with complicated course (reference: bacterial pneumonia; OR, 3.58; CI 95 %, 1.16–11; p = 0.03). The subgroup analysis of bacteria-matched patients confirmed these findings.
Conclusions
Viral-bacterial coinfection during severe CAP in adults is associated with an impaired presentation and a complicated course.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-016-1517-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-016-1517-9
PMCID: PMC5112669  PMID: 27852281
Pneumonia; Viral pneumonia; Respiratory viruses; Intensive care
2.  The HIV Cure Research Agenda: The Role of Mathematical Modelling and Cost-Effectiveness Analysis 
Journal of virus eradication  2015;1(4):245-249.
The research agenda towards an HIV cure is building rapidly. In this article, we discuss the reasons for and methodological approach to using mathematical modeling and cost-effectiveness analysis in this agenda. We provide a brief description of the proof of concept for cure and the current directions of cure research. We then review the types of clinical economic evaluations, including cost analysis, cost-benefit analysis, and cost-effectiveness analysis. We describe the use of mathematical modeling and cost-effectiveness analysis early in the HIV epidemic as well as in the era of combination antiretroviral therapy. We then highlight the novel methodology of Value of Information analysis and its potential role in the planning of clinical trials. We close with recommendations for modeling and cost-effectiveness analysis in the HIV cure agenda.
PMCID: PMC4748959  PMID: 26878073
HIV/AIDS; cure; mathematical modeling; cost-effectiveness
3.  Antiretroviral-Experienced HIV-1-Infected Patients Treated with Maraviroc: Factors Associated with Virological Response 
Abstract
There are few data on the clinical and virological factors associated with the virological response (VR) of maraviroc (MVC) in clinical practice. This study aimed to identify factors associated with the VR to MVC-containing regimens in 104 treatment-experienced but CCR5 inhibitor-naive HIV-1 patients. VR was defined at month 3 (M3) as HIV-1 RNA viral load (VL) <50 copies/ml. The impact on VR of age, sex, baseline tropism, HIV subtype (B vs. non-B), nadir CD4 cell count and CD4 cell count, baseline VL, genotypic susceptibility score of treatment, once or twice daily treatment, presence of raltegravir in optimized background therapy, and MVC concentrations was investigated. Median baseline VL was 3.3 log10 copies/ml (range 1.7–6.0 log10 copies/ml) and CD4 cell count was 299 cells/mm3 (range 7–841 cells/mm3). At M3, 53.8% of patients were responders. In univariate analysis, a better efficacy of the MVC-containing regimen was associated with a high CD4 cell count (p=0.0069) and there was a trend for low baseline VL, high nadir CD4 cell count, and HIV subtype (B versus non-B). Only low baseline VL remained significantly associated with better VR in the multivariate analysis. This study demonstrated a VR of an optimized antiretroviral treatment including MVC in clinical practice similar to that observed in clinical trials. The factors associated with VR were higher baseline CD4 cell count in univariate analysis and lower baseline VL in multivariate analysis.
doi:10.1089/aid.2014.0223
PMCID: PMC4426320  PMID: 25420695
4.  Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea 
Sissoko, Daouda | Laouenan, Cedric | Folkesson, Elin | M’Lebing, Abdoul-Bing | Beavogui, Abdoul-Habib | Baize, Sylvain | Camara, Alseny-Modet | Maes, Piet | Shepherd, Susan | Danel, Christine | Carazo, Sara | Conde, Mamoudou N. | Gala, Jean-Luc | Colin, Géraldine | Savini, Hélène | Bore, Joseph Akoi | Le Marcis, Frederic | Koundouno, Fara Raymond | Petitjean, Frédéric | Lamah, Marie-Claire | Diederich, Sandra | Tounkara, Alexis | Poelart, Geertrui | Berbain, Emmanuel | Dindart, Jean-Michel | Duraffour, Sophie | Lefevre, Annabelle | Leno, Tamba | Peyrouset, Olivier | Irenge, Léonid | Bangoura, N’Famara | Palich, Romain | Hinzmann, Julia | Kraus, Annette | Barry, Thierno Sadou | Berette, Sakoba | Bongono, André | Camara, Mohamed Seto | Munoz, Valérie Chanfreau | Doumbouya, Lanciné | Harouna, Souley | Kighoma, Patient Mumbere | Koundouno, Fara Roger | Lolamou, Réné | Loua, Cécé Moriba | Massala, Vincent | Moumouni, Kinda | Provost, Célia | Samake, Nenefing | Sekou, Conde | Soumah, Abdoulaye | Arnould, Isabelle | Komano, Michel Saa | Gustin, Lina | Berutto, Carlotta | Camara, Diarra | Camara, Fodé Saydou | Colpaert, Joliene | Delamou, Léontine | Jansson, Lena | Kourouma, Etienne | Loua, Maurice | Malme, Kristian | Manfrin, Emma | Maomou, André | Milinouno, Adele | Ombelet, Sien | Sidiboun, Aboubacar Youla | Verreckt, Isabelle | Yombouno, Pauline | Bocquin, Anne | Carbonnelle, Caroline | Carmoi, Thierry | Frange, Pierre | Mely, Stéphane | Nguyen, Vinh-Kim | Pannetier, Delphine | Taburet, Anne-Marie | Treluyer, Jean-Marc | Kolie, Jacques | Moh, Raoul | Gonzalez, Minerva Cervantes | Kuisma, Eeva | Liedigk, Britta | Ngabo, Didier | Rudolf, Martin | Thom, Ruth | Kerber, Romy | Gabriel, Martin | Di Caro, Antonino | Wölfel, Roman | Badir, Jamal | Bentahir, Mostafa | Deccache, Yann | Dumont, Catherine | Durant, Jean-François | El Bakkouri, Karim | Uwamahoro, Marie Gasasira | Smits, Benjamin | Toufik, Nora | Van Cauwenberghe, Stéphane | Ezzedine, Khaled | D’Ortenzio, Eric | Pizarro, Louis | Etienne, Aurélie | Guedj, Jérémie | Fizet, Alexandra | de Sainte Fare, Eric Barte | Murgue, Bernadette | Tran-Minh, Tuan | Rapp, Christophe | Piguet, Pascal | Poncin, Marc | Draguez, Bertrand | Duverger, Thierry Allaford | Barbe, Solenne | Baret, Guillaume | Defourny, Isabelle | Carroll, Miles | Raoul, Hervé | Augier, Augustin | Eholie, Serge P. | Yazdanpanah, Yazdan | Levy-Marchal, Claire | Antierrens, Annick | Van Herp, Michel | Günther, Stephan | de Lamballerie, Xavier | Keïta, Sakoba | Mentre, France | Anglaret, Xavier | Malvy, Denis
PLoS Medicine  2016;13(4):e1002009.
