Charles Cazanave

Incidence and Risk Factors for New-Onset Diabetes in HIV-Infected Patients: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study

OBJECTIVE—The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS—D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes and exposure to cART after adjusting for known risk factors for diabetes, CD4 count, lipids, and lipodystrophy. RESULTS—Over 130,151 person-years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31–6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes. CONCLUSION—Stavudine and zidovudine are significantly associated with diabetes after adjustment for risk factors for diabetes and lipids. Adjustment for lipodystrophy did not modify the relationship, suggesting that the two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity.

Incidence and risk factors for new onset diabetes mellitus in HIV infected patients: the D:A:D study

OBJECTIVE—The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS—D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes and exposure to cART after adjusting for known risk factors for diabetes, CD4 count, lipids, and lipodystrophy. RESULTS—Over 130,151 person-years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31–6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes. CONCLUSION—Stavudine and zidovudine are significantly associated with diabetes after adjustment for risk factors for diabetes and lipids. Adjustment for lipodystrophy did not modify the relationship, suggesting that the two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity.

Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies

Summary Background Health care for people living with HIV has improved substantially in the past two decades. Robust estimates of how these improvements have affected prognosis and life expectancy are of utmost importance to patients, clinicians, and health-care planners. We examined changes in 3 year survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013. Methods We analysed data from 18 European and North American HIV-1 cohorts. Patients (aged ≥16 years) were eligible for this analysis if they had started ART with three or more drugs between 1996 and 2010 and had at least 3 years of potential follow-up. We estimated adjusted (for age, sex, AIDS, risk group, CD4 cell count, and HIV-1 RNA at start of ART) all-cause and cause-specific mortality hazard ratios (HRs) for the first year after ART initiation and the second and third years after ART initiation in four calendar periods (1996–99, 2000–03 [comparator], 2004–07, 2008–10). We estimated life expectancy by calendar period of initiation of ART. Findings 88 504 patients were included in our analyses, of whom 2106 died during the first year of ART and 2302 died during the second or third year of ART. Patients starting ART in 2008–10 had lower all-cause mortality in the first year after ART initiation than did patients starting ART in 2000–03 (adjusted HR 0·71, 95% CI 0·61–0·83). All-cause mortality in the second and third years after initiation of ART was also lower in patients who started ART in 2008–10 than in those who started in 2000–03 (0·57, 0·49–0·67); this decrease was not fully explained by viral load and CD4 cell count at 1 year. Rates of non-AIDS deaths were lower in patients who started ART in 2008–10 (vs 2000–03) in the first year (0·48, 0·34–0·67) and second and third years (0·29, 0·21–0·40) after initiation of ART. Between 1996 and 2010, life expectancy in 20-year-old patients starting ART increased by about 9 years in women and 10 years in men. Interpretation Even in the late ART era, survival during the first 3 years of ART continues to improve, which probably reflects transition to less toxic antiretroviral drugs, improved adherence, prophylactic measures, and management of comorbidity. Prognostic models and life expectancy estimates should be updated to account for these improvements. Funding UK Medical Research Council, UK Department for International Development, EU EDCTP2 programme.

Mycoplasma genitalium, an emerging sexually transmitted pathogen

Mycoplasma genitalium is a sexually transmitted organism associated with non-gonococcal urethritis in men and several inflammatory reproductive tract syndromes in women such as cervicitis, pelvic inflammatory disease, and infertility. There was evidence for an association of M. genitalium with endometritis and pelvic inflammatory disease (PID), but additional studies are necessary to confirm this. The evidence as to whether M. genitalium can cause adverse pregnancy outcomes such as preterm labor is conflicting. But the authors of some studies on M. genitalium as a cause of infertility have reported this association. This species is very difficult to culture; thus, nucleic acid amplification testing is the only method available for M. genitalium detection. The lack of a cell wall makes M. genitalium intrinsically resistant to antibiotics acting at this level, such as beta-lactams. The treatment of M. genitalium infections is not standardized. Macrolides are recommended, especially single-dose azithromycin; tetracyclines are responsible for a great number of therapeutic failures even no resistance mechanism has yet been demonstrated. Acquired resistance to macrolides and fluoroquinolones leading to therapeutic failure has also been reported. All this raises the issue of the most appropriate therapeutic management and requires drafting diagnostic and therapeutic guidelines for the treatment of M. genitalium infections.

