Hepatitis B, C, and delta in the general population in Mayotte: hepatitis B as a major public health concern.

BACKGROUND: Located in southwestern Indian Ocean, Mayotte is a French territory, with a very specific demographic, social and health context. To date, epidemiological data on infections by hepatitis B (HBV), C (HCV), and delta (HDV) viruses in Mayotte have been sparse. We aimed to estimate, in the 15-69-year-old general population living in Mayotte, the prevalence of infections by hepatitis B (HBV), C (HCV), and delta (HDV) viruses and the distribution of HBV status: current infection with positive HBs antigen (Ag); resolved infection with positive HBc antibodies and negative HBsAg; immunisation by vaccination with only positive HBs antibodies; and no infection/no immunisation with negative markers. We also described the characteristics of infected people and assessed the determinants of lifetime HBV infection. METHODS: The Unono Wa Maore survey, implemented in a random sample of the general population in 2018-2019, consisted of an at-home collection of epidemiological data and venous blood samples. Detection of hepatitis B, C, and delta serological and molecular markers was performed. RESULTS: Among 5207 eligible people, 4643 responded to the questionnaire (89.2%), with 2917 being tested for HBV and HCV (62.8%). Estimated HBV status was as follows: current infection 3.0% (95% confidence interval [CI]: 2.3-3.9%) (n = 76); resolved infection 27.8% (95% CI: 25.8-29.9); immunisation by vaccination 27.7% (95% CI: 25.9-29.7); and no infection/no immunisation 41.5% (95% CI: 39.3-43.7). One participant was positive for HDV antibodies (Ab) (0.65%) with a negative HDV-RNA viral load. The risk of lifetime HBV infection was higher in men (adjusted prevalence ratio (aPR): 1.55, 95% CI: 1.29-1.89); in people aged 30-49 years (aPR: 3.83, 95% CI: 1.49-9.81) or 50-69 years (aPR: 4.52, 95% CI: 1.77-11.53) compared to those under 20; in individuals who reported no condom use during their first sexual intercourse (aPR: 1.46, 95% CI: 1.01-2.14); and in those living in Dembeni-Mamoudzou (aPR: 1.40, 95% CI: 1.09-1.80) compared to the West-Centre of Mayotte. Finally, six individuals were positive for HCV antibodies (0.21%), including three positive for HCV RNA. CONCLUSIONS: Mayotte is an area of intermediate endemicity for HBV and low endemicity for HCV and HDV. With a prevalence of HBsAg 10 times higher than in mainland France, a high proportion of people susceptible to HBV infection, and a demographic, health, and social context that may favour its transmission, hepatitis B is a major public health concern in Mayotte.

Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing Escherichia coli, an overview of 10 years of surveillance in France, 2007 to 2016.

IntroductionHaemolytic uraemic syndrome (HUS) related to Shiga toxin-producing Escherichia coli (STEC) is the leading cause of acute renal failure in young children. In France, HUS surveillance in children aged < 15 years was implemented starting from 1996.AimWe present the results of this surveillance between 2007 and 2016.MethodsA voluntary nationwide network of 32 paediatric departments notifies cases. Two national reference centres perform microbiological STEC confirmation.ResultsOver the study period, the paediatric HUS incidence rate (IR) was 1.0 per 100,000 children-years, with a median of 116 cases/year. In 2011, IR peaked at 1.3 per 100,000 children-years, and decreased to 1.0 per 100,000 children-years in 2016. STEC O157 associated HUS peaked at 37 cases in 2011 and decreased to seven cases in 2016. Cases of STEC O26-associated HUS have increased since 2010 and STEC O80 associated HUS has emerged since 2012, with 28 and 18 cases respectively reported in 2016. Four STEC-HUS food-borne outbreaks were detected (three STEC O157 linked to ground beef and raw-milk cheese and one STEC O104 linked to fenugreek sprouts). In addition, two outbreaks related to person-to-person transmission occurred in distinct kindergartens (STEC O111 and O26).ConclusionsNo major changes in HUS IRs were observed over the study period of 10 years. However, changes in the STEC serogroups over time and the outbreaks detected argue for continuing epidemiological and microbiological surveillance.

Ongoing nationwide outbreak of Salmonella Agona associated with internationally distributed infant milk products, France, December 2017.