doi:10.1371/journal.pmed.1002009
PMCID: PMC4821578  PMID: 27046271
5.  Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea 
Sissoko, Daouda | Laouenan, Cedric | Folkesson, Elin | M’Lebing, Abdoul-Bing | Beavogui, Abdoul-Habib | Baize, Sylvain | Camara, Alseny-Modet | Maes, Piet | Shepherd, Susan | Danel, Christine | Carazo, Sara | Conde, Mamoudou N. | Gala, Jean-Luc | Colin, Géraldine | Savini, Hélène | Bore, Joseph Akoi | Le Marcis, Frederic | Koundouno, Fara Raymond | Petitjean, Frédéric | Lamah, Marie-Claire | Diederich, Sandra | Tounkara, Alexis | Poelart, Geertrui | Berbain, Emmanuel | Dindart, Jean-Michel | Duraffour, Sophie | Lefevre, Annabelle | Leno, Tamba | Peyrouset, Olivier | Irenge, Léonid | Bangoura, N’Famara | Palich, Romain | Hinzmann, Julia | Kraus, Annette | Barry, Thierno Sadou | Berette, Sakoba | Bongono, André | Camara, Mohamed Seto | Chanfreau Munoz, Valérie | Doumbouya, Lanciné | Souley Harouna,  | Kighoma, Patient Mumbere | Koundouno, Fara Roger | Réné Lolamou,  | Loua, Cécé Moriba | Massala, Vincent | Moumouni, Kinda | Provost, Célia | Samake, Nenefing | Sekou, Conde | Soumah, Abdoulaye | Arnould, Isabelle | Komano, Michel Saa | Gustin, Lina | Berutto, Carlotta | Camara, Diarra | Camara, Fodé Saydou | Colpaert, Joliene | Delamou, Léontine | Jansson, Lena | Kourouma, Etienne | Loua, Maurice | Malme, Kristian | Manfrin, Emma | Maomou, André | Milinouno, Adele | Ombelet, Sien | Sidiboun, Aboubacar Youla | Verreckt, Isabelle | Yombouno, Pauline | Bocquin, Anne | Carbonnelle, Caroline | Carmoi, Thierry | Frange, Pierre | Mely, Stéphane | Nguyen, Vinh-Kim | Pannetier, Delphine | Taburet, Anne-Marie | Treluyer, Jean-Marc | Kolie, Jacques | Moh, Raoul | Gonzalez, Minerva Cervantes | Kuisma, Eeva | Liedigk, Britta | Ngabo, Didier | Rudolf, Martin | Thom, Ruth | Kerber, Romy | Gabriel, Martin | Di Caro, Antonino | Wölfel, Roman | Badir, Jamal | Bentahir, Mostafa | Deccache, Yann | Dumont, Catherine | Durant, Jean-François | El Bakkouri, Karim | Gasasira Uwamahoro, Marie | Smits, Benjamin | Toufik, Nora | Van Cauwenberghe, Stéphane | Ezzedine, Khaled | Dortenzio, Eric | Pizarro, Louis | Etienne, Aurélie | Guedj, Jérémie | Fizet, Alexandra | Barte de Sainte Fare, Eric | Murgue, Bernadette | Tran-Minh, Tuan | Rapp, Christophe | Piguet, Pascal | Poncin, Marc | Draguez, Bertrand | Allaford Duverger, Thierry | Barbe, Solenne | Baret, Guillaume | Defourny, Isabelle | Carroll, Miles | Raoul, Hervé | Augier, Augustin | Eholie, Serge P. | Yazdanpanah, Yazdan | Levy-Marchal, Claire | Antierrens, Annick | Van Herp, Michel | Günther, Stephan | de Lamballerie, Xavier | Keïta, Sakoba | Mentre, France | Anglaret, Xavier | Malvy, Denis
PLoS Medicine  2016;13(3):e1001967.
Background
Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care.
Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies.
Methods and Findings
Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in “cycle threshold” [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A “target value” of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis.
Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%–32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%–91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated.
Conclusions
In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia.
Trial registration
ClinicalTrials.gov NCT02329054
In the context the recent Ebola outbreak, Xavier Anglaret and colleagues test an experimental treatment, favipiravir, for Ebola virus disease in a multicenter non-randomized trial.
Editors' Summary
Background
In 2014 and 2015, an Ebola virus outbreak larger than any known before occurred in West Africa. Ebola virus disease (EVD) is highly contagious, and many infected people die. Central to the emergency response to the recent outbreak were local Ebola treatment centers where patients were diagnosed, were isolated, and received supportive care. With thousands of patients dying and many health workers contracting the disease, fear was ubiquitous and distrust abundant. While conducting research in this environment was extremely challenging, the urgent need for treatments and the opportunity to conduct studies that could bring such treatments closer to reality was also recognized. In September 2014, WHO released a short list of existing drugs that were candidates for clinical trials among patients infected in the outbreak. Favipiravir, an antiviral drug developed in Japan for patients with severe influenza, was on the list.
Why Was This Study Done?