Detection of macrolide resistance in Mycoplasma genitalium in France

OBJECTIVES Mycoplasma genitalium is a sexually transmitted organism associated with non-gonococcal urethritis in men and several inflammatory reproductive tract syndromes in women. Resistance to macrolides has been recently associated with point mutations in the 23S rRNA gene. The aim of this study was to detect these mutations using a large French collection of M. genitalium-positive specimens. We evaluated whether these mutations were related to azithromycin treatment failure and whether macrolide-resistant M. genitalium may be spreading. PATIENTS AND METHODS A retrospective study conducted in France between 2003 and 2010 included 156 urogenital clinical specimens from 136 patients that were positive for M. genitalium. Mutations in domain V of M. genitalium 23S rRNA were detected using amplification and sequencing. The mutated strains were genotyped by studying single nucleotide polymorphisms in the mgpB gene. RESULTS We have detected macrolide resistance-associated mutations in M. genitalium since 2006 at a rate of 13.2%, ranging from 10% to 15.4% of patients per year. Nine mutations at position 2059 as well as two A2058G substitutions, one A2062T substitution and one C2038T substitution (Escherichia coli numbering) were identified in M. genitalium. These patients had treatment failure with azithromycin in 75% (6/8) of cases. For one patient, genotyping showed selection for the mutation during treatment with azithromycin. CONCLUSIONS For the first time, we describe macrolide resistance for M. genitalium in France and demonstrate that its detection has increased since 2006. Epidemiological surveillance of M. genitalium is necessary to adapt treatments to M. genitalium infections.

Cause-Specific Mortality in HIV-Positive Patients Who Survived Ten Years after Starting Antiretroviral Therapy

Objectives To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996–1999 and survived for more than ten years. Methods We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. Results During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years. Conclusions Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes.

Septic shock sera containing circulating histones induce dendritic cell-regulated necrosis in fatal septic shock patients.

Objectives:Innate immune system alterations, including dendritic cell loss, have been reproducibly observed in patients with septic shock and correlated to adverse outcomes or nosocomial infections. The goal of this study is to better understand the mechanisms behind this observation in order to better assess septic shock pathogenesis. Design:Prospective, controlled experimental study. Setting:Research laboratory at an academic medical center. Subjects:The study enrolled 71 patients, 49 with septic shock and 22 with cardiogenic shock. Seventeen healthy controls served as reference. In vitro monocyte-derived dendritic cells were generated from healthy volunteers. Interventions:Sera were assessed for their ability to promote in vitro dendritic cell death through flow cytometry detection in each group of patients. The percentage of apoptotic or necrotic dendritic cells was evaluated by annexin-V and propidium iodide staining. Measurements and Main Results:We observed that only patients with septic shock and not patients with pure cardiogenic shock were characterized by a rapid and profound loss of circulating dendritic cells. In vitro analysis revealed that sera from patients with septic shock induced higher dendritic cell death compared to normal sera or cardiogenic shock (p < 0.005). Sera from surviving patients induced dendritic cell death through a caspase-dependent apoptotic pathway, whereas sera from nonsurviving patients induced dendritic cell–regulated necrosis. Dendritic cell necrosis was not due to necroptosis but was dependent of the presence of circulating histone. The toxicity of histones toward dendritic cell could be prevented by recombinant human activated protein C. Finally, we observed a direct correlation between the levels of circulating histones in patients and the ability of the sera to promote dendritic cell–regulated necrosis. Conclusions:The study demonstrates a differential mechanism of dendritic cell death in patients with septic shock that is dependent on the severity of the disease.

Contribution of PET Imaging to the Diagnosis of Septic Embolism in Patients With Pacing Lead Endocarditis.

