Jérôme Pacanowski

Campylobacter Bacteremia: Clinical Features and Factors Associated with Fatal Outcome

BACKGROUND Campylobacter bacteremia is uncommon. The influence of underlying conditions and of the impact of antibiotics on infection outcome are not known. METHODS From January 2000 through December 2004, 183 episodes of Campylobacter bacteremia were identified in 23 hospitals in the Paris, France, area. The medical records were reviewed. Characteristics of bacteremia due to Campylobacter fetus and to other Campylobacter species were compared. Logistic regression analysis was performed to identify risk factors for fatal outcome within 30 days. RESULTS Most affected patients were elderly or immunocompromised. C. fetus was the most commonly identified species (in 53% of patients). The main underlying conditions were liver disease (39%) and cancer (38%). The main clinical manifestations were diarrhea (33%) and skin infection (16%). Twenty-seven patients (15%) died within 30 days. Compared with patients with bacteremia due to other Campylobacter species, patients with C. fetus bacteremia were older (mean age, 69.5 years vs. 55.6 years; P = .001) and were more likely to have cellulitis (19% vs. 7%; P = .03), endovascular infection (13% vs. 1%; P = .007), or infection associated with a medical device (7% vs. 0%; P = .02). Independent risk factors for death were cancer (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.2-20.8) and asymptomatic infection (OR, 6.7; 95% CI, 1.5-29.4) for C. fetus bacteremia, the absence of prescription of appropriate antibiotics (OR, 12.2; 95% CI, 0.9-157.5), and prescription of third-generation cephalosporins (OR, 10.2; 95% CI, 1.9-53.7) for bacteremia caused by other species. CONCLUSIONS Campylobacter bacteremia occurs mainly in immunocompromised patients. Clinical features and risk factors of death differ by infection species.

Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients

ABSTRACT Acquired human immunodeficiency virus type 1(HIV-1) resistance to the fusion inhibitor enfuvirtide (ENF) is primarily associated with mutations within the highly conserved first heptad repeat (HR1) region of gp41. Viral env sequences, however, are remarkably variable, and the envelope genetic background could have an important impact on optimal expression of HR1 mutations. We have examined the genetic evolution of env sequences, ENF susceptibility, and Env replicative capacity in patients failing ENF treatment. Sequential plasma-derived virus populations, obtained from six patients initiating ENF treatment as part of a salvage therapy, were studied using a recombinant phenotypic assay evaluating the entire gp120 and the gp41 ectodomains. Regardless of major differences in the baseline ENF susceptibilities, viral populations with similar phenotypic ENF resistance (50% inhibitory concentration, >3,000 ng/ml) were selected under treatment in four of six patients. As expected, in all patients ENF-resistant viruses harbored one or more HR1 mutations (positions 36, 38, and 43). Interestingly, in five patients the emergence of resistance mutations was not associated with reduced Env replicative capacity. Phylogenetic analysis of env sequences in sequential samples from two patients showed that the HR1 mutations had emerged in the context of env quasi-species that were different from those prevalent at baseline. Thus, the envelope genetic context appears to play a critical role in the selection of HR1 mutations and the expression of ENF resistance, thereby conditioning the evolution of HIV-1 under fusion inhibitor selective pressure.

Risk of AIDS-Defining Cancers Among HIV-1–Infected Patients in France Between 1992 and 2009: Results From the FHDH-ANRS CO4 Cohort