Because of the urgent need to find drugs that could reduce deaths caused by Ebola, the researchers decided to conduct a clinical trial using favipiravir in patients with EVD in Guinea. In view of the circumstances, they decided against a randomized controlled trial and instead designed a study where all participants would receive the same treatment. In randomized controlled trials only some participants receive the treatment in addition to standard care, while others serve as a control group and receive standard care only, or standard care plus a placebo. Such studies allow stronger conclusions to be drawn about whether a treatment is safe and whether it works or not. The researchers had two main reasons for this decision. First, patients from the same family or village often sought EVD treatment at the same time, and the researchers felt that it was ethically unacceptable to randomize such groups, with only some of them receiving the experimental drug. Second, the strict isolation procedures imposed to interrupt virus transmission had intensified fear in affected communities and fueled rumors of illicit drug experimentation and organ theft at the treatment centers. In this context, the researchers worried that a randomized study might increase distrust among the community and the reluctance of patients to seek care.
Rather than seeking definitive answers about the safety and efficacy of favipiravir in patients with EVD, the objectives of the study as it was designed were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak and to learn lessons from the experience. In addition, the researchers planned to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD in the hope that their preliminary findings could improve the design of subsequent trials and the chance to provide conclusive answers.
What Did the Researchers Do and Find?
After 13 weeks of preparation, the trial took place from December 2014 to April 2015 at four separate Ebola treatment centers, three in rural areas and one in an urban setting. In addition to standard care (which included rehydration, antimalarial and antibacterial therapies, and medication to reduce fever, pain, and nausea), all participants were given favipiravir by mouth for ten days, at doses substantially higher than those recommended for patients with influenza. Outcomes measured were mortality, viral load changes over time (based on blood samples), and adverse events.
EVD was confirmed with an assay that used patient blood and provided an estimate of the viral load, that is, of how much virus the blood contained. Because viral load was known to influence the course of EVD, the researchers analyzed the participants in two groups, namely, those with a viral load estimate above a certain threshold and those with viral load estimate below the threshold. They also used existing data from Guinean patients diagnosed with Ebola earlier in the outbreak who had received only standard care and calculated an expected mortality rate for patients above and below the viral load threshold.
The researchers were able to enroll 126 participants in the trial. Of these, 111 were included in the final analysis. Of 99 adult and adolescent participants 13 years and older, 55 were in the lower viral load group and 44 in the higher viral load group. Mortality was 20% in the former and 91% in the latter. Neither mortality rate was significantly different from that of earlier patients who had received only standard care. The researchers also found that favipiravir was well tolerated. None of the patients stopped the course of treatment, vomiting following drug intake was rare, and no severe adverse events were attributed to the drug. The researchers did not see a difference in mortality between patients who reported onset of symptoms less than three days before the start of treatment and those whose symptoms had started more than three days the start of treatment.
What Do these Findings Mean?
The report shows that it is possible to conduct an emergency trial during an outbreak in a low-resource setting. In fact, at the time of its acceptance, this paper reported on an Ebola treatment trial larger than any other yet published. The experience described should be useful for similar undertakings in the future. The following conditions contributed to the success of the trial: close collaboration between researchers, local health officials, and affected communities on one hand, and flexibility in design, conduct, and analysis based on close monitoring and interim assessments on the other. Besides using interim results to influence the conduct and analysis of their own trial, the researchers also shared these results with the scientific community in real time, and this feedback influenced other research during the outbreak.
The trial could not answer definitively whether favipiravir treatment was safe or reduced mortality in patients with EVD. The results suggest that the drug is unlikely to be beneficial for patients with very high viral loads, at least when given by itself. They also suggest that favipiravir is safe in patients with lower viral loads, and that in such patients additional efficacy studies are warranted. Intermediate analysis of various measurements in trial participants showed that the estimate of viral load from the field EVD diagnosis test is a good proxy for the actual viral load (determined after the samples were shipped to and analyzed in a reference laboratory in France) and suitable as a surrogate marker. The results also confirm that viral load is a strong predictor of mortality.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001967.
The World Health Organization has pages on Ebola virus disease, trials of Ebola treatments and vaccines, and the current update of the list of suitable drugs for testing or use in patients infected with Ebola (originally compiled in September 2014)
US Centers for Disease Control and Prevention has information on the Ebola outbreak in West Africa
The European Centre for Disease Prevention and Control also has information on the Ebola outbreak in West Africa
doi:10.1371/journal.pmed.1001967
PMCID: PMC4773183  PMID: 26930627
6.  Costs associated with implementation of a strict policy for controlling spread of highly resistant microorganisms in France 
BMJ Open  2016;6(1):e009029.
Objective
To assess costs associated with implementation of a strict ‘search and isolate’ strategy for controlling highly drug-resistant organisms (HDRO).
Design
Review of data from 2-year prospective surveillance (01/2012 to 12/2013) of HDRO.
Setting
Three university hospitals located in northern Paris.
Methods
Episodes were defined as single cases or outbreaks of glycopeptide-resistant enterococci (GRE) or carbapenemase-producing Enterobacteriacae (CPE) colonisation. Costs were related to staff reinforcement, costs of screening cultures, contact precautions and interruption of new admissions. Univariate analysis, along with simple and multiple linear regression analyses, was conducted to determine variables associated with cost of HDRO management.
Results
Overall, 41 consecutive episodes were included, 28 single cases and 13 outbreaks. The cost (mean±SD) associated with management of a single case identified within and/or 48 h after admission was €4443±11 552 and €11 445±15 743, respectively (p<0.01). In an outbreak, the total cost varied from €14 864 ±17 734 for an episode with one secondary case (€7432±8867 per case) to €136 525 ±151 231 (€12 845±5129 per case) when more than one secondary case occurred. In episodes of single cases, contact precautions and microbiological analyses represented 51% and 30% of overall cost, respectively. In outbreaks, cost related to interruption of new admissions represented 77–94% of total costs, and had the greatest financial impact (R2=0.98, p<0.01).
