Dominique Salmon-Ceron

Emergence of Legionella pneumophila Pneumonia in Patients Receiving Tumor Necrosis Factor–α Antagonists

BACKGROUND Patients treated with tumor necrosis factor-alpha (TNF-alpha) antagonists have an increased risk of infection, but infection due to Legionella pneumophila has rarely been described in patients receiving such therapy. METHODS A registry involving 486 clinical departments in France was designed by a multidisciplinary group (Recherche Axée sur la Tolérance des Biothérapies [RATIO]) to collect data on opportunistic and severe infections occurring in patients treated with TNF-alpha antagonists. All cases are reported to RATIO in accordance with national health authorities and validated by infectious disease experts. The legionellosis rate among patients treated with TNF-alpha antagonists was compared with the rate in France overall. RESULTS We report a 1-year consecutive series of 10 cases of L. pneumophila pneumonia in France in 2004, including 6 cases treated with adalimumab, 2 treated with etanercept, and 2 treated with infliximab. The median patient age was 51 years (range, 40-69 years). Eight patients were treated for rheumatoid arthritis, 1 was treated for cutaneous psoriasis, and 1 was treated for pyoderma gangrenosum. The median duration of TNF-alpha antagonist treatment at onset of infection was 38.5 weeks (range, 3-73 weeks). Eight patients were receiving concomitant treatment with corticosteroids, and 6 were receiving treatment with methotrexate. The relative risk of legionellosis when receiving treatment with a TNF-alpha antagonist, compared with the relative risk in France overall, was estimated to be between 16.5 and 21.0. We also report a second episode of confirmed legionellosis following the reintroduction of infliximab therapy. CONCLUSIONS L. pneumophila pneumonia is a potentially severe but curable infection that might complicate anti-TNF-alpha therapy. In patients receiving anti-TNF-alpha who develop pneumonia, legionellosis should be systematically investigated, and first-line antibiotic therapy should be efficient against L. pneumophila.

Manifestations and treatment of ocular syphilis during an epidemic in France

Objectives: To review cases of ocular syphilis presenting to a tertiary uveitis clinic during a syphilis epidemic in France between January 2001 and January 2004. Study Design: Retrospective chart and patient database review. Results: Ten patients who presented with symptoms and signs of uveitis tested positive for active syphilis. Some of the patients also presented with a rash or headache. Human immunodeficiency virus (HIV) antibody testing was positive in eight of the 10 patients, with CD4 cell counts >200 cells/mm3 in seven of the patients. Ocular inflammation resolved and visual acuity improved in all patients after treatment. Conclusions: A diagnosis of ocular syphilis should be considered in any patient with visual loss associated with a rash or headache, irrespective of the patients CD4 cell count. Ocular syphilis in HIV-positive patients should be treated as neurosyphilis, whereas ocular syphilis in non-HIV patients can be treated as secondary syphilis.

Immunogenicity and safety of an HIV-1 lipopeptide vaccine in healthy adults: a phase 2 placebo-controlled ANRS trial

Background:French National Agency for Research on AIDS and Viral Hepatitiss HIV-LIPO-5 vaccine includes five HIV-1 peptides, containing multiple CD8+ and CD4+ T-cell epitopes and coupled to a palmitoyl tail. Whether HIV-LIPO-5 immunogenicity varies with the dose is unknown. Methods:HIV-negative volunteers were randomized to receive HIV-LIPO-5 vaccine at 50 μg/lipopeptide (N = 32), 150 μg/lipopeptide (N = 32), 500 μg/lipopeptide (N = 33) or placebo (N = 34) at weeks 0, 4, 12 and 24. HIV-1-specific CD8+ (interferon-γ ELISpot on peripheral blood mononuclear cells cultured for 12 days) and CD4+ responses (peripheral blood mononuclear cell lymphoproliferation) were assessed at baseline, after each injection and at week 48. Results:Local reactions were dose-dependent but no differences in systemic reactions appeared between groups. Sustained (at least on two separate occasions) CD8+ response rates to at least one given HIV-1 pool were obtained in 22 of 32 (69%), 21 of 33 (64%) and 21 of 34 (62%) individuals for LIPO-5 50, 150 and 500 groups, respectively (P ≤ 0.0001 for all comparisons to the placebo). Cumulative CD4+ response rates were obtained in 15 of 32 (47%), 18 of 33 (55%) and 15 of 34 (44%) individuals (P < 0.0001 for all comparisons to placebo). At week 48, CD8+ responses persisted in 47 of 91 (52%) HIV-LIPO-5 recipients. Conclusion:Doses of 50, 150 and 500 μg of French National Agency for Research on AIDS and Viral Hepatitiss HIV-LIPO-5 vaccine were able to elicit HIV-specific sustained CD8+ and CD4+ T-cell responses in healthy adults. Safety is good and all doses appear appropriate in further ‘prime-boost’ trials.

