Psychiatric and substance use disorders in HIV/hepatitis C virus (HCV)-coinfected patients: does HCV clearance matter? [Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) HEPAVIH CO13 cohort].

OBJECTIVES: The objective of this nested study was to assess the prevalence of psychiatric disorders in a sample of HIV/hepatitis C virus (HCV)-coinfected patients according to their HCV status. METHODS: The nested cross-sectional study, untitled HEPAVIH-Psy survey, was performed in a subset of HIV/HCV-coinfected patients enrolled in the French Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) CO13 HEPAVIH cohort. Psychiatric disorders were screened for using the Mini International Neuropsychiatric Interview (MINI 5.0.0). RESULTS: Among the 286 patients enrolled in the study, 68 (24%) had never received HCV treatment, 87 (30%) were treatment nonresponders, 44 (15%) were currently being treated and 87 (30%) had a sustained virological response (SVR). Of the 286 patients enrolled, 121 patients (42%) screened positive for a psychiatric disorder other than suicidality and alcohol/drug abuse/dependence, 40 (14%) screened positive for alcohol abuse/dependence, 50 (18%) screened positive for drug abuse/dependence, 50 (17.5%) were receiving an antidepressant treatment and 69 (24%) were receiving an anxiolytic. Patients with an SVR did not significantly differ from the other groups in terms of psychiatric disorders. Patients receiving HCV treatment screened positive less often for an anxiety disorder. The highest rate of drug dependence/abuse was among HCV treatment-naïve patients. CONCLUSIONS: Psychiatric disorders were frequent in HIV/HCV-coinfected patients and their rates were comparable between groups, even for patients achieving an SVR. Our results emphasize the need for continuous assessment and care of coinfected patients, even after HCV clearance. Drug addiction remains an obstacle to access to HCV treatment. Despite the recent advent and continued development of directly acting antiviral agents (DAAs), it is still crucial to offer screening and comprehensive care for psychiatric and addictive disorders.

CCR6(-) regulatory T cells blunt the restoration of gut Th17 cells along the CCR6-CCL20 axis in treated HIV-1-infected individuals.

The gut CD4(+) T cells, particularly the T helper type 17 (Th17) subset, are not completely restored in most HIV-1-infected individuals despite combined antiretroviral therapy, when initiated at the chronic phase of infection. We show here that the CCR6-CCL20 chemotactic axis is altered, with reduced CCL20 production by small intestine epithelial cells in treated HIV-1-infected individuals. This leads to impaired CCR6(+)CD4(+) T-cell homing, particularly Th17 cells, to the small intestine mucosa. In contrast, the frequency of gut FoxP3(+) T regulatory (Treg) cells, specifically the CCR6(-) subset, was increased. The resulting imbalance in the Th17/CCR6(-) Treg ratio and the associated shift from interleukin (IL)-17 to IL-10 and transforming growth factor-ß (TGF-ß) blunts CCL20 production by enterocytes, perpetuating a negative feedback for the recruitment of CCR6(+)CD4(+) T cells to the small intestine in treated HIV-1-infected individuals.

Minority resistant HIV-1 variants and the response to first-line NNRTI therapy.

BACKGROUND: The presence of low-frequency HIV-1 variants with mutations making them resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) could influence the virological response to first-line NNRTI therapy. OBJECTIVES: This study was designed to describe the proportions and quantities of NRTI and NNRTI-resistant variants in patients with successful first-line NNRTI therapy. STUDY DESIGN: We evaluated the presence of drug-resistance mutations (DRMs) prior to treatment initiation in 131 naive chronically HIV-1-infected patients initiating NNRTI-based first-line therapy. DRMs were detected by ultradeep pyrosequencing (UDPS) on a GS Junior instrument (Roche). RESULTS: The mean HIV RNA concentration was 4.78 ± 0.74 log copies/mL and the mean CD4 cell count was 368 ± 184 CD4 cells/mm(3). Patients were mainly infected with subtype B (68%) and 96% were treated with efavirenz. The sensitivity threshold for each mutation was 0.13-1.05% for 2000 reads. Major NRTI-resistant or NNRTI-resistant mutations were detected in 40 patients (33.6%). The median frequency of major NRTI-resistant mutations was 1.37% [IQR: 0.39-84.1], i.e.: a median of 556 copies/mL [IQR: 123-37,553]. The median frequency of major NNRTI-resistant DRMs was 0.78% [IQR: 0.67-7.06], i.e.: a median of 715 copies/mL [IQR: 391-3452]. The genotypic susceptibility score (GSS) of 9 (7.3%) patients with mutations to given treatment detected by UDPS was 1.5 or 2. CONCLUSIONS: First-line NNRTI-based treatment can produce virological success in naïve HIV-1-infected patients harboring low-frequency DRMs representing <1% of the viral quasispecies. Further studies are needed to determine the clinical cut-off of low-frequency resistant variants associated to virological failure.

[Descriptive analysis of Plasmodium falciparum malaria in an expatriate community in Yaounde-Cameroon]. / Analyse descriptive du paludisme à Plasmodium falciparum dans une communauté expatriée à Yaoundé-Cameroun.