Conclusions
In HDRO episodes occurring at three university hospitals, interruption of new admissions constituted the most costly measure in an outbreak situation.
doi:10.1136/bmjopen-2015-009029
PMCID: PMC4735214  PMID: 26826145
EPIDEMIOLOGY
7.  Durability and Effectiveness of Maraviroc-Containing Regimens in HIV-1-Infected Individuals with Virological Failure in Routine Clinical Practice 
PLoS ONE  2015;10(12):e0144746.
Introduction
Limited data are available on the durability and effectiveness of maraviroc in routine clinical practice. We assessed the durability of maraviroc-containing regimens during a 30-month period, as well as their immunovirological and clinical efficacy, according to viral tropism in treatment-experienced individuals with viral load (VL) >50 copies/ml in the French Hospital Database on HIV.
Methods
Virological success was defined as VL<50 copies/ml, immunological success as a confirmed increase of at least 100 CD4 cells/mm3 measured twice at least one month apart, and clinical failure as hospitalization for a non-AIDS event, an AIDS event, or death. Multivariable Cox regression models adjusted for potential confounders were used to assess the influence of viral tropism on durability, the immunovirological responses, and clinical outcome.
Results
356 individuals started maraviroc with VL>50 copies/ml of whom 223 harbored R5 viruses, 44 non-R5 viruses and 89 viruses of unknown tropism. Individuals with non-R5 viruses were more likely than individuals with R5 viruses to discontinue maraviroc (75% vs 34%, p<0.0001). At 30 months, the estimated rates of virological and immunological success were respectively 89% and 51% in individuals with R5 viruses and 48% and 23% in individuals with non-R5 viruses. In multivariable analysis, non-R5 viruses were associated with a lower likelihood of both virological success (hazard ratio (HR): 0.42; 95% confidence interval (CI), 0.25–0.70) and immunological success (HR: 0.37; 95% CI, 0.18–0.77). No difference in clinical outcome was found between individuals with R5 and non-R5 viruses. The effectiveness of maraviroc-containing regimens in individuals with unknown viral tropism was not significantly different from that in individuals with R5 viruses. A limitation of the study is the absence of genotypic susceptibility score.
Conclusion
In this observational study, maraviroc-containing regimens yielded high rates of viral suppression and immunological responses in individuals with R5 viruses in whom prior regimens had failed.
doi:10.1371/journal.pone.0144746
PMCID: PMC4695083  PMID: 26714012
8.  The HIV cure research agenda: the role of mathematical modelling and cost-effectiveness analysis 
Journal of Virus Eradication  null;1(4):245-249.
Abstract
The research agenda towards an HIV cure is building rapidly. In this article, we discuss the reasons for and methodological approach to using mathematical modelling and cost-effectiveness analysis in this agenda. We provide a brief description of the proof of concept for cure and the current directions of cure research. We then review the types of clinical economic evaluations, including cost analysis, cost-benefit analysis and cost-effectiveness analysis. We describe the use of mathematical modelling and cost-effectiveness analysis early in the HIV epidemic as well as in the era of combination antiretroviral therapy. We then highlight the novel methodology of Value of Information (VOI) analysis and its potential role in the planning of clinical trials. We close with recommendations for modelling and cost-effectiveness analysis in the HIV cure agenda.
PMCID: PMC4748959  PMID: 26878073
HIV/AIDS; cure; mathematical modelling; cost-effectiveness
9.  Sternal Wound Infection after Cardiac Surgery: Management and Outcome 
PLoS ONE  2015;10(9):e0139122.
Background
Sternal Wound Infection (SWI) is a severe complication after cardiac surgery. Debridement associated with primary closure using Redon drains (RD) is an effective treatment, but data on RD management and antibiotic treatment are scarce.
Methods
We performed a single-center analysis of consecutive patients who were re-operated for SWI between 01/2009 and 12/2012. All patients underwent a closed drainage with RD (CDRD). Patients with endocarditis or those who died within the first 45 days were excluded from management analysis. RD fluid was cultured twice weekly. Variables recorded were clinical and biological data at SWI diagnosis, severity of SWI based on criteria for mediastinitis as defined by the Centers for Disease Control (CDC), antibiotic therapy, RD management and patient’s outcome.
Results
160 patients developed SWI, 102 (64%) fulfilled CDC criteria (CDC+) and 58 (36%) did not (CDC- SWI). Initial antibiotic treatment and surgical management were similar in CDC+ and CDC- SWI. Patients with CDC+ SWI had a longer duration of antibiotic therapy and a mortality rate of 17% as compared to 3% in patients with CDC- SWI (p = 0.025). Rates of superinfection (10% and 9%) and need for second reoperation (12% and 17%) were similar. Failure (death or need for another reoperation) was associated with female gender, higher EuroScore for prediction of operative mortality, and stay in the ICU.
Conclusion
In patients with SWI, initial one-stage surgical debridement with CDRD is associated with favorable outcomes. CDC+ and CDC- SWI received essentially the same management, but CDC+ SWI has a more severe outcome.
doi:10.1371/journal.pone.0139122
PMCID: PMC4589393  PMID: 26422144
10.  Use of PCR Signal and Therapeutic Drug Monitoring in a Switch Cohort Study to Tenofovir/Emtricitabine/Rilpivirine: A W96 Follow-Up 
PLoS ONE  2015;10(7):e0134430.
Objective
To assess, in a clinical cohort, the efficacy of switching treatment in virologically-suppressed patients to tenofovir/emtricitabine/rilpivirine as a single-tablet regimen (STR) using the PCR signal of the viral load (VL) assay and plasma drug determination (C24h).
Patients and methods
An observational single-centre study enrolling patients with VL<50 copies/mL initiating rilpivirine-based STR. C24h and VL were performed until W48 and W96 of STR, respectively. PCRneg was defined as an undetected PCR signal. Medians (IQR) were presented.