On 1 December 2017, an outbreak of Salmonella Agona infections among infants was identified in France. To date, 37 cases (median age: 4 months) and two further international cases have been confirmed. Five different infant milk products manufactured at one facility were implicated. On 2 and 10 December, the company recalled the implicated products; on 22 December, all products processed at the facility since February 2017. Trace-forward investigations indicated product distribution to 66 countries.

Estimated Annual Numbers of Foodborne Pathogen-Associated Illnesses, Hospitalizations, and Deaths, France, 2008-2013.

Estimates of the annual numbers of foodborne illnesses and associated hospitalizations and deaths are needed to set priorities for surveillance, prevention, and control strategies. The objective of this study was to determine such estimates for 2008-2013 in France. We considered 15 major foodborne pathogens (10 bacteria, 3 viruses, and 2 parasites) and estimated that each year, the pathogens accounted for 1.28-2.23 million illnesses, 16,500-20,800 hospitalizations, and 250 deaths. Campylobacter spp., nontyphoidal Salmonella spp., and norovirus accounted for >70% of all foodborne pathogen-associated illnesses and hospitalizations; nontyphoidal Salmonella spp. and Listeria monocytogenes were the main causes of foodborne pathogen-associated deaths; and hepatitis E virus appeared to be a previously unrecognized foodborne pathogen causing ≈68,000 illnesses in France every year. The substantial annual numbers of foodborne illnesses and associated hospitalizations and deaths in France highlight the need for food-safety policymakers to prioritize foodborne disease prevention and control strategies.

Enterohemorrhagic Escherichia coli Hybrid Pathotype O80:H2 as a New Therapeutic Challenge.

We describe the epidemiology, clinical features, and molecular characterization of enterohemorrhagic Escherichia coli (EHEC) infections caused by the singular hybrid pathotype O80:H2, and we examine the influence of antibiotics on Shiga toxin production. In France, during 2005-2014, a total of 54 patients were infected with EHEC O80:H2; 91% had hemolytic uremic syndrome. Two patients had invasive infections, and 2 died. All strains carried stx2 (variants stx2a, 2c, or 2d); the rare intimin gene (eae-ξ); and at least 4 genes characteristic of pS88, a plasmid associated with extraintestinal virulence. Similar strains were found in Spain. All isolates belonged to the same clonal group. At subinhibitory concentrations, azithromycin decreased Shiga toxin production significantly, ciprofloxacin increased it substantially, and ceftriaxone had no major effect. Antibiotic combinations that included azithromycin also were tested. EHEC O80:H2, which can induce hemolytic uremic syndrome complicated by bacteremia, is emerging in France. However, azithromycin might effectively combat these infections.

Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients.

BACKGROUND: Patterns of cause-specific mortality in individuals infected with human immunodeficiency virus type 1 (HIV-1) are changing dramatically in the era of antiretroviral therapy (ART). METHODS: Sixteen cohorts from Europe and North America contributed data on adult patients followed from the start of ART. Procedures for coding causes of death were standardized. Estimated hazard ratios (HRs) were adjusted for transmission risk group, sex, age, year of ART initiation, baseline CD4 count, viral load, and AIDS status, before and after the first year of ART. RESULTS: A total of 4237 of 65 121 (6.5%) patients died (median, 4.5 years follow-up). Rates of AIDS death decreased substantially with time since starting ART, but mortality from non-AIDS malignancy increased (rate ratio, 1.04 per year; 95% confidence interval [CI], 1.0-1.1). Higher mortality in men than women during the first year of ART was mostly due to non-AIDS malignancy and liver-related deaths. Associations with age were strongest for cardiovascular disease, heart/vascular, and malignancy deaths. Patients with presumed transmission through injection drug use had higher rates of all causes of death, particularly for liver-related causes (HRs compared with men who have sex with men: 18.1 [95% CI, 6.2-52.7] during the first year of ART and 9.1 [95% CI, 5.8-14.2] thereafter). There was a persistent role of CD4 count at baseline and at 12 months in predicting AIDS, non-AIDS infection, and non-AIDS malignancy deaths. Lack of viral suppression on ART was associated with AIDS, non-AIDS infection, and other causes of death. CONCLUSIONS: Better understanding of patterns of and risk factors for cause-specific mortality in the ART era can aid in development of appropriate care for HIV-infected individuals and inform guidelines for risk factor management.

Short- and long-term mortality and causes of death in HIV/tuberculosis patients in Europe.