BACKGROUND We examined trends in the incidence of the 3 AIDS-defining cancers (ADCs; Kaposi sarcoma [KS], non-Hodgkin lymphoma [NHL], and cervical cancer) among human immunodeficiency virus (HIV)-infected patients relative to the general population between 1992 and 2009 in France, focusing on age at ADC diagnosis and on patients with controlled viral load and restored immunity on combination antiretroviral therapy (cART). METHODS Age- and sex-standardized incidence rates were estimated in patients enrolled in the French hospital database on HIV, and in the general population in France during 4 calendar periods (1992-1996, 1997-2000, 2001-2004, and 2005-2009). Standardized incidence ratios (SIRs) were calculated for all periods and separately for patients on cART, with CD4 counts ≥500 cells/µL for at least 2 years and viral load ≤500 copies/mL. RESULTS Although the incidence of ADCs fell significantly across the calendar periods, the risk remained constantly higher in HIV-infected patients than in the general population. In patients with restored immunity, the relative risk remained significantly elevated for KS (SIR = 35.4; 95% confidence interval [CI], 18.3-61.9), and was similar to that of the general population for NHL (SIR = 1.0; 95% CI, .4-1.8). ADCs were diagnosed at a younger age in HIV-infected patients, with a particularly marked difference for NHL (-11.3 years, P < .0001). CONCLUSIONS The incidence of all ADCs continued to fall, including cervical cancer, in the cART period, but the risk remained higher than in the general population in 2005-2009. In patients with stably restored immunity, KS remained significantly more frequent than in the general population.

HIV-associated kidney glomerular diseases: changes with time and HAART

BACKGROUND Treatment and co-morbidities of human immunodeficiency virus (HIV)-infected individuals have changed dramatically in the last 20 years with a potential impact on renal complications. Our objective was to assess the change in distribution of the glomerular diseases in HIV patients. METHODS We retrospectively analysed demographic, clinical, laboratory and renal histopathological data of 88 HIV-infected patients presenting with a biopsy-proven glomerular disease between 1995 and 2007. RESULTS In our study including 66% Black patients, HIV-associated nephropathy (HIVAN) was observed in 26 cases, classic focal segmental glomerulosclerosis (FSGS) in 23 cases, immune complex glomerulonephritis in 20 cases and other glomerulopathies in 19 patients. HIVAN decreased over time, while FSGS emerged as the most common cause of glomerular diseases (46.9%) in HIV-infected individuals undergoing kidney biopsy in the last 2004-07 period. Patients with HIVAN were usually Black (97%), with CD4 <200/mL (P = 0.01) and glomerular filtration rate <30 mL/min/1.73 m(2) (P < 0.01). Compared to HIVAN, patients with classic FSGS were less often Black (P < 0.01), have been infected for longer (P = 0.03), were more often co-infected with hepatitis C virus (P = 0.05), showed more often cardiovascular (CV) risk factors (P < 0.01), had less often CD4 <200/mL (P = 0.01), lower HIV viral load (P = 0.01) and tended to be older (P = 0.06). CONCLUSIONS Classic FSGS associated with metabolic and CV risk factors has overcome HIVAN in HIV-infected patients. Compared with other glomerulopathies, HIVAN remains strongly associated with severe renal failure, Black origin and CD4 lower than 200/mL at presentation.

Early Plasmacytoid Dendritic Cell Changes Predict Plasma HIV Load Rebound during Primary Infection

During human immunodeficiency virus (HIV) infection, interruption of highly active antiretroviral therapy (HAART) is usually followed by virus load rebound. Previous data have suggested a role for plasmacytoid dendritic cells (pDCs) in anti-HIV innate immunity. Here, the number of pDCs was measured by flow cytometry before, during, and after receipt of HAART in 7 patients with documented primary HIV-1 infection. A negative correlation was evidenced between pDC counts after 1 month of HAART and mean plasma virus load after interruption of HAART (r2=0.85; Spearmans partial rho =-0.92; P=.03). pDC counts during treatment might help predict immune replication control after interruption of HAART.

