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1.  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.
PMCID: PMC3811458  PMID: 23856784
2.  Cost-effectiveness of Telaprevir Combination Therapy for Chronic Hepatitis C 
PLoS ONE  2014;9(3):e90295.
To explore the expected long-term health and economic outcomes of telaprevir (TVR) plus peginterferon alfa-2a and ribavirin (PR), a regimen that demonstrated substantially increased sustained virologic response (SVR) compared with PR alone in adults with chronic genotype 1 hepatitis C virus (HCV) and compensated liver disease in the Phase III studies ADVANCE (treatment-naïve patients) and REALIZE (relapsers, partial responders, and null responders to previous PR treatment).
Study Design
A decision-analytic model was developed to assess the cost-effectiveness of TVR+PR vs. PR in the United States (US).
Patients first moved through the 72-week decision-tree treatment phase of the model and then entered the cyclic Markov post-treatment phase. Clinical data (patient characteristics, SVR rates, and adverse event rates and durations) were obtained from ADVANCE and REALIZE. Health-state transition probabilities, drug and other costs (in 2012/2013 US dollars), and utility values were obtained from the trials, published studies, and publicly available sources. Outcomes were discounted at 3% per year.
Regardless of treatment history, patients receiving TVR+PR were projected to experience fewer liver-disease complications, more life-years, and more quality-adjusted life-years (QALYs) than patients receiving PR. In prior relapsers, TVR+PR was dominant, with lower total medical costs and more QALYs. For the other patient subgroups, incremental costs per QALY gained were between $16,778 (treatment-naïve patients) and $34,279 (prior null responders). Extensive sensitivity analyses confirmed robust model results.
At standard willingness-to-pay thresholds, TVR+PR represents a cost-effective treatment option compared with PR alone for patients with chronic genotype 1 HCV and compensated liver disease in the US. Future analyses are needed to compare TVR+PR with all existing HCV treatment options.
PMCID: PMC3946047  PMID: 24603445
3.  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.
PMCID: PMC3940424  PMID: 24594873
4.  Timing of Antiretroviral Therapy Initiation after a First AIDS-Defining Event: Temporal Changes in Clinical Attitudes in the ICONA Cohort 
PLoS ONE  2014;9(2):e89861.
Time of starting antiretroviral therapy (ART) after diagnosis of specific AIDS-defining event (ADE) is a crucial aspect. Objectives of this study were to evaluate if in patients diagnosed with ADE the time to ART initiation may vary according to year of diagnosis and type of ADE.
All HIV+ persons diagnosed with an ADE over the 6 months prior to or after enrolment in the Icona Foundation study cohort and while ART-naive were grouped according to type of diagnosis: Those with ADE requiring medications interacting with ART [group A], those with ADE treatable only with ART [B] and other ADE [C]. Survival analysis by Kaplan-Meier was used to estimate the percentage of people starting ART, overall and after stratification for calendar period and ADE group. Multivariable Cox regression model was used to investigate association between calendar year of specific ADE and time to ART initiation.
720 persons with first ADE were observed over 1996–2013 (group A, n = 171; B, n = 115; C, n = 434). By 30 days from diagnosis, 27% (95% CI: 22–32) of those diagnosed in 1996–2000 had started ART vs. 32% (95% CI: 24–40) in 2001–2008 and 43% (95% CI: 33–47) after 2008 (log-rank p = 0.001). The proportion of patients starting ART by 30 days was 13% (95% CI 7–19), 40% (95% CI: 30–50) and 38% (95% CI 33–43) in ADE groups A, B and C (log-rank p = 0.0001). After adjustment for potential confounders, people diagnosed after 2008 remained at increased probability of starting ART more promptly than those diagnosed in 1996–1999 (AHR 1.72 (95% CI 1.16–2.56).
In our “real-life” setting, the time from ADE to ART initiation was significantly shorter in people diagnosed in more recent years, although perhaps less prompt than expected.
PMCID: PMC3937396  PMID: 24587081
5.  Predictive Factors of Cytomegalovirus Seropositivity among Pregnant Women in Paris, France 
PLoS ONE  2014;9(2):e89857.
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.
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.
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.
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.