Mortality of HIV/tuberculosis (TB) patients in Eastern Europe is high. Little is known about their causes of death. This study aimed to assess and compare mortality rates and cause of death in HIV/TB patients across Eastern Europe and Western Europe and Argentina (WEA) in an international cohort study. Mortality rates and causes of death were analysed by time from TB diagnosis (<3 months, 3-12 months or >12 months) in 1078 consecutive HIV/TB patients. Factors associated with TB-related death were examined in multivariate Poisson regression analysis. 347 patients died during 2625 person-years of follow-up. Mortality in Eastern Europe was three- to ninefold higher than in WEA. TB was the main cause of death in Eastern Europe in 80%, 66% and 61% of patients who died <3 months, 3-12 months or >12 months after TB diagnosis, compared to 50%, 0% and 15% in the same time periods in WEA (p<0.0001). In multivariate analysis, follow-up in WEA (incidence rate ratio (IRR) 0.12, 95% CI 0.04-0.35), standard TB-treatment (IRR 0.45, 95% CI 0.20-0.99) and antiretroviral therapy (IRR 0.32, 95% CI 0.14-0.77) were associated with reduced risk of TB-related death. Persistently higher mortality rates were observed in HIV/TB patients in Eastern Europe, and TB was the dominant cause of death at any time during follow-up. This has important implications for HIV/TB programmes aiming to optimise the management of HIV/TB patients and limit TB-associated mortality in this region.

AIDS and non-AIDS severe morbidity associated with hospitalizations among HIV-infected patients in two regions with universal access to care and antiretroviral therapy, France and Brazil, 2000-2008: hospital-based cohort studies.

BACKGROUND: In high-income settings, the spectrum of morbidity and mortality experienced by Human Immunodeficiency Virus (HIV)-infected individuals receiving combination antiretroviral therapy (cART) has switched from predominantly AIDS-related to non-AIDS-related conditions. In the context of universal access to care, we evaluated whether that shift would apply in Brazil, a middle-income country with universal access to treatment, as compared to France. METHODS: Two hospital-based cohorts of HIV-infected individuals were used for this analysis: the ANRS CO3 Aquitaine Cohort in South Western France and the Evandro Chagas Research Institute (IPEC) Cohort of the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil. Severe morbid events (AIDS- and non-AIDS-related) were defined as all clinical diagnoses associated with a hospitalization of ≥48 hours. Trends in the incidence rate of events and their determinants were estimated while adjusting for within-subject correlation using generalized estimating equations models with an auto-regressive correlation structure and robust standard errors. RESULT: Between January 2000 and December 2008, 7812 adult patients were followed for a total of 41,668 person-years (PY) of follow-up. Throughout the study period, 90% of the patients were treated with cART. The annual incidence rate of AIDS and non-AIDS events, and of deaths significantly decreased over the years, from 6.2, 21.1, and 1.9 AIDS, non-AIDS events, and deaths per 100 PY in 2000 to 4.3, 14.9, and 1.5/100 PY in 2008. The annual incidence rates of non-AIDS events surpassed that of AIDS-events during the entire study period. High CD4 cell counts were associated with a lower incidence rate of AIDS and non-AIDS events as well as with lower rates of specific non-AIDS events, such as bacterial, hepatic, viral, neurological, and cardiovascular conditions. Adjusted analysis showed that severe morbidity was associated with lower CD4 counts and higher plasma HIV RNAs but not with setting (IPEC versus Aquitaine). CONCLUSIONS: As information on severe morbidities for HIV-infected patients remain scarce, data on hospitalizations are valuable to identify priorities for case management and to improve the quality of life of patients with a chronic disease requiring life-long treatment. Immune restoration is highly effective in reducing AIDS and non-AIDS severe morbid events irrespective of the setting.

HIV-induced immune deficiency is associated with a higher risk of hepatocarcinoma, ANRS CO3 Aquitaine Cohort, France, 1998-2008.