Tubulointerstitial Nephropathies in HIV-Infected Patients over the Past 15 Years: A Clinico-Pathological Study

BACKGROUND AND OBJECTIVES The therapy and outcome of HIV infection have dramatically changed over the last 15 years, resulting in a change in renal complications. This study analyzed the characteristics of HIV-infected patients and biopsy-proven tubulointerstitial nephropathies to define disease patterns and therapeutic implications. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A clinico-pathologic retrospective study of 59 consecutive renal biopsies showing predominant tubular and/or interstitial lesions in HIV-infected patients referred to the nephrology department between 1995 and 2011 was performed. HIV-associated nephropathy and vascular diseases were excluded from the study. RESULTS Tubulointerstitial nephropathies accounted for 26.6% of 222 native renal biopsies performed in HIV-infected patients. Two pathologic groups were analyzed, tubulopathy and interstitial nephritis, which represented 49% and 51% of tubulointerstitial nephropathies, respectively. Most patients presented with AKI (76.3%) and high-grade proteinuria (57.7%). Drug-related nephrotoxicity was the leading cause (52.5%). Alternative etiologies included infections (15.2%), dysimmune disorders (8.5%), malignancies (3.4%), and chronic (10.2%) and acute (10.2%) tubulointerstitial nephropathies of undetermined origin. Tubulopathy was strongly associated with antiretroviral drug toxicity (75.9%) and mostly caused by tenofovir (55.2%), which was associated with proximal tubular dysfunction (87.5%), overt Fanconis syndrome (37.5%), and nephrogenic diabetes insipidus (12.5%). Interstitial nephritis was associated with a broader spectrum of pathologic lesions and etiologies. CONCLUSIONS In this series, tubulointerstitial nephropathies accounted for 26.6% of renal diseases in HIV-infected patients. Considering the therapeutic implications of diagnoses of drug toxicity, infection, and dysimmune syndromes, this study underscores the importance of monitoring renal parameters in HIV-infected patients and points to the relevance of kidney biopsy to allow an accurate diagnosis.

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

BackgroundIn HIV-infected patients, data on immunogenicity of Yellow fever immunization are scarce, and there is conflicting evidence of the influence of CD4 T-cell count and plasma HIV RNA on neutralizing antibody titer (NT) after vaccine injection. MethodsIn this prospective cohort study, NT was measured in all consecutive HIV outpatients who had previously received at least 1 injection of Yellow fever vaccine. Risk factors for vaccine failure (NT < 1:10) and magnitude of NT according to dates of HIV diagnosis and immunization were assessed by logistic regression and general linear models. ResultsAmong 364 included patients, 24 (7%) had NT <1:10 after a mean delay of 8.4 years after immunization. Among patients immunized after HIV diagnosis (n = 240), NT <1:10 was associated only with detectable plasma HIV RNA at immunization. Among 79 patients with primary vaccination after diagnosis of HIV infection, higher HIV RNA at immunization was the unique independent risk factor for NT <1:10 [adjusted odds ratio (OR) = 3.73 per log10, 95% confidence interval (CI): 1.14 to 12.28]. Lower values of NT were independently associated with a shorter duration of undetectable plasma HIV RNA (OR = 1.05 per year, 95% CI: 1.005 to 1.09) and higher plasma HIV RNA (OR = 0.91 per log10, 95% CI: 0.84 to 0.99) at immunization. ConclusionsThe key determinant of antibody response was the HIV replication status at immunization. No association was found between antibody response and CD4 T-cell count.

Trends in survival after cancer diagnosis among HIV-infected individuals between 1992 and 2009. Results from the FHDH-ANRS CO4 cohort

Although the decline in cancer mortality rates with the advent of combination antiretroviral therapy (cART) in HIV‐infected individuals can be mostly explained by a decrease in cancers incidence, we looked here if improved survival after cancer diagnosis could also contribute to this decline. Survival trends were analyzed for most frequent cancers in the HIV‐infected population followed in the French Hospital Database on HIV: 979 and 2,760 cases of visceral and non‐visceral Kaposis sarcoma (KS), 2,339 and 461 cases of non‐Hodgkin lymphoma (NHL) and Hodgkins lymphoma (HL), 446 lung, 312 liver and 257 anal cancers. Five‐year Kaplan–Meier survival rates were estimated for four periods: 1992–1996, 1997–2000, 2001–2004 and 2005–2009. Cox proportional hazard models were used to compare survival across the periods, after adjustment for confounding factors. For 2001–2004, survival was compared to the general population after standardization on age and sex. Between the pre‐cART (1992–1996) and early‐cART (1997–2000) periods, survival improved after KS, NHL, HL and anal cancer and remained stable after lung and liver cancers. During the cART era, 5‐year survival improved after visceral and non‐visceral KS, NHL, HL and liver cancer, being 83, 92, 65, 87 and 19% in 2005–2009, respectively, and remained stable after lung and anal cancers, being 16 and 65%, respectively. Compared with the general population, survival in HIV‐infected individuals in 2001–2004 was poorer for hematological malignancies and similar for solid tumors. For hematological malignancies, survival continues to improve after 2004, suggesting that the gap between the HIV‐infected and general populations will close in the future.