PMCID: PMC3933677  PMID: 24587077
6.  The Cost and Cost-Effectiveness of Scaling up Screening and Treatment of Syphilis in Pregnancy: A Model 
PLoS ONE  2014;9(1):e87510.
Syphilis in pregnancy imposes a significant global health and economic burden. More than half of cases result in serious adverse events, including infant mortality and infection. The annual global burden from mother-to-child transmission (MTCT) of syphilis is estimated at 3.6 million disability-adjusted life years (DALYs) and $309 million in medical costs. Syphilis screening and treatment is simple, effective, and affordable, yet, worldwide, most pregnant women do not receive these services. We assessed cost-effectiveness of scaling-up syphilis screening and treatment in existing antenatal care (ANC) programs in various programmatic, epidemiologic, and economic contexts.
Methods and Findings
We modeled the cost, health impact, and cost-effectiveness of expanded syphilis screening and treatment in ANC, compared to current services, for 1,000,000 pregnancies per year over four years. We defined eight generic country scenarios by systematically varying three factors: current maternal syphilis testing and treatment coverage, syphilis prevalence in pregnant women, and the cost of healthcare. We calculated program and net costs, DALYs averted, and net costs per DALY averted over four years in each scenario. Program costs are estimated at $4,142,287 – $8,235,796 per million pregnant women (2010 USD). Net costs, adjusted for averted medical care and current services, range from net savings of $12,261,250 to net costs of $1,736,807. The program averts an estimated 5,754 – 93,484 DALYs, yielding net savings in four scenarios, and a cost per DALY averted of $24 – $111 in the four scenarios with net costs. Results were robust in sensitivity analyses.
Eliminating MTCT of syphilis through expanded screening and treatment in ANC is likely to be highly cost-effective by WHO-defined thresholds in a wide range of settings. Countries with high prevalence, low current service coverage, and high healthcare cost would benefit most. Future analyses can be tailored to countries using local epidemiologic and programmatic data.
PMCID: PMC3906198  PMID: 24489931
7.  Effectiveness and Cost Effectiveness of Oral Pre-Exposure Prophylaxis in a Portfolio of Prevention Programs for Injection Drug Users in Mixed HIV Epidemics 
PLoS ONE  2014;9(1):e86584.
Pre-exposure prophylaxis with oral antiretroviral treatment (oral PrEP) for HIV-uninfected injection drug users (IDUs) is potentially useful in controlling HIV epidemics with a significant injection drug use component. We estimated the effectiveness and cost effectiveness of strategies for using oral PrEP in various combinations with methadone maintenance treatment (MMT) and antiretroviral treatment (ART) in Ukraine, a representative case for mixed HIV epidemics.
Methods and Findings
We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs who inject opiates, and IDUs in MMT, adding an oral PrEP program (tenofovir/emtricitabine, 49% susceptibility reduction) for uninfected IDUs. We analyzed intervention portfolios consisting of oral PrEP (25% or 50% of uninfected IDUs), MMT (25% of IDUs), and ART (80% of all eligible patients). We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, HIV infections averted, and incremental cost effectiveness. A combination of PrEP for 50% of IDUs and MMT lowered HIV prevalence the most in both IDUs and the general population. ART combined with MMT and PrEP (50% access) averted the most infections (14,267). For a PrEP cost of $950, the most cost-effective strategy was MMT, at $520/QALY gained versus no intervention. The next most cost-effective strategy consisted of MMT and ART, costing $1,000/QALY gained compared to MMT alone. Further adding PrEP (25% access) was also cost effective by World Health Organization standards, at $1,700/QALY gained. PrEP alone became as cost effective as MMT at a cost of $650, and cost saving at $370 or less.
Oral PrEP for IDUs can be part of an effective and cost-effective strategy to control HIV in regions where injection drug use is a significant driver of the epidemic. Where budgets are limited, focusing on MMT and ART access should be the priority, unless PrEP has low cost.
PMCID: PMC3904940  PMID: 24489747
8.  Routine HIV Screening in Portugal: Clinical Impact and Cost-Effectiveness 
PLoS ONE  2013;8(12):e84173.
To compare the clinical outcomes and cost-effectiveness of routine HIV screening in Portugal to the current practice of targeted and on-demand screening.