Results
116 patients were enrolled. At STR baseline, time since first antiretroviral therapy and time of virological suppression were 6 years (2–9) and 17 months (7–43), respectively. Before STR initiation, patients were receiving protease inhibitors and non-nucleoside reverse transcriptase inhibitors-based regimen in 44% and 47% of cases, respectively. Historical genotype showed virus resistant to one drug of the STR in 6 patients (5%). At W96, 17 (15%) discontinued STR due to adverse events. The proportion of patients maintaining VL <50 copies/mL on treatment was 98%, 99%, 100%, 100%, 100% and 100% at W12, W24, W36, W48, W72 and W96, respectively. Among them, 70%, 66%, 68%, 59%, 74%, 68% and 60% were PCRneg at baseline, W12, W24, W36, W48, W72 and W96, respectively. Median rilpivirine C24h was 91 ng/mL (57–141, n = 285), with 91% of rilpivirine C24h >50 ng/mL, the target effective concentration.
Conclusions
In this clinical cohort of virologically-suppressed patients switching to a new STR, most subjects had adequate rilpivirine C24h and displayed a high level of virological suppression with no residual viremia until W96.
doi:10.1371/journal.pone.0134430
PMCID: PMC4520481  PMID: 26226257
11.  The French Connection: The First Large Population-Based Contact Survey in France Relevant for the Spread of Infectious Diseases 
PLoS ONE  2015;10(7):e0133203.
Background
Empirical social contact patterns are essential to understand the spread of infectious diseases. To date, no such data existed for France. Although infectious diseases are frequently seasonal, the temporal variation of contact patterns has not been documented hitherto.
Methods
COMES-F is the first French large-scale population survey, carried out over 3 different periods (February-March, April, April-May) with some participants common to the first and the last period. Participants described their contacts for 2 consecutive days, and reported separately on professional contacts when typically over 20 per day.
Results
2033 participants reported 38 881 contacts (weighted median [first quartile-third quartile]: 8[5–14] per day), and 54 378 contacts with supplementary professional contacts (9[5–17]). Contrary to age, gender, household size, holidays, weekend and occupation, period of the year had little influence on the number of contacts or the mixing patterns. Contact patterns were highly assortative with age, irrespective of the location of the contact, and gender, with women having 8% more contacts than men. Although most contacts occurred at home and at school, the inclusion of professional contacts modified the structure of the mixing patterns. Holidays and weekends reduced dramatically the number of contacts, and as proxies for school closure, reduced R0 by 33% and 28%, respectively. Thus, school closures could have an important impact on the spread of close contact infections in France.
Conclusions
Despite no clear evidence for temporal variation, trends suggest that more studies are needed. Age and gender were found important determinants of the mixing patterns. Gender differences in mixing patterns might help explain gender differences in the epidemiology of infectious diseases.
doi:10.1371/journal.pone.0133203
PMCID: PMC4503306  PMID: 26176549
12.  Clinical impact and cost-effectiveness of making third-line antiretroviral therapy available in sub-Saharan Africa: A model-based analysis in Côte d’Ivoire 
Objective
In sub-Saharan Africa, HIV-infected adults who fail 2nd-line antiretroviral therapy (ART) often do not have access to 3rd-line ART. We examined the clinical impact and cost-effectiveness of making 3rd-line ART available in Côte d’Ivoire.
Methods
We used a simulation model to compare four strategies following 2nd-line ART failure: continue 2nd-line ART [C-ART2]; continue 2nd-line ART with an adherence reinforcement intervention [AR-ART2]; immediate switch to 3rd-line ART [IS-ART3]; and continue 2nd-line ART with adherence reinforcement, switching patients with persistent failure to 3rd-line ART [AR-ART3]. Third-line ART consisted of a boosted-darunavir plus raltegravir-based regimen. Primary outcomes were 10-year survival and lifetime incremental cost effectiveness ratios (ICERs), in $/year of life saved (YLS). ICERs below $3,585 (3 times the country per capita GDP) were considered cost-effective.
Results
Ten-year survival was 6.0% with C-ART2, 17.0% with AR-ART2, 35.4% with IS-ART3, and 37.2% with AR-ART3. AR-ART2 was cost-effective ($1,100/YLS). AR-ART3 had an ICER of $3,600/YLS and became cost-effective if the cost of 3rd-line ART decreased by <1%. IS-ART3 was less effective and more costly than AR-ART3. Results were robust to wide variations in the efficacy of 3rd-line ART and of the adherence reinforcement, as well as in the cost 2nd-line ART.
Conclusion
Access to 3rd-line ART combined with an intense adherence reinforcement phase, used as a tool to distinguish between patients who can still benefit from their current 2nd-line regimen and those who truly need 3rd-line ART would provide substantial survival benefits. With minor decreases in drug costs, this strategy would be cost-effective.
doi:10.1097/QAI.0000000000000166
PMCID: PMC4146647  PMID: 24732870
13.  A Case of Aggregatibacter aphrophilus Multiple Abscess 
Open Forum Infectious Diseases  2015;2(2):ofv031.
We report a case of brain and lung abscesses caused by Agreggatibacter aphrophilus in a 43-YEAR-OLD man with past history of splenectomy and drug addiction, in the absence of endocarditis. Microbiological samples remain negatives and diagnosis was made by 16S rDNA PCR performance on abscess fluid for this coccobacillus that belongs to the HACEK group. The patient’s clinical symptoms resolved within 6 weeks of treatment with cefotaxim.
doi:10.1093/ofid/ofv031
PMCID: PMC4566307  PMID: 26380332
Aggregatibacter aphrophilus; brain abscess; HACEK; lung abscess; 16S rDNA
14.  Effectiveness and cost of quick diagnostic tests to determine tetanus immunity in patients with a wound in french emergency departments 
BMC Infectious Diseases  2014;14:603.