OBJECTIVES The aim of this study was to investigate the role of 18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scanning in identifying septic embolism in patients with lead endocarditis. BACKGROUND Lead endocarditis may be associated with septic embolism, in which case the administration mode, type, and duration of antibiotic therapy must be adapted. However, diagnosis can be challenging: magnetic resonance imaging (MRI) cannot be performed in the vast majority of patients with cardiac implantable electronic devices (CIEDs). FDG PET/CT scanning has been proposed as a diagnostic tool for suspected CIED infection. METHODS Thirty-five consecutive patients with lead endocarditis were prospectively studied. FDG PET/CT scanning was performed and analyzed blindly by experienced nuclear medicine physicians to assess for the presence of septic embolism 2 days before lead extraction. RESULTS FDG PET/CT scanning identified septic emboli in 10 patients (29%): 7 with spondylodiscitis, 2 with septic pulmonary emboli, and 1 with an infected vascular prosthesis. Among the 7 patients with occult spondylodiscitis, 4 were asymptomatic, and 3 had back pain with negative CT imaging, MRI being contraindicated due to non MRI-compatible CIEDs. Antimicrobial therapy was adapted (double antibiotic therapy with good bone penetration) and prolonged. Among other important ancillary findings, 3 patients presented focal FDG uptake in the colon (1 adenocarcinoma, and 2 resected polyps) and 2 in the esophagus (both cases confirmed as neoplasia). CONCLUSIONS This study emphasizes the potential utility of FDG PET/CT scanning as a diagnostic tool for septic emboli in patients with pacing lead endocarditis. This promising diagnostic tool may be integrated in the diagnostic algorithm of patients with lead endocarditis because diagnosis of septic embolisms has a direct and significant impact on the therapeutic care pathway.

Method comparison for molecular typing of French and Tunisian Mycoplasma genitalium-positive specimens.

In this study, 76 French and Tunisian urogenital specimens were subjected to molecular typing by using the two main Mycoplasma genitalium molecular typing methods, the mgpB single nucleotide polymorphism (SNP) typing method and the combination analysis of a variable-number tandem-repeat (VNTR) marker in MG309 and mgpB SNP. Furthermore, we tried to develop a multiple-locus VNTR analysis (MLVA) method. The genome of M. genitalium G37(T) was analysed for VNTRs and four VNTRs were used for an MLVA. The method, applied directly on clinical specimens, was based on a genescan analysis of VNTR loci labelled with fluorescent dyes by using multiplex PCR and capillary electrophoresis. This method had a 1.00 diversity index (DI) while the mgpB SNP typing and the combination of MG309 and mgpB SNPs had DIs of 0.853 and 0.989, respectively. However, among the sets of two concurrent specimens, taken at the same time from the urogenital tracts of 12 patients, only nine had matching MLVA profiles, while the two other methods gave identical profiles for all specimens amplified, except for one set. Moreover, eight new sequence types were described with the mgpB SNP typing method. The three molecular typing methods revealed a genetic heterogeneity, suggesting that M. genitalium was endemic in France and Tunisia and that the infections were not due to the clonal dissemination of one strain. Comparison of the typing results obtained with the three methods showed that the MLVA assay seemed too discriminatory to be used in future studies of sexual networks of M. genitalium infection. According to the discriminatory power and the feasibility of each mgpB-based method, we recommend that the mgpB analysis be used for general epidemiological studies and that the combination of MG309-STR and mgpB SNP methods should be used for sexual-network studies of M. genitalium infection.

Hépatite auto-immune chez une patiente co-infectée VIH-VHC : difficultés diagnostiques et thérapeutiques

INTRODUCTION Autoimmune hepatitis (AIH) is a chronic inflammatory hepatic disorder, characterized by hypergammaglobulinemia and autoantibodies. In some cases, AIH can be associated with another liver disease; such as the hepatitis C-AIH overlap syndrome, which diagnosis and treatment may be delicate. EXEGESE We report a type 1 AIH case in a HIV-HCV co-infected woman. AIH remission and HCV eradication were obtained with prednisone and interferon plus ribavirine. AIH relapse appeared with corticosteroid withdrawal and a new remission was obtained with immunosuppressive treatment associating prednisone and azathioprine, without opportunistic infection. CONCLUSION This case illustrates diagnostic and therapeutic difficulties of hepatitis C-AIH overlap syndromes in an HIV-infected patient. To our knowledge, it is the first AIH case report in a HIV-HCV co-infected patient.