Raltegravir as functional monotherapy leads to virological failure and drug resistance in highly treatment-experienced HIV-infected patients

Abstract The objective of this study was to evaluate the development of resistance to raltegravir (RAL) in patients with viraemia between 40 and 400 copies/ml. All HIV-1-infected patients with multidrug-resistant virus, plasma HIV-1 RNA >1000 copies/ml and starting RAL were enrolled in this observational study and followed up until week 48. Sixty-seven patients with median plasma HIV-1 RNA at 4.3 log10 copies/ml and CD4 at 177 cells/mm3 were included. At week 24, 43 achieved full viral suppression (FVS; plasma HIV-1 RNA <40 copies/ml), 18 had incomplete viral suppression (IVS; plasma HIV-1 RNA 40–≤400 copies/ml) and 6 experienced virological failure (VF; plasma HIV-1 RNA >400 copies/ml). At week 48, all the FVS were sustained, 16 of the IVS patients retained a plasma HIV-1 RNA <400 copies/ml and only 2 of the IVS at week 24 experienced VF. No RAL resistance was detected in the persistent low viraemia. In contrast, integrase mutation was detected in 6 of the patients with VF. A genotypic sensitivity score equal to 0 was associated with plasma HIV-1 RNA >40 copies/ml at week 24 (OR 20.9, 95% CI 2.0–215.1) and with RAL resistance (OR 14.2, 95% CI 2.1–94.7). This study confirmed the high efficacy of a RAL-containing regimen under routine clinical conditions in infections caused by multidrug-resistant virus. If persistent low viraemia is observed over more than 48 weeks without the emergence of resistance, RAL should never be given as functional monotherapy, as it is associated with a maximal risk of VF and the emergence of RAL resistance.

Risk factors for 'unmasking immune reconstitution inflammatory syndrome' presentation of tuberculosis following combination antiretroviral therapy initiation in HIV-infected patients.

Objective:To determine characteristics and risk factors for unmasking tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRIS) following initiation of combination antiretroviral therapy (cART) in HIV-infected patients, which have not yet been assessed to date. Design:Retrospective single-center cohort study. Methods:Medical records of HIV-infected patients diagnosed with tuberculosis following cART initiation were reviewed. Cases of unmasking IRIS were identified using provisional consensus definitions. Characteristics of patients with and without unmasking TB-IRIS were compared. A case–control design was used to identify risk factors for unmasking TB-IRIS in patients initiating cART. Results:Among 47 patients on cART at TB diagnosis, 11 experienced unmasking IRIS (23%). They had lower CD4% (9 vs. 14, P = 0.02), higher HIV-RNA load at baseline (5.2 vs. 4.0 log, P = 0.005), and a stronger CD4% increase with HIV-RNA decline after 1 month on cART (+7 vs. +3 log, P = 0.02, and −3.2 vs. −0.8 log, P = 0.005) than the 36 remaining patients without unmasking IRIS. In the case–control study, risk factors for unmasking IRIS were African country of origin (65 vs. 18%, P = 0.007), higher baseline HIV-RNA load (5.2 vs. 4.7 log, P = 0.01), stronger CD4% increase (+7 vs. +2, P = 0.0001), and HIV-RNA decline of more than 3 log after 1 month on cART (73 vs. 27%, P = 0.02). Conclusion:Patients with African origins, advanced HIV infection, or a strong response to cART are at greater risk of unmasking TB-IRIS.