Background
Tétanos Quick Stick® (TQS) is a test for tetanus immunity screening for wounded patients in emergency departments (EDs), but represents additional costs compared with a medical interview on vaccination history. The study objective was to assess the effectiveness and cost of the TQS in French EDs.
Methods
We performed a model-based analysis that simulates screening of tetanus immunity and risk of tetanus based on prophylaxis administration. Strategies compared were: i) diagnosis of tetanus immunity by “TQS”; ii) “Medical Interview” (current practice). The study population was 1,658,000 French adults seeking ED care for a wound in 2012. Model parameters were estimated based on French national surveillance data, and published literature. Outcome measures were number of tetanus cases, life years gained and costs (2012 €) from a societal perspective.
Results
Use of TQS had negligible impact on health outcomes (0.02 tetanus cases/year in France vs. 0.41 for “Medical Interview”), but resulted in a decrease in annual costs of €2,203,000 (−42%). Base case and sub-group analysis showed that with the same effectiveness, the average cost per patient was: €13 with “Medical Interview” vs. €11.7 with TQS for the overall cohort; €28.9 with “Medical Interview” vs. €21 with “TQS” for tetanus-prone wounds; €15 with “Medical Interview” vs. €14.1 with “TQS” for patients aged ≥65 years; and €6.2 with “Medical Interview” vs. €7.8 with “TQS” for non-tetanus-prone wounds.
Conclusions
Use of TQS is as effective and less costly than “Medical Interview” when applied in ED to wounded patients with tetanus-prone wounds or aged ≥65 years. However, it is more expensive in patients with non-tetanus-prone wounds.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0603-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0603-3
PMCID: PMC4246690  PMID: 25407690
Tetanus immunity; Diagnostic tests; Cost-effectiveness; Emergency department
15.  Trends in Condom Use and Risk Behaviours after Sexual Exposure to HIV: A Seven-Year Observational Study 
PLoS ONE  2014;9(8):e104350.
Objective
We aimed to determine the trends in numbers and percentages of sexually exposed persons to HIV (SE) consulting an ED for post-exposure prophylaxis (PEP), as well as predictors of condom use.
Study Design
We conducted a prospective-observational study.
Methods
We included all SE attendances in our Emergency Department (ED) during a seven-year study-period (2006–2012). Trends were analyzed using time-series analysis. Logistic Regression was used to define indicators of condom use.
Results
We enrolled 1851 SE: 45.7% reported intercourse without condom-use and 12.2% with an HIV-infected partner. Significant (p<0.01) rising trends were observed in the overall number of SE visits (+75%), notably among men having sex with men (MSM) (+126%). There were rising trends in the number and percentage of those reporting intercourse without condom-use in the entire population +91% (p<0.001) and +1% (p>0.05), in MSM +228% (p<0.001) and +49% (p<0.001), in Heterosexuals +68% (p<0.001) and +10% (p = 0.08). Among MSM, significant rising trends were found in those reporting high-risk behaviours: anal receptive (+450% and +76%) and anal insertive (+l33% and +70%) intercourses. In a multivariate logistic regression analysis, heterosexuals, vaginal intercourse, visit during the night-shift and short time delay between SE and ED visit, were significantly associated with condom-use.
Conclusion
We report an increasing trend in the number of SE, mainly among MSM, and rising trends in high-risk behaviours and unprotected sexual intercourses among MSM. Our results indicate that SE should be considered as a high-risk population for HIV and sexually transmitted diseases.
doi:10.1371/journal.pone.0104350
PMCID: PMC4144812  PMID: 25157477
16.  Characterization of Binding of Raltegravir to Plasma Proteins 
Antimicrobial Agents and Chemotherapy  2013;57(10):5147-5150.
The objective of this study was to characterize raltegravir (RAL) binding to albumin and alpha-1-acid glycoprotein (AAG). Unbound and bound RAL were separated by ultrafiltration. The association constant (Ka) was estimated by a graphical method. In HIV-infected patients, the average plasma protein binding is 76%. RAL did not bind to AAG but bound to nonsaturable, low-affinity albumin sites with an n (number of sites) · Ka product of 9.8 × 102 liters/mol. A pH increase of 0.2 U led to a 2% increase in the bound fraction.
doi:10.1128/AAC.00625-13
PMCID: PMC3811458  PMID: 23856784
17.  Is expert opinion reliable when estimating transition probabilities? The case of HCV-related cirrhosis in Egypt 
Background
Data on HCV-related cirrhosis progression are scarce in developing countries in general, and in Egypt in particular. The objective of this study was to estimate the probability of death and transition between different health stages of HCV (compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma) for an Egyptian population of patients with HCV-related cirrhosis.
Methods
We used the “elicitation of expert opinions” method to obtain collective knowledge from a panel of 23 Egyptian experts (among whom 17 were hepatologists or gastroenterologists and 2 were infectiologists). The questionnaire was based on virtual medical cases and asked the experts to assess probability of death or probability of various cirrhosis complications. The design was a Delphi study: we attempted to obtain a consensus between experts via a series of questionnaires interspersed with group response feedback.
Results
We found substantial disparity between experts’ answers, and no consensus was reached at the end of the process. Moreover, we obtained high death probability and high risk of hepatocellular carcinoma. The annual transition probability to death was estimated at between 10.1% and 61.5% and the annual probability of occurrence of hepatocellular carcinoma was estimated at between 16.8% and 58.9% (depending on age, gender, time spent in cirrhosis and cirrhosis severity).
Conclusions
Our results show that eliciting expert opinions is not suited for determining the natural history of diseases due to practitioners’ difficulties in evaluating quantities. Cognitive bias occurring during this type of study might explain our results.
doi:10.1186/1471-2288-14-39
PMCID: PMC4003824  PMID: 24635942
Delphi method; Expert knowledge elicitation; Methodological bias; Risk perception; Cognitive bias; HCV in Egypt
18.  Timing of Intermittent Seminal HIV-1 RNA Shedding in Patients with Undetectable Plasma Viral Load under Combination Antiretroviral Therapy 
PLoS ONE  2014;9(3):e88922.