We used Portuguese national clinical and economic data to conduct a model-based assessment.
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.
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.
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.
PMCID: PMC3867470  PMID: 24367639
9.  Will an Unsupervised Self-Testing Strategy for HIV Work in Health Care Workers of South Africa? A Cross Sectional Pilot Feasibility Study 
PLoS ONE  2013;8(11):e79772.
In South Africa, stigma, discrimination, social visibility and fear of loss of confidentiality impede health facility-based HIV testing. With 50% of adults having ever tested for HIV in their lifetime, private, alternative testing options are urgently needed. Non-invasive, oral self-tests offer a potential for a confidential, unsupervised HIV self-testing option, but global data are limited.
A pilot cross-sectional study was conducted from January to June 2012 in health care workers based at the University of Cape Town, South Africa. An innovative, unsupervised, self-testing strategy was evaluated for feasibility; defined as completion of self-testing process (i.e., self test conduct, interpretation and linkage). An oral point-of-care HIV test, an Internet and paper-based self-test HIV applications, and mobile phones were synergized to create an unsupervised strategy. Self-tests were additionally confirmed with rapid tests on site and laboratory tests. Of 270 health care workers (18 years and above, of unknown HIV status approached), 251 consented for participation.
Overall, about 91% participants rated a positive experience with the strategy. Of 251 participants, 126 evaluated the Internet and 125 the paper-based application successfully; completion rate of 99.2%. All sero-positives were linked to treatment (completion rate:100% (95% CI, 66.0–100). About half of sero-negatives were offered counselling on mobile phones; completion rate: 44.6% (95% CI, 38.0–51.0). A majority of participants (78.1%) were females, aged 18–24 years (61.4%). Nine participants were found sero-positive after confirmatory tests (prevalence 3.6% 95% CI, 1.8–6.9). Six of nine positive self-tests were accurately interpreted; sensitivity: 66.7% (95% CI, 30.9–91.0); specificity:100% (95% CI, 98.1–100).
Our unsupervised self-testing strategy was feasible to operationalize in health care workers in South Africa. Linkages were successfully operationalized with mobile phones in all sero-positives and about half of the sero-negatives sought post-test counselling. Controlled trials and implementation research studies are needed before a scale-up is considered.
PMCID: PMC3842310  PMID: 24312185
10.  Nevirapine-Based Regimens in HIV-Infected Antiretroviral-Naive Patients: Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(10):e76587.
Nevirapine belongs to the group of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and is commonly administered in first-line treatment of HIV infection.
Systematic review and meta-analysis was undertaken to compare effectiveness of nevirapine-based regimens with other antiretroviral schedules used as an initial treatment of HIV-infected antiretroviral-naive subjects.
Electronic databases (PubMed, EMBASE, the Cochrane Library, Trip Database) were searched up to 28 December 2012 for randomized controlled trials (RCTs) published as a full text and regarding nevirapine-based regimens used as a initial treatment for HIV infection. Meta-analysis was performed with RevMan® V 5.2 software.
Twelve RCTs were included in the systematic review and all of them were suitable for meta-analysis. Results of the meta-analysis have shown that nevirapine, efavirenz, and ritonavir-boosted protease inhibitor, added to the background regimens, were equally effective in terms of reaching undetectable plasma HIV RNA level as well as risk of disease progression or death. Compared with ritonavir-boosted protease inhibitor-based regimens, nevirapine-based regimens statistically significantly increased the risk of discontinuation of assigned treatment (RR=3.10; 95% CI: 1.14-8.41; p<0.05).
Despite limited RCTs data available for particular comparisons, our results suggest that nevirapine-based regimens may be considered for first-line treatment of HIV-infected adults, due to their comparable efficacy to the other currently recommended initial antiretroviral therapies.
PMCID: PMC3792044  PMID: 24116123
11.  Comparing Same Day Sputum Microscopy with Conventional Sputum Microscopy for the Diagnosis of Tuberculosis – Chhattisgarh, India 
PLoS ONE  2013;8(9):e74964.
The World Health Organization (WHO) recommends same day sputum microscopy (spot-spot) in preference to conventional strategy (spot-morning) for the diagnosis of smear positive tuberculosis with the view that completing diagnosis on a single day may be more convenient to the patients and reduce pre-treatment losses to follow-up.