Malaria is an endemic disease in Cameroon. Expatriate population is also affected by malaria risk. Many studies are published on malaria, but few are focused on the expatriate population. The objective was to describe epidemiological characteristics andmanagement ofmalaria at Plasmodium falciparum in Yaounde expatriate population. This is a retrospective analysis of all patients treated at health center of the French Embassy in Yaounde in 2013 with a diagnosis of malaria. 103 cases were recruited. Out of them, 32.7% came from the outskirts of Yaounde, 25.2% from the coastal area of Cameroon, and 20.4% from the center of Yaounde. 22 patients were hospitalized, including 6 in Emergency department. 3 deaths were reported during this period. Severe malaria cases are regularly detected in expatriate population inYaounde and preferentially patients, who are over 50 years old, long stay residents in Cameroon and they paid less attention on prevention and vector control. This study confirms the presence of urban malaria in Yaounde and the need to adopt measures including prophylaxis. To the ignorance of risk and the poor adherence to prophylactic measures, it appears important that the various embassies in northern countries have specific information to their expatriates living in endemic areas.

Contribution of molecular diagnosis to the management of cutaneous leishmaniasis in travellers.

Cutaneous leishmaniasis is one of the most frequent skin diseases occurring after travelling in endemic areas. Optimal management requires identification of the species of Leishmania involved. In this study we aimed to evaluate the use of molecular diagnosis as routine, in comparison with direct examination and culture. Thirty positive diagnoses were carried out between 2007 and 2013. Classical PCR enabled 11 positive cases to be identified that were found to be negative by conventional methods. Sequencing led to the identification of eight different species. Routine use of PCR and sequencing appears very efficient in the management of cutaneous leishmaniasis.

FDG-PET/CT findings during immune reconstitution in an HIV-1 patient infected with visceral leishmaniasis.

Visceral leishmaniasis can rarely be unmasked by immune reconstitution in human immunodeficiency virus (HIV)-1-infected patients. We report the first case of immune reconstitution associated with leishmaniasis in an HIV patient to be imaged with [(18)F]fluorodeoxyglucose positron emission tomography (FDG/PET), at both baseline and after therapy.

Factors associated with guideline-based hepatitis C virus (HCV) treatment initiation in HIV/HCV-coinfected patients: role of comorbidities and physicians' perceptions.

OBJECTIVES: Many HIV-infected patients with chronic hepatitis C virus (HCV) infection do not receive treatment for HCV infection, often because of contraindications or poor adherence to anti-HIV therapy. The aim of this study was to identify factors influencing guideline-based HCV treatment initiation in a large cohort of HIV/HCV-coinfected patients. METHODS: Between 2005 and 2011, 194 (40.5%) of 479 coinfected patients not previously treated for HCV infection started this treatment based on current recommendations, i.e. a Metavir score >F1 for liver fibrosis; HCV genotype 2 or 3 infection; or HCV genotype 1 or 4 infection and low HCV viral load (<800000 IU/mL), whatever the fibrosis score. Clinical and biological data were compared between patients who started HCV therapy during follow-up and those who did not. RESULTS: In multivariate analyses, good adherence to treatment for HIV infection, as judged by the patient's physician, was associated with HCV treatment initiation [odds ratio (OR) 2.37; 95% confidence interval (CI) 1.17-4.81; P=0.017], whereas patients with children (OR 0.53; 95% CI 0.30-0.91; P=0.022) and those with cardiovascular disease or respiratory distress (OR 0.10; 95% CI 0.01-0.78; P=0.03) were less likely to be treated. CONCLUSIONS: Adherence to treatment for HIV infection, as judged by the patient's physician, appears to have a major influence on the decision to begin treatment for HCV infection in coinfected patients. This calls for specific therapeutic education and adherence support in order to ensure timely anti-HCV therapy in this population.

Minority variants associated with resistance to HIV-1 nonnucleoside reverse transcriptase inhibitors during primary infection.

BACKGROUND: Recent data suggest that subjects harbouring low-frequency variants of HIV that are resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) could suffer virological failure when treated with NNRTI-based therapy. Rilpivirine, a second-generation NNRTI, will be used in first-line regimen therapy, but the prevalence of minority variants that are resistant to rilpivirine is unknown. OBJECTIVES: We evaluated the presence of low-frequency NNRTI resistance associated mutations (RAMs) in 27 patients with a primary HIV-1 infection. STUDY DESIGN: We performed genotypic resistance test at baseline and used ultradeep pyrosequencing (UDPS) to detect minority RAMs. RESULTS: Bulk genotyping identified NNRTI-resistant RAMs in 3/27 (11%) patients while UDPS identified NNRTI-resistant RAMs in 10/27 (37%) patients. The 11 RAMs not detected by bulk sequencing were A98G (n=2), L100I (n=3), K101E (n=2), V106I (n=3) and E138G (n=1). The prevalence of these minority variants was 0.34-18.26%. The absolute copy numbers of minority resistant variants were 3.21-5.53 log copies/mL. CRF02 harboured more minority resistant variants than subtypes B (P<0.05). Four samples (15%) had a major rilpivirine resistant mutation (E138G, K101E and E138A), 3 of which were detected by UDPS. CONCLUSION: In these primary HIV infected patients, as regards to the detection of RAMs at the cut-off level>15-25% of the virus population, the concordance between bulk genotypic and UDPS was perfect. UDPS detected additional major NNRTI-resistant mutations, including rilpivirine resistant variants. Further studies are needed to assess the impact of these minority variants on treatment efficacy.

Comparison of resistance mutation patterns in historical plasma HIV RNA genotypes with those in current proviral HIV DNA genotypes among extensively treated patients with suppressed replication.

OBJECTIVES: Heavily treatment-experienced patients with good virological control could be at risk of virological failure