BACKGROUND & AIMS: HIV and viral hepatitis co-infected patients are at high risk for hepatocarcinoma. The contribution of immunodeficiency is not well documented. We aimed at estimating the relationship between the occurrence of hepatocarcinoma and both types of measures of immunodeficiency, current and cumulative (time below a given threshold), to assess their independent effects. METHODS: HIV-infected adults included in the ANRS CO3 Aquitaine Cohort with no history of cancer, ≥ 3 months of follow-up between 1998 and 2008, ≥ 1 CD4+ cell count (CD4+), and documented hepatitis virus status were eligible. Extended Cox proportional hazards models with delayed entry were used to estimate the risk of hepatocarcinoma. Exposure to a CD4+ < 350 or <500 cells/mm(3) (current and cumulative duration) was time-updated. Hepatitis B or C virus co-infection and gender were fixed-effect variables. RESULTS: Sixteen cases of hepatocarcinoma were diagnosed among the 2864 eligible patients, the incidence rate was 0.78 case/1000 person-years (95% Confidence Interval [CI]: 0.40-1.16). Current CD4+ < 350 or < 500 was independently associated with a higher risk of hepatocarcinoma (Hazard Ratio [HR]: 5.0, CI 1.5-16.8, p = 0.009 and HR = 10.3, CI 1.3-82.8, p = 0.029, respectively). The occurrence of hepatocarcinoma was independent of the cumulative exposure to a CD4+ < 350 or < 500 (p = 0.38 or p = 0.80, respectively). CONCLUSIONS: Presenting with CD4+ < 500 was associated with a higher risk of hepatocarcinoma, whereas the cumulative duration with immunodeficiency was not. These results suggest that moving CD4+ count above 500 following antiretroviral therapy initiation is associated with a decreased risk of hepatocarcinoma, regardless of the duration of HIV-induced immunodeficiency.

Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients are at higher risk of malignancies. In addition to traditional determinants, a specific deleterious effect of HIV and immunodeficiency is speculated. We aimed at studying the association between immunological and virological characteristics of HIV-infected patients in care and the risk of acquired immunodeficiency syndrome (AIDS)-defining and non-AIDS-defining malignancies. METHODS: Patients consecutively enrolled in the hospital-based Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort were included if the duration of follow-up was >3 months during the period 1998-2006. Multivariate modeling used an extended Cox proportional hazards model for time-dependent covariates and delayed entry. RESULTS: The 4194 patients included in the study developed 251 first malignancies during 22,389 person-years. A higher incidence of AIDS-defining malignancies (107 cases) was independently associated with (1) both longer and current exposures to a plasma HIV RNA level >500 copies/mL (hazard ratio [HR], 1.27 per year [P<.001] and 3.30 [P<.001], respectively) and (2) both longer and current exposure to a CD4(+) cell count <200 cells/mm(3) (HR, 1.36 per year [P<.001] and 6.33 [P<.001], respectively). A higher incidence of non-AIDS-defining malignancies (144 cases) was independently associated with longer and current exposure to a CD4(+) cell count <500 cells/mm(3) (HR, 1.13 per year [P=.01] and 2.07 [P<.001], respectively) and male sex (HR, 1.69; P=.02) but not with plasma HIV RNA level (P=.49 and P=.10 for cumulative and current exposures, respectively). CONCLUSIONS: Uncontrolled plasma HIV RNA level was independently associated with a higher likelihood of developing AIDS-defining malignancies, whereas immunosuppression was associated with a higher risk of developing any type of malignancies. Antiretroviral treatment should aim at reaching and maintaining a CD4(+) count >500 cells/mm(3) to prevent the occurrence of malignancy, this should be integrated to malignancy-prevention policies.

HIV type-1 transmission dynamics in recent seroconverters: relationship with transmission of drug resistance and viral diversity.

BACKGROUND: HIV type-1 (HIV-1) has been shown to be frequently transmitted by acutely infected patients. We investigated the relationship between the dynamics of HIV-1 transmission within recently infected patients, the HIV-1 variability and the transmission of antiretroviral drug resistance. METHODS: We included patients infected between 1996 and 2006, with a plasma sample obtained <18 months after seroconversion and prior to antiretroviral therapy initiation. Reverse transcriptase (RT) and protease sequences were determined by direct population sequencing from plasma samples. Genotypic resistance was interpreted with the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales 2006 algorithm and International AIDS Society-USA list. Phylogenetic analysis (neighbour-joining and maximum likelihood methods) of RT sequences was used to determine the HIV-1 subtype and the interrelationship between sequences. RESULTS: Genotypic resistance was detected in 37/263 (14.1%) patients. Patients were infected by HIV-1 clade B in 222 (84%) cases and with non-B subtypes in 41 (16%). A total of 80 (30.4%) RT sequences were segregated in 24 clusters with bootstrap values >98% for 22 clusters. The frequency of grouping in clusters was higher within B sequences compared with non-B sequences (35.1% versus 4.9%; P<2.10(-4)). Drug-resistant isolates were retrieved in only 3 clusters, but the prevalence of resistance in clustering viruses (10/80, 12.5%) was not different than in isolated sequences. CONCLUSIONS: The segregation into clusters suggested frequent forward transmission events in patients infected with HIV-1 subtype B, including the possibility of transmission of drug-resistant isolates. These findings warrant increasing prevention efforts and serological screening in the at-risk populations.