We conducted a cross-sectional study in seven selected district level hospitals of Chhattisgarh State, India. During October 2012 – March 2013, two sputum specimens (spot-early morning) were collected from consecutively enrolled adult (≥18 years) presumptive TB patients as per current national guidelines. In addition, a second sample was collected (one hour after the collection of first spot sample) from the same patients. All the samples were examined by ziehl-Neelsen (ZN) microscopy. McNemar’s test was used to compare statistical differences in the proportion smear positive between the two approaches (spot-spot versus spot-morning).
Of 2551 presumptive TB patients, 69% were male. All patients provided the first spot specimen, 2361 (93%) provided the second spot specimen, and 2435 (96%) provided an early morning specimen. 72% of specimens were mucopurulent in conventional strategy as compared to 60% in same day strategy. The proportion of smear-positive patients diagnosed by same day microscopy was 14%, as compared to 17% by the conventional method (p<0.001). A total of 73 (16.9%) potential cases were missed by the same day method compared to only 2 (0.5%) by the conventional method.
Same-day microscopy method missed 17% of smear-positive cases and contrary to prior perception, did not increase the proportion of suspects providing the second sample. These findings call for an urgent need to revisit the WHO recommendation of switching to same-day diagnosis over the current policy.
PMCID: PMC3781139  PMID: 24086412
12.  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.
PMCID: PMC3553717  PMID: 23165467
13.  HIV Risk-Reduction Counseling and Testing on Behavior Change of MSM 
PLoS ONE  2013;8(7):e69740.
HIV and AIDS incidence in China is high among men who have sex with men (MSM) and ours was one of few studies in China to evaluate the role of HIV risk reduction counseling and testing. Respondent-driven sampling (RDS) was used to recruit 430 MSM. Participants were followed up at 6, 12 and 18 months to evaluate behavioral changes after counseling to reduce risk behaviors. At baseline, HIV prevalence was 4.7%, whereas HIV incidence was 5.2 per 100 person-years. The incidence was 3.8 during six to 12 months, and 1.1 during 12 to 18 months. During the study period, the reported unprotected anal intercourse (UAI) significantly decreased from 60.9% to 42.9%. The proportion of participants who had one or no partner significantly increased from 40.9% to 48.0%. The study also found that some risk behaviors decreased between baseline and 12 months, followed by a slight increase between 12 and 18 months. Reductions in UAI can be achieved through counseling and testing, but may wane over time. Future programs should consider HIV risk-reduction counseling and testing for interventions in MSM in China.
PMCID: PMC3726787  PMID: 23922787
14.  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.
PMCID: PMC3653877  PMID: 23691172
15.  Missed opportunities for HIV testing in newly-HIV-diagnosed patients, a cross sectional study 
BMC Infectious Diseases  2013;13:200.
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.
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.
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.
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.
PMCID: PMC3652743  PMID: 23638870
HIV/AIDS; HIV testing; Late diagnosis; Risk assessment; Access to care
16.  Changing Mortality Profile among HIV-Infected Patients in Rio de Janeiro, Brazil: Shifting from AIDS to Non-AIDS Related Conditions in the HAART Era 
PLoS ONE  2013;8(4):e59768.
We describe temporal trends in the mortality rates and factors associated with AIDS and non-AIDS related mortality at the Evandro Chagas Clinical Research Institute (IPEC), Oswaldo Cruz Foundation (FIOCRUZ).
Adult patients enrolling from 1986 through 2009 with a minimum follow up of 60 days were included. Vital status was exhaustively checked using patients’ medical charts, through active contact with individuals and family members and by linkage with the Rio de Janeiro Mortality database using a previously validated algorithm. The CoDe protocol was used to establish the cause of death. Extended Cox proportional hazards models were used for multivariate modeling.
A total of 3530 individuals met the inclusion criteria, out of which 868 (24.6%) deceased; median follow up per patient was 3.9 years (interquartile range 1.7–9.2 years). The dramatic decrease in the overall mortality rates was driven by AIDS-related causes that decreased from 9.19 deaths/100PYs n 1986–1991 to 1.35/100PYs in 2007–2009. Non-AIDS related mortality rates remained stable overtime, at around 1 death/100PYs. Immunodeficiency significantly increased the hazard of both AIDS-related and non-AIDS-related causes of death, while HAART use was strongly associated with a lower hazard of death from either cause.
Our results confirm the remarkable decrease in AIDS-related mortality as the HIV epidemic evolved and alerts to the conditions not traditionally related to HIV/AIDS which are now becoming more frequent, needing careful monitoring.
PMCID: PMC3618173  PMID: 23577074
17.  Predictive Value of Liver Enzymes and Inflammatory Biomarkers for the Severity of Liver Fibrosis Stage in HIV/HCV Co-Infected Patients 
PLoS ONE  2013;8(3):e59205.
The aim of our study was to assess a possible association between plasma inflammatory biomarkers (CRP, IL-6, soluble CD14) and the extent of fibrosis or cirrhosis using a FibroScan® in HIV/HCV co-infected patients.
This cross-sectional study assessed 60 HIV/HCV co-infected patients who had paired plasma samples and FibroScan® values available. All included patients were controlled for HIV infection (HIV-1 RNA <50 copies/mL) and had detectable HCV RNA levels. Levels of three biomarkers were measured in all samples using commercial ELISA kits. Multivariate logistic regression models identified factors associated with the METAVIR stages of fibrosis (F0–F2 vs. F3–F4).
In univariate logistic regression analyses, in addition to sCD14 (odds ratio [OR] = 3.23, 95% confidence interval [95%CI] = 1.30–7.97, P = 0.01), aspartate aminotransferase (AST), alanine aminotransferase, platelet counts, and CD4 cell counts were associated with the stage of liver fibrosis and, thus, were introduced into the model. However, only AST (OR = 1.06, 95%CI = 1.02–1.10, P = 0.0009) was independently associated with F3–F4 stage liver fibrosis.
In our study of HIV/HCV co-infected patients, sCD14 plasma level, a biomarker of monocyte activation, was not independently associated with the F3–F4 stage of liver fibrosis. We hypothesize that the higher levels of inflammation markers observed in HIV/HCV co-infected patients, compared to HCV mono-infected patients, prevent this association being observed within this population.
PMCID: PMC3602202  PMID: 23527135
18.  Average Adherence to Boosted Protease Inhibitor Therapy, rather than the Pattern of Missed Doses, as a Predictor of HIV RNA Replication 
Consecutive missed doses may differentially impact the efficacy of antiretroviral therapy associated with the use of a nonnucleoside reverse-transcriptase inhibitor (NNRTI) and a ritonavir-boosted protease inhibitor (PI). In a cohort of 72 subjects receiving a boosted PI, average adherence to dosage was a better predictor of human immunodeficiency virus (HIV) replication than was the duration or frequency of treatment interruption. In contrast with an NNRTI, consecutive missed doses of a boosted PI did not emerge as a major risk factor for HIV replication.
PMCID: PMC3591724  PMID: 20210643
19.  Role of Baseline HIV-1 DNA Level in Highly-Experienced Patients Receiving Raltegravir, Etravirine and Darunavir/Ritonavir Regimen (ANRS139 TRIO Trial) 
PLoS ONE  2013;8(1):e53621.
In the ANRS 139 TRIO trial, the use of 3 new active drugs (raltegravir, etravirine, and darunavir/ritonavir), resulted in a potent and sustained inhibition of viral replication in multidrug-resistant treatment-experienced patients. The aim of this virological sub-study of the ANRS 139 TRIO trial was to assess: (i) the evolution of HIV-1 DNA over the first year; and (ii) the association between baseline HIV-1 DNA and virological outcome.
Among the 103 HIV-1-infected patients included in the ANRS-139 TRIO trial, HIV-1 DNA specimens were available for 92, 84, 88, and 83 patients at Week (W)0, W12, W24, and W48, respectively. Quantification of total HIV-1 DNA was performed by using the commercial kit “Generic HIV DNA Cell” (Biocentric, Bandol, France).