It was demonstrated that combination antiretroviral therapy (cART) reduces the HIV-1 viral load (VL) in the blood and the seminal compartment. Some studies have reported that the seminal HIV-1 VL is undetectable in individuals with an undetectable blood plasma viral load (bpVL) under cART. However, some recent studies have demonstrated that seminal HIV-1 RNA may still be detected, and potentially infectious, even in the case of an undetectable bpVL. The aim of this retrospective study was to determine the detection rate of a seminal VL and whether shedding could be intermittent over a very short time.
From January 2006 to December 2011, 88 HIV-1 infected men, enrolled in an Assisted Reproduction program, provided 306 semen samples, corresponding to 177 frozen sperm samples (two samples delivered at a one-hour interval (n = 129) or one sample (n = 48)). All enrolled men were under cART, with an undetectable bpVL for more than 6 months. HIV-1 RNA was quantified in seminal plasma using a Roche COBAS Ampliprep COBAS TaqMan HIV-1 test.
Seminal HIV-1 RNA was detected in 23 samples (7.5%) from 17 patients (19.3%). This detection rate was stable over years. With regards to the freezing of two samples delivered at a one-hour interval, the proportion of discordance between the first and second samples was 9.3% (12/129).
Our results confirm the intermittent shedding of HIV-1 in semen. While this finding has been shown by studies examining longer time intervals, to our knowledge, this has never been demonstrated over such a short time interval.
doi:10.1371/journal.pone.0088922
PMCID: PMC3940424  PMID: 24594873
19.  Predictive Factors of Cytomegalovirus Seropositivity among Pregnant Women in Paris, France 
PLoS ONE  2014;9(2):e89857.
Background
Cytomegalovirus (CMV) is the most frequent cause of congenital infection. The objective of this study was to evaluate predictive factors for CMV seronegativity in a cohort of pregnant women in Paris, France.
Methods
Pregnant women enrolled in a prospective cohort during the 2009 A/H1N1 pandemic were tested for CMV IgG antibodies. Variables collected were age, geographic origin, lifestyle, work characteristics, socioeconomic status, gravidity, parity and number of children at home. A multivariate logistic regression model was used to identify independent predictive factors for CMV seropositivity.
Results
Among the 826 women enrolled, 389 (47.1%) were primiparous, and 552 (67.1%) had Metropolitan France as a geographic origin. Out of these, 355 (i.e. 57.0%, 95% confidence interval (CI): [53.6%–60.4%]) were CMV seropositive: 43.7% (95% CI:[39.5%–47.9%]) in those whose geographic origin was Metropolitan France and 84.1% in those with other origins (95% CI:[79.2%–88.3%]).
Determinants associated with CMV seropositivity in a multivariate logistic regression model were: (i) geographic origin (p<0.001(compared with Metropolitan France, geographic origins of Africa adjusted odds ratio (aOR) 21.2, 95% CI:[9.7–46.5], French overseas departments and territories and other origin, aOR 7.5, 95% CI:[3.9–14.6], and Europe or Asia, aOR 2.2, 95% CI: [1.3–3.7]); and (ii) gravidity (p = 0.019), (compared with gravidity = 1, if gravidity≥3, aOR = 1.5, 95% CI: [1.1–2.2]; if gravidity = 2, aOR = 1.0, 95% CI: [0.7–1.4]). Work characteristics and socioeconomic status were not independently associated with CMV seropositivity.
Conclusions
In this cohort of pregnant women, a geographic origin of Metropolitan France and a low gravidity were predictive factors for CMV low seropositivity. Such women are therefore the likely target population for prevention of CMV infection during pregnancy in France.
doi:10.1371/journal.pone.0089857
PMCID: PMC3933677  PMID: 24587077
20.  Routine HIV Screening in Portugal: Clinical Impact and Cost-Effectiveness 
PLoS ONE  2013;8(12):e84173.
Objective
To compare the clinical outcomes and cost-effectiveness of routine HIV screening in Portugal to the current practice of targeted and on-demand screening.
Design
We used Portuguese national clinical and economic data to conduct a model-based assessment.
Methods
We compared current HIV detection practices to strategies of increasingly frequent routine HIV screening in Portuguese adults aged 18-69. We considered several subpopulations and geographic regions with varying levels of undetected HIV prevalence and incidence. Baseline inputs for the national case included undiagnosed HIV prevalence 0.16%, annual incidence 0.03%, mean population age 43 years, mean CD4 count at care initiation 292 cells/μL, 63% HIV test acceptance, 78% linkage to care, and HIV rapid test cost €6 under the proposed routine screening program. Outcomes included quality-adjusted survival, secondary HIV transmission, cost, and incremental cost-effectiveness.
Results
One-time national HIV screening increased HIV-infected survival from 164.09 quality-adjusted life months (QALMs) to 166.83 QALMs compared to current practice and had an incremental cost-effectiveness ratio (ICER) of €28,000 per quality-adjusted life year (QALY). Screening more frequently in higher-risk groups was cost-effective: for example screening annually in men who have sex with men or screening every three years in regions with higher incidence and prevalence produced ICERs of €21,000/QALY and €34,000/QALY, respectively.
Conclusions
One-time HIV screening in the Portuguese national population will increase survival and is cost-effective by international standards. More frequent screening in higher-risk regions and subpopulations is also justified. Given Portugal’s challenging economic priorities, we recommend prioritizing screening in higher-risk populations and geographic settings.
doi:10.1371/journal.pone.0084173
PMCID: PMC3867470  PMID: 24367639
21.  Rapid detection of glycopeptide-resistant enterococci: impact on decision-making and costs 
Background
According to French national recommendations, the detection of a patient colonized with glycopeptide-resistant enterococci (GRE) leads to interruption of new admissions and transfer of contact patients (CPs) to another unit or healthcare facility, with weekly screening of CPs.