Interest of transjugular liver biopsy in adult patients with haemophilia or other congenital bleeding disorders infected with hepatitis C virus.

Liver histology is important for prognosis and treatment strategy in patients with hepatitis C. We report a 10‐year experience of transjugular liver biopsy (TJLB) in patients with haemophilia and other congenital bleeding disorders (CBD) in terms of safety, efficiency and therapeutic consequences. TJLB was proposed to patients who were regularly followed for CBD, and were hepatitis C virus (HCV) positive by polymerase chain reaction. Patients with inhibitors or who were human immunodeficiency virus (HIV) positive with CD4 cells <0·2 × 109/l or with evidence of liver failure were excluded. TJLB was performed during a short hospitalization with factor replacement. Between 1992 and 2002, 88 TJLB were performed in 69 of 151 adult HCV patients (39% HIV positive). CBD was haemophilia A in 68% and haemophilia B in 24%. Few mild adverse events were recorded. Histology was assessable in 78 of 88 procedures (89%). Twenty‐nine (37%) cases demonstrated minimal change (METAVIR A ≤ 1 and F ≤ 1). Extended fibrosis or cirrhosis was recorded in 23 procedures (26%), all in patients whose infection period was longer than 20 years. No relationship between liver histology, HIV status or HCV genotype was found. TJLB appears to be safe and useful in HCV patients with CBD. One‐third of patients had minimal histological changes and could avoid systematic anti‐HCV treatment.

Incidence and sexual risk factors of cytomegalovirus seroconversion in HIV-infected subjects. The SEROCO Study Group.

Background: Data on incidence of cytomegalovirus (CMV) seroconversion in HIV‐infected (HIV(+)) subjects was sparse. Goal: To determine the incidence of CMV seroconversion in sexually active HIV(+) subjects and sexual factors associated with CMV seroconversion. Study design: One hundred eighty four persons not infected by CMV at enrollment in a cohort of HIV(+) persons were studied. A case‐control study within the cohort was conducted to determine the effect of sexual behavior in the 6 months prior to CMV seroconversion. Thirty seven cases of CMV seroconversion were compared with 136 controls. Results: The overall incidence of CMV seroconversion was 9.18 per 100 person‐years (95% confidence interval (CI), 6.67‐12.28) and was particularly high among homosexual men. After adjustment for age, socio‐professional category, sexual orientation, and casual sex, the risk of CMV seroconversion was higher in subjects who never used condoms than in those who used them systematically (adjusted odds ratio (OR) 3.37; 95% CI, 1.05‐11.00). Conclusions: In addition to the need to protect their sexual partners from HIV infection, HIV(+) subjects free of CMV infection should use condoms to avoid CMV infection and its complications.

Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies?

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.

Short Communication: Long-Term Persistence of Vaccine-Induced HIV Seropositivity among Healthy Volunteers

Long-term persistence of HIV vaccine-induced seropositivity in uninfected HIV vaccine recipients remains unknown. The duration of HIV humoral-induced responses was assessed in 72 volunteers who had received rgp160 and/or HIV recombinant canarypox virus constructs able to induce immune responses detectable using standard serological tests. Among the 43 rgp160 recipients, 94% and 83% remained HIV seropositive after 5 and 8 years of follow-up, respectively, while all the 29 volunteers who had received canarypox constructs alone were seronegative after 5 years. Because rgp160 induces long-term persistence (>8 years) of vaccine-induced HIV seropositivity, volunteers should be offered long-term follow-up to monitor their serological evolution.

Benefit of therapeutic drug monitoring of protease inhibitors in HIV-infected patients depends on PI used in HAART regimen - ANRS 111 trial.

As a result of high inter‐patient variability, and efficacy–concentration and toxicity–concentration relationships, optimization of HIV‐protease inhibitor (PI) doses based on plasma concentrations could be beneficial. During a 48‐week open prospective non‐randomized interventional study of 115 protease inhibitor‐naïve patients initiating an indinavir/ritonavir‐ or lopinavir/ritonavir‐, or nelfinavir‐containing therapy, protease inhibitor dose was modified when plasma trough concentrations (Ctrough) at weeks 2, 8, 16 and 24 were outside predefined optimal concentration ranges. Failure of the strategy was defined as the proportions of patients with HIV‐RNA above 200 copies/mL from weeks 24 to 48 and/or experiencing grades 2, 3 or 4 PI‐related adverse events during the study; proportion of patients with last Ctrough measurement outside the concentration range was determined at each visit. Virological failure and/or occurrence of adverse event were observed in 37/94 assessable patients (39%; 95% CI: 29.4–50.0). In the on‐treatment analysis, failure of the strategy was noted in 16% of indinavir/r‐ or lopinavir/r‐treated patients (8/51; 95% CI: 7.0–28.6; virological failure: 2; adverse event: 6) but in 44% of nelfinavir‐treated patients (11/25; 95% CI: 24.4–65.1; virological failure: 10; adverse event: 1); Ctrough concentrations outside the range were less frequent at the last measurement than at W2 (41% vs. 66%; P < 0.05), with proportions of 35% for indinavir/r‐ or lopinavir/r‐treated patients, but 57% for nelfinavir‐treated patients. The proposed strategy of therapeutic drug monitoring may be beneficial to indinavir/r‐ and lopinavir/r‐treated patients, but failed to move concentrations into the predefined range and to produce the expected virological success for nelfinavir‐treated patients.

Impact of HCV treatment and depressive symptoms on adherence to HAART among coinfected HIV-HCV patients: results from the ANRS-CO13-HEPAVIH cohort.

BACKGROUND The additional burden of HCV infection in HIV-HCV-coinfected individuals may have some consequences on adherence to HAART. Few studies have explored the pattern of correlates of non-adherence to HAART while simultaneously considering the impact of HCV treatment and depressive symptoms on adherence to HAART. We used longitudinal data to assess factors associated with non-adherence to HAART. METHODS The French national prospective cohort ANRS-CO13-HEPAVIH is a multicentrer cohort, which recruited 1,175 HIV-HCV-coinfected patients in 17 hospital outpatient units delivering HIV and HCV care in France between October 2006 and June 2008. For this analysis, we selected participants on HAART with self-reported data for adherence to HAART (n=727 patients, 1,190 visits). Data were collected using self-administered questionnaires and medical records. A mixed logistic regression model based on an exchangeable correlation matrix was used to identify factors associated with non-adherence to HAART. RESULTS Patients reported non-adherence to HAART in 808 (68%) of the 1,190 visits. Four variables remained associated with non-adherence to HAART after multivariate analysis: hazardous alcohol consumption, cocaine use and depressive symptoms, regardless of whether treatment for depression was being received. Finally, patients being treated for HCV infection were less likely to be non-adherent to HAART. CONCLUSIONS Besides the problem of polydrug use, two other dimensions deserve special attention when considering adherence to HAART in HIV-HCV-coinfected patients. Access to HCV treatment should be encouraged as well adequate treatment for depression in this population to improve adherence and response to HAART.

Positive impact of hepatitis C virus (HCV) treatment on antiretroviral treatment adherence in human immunodeficiency virus–HCV coinfected patients: one more argument for expanded access to HCV treatment for injecting drug users

AIMS Treatment for the hepatitis C virus (HCV) may be delayed significantly in human immunodeficiency virus (HIV)/HCV coinfected patients on antiretroviral treatment (ART) for fear that its burden could compromise ART adherence. However, the effect such treatment has on ART adherence in observational settings remains largely unknown. Longitudinal data were used to investigate the relationship between initiating HCV treatment and adherence to ART in HIV/HCV coinfected patients. DESIGN The French national prospective cohort of patients coinfected with HIV and HCV (ANRS-CO-13-HEPAVIH) is a multi-centre cohort. SETTING Seventeen out-patient hospital services delivering HIV and HCV care in France. PARTICIPANTS HIV/HCV coinfected patients on ART (n = 593 patients, 976 visits). MEASUREMENTS Self-administered questionnaires and medical records. A mixed logistic regression model based on generalized estimates equations (GEE) to identify factors associated with non-adherence to ART. FINDINGS Among the 593 patients, 36% were classified as non-adherent to ART at the enrolment visit and 12% started HCV treatment during follow-up. ART adherence was not associated statistically with HCV treatment initiation. The proportion of patients maintaining adherence or becoming adherent to ART for those starting HCV treatment was higher than in the rest of the sample (P = 0.07). After multiple adjustment for known correlates, such as poor housing conditions, binge drinking, recent drug use and depressive symptoms, patients who initiated HCV treatment were less likely to be non-adherent to ART [odds ratio (95% confidence interval) = 0.41 (0.24-0.71)]. CONCLUSIONS Engaging human immunodeficiency virus/hepatitis C virus coinfected individuals in hepatitis C virus treatment is associated with high adherence to antiretroviral treatment. Physicians should prioritize hepatitis C virus treatment as part of a multi-disciplinary approach.