Baseline median HIV-1 DNA of patients displaying virological success (n  = 61), viral blip (n  = 20), and virological failure (n  = 11) were 2.34 log10 copies/106 PBMC (IQR  = 2.15–2.66), 2.42 (IQR  = 2.12–2.48), and 2.68 (IQR  = 2.46–2.83), respectively. Although not statistically significant, patients exhibiting virological success or viral blip had a tendency to display lower baseline HIV-1 DNA than patients experiencing virological failure (P  = 0.06). Median decrease of HIV-1 DNA between baseline and W48 was -0.13 log10 copies/106 PBMC (IQR = -0.34 to +0.10), mainly explained by the evolution from W0 to W4. No more changes were observed in the W4-W48 period.
In highly-experienced multidrug-resistant patients, HIV-1 DNA slightly decreased during the first month and then remained stable during the first year of highly potent antiretroviral regimen. In this population, baseline HIV-1 DNA might help to better predict the virological response and to tailor clinical therapeutic management as more aggressive therapeutic choices in patients with higher baseline HIV-1 DNA.
PMCID: PMC3547918  PMID: 23349724
20.  Impact of Herpes simplex virus load and red blood cells in cerebrospinal fluid upon herpes simplex meningo-encephalitis outcome 
BMC Infectious Diseases  2012;12:356.
Herpes simplex encephalitis (HSE) often leads to severe disability or death. Factors usually associated with outcome include Simplified Acute Physiology Score, age and delay of initiation of acyclovir treatment.
Our aim was to determine the impact of Herpes simplex virus (HSV) load in cerebrospinal fluid (CSF) upon HSE outcome.
We retrospectively determined HSV load in the CSF of 43 patients with confirmed HSE, hospitalized in northern France from 1998 to 2005, using CSF samples collected the day of hospital admission and stored at −20°C. We analyzed the association between HSV load and mortality/morbidity by the Glasgow Outcome Scale. Fisher’s exact test and Wilcoxon’s test were used for statistical analysis.
The M/F sex ratio was 1.7 and median patient age was 61 years. Median HSV load in CSF was 2.0 log copies/μL (IQR 25-75=1.2-2.6). The mortality rate was 32.6% six months after HSE diagnosis. Higher age was associated with mortality (p=0.03). Longer delay in acyclovir initiation tended to be associated with higher mortality but did not reach statistical significance (p=0.08). Severe disability and death due to HSV were associated with a higher Knaus score (p=0.004), later acyclovir initiation (p=0.006), older age (p=0.04) and presence of red blood cells in CSF (p=0.05). HSV load in CSF was neither associated with mortality (p=1.00) nor with morbidity (p=0.90).
In this study, HSV load in CSF was not found to be associated with poor outcome in patients with HSE. These data do not support measurement of HSV load at admission in patients with HSE.
PMCID: PMC3560250  PMID: 23245564
Herpes virus; Prognosis; Neurological/brain; Viral load
21.  Pharmacologic Boosting of Atazanavir in Maintenance HIV-1 Therapy: The COREYA Propensity-Score Adjusted Study 
PLoS ONE  2012;7(11):e49289.
Among HIV-1 infected patients who achieved virologic suppression, the use of atazanavir without pharmacologic boosting is debated. We evaluated the efficacy and tolerance of maintenance therapy with unboosted atazanavir in clinical practice.
Methods and Results
This multicenter retrospective cohort study evaluated the efficacy of switching HIV-1-infected patients controlled on triple therapy to unboosted (ATV0, n = 98) versus ritonavir-boosted atazanavir (ATV/r, n = 254) +2 nucleos(t)ide reverse transcriptase inhibitors. The primary endpoint was time to virologic failure (VF, >200 copies/mL). ATV groups were compared controlling for potential confounding bias by inverse probability weighted Cox analysis and propensity-score matching. Overall and adjusted VF rates were similar for both strategies. Both strategies improved dyslipidemia and creatininemia, with less jaundice in the ATV0 group.
In previously well-suppressed patients, within an observational cohort setting, ATV0–based triple-therapy appeared as effective as ATV/r- based triple-therapy to maintain virologic suppression, even if co-administered with TDF, but was better tolerated.
PMCID: PMC3494679  PMID: 23152890
22.  Should highly active antiretroviral therapy be prescribed in critically ill HIV-infected patients during the ICU stay? A retrospective cohort study 
The impact of highly active antiretroviral therapy (HAART) in HIV-infected patients admitted to the intensive care unit (ICU) remains controversial. We evaluate impact of HAART prescription in HIV-infected patients admitted to the ICU of Tourcoing Hospital from January 2000 to December 2009.
There were 91 admissions concerning 85 HIV-infected patients. Reasons for ICU admission were an AIDS-related diagnosis in 46 cases (51%). Fifty two patients (57%) were on HAART at the time of ICU admission, leading to 21 immunovirologic successes (23%). During the ICU stay, HAART was continued in 29 patients (32%), and started in 3 patients (3%). Only one patient experienced an adverse event related to HAART. Mortality rate in ICU and 6 months after ICU admission were respectively 19% and 27%. Kaplan-Meier estimates of the cumulative unajusted survival probability over 6 months were higher in patients treated with HAART during the ICU stay (Log rank: p = 0.04). No benefit of HAART in ICU was seen in the adjusted survival proportion at 6 months or during ICU stay. Prescription of HAART during ICU was associated with a trend to lower incidence of new AIDS-related events at 6 months (respectively 17% and 34% with and without HAART, p = 0.07), and with higher incidence of antiretroviral resistance after ICU stay (respectively 25% and 7% with and without HAART, p = 0.02).
Our results suggest a lower death rate over 6 months in critically ill HIV-infected patients taking HAART during ICU stay. The optimal time to prescribe HAART in critically ill patients needs to be better defined.
PMCID: PMC3544704  PMID: 23020962
HIV; Intensive care; HAART
23.  Is Universal HBV Vaccination of Healthcare Workers a Relevant Strategy in Developing Endemic Countries? The Case of a University Hospital in Niger 
PLoS ONE  2012;7(9):e44442.
Exposure to hepatitis B virus (HBV) remains a serious risk to healthcare workers (HCWs) in endemic developing countries owing to the strong prevalence of HBV in the general and hospital populations, and to the high rate of occupational blood exposure. Routine HBV vaccination programs targeted to high-risk groups and especially to HCWs are generally considered as a key element of prevention strategies. However, the high rate of natural immunization among adults in such countries where most infections occur perinatally or during early childhood must be taken into account.
Methodology/Principal Findings
We conducted a cross sectional study in 207 personnel of 4 occupational groups (medical, paramedical, cleaning staff, and administrative) in Niamey’s National Hospital, Niger, in order to assess the prevalence of HBV markers, to evaluate susceptibility to HBV infection, and to identify personnel who might benefit from vaccination. The proportion of those who declared a history of occupational blood exposure ranged from 18.9% in the administrative staff to 46.9% in paramedical staff. Only 7.2% had a history of vaccination against HBV with at least 3 injections. Ninety two percent were anti-HBc positive. When we focused on170 HCWs, only 12 (7.1%) showed no biological HBV contact. Twenty six were HBsAg positive (15,3%; 95% confidence interval: 9.9%–20.7%) of whom 8 (32%) had a viral load >2000 IU/ml.
The very small proportion of HCWs susceptible to HBV infection in our study and other studies suggests that in a global approach to prevent occupational infection by bloodborne pathogens, a universal hepatitis B vaccination of HCWs is not priority in these settings. The greatest impact on the risk will most likely be achieved by focusing efforts on primary prevention strategies to reduce occupational blood exposure. HBV screening in HCWs and treatment of those with chronic HBV infection should be however considered.
PMCID: PMC3436880  PMID: 22970218
24.  ANRS–COM'TEST: description of a community-based HIV testing intervention in non-medical settings for men who have sex with men 
BMJ Open  2012;2(2):e000693.
To describe a community-based HIV testing programme.
Design and setting
An intervention of HIV voluntary testing conducted in non-medical settings in four French cities.
Men who have sex with men (MSM).
Counselling and rapid HIV testing staffed by trained personnel from an HIV/AIDS community-based organisation.
Primary and secondary outcome measures
The population that has taken hold of the intervention and the satisfaction of participants. Data were collected on demographics, HIV testing history, sexual practices and satisfaction with the testing programme.
532 MSM were tested between February 2009 and June 2010, of whom 49 (9%) were tested two or more times. 468 MSM (88%) had casual male partners in the previous 6 months, and 152 (35%) reported having unprotected anal intercourse with risky casual partners (HIV infected or HIV serostatus unknown). 159 men (30%) had not been tested in the previous 2 years, and 50 (31%) of whom had unprotected anal intercourse with risky casual partners. Among the 15 patients who tested positive (2.8%), 12 (80%) received confirmation and were linked to care (median CD4 cell count =550/mm3). Satisfaction was high: 92% reported being ‘very satisfied’ with their experience. Steps of counselling and testing procedure were respected by testers and difficulties in handling tests were rare.
This community-based HIV testing programme reached high-risk MSM, of whom a substantial proportion had not been tested lately. This novel service supplements pre-existing HIV testing services and increases access to HIV testing in high-risk groups.
Article summary
Article focus
How extend testing facilities to reach and test for HIV more MSM and diagnose HIV-infected MSM earlier?
The presence of peers and non-clinical staff members who address sexuality more openly and avoid medical jargon during counselling sessions could offset cultural barriers and reduce fears of HIV and associated stigma.
The article describes an experimental programme of community-based HIV testing: the population reached, the quality of the programme and the satisfaction of participants.
Key messages
This community-based HIV testing and counselling programme reaches MSM with high-risk sexual behaviour, a substantial proportion of whom has not tested for HIV recently.
Community testers are able to perform rapid HIV test into a comprehensive prevention approach in line with participant's life.
2.8% of participants tested positive. Infection was confirmed in all cases, 80% were linked to care. Cases were diagnosed at early stages of disease.
Strengths and limitations of this study
This HIV testing and counselling programme is exclusively based on MSM community, and continuing the prevention counselling with the awareness of the HIV serostatus includes testing into a comprehensive prevention approach.
Community-based HIV testing programmes may be attractive and efficient in large urban areas (like Paris), but perhaps less so in smaller cities, where an outreach approach may work better.
The number of HIV diagnoses was small; the prevalence and median CD4 count among the few HIV-infected participants should therefore be interpreted with caution.
PMCID: PMC3323802  PMID: 22466158
25.  CD4-guided structured treatment interruptions of antiretroviral therapy in HIV disease: Projecting beyond clinical trials 
Antiviral therapy  2010;15(3):351-361.
International trials have shown that CD4-guided structured treatment interruptions (STI) of antiretroviral therapy (ART) lead to worse outcomes than continuous treatment. We simulated continuous ART and STI strategies with higher CD4 interruption/reintroduction thresholds than those assessed in the trials.
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Model to simulate cohorts of African adults with different CD4 counts at presentation (≤200/μl, 201–350/μl, 351–500/μl). We varied ART initiation criteria (immediate, CD4<350/μl or severe opportunistic event, CD4<200/μl or severe opportunistic event), and ART interruption/reintroduction CD4 thresholds (e.g. 350/250/μl, 500/350/μl, 700/500/μl). First-line therapy was non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and 2nd-line was protease inhibitor (PI)-based.
STI generally led to a lower life expectancy than continuous ART, regardless of ART initiation criteria and interruption/reintroduction thresholds. Life expectancy increased with earlier ART initiation and higher interruption/reintroduction thresholds. STI reduced life expectancy by 48–69 months and by 11–30 months, compared to continuous ART when interruption/reintroduction thresholds were 350/250/μl and 500/350/μl, depending on ART initiation criteria. When patients interrupted/reintroduced ART at CD4 700/500/μl, life expectancies for STI ranged from 2 months lower to 1 month higher than continuous ART. Life expectancy for patients on STI increased with decreased risk of virologic resistance after ART interruptions.
STI with NNRTI-based regimens was almost always less effective than continuous treatment, regardless of interruption/reintroduction thresholds. The risks associated with STI decrease only if patients start ART earlier, interrupt/reintroduce treatment at very high CD4 thresholds (700/500/μl) and use first-line medications with higher resistance barriers, such as PIs.
PMCID: PMC3220615  PMID: 20516555
Africa; antiretroviral therapy; CD4-guided structured treatment interruptions; models/projections

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