Findings
We evaluated the medical and economic impact of a pragmatic adaptation of national guidelines associated with a real-time PCR (RTP) (Cepheid Xpert™ vanA/vanB) as part of the strategy for controlling GRE spread in two medical wards. Screening was previously performed using chromogenic selective medium (CSM). Turn around time (TAT), costs of tests and cost of missed patient days were prospectively collected. In February 2012, the identification of GRE in one patient in the diabetology ward led to the screening of 31 CPs using CSM; one secondary case was identified in a CP already transferred to the Nephrology ward. Awaiting the results of SCM (median TAT, 70.5 h), 41 potential patient days were missed, due to interruption of admissions. The overall cost (screening tests + missing patient.days) was estimated at 14, 302.20 €. The secondary case led to screening of 22 CPs in the Nephrology ward using RTP. Because of a short median TAT of 4.6 h, we did not interrupt admissions and patients’ transfers. Among 22 CPs, 19 (86%) were negative for vanA, 2 were positive for vanB and 3 had invalid results needing CSM. The overall cost of the strategy was estimated at 870.40 € (cost of screening tests only), without missing patient days.
Conclusion
The rapid PCR test for vanA-positive GRE detection both allowed rapid decision about the best infection control strategy and prevented loss of income due to discontinuation of patient transfers and admissions.
doi:10.1186/2047-2994-2-30
PMCID: PMC4175105  PMID: 24180674
Screening; Glycopeptide; Resistant; Enterococci; Cost; Decision-making; Search and isolate
22.  Intensification of Antiretroviral Therapy through Addition of Enfuvirtide in Naive HIV-1-Infected Patients with Severe Immunosuppression Does Not Improve Immunological Response: Results of a Randomized Multicenter Trial (ANRS 130 Apollo) 
We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm3 or stage B/C disease with CD4 counts of <200/mm3. Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥200/mm3 at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm3, and the median HIV-1 RNA load was 5.4 log10 copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥200/mm3 at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.
doi:10.1128/AAC.01662-12
PMCID: PMC3553717  PMID: 23165467
23.  Investigating Recent Testing among MSM: Results from Community-Based HIV Rapid Testing Attendees in France 
Background. We aimed to identify factors associated with recent HIV testing in MSM who attended two experimental community-based and nonmedicalized voluntary counselling and testing programmes (CB-VCT) targeting MSM in France. Methods. This analysis was based on data collected in 2009–2011 through a self-administered pretesting questionnaire. An index measuring the level of participants' sexual orientation disclosure was built: the higher the index, the greater the disclosure. Factors associated with recent HIV testing (last test ≤ 1 year) were identified using a multivariate logistic regression model adjusted for the CB-VCT programme of enrolment. Results. 716 MSM provided data on testing history. Overall, 49% were recently tested for HIV and 51% were not. Recently tested MSM had a higher homosexuality disclosure index (adjusted OR [95% confidence interval]: aOR = 1.2 [1.1–1.4]), reported more inconsistent condom use during anal sex with men (aOR = 1.6 [1.2–2.1]), and were less likely to have sex under the influence of club drugs (aOR = 0.6 [0.4–1.0]). Conclusion. New testing strategies should focus on those who live their homosexuality relatively secretly and those who use club drugs before sex. Governments should develop policies which encourage improved social acceptance of homosexuality as concealment of sexual orientation represents a major barrier to testing.
doi:10.1155/2013/648791
PMCID: PMC4437427  PMID: 26316962
24.  A Single HIV-1 Cluster and a Skewed Immune Homeostasis Drive the Early Spread of HIV among Resting CD4+ Cell Subsets within One Month Post-Infection 
PLoS ONE  2013;8(5):e64219.
Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3−CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that subset activation and skewed immune homeostasis determine the conditions of viral dissemination and early establishment of the HIV reservoir.
doi:10.1371/journal.pone.0064219
PMCID: PMC3653877  PMID: 23691172
25.  Missed opportunities for HIV testing in newly-HIV-diagnosed patients, a cross sectional study 
BMC Infectious Diseases  2013;13:200.
Background
In France, 1/3 HIV-infected patients is diagnosed at an advanced stage of the disease. We describe missed opportunities for earlier HIV testing in newly-HIV-diagnosed patients.
Methods
Cross sectional study. Adults living in France for ≥1 year, diagnosed with HIV-infection ≤6 months earlier, were included from 06/2009 to 10/2010. We collected information on patient characteristics at diagnosis, history of HIV testing, contacts with healthcare settings, and occurrence of HIV-related events 3 years prior to HIV diagnosis. During these 3 years, we assessed whether or not HIV testing had been proposed by the healthcare provider upon first contact in patients notifying that they were MSM or had HIV-related conditions.
Results
1,008 newly HIV-diagnosed patients (mean age: 39 years; male: 79%; MSM: 53%; diagnosed with an AIDS-defining event: 16%). During the 3-year period prior to HIV diagnosis, 99% of participants had frequented a healthcare setting and 89% had seen a general practitioner at least once a year. During a contact with a healthcare setting, 91/191 MSM (48%) with no HIV-related conditions, said being MSM; 50 of these (55%) did not have any HIV test proposal. Only 21% (41/191) of overall MSM who visited a healthcare provider received a test proposal. Likewise, 299/364 patients (82%) who sought care for s had a missed opportunity for HIV testing.
Conclusions
Under current screening policies, missed opportunities for HIV testing remain unacceptably high. This argues in favor of improving risk assessment, and HIV-related conditions recognition in all healthcare facilities.
doi:10.1186/1471-2334-13-200
PMCID: PMC3652743  PMID: 23638870
HIV/AIDS; HIV testing; Late diagnosis; Risk assessment; Access to care

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