Emerging Shiga-toxin-producing Escherichia coli serogroup O80 associated hemolytic and uremic syndrome in France, 2013-2016: Differences with other serogroups.

To generate hypotheses on possible sources of Shiga toxin-producing Escherichia coli (STEC) serogroup O80 associated hemolytic-uremic syndrome (HUS), we explored differences in factors associated with STEC O80 associated HUS, compared with STEC O157 or STEC of other serogroups, in France during 2013-16. STEC was isolated from 153/521 (30%) reported HUS cases: 45 serogroup O80, 46 O157 and 62 other serogroups. Median ages were 1.1 years, 4.0 years and 1.8 years, respectively. O80 infected patients were less likely to report ground beef consumption (aOR [adjusted Odds Ratio] 0.14 95% CI [Confidence Interval] 0.02-0.80) or previous contact with a person with diarrhea or HUS (aOR 0.13 95%CI 0.02-0.78) than patients infected with STEC O157. They were also less likely to report previous contact with a person presenting with diarrhea/HUS than patients infected with other serogroups (aOR 0.13 95%CI 0.02-0.78). STEC O80 spread all over France among young children less exposed to known risk factors of O157 or other STEC infections, suggesting the existence of different reservoirs and transmission patterns.

Incidence and Risk Factors for Severe Bacterial Infections in People Living with HIV. ANRS CO3 Aquitaine Cohort, 2000-2012.

Severe non-AIDS bacterial infections (SBI) are the leading cause of hospital admissions among people living with HIV (PLHIV) in industrialized countries. We aimed to estimate the incidence of SBI and their risk factors in a large prospective cohort of PLHIV patients over a 13-year period in France. Patients followed up in the ANRS CO3 Aquitaine cohort between 2000 and 2012 were eligible; SBI was defined as a clinical diagnosis associated with hospitalization of ≥48 hours or death. Survival analysis was conducted to identify risk factors for SBI.Total follow-up duration was 39,256 person-years [PY] (31,370 PY on antiretroviral treatment [ART]). The incidence of SBI decreased from 26.7/1000 PY [95% CI: 22.9-30.5] over the period 2000-2002 to 11.9/1000 PY [10.1-13.8] in 2009-2012 (p <0.0001). Factors independently associated to increased risk of SBI were: plasma HIVRNA>50 copies/mL (Hazard Ratio [HR] = 5.1, 95% Confidence Interval: 4.2-6.2), CD4 count <500 cells/mm3 and CD4/CD8 ratio <0.8 (with a dose-response relationship for both markers), history of cancer (HR = 1.4 [1.0-1.9]), AIDS stage (HR = 1.7 [1.3-2.1]) and HCV coinfection (HR = 1.4, [1.1-1.6]). HIV-positive patients with diabetes were more prone to SBI (HR = 1.6 [0.9-2.6]). Incidence of SBI decreased over a 13-year period due to the improvement in the virological and immune status of PLHIV on ART. Risk factors for SBI include low CD4 count and detectable HIV RNA, but also CD4/CD8 ratio, HCV coinfection, history of cancer and diabetes, comorbid conditions that have been frequent among PLHIV in recent years.

Tuberculosis-related mortality in people living with HIV in Europe and Latin America: an international cohort study.

BACKGROUND: Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study. METHODS: Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models. FINDINGS: Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0·0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0·0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0·23 (95% CI 0·16-0·31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3·17; 95% CI 1·83-5·49) as were those who did not have baseline drug-susceptibility tests (2·24; 1·31-3·83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0·0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0·0001). INTERPRETATION: Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe. FUNDING: EU Seventh Framework Programme.

Protease inhibitors exposure is not related to lung cancer risk in HIV smoker patients: a nested case-control study.

OBJECTIVE: We aimed at assessing in persons living with HIV with a smoking history an association between lung cancer risk and protease inhibitors exposure, especially ritonavir. DESIGN: A nested case-control study was conducted within the ANRS CO4 FHDH, CO3 Aquitaine and Tenon's Hospital Cohorts. METHODS: Cases and controls were eligible if they were ex-smokers or current smokers at the index date, and had a CD4 cell count reported in the year preceding the index date. Cases were incident cases of lung cancer diagnosed between 1 January 2000 and 31 December 2011. All cancer cases were validated and histological types identified when available. Three controls were randomly selected by incidence density sampling using calendar time as the time axis, with individual matching on cohort, age (± 5 years), route of HIV acquisition, sex and hospital. Analyses were performed using conditional logistic regression adjusted for nadir CD4 cell count and smoking status. Ritonavir and protease inhibitors exposures were represented in separate models using categorical variables (never exposed, ever exposed). Several sensitivity analyses were performed. RESULTS: This study performed in 1447 persons living with HIV with a smoking history (383 lung cancer cases and 1064 control patients) did not evidence any association between lung cancer risk and protease inhibitors exposure including ritonavir. CONCLUSION: These results suggest that the risk of lung cancer is not influenced by pharmacologically induced P450 cytochrome protease inhibitors inhibition among smokers or ex-smokers.

Switch to Rilpivirine/Emtricitabine/Tenofovir Single-Tablet Regimen of Human Immunodeficiency Virus-1 RNA-Suppressed Patients, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales CO3 Aquitaine Cohort, 2012-2014.

Background. The purpose of this study was to assess the efficacy and tolerability of combined antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-1 virologically suppressed patients who switched to rilpivirine (RPV)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) as a single-tablet regimen (STR). Methods. A retrospective multicenter cohort study was performed between September 2012 and February 2014 in Bordeaux University Hospital-affiliated clinics. Patients with a plasma HIV viral load (VL) lower than 50 copies/mL and switching to STR were evaluated at baseline, 3, 6, 9, and 12 months from switch time (M3, M6, M9, M12) for VL and other biological parameters. Change from baseline in CD4 cell counts was evaluated at M6 and M12. Virological failure (VF) was defined as 2 consecutive VL >50 copies/mL. Results. Three hundred four patients were included in the analysis. Single-tablet regimen switch was proposed to 116 patients with adverse events, mostly efavirenz (EFV)-based (n = 59), and to 224 patients for cART simplification. Thirty of 196 patients with available genotype resistance test results displayed virus with ≥1 drug resistance mutation on reverse-transcriptase gene. After 12 months of follow-up, 93.4% (95.5% confidence interval, 89.9-96.2) of patients remained virologically suppressed. There was no significant change in CD4 cell count. During the study period, 5 patients experienced VF, one of them harboring RPV resistance mutation. Clinical cART tolerability improved in 79 patients overall (29.9%) at M6, especially neurological symptoms related to EFV. Fasting serum lipid profiles improved, but a significant estimated glomerular function rate decrease (-11 mL/min/1.73 m(2); P < 10(-4)) was observed. Conclusions. Overall, virologic suppression was maintained in patients after switching to RPV/TDF/ FTC. This STR strategy was associated with improved tolerability.

Diabetes and cognitive decline in a French cohort of patients infected with HIV-1.

OBJECTIVE: We investigated the relationship of diabetes and prediabetes with cognitive performances, assessed through raw test and z scores and according to neurocognitive impairment (NCI) classification in a cohort of individuals infected with HIV. METHODS: The ANRS CO3 Aquitaine cohort is a prospective hospital-based cohort of HIV-1-infected patients under routine clinical management in 6 public hospitals in southwestern France. Between 2007 and 2009, an ancillary study consisted of a neuropsychological battery of 10 tests at baseline and 2-year follow-up. The severity of NCI (normal, asymptomatic, mild, HIV dementia) was assessed according to international guidelines. RESULTS: At baseline (400 patients, 33 with prediabetes, 39 with diabetes), in cross-sectional multivariable analyses, patients with diabetes performed significantly worse on 9 neuropsychological tests that assessed memory, executive functions, attention, psychomotor speed, language, and manual dexterity. Participants with prediabetes had worse performances compared with those who had normal glycemia in 5 tests. The longitudinal analysis of the association between glycemia status at baseline and change in cognitive performances over 2-year follow-up (n = 283) suggested that patients with diabetes also showed a slightly higher decline on 5 of the 10 tests, those involving executive functions and memory functioning. Glycemia status at baseline was not significantly associated with NCI severity in cross-sectional (p = 0.44) and longitudinal (p = 0.64) analyses. CONCLUSIONS: In this hospital-based cohort of people living with HIV, diabetes, but not the other cardiovascular risk factors, is associated with worse cognitive performances in several cognitive domains and with larger decline in fewer domains over the short term.

Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the D: A: D study.

BACKGROUND: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS: Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Multivariable Poisson regression models assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and the incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma). RESULTS: A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1832 cancers were diagnosed [incidence rate: 0.76/100 PY (95% confidence interval: 0.72 to 0.79)], 718 ADC [0.30/100 PY (0.28-0.32)], and 1114 NADC [0.46/100 PY (0.43-0.49)]. Longer exposure to cART was associated with a lower ADC risk [adjusted rate ratio: 0.88/year (0.85-0.92)] but a higher NADC risk [1.02/year (1.00-1.03)]. Both PI and NNRTI use were associated with a lower ADC risk [PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91)]. PI use was associated with a higher NADC risk [1.03/year (1.01-1.05)]. Although this was largely driven by an association with anal cancer [1.08/year (1.04-1.13)], the association remained after excluding anal cancers from the end point [1.02/year (1.01-1.04)]. No association was seen between NNRTI use and NADC [1.00/year (0.98-1.02)]. CONCLUSIONS: Cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.

Major Challenges in Clinical Management of TB/HIV Coinfected Patients in Eastern Europe Compared with Western Europe and Latin America.

OBJECTIVES: Rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in EE, Western Europe (WE) and Latin America (LA). DESIGN AND METHODS: Between January 1, 2011, and December 31, 2013, 1413 TB/HIV patients (62 clinics in 19 countries in EE, WE, Southern Europe (SE), and LA) were enrolled. RESULTS: Significant differences were observed between EE (N = 844), WE (N = 152), SE (N = 164), and LA (N = 253) in the proportion of patients with a definite TB diagnosis (47%, 71%, 72% and 40%, p<0.0001), MDR-TB (40%, 5%, 3% and 15%, p<0.0001), and use of combination antiretroviral therapy (cART) (17%, 40%, 44% and 35%, p<0.0001). Injecting drug use (adjusted OR (aOR) = 2.03 (95% CI 1.00-4.09), prior anti-TB treatment (3.42 (1.88-6.22)), and living in EE (7.19 (3.28-15.78)) were associated with MDR-TB. Among 585 patients with drug susceptibility test (DST) results, the empiric (i.e. without knowledge of the DST results) anti-TB treatment included ≥3 active drugs in 66% of participants in EE compared with 90-96% in other regions (p<0.0001). CONCLUSIONS: In EE, TB/HIV patients were less likely to receive a definite TB diagnosis, more likely to house MDR-TB and commonly received empiric anti-TB treatment with reduced activity. Improved management of TB/HIV patients in EE requires better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART.

Decline in locomotor functions over time in HIV-infected patients.

OBJECTIVES: To assess changes in locomotor function in HIV-infected patients and to evaluate the determinants of variations in lower limb muscle performance. DESIGN: Longitudinal study within the ANRS CO3 Aquitaine Cohort. METHODS: Standardized locomotor tests, including global functional capacity [6-min walk distance (6MWD)] and lower limb muscle performance tests [five times sit-to-stand (5STS) test], were performed in HIV-infected adults at baseline and 2-year follow-up. Evolution of performances and determinants of 5STS time were studied in linear mixed-effects models. RESULTS: At baseline (354 patients, 90% on antiretroviral treatment), median 5STS time was 9.8 s and 6MWD 549 m. Poorer performances were associated with falls, reported by 12% of 178 patients at follow-up. Estimated mean deterioration was +0.24 s/year (P < 10) for 5STS time and -11 m/year (P < 10) for 6MWD. In multivariable analyses, older age was associated with worse baseline 5STS time (+0.47 s/10-year age increase; P = 10), but not with further deterioration. Deterioration was greater in prior injecting drug users compared to others (difference in slope +0.62 s/year; P = 0.04). 5STS time at any time point was worse in patients with history of cerebral AIDS conditions (+2.47 s; P < 10) and diabetes (+0.95 s; P = 0.02) than in others. No significant associations were found for antiretroviral treatment type, viral load or CD4 cell count. CONCLUSION: Compared to published data from healthy persons of similar age, baseline 5STS time and 6MWD were poorer in HIV-infected adults and associated with subsequent falls. Test performances deteriorated further over time. Age, diabetes, neurologic complications and injection drug use, rather than virologic factors, contribute to variations in lower limb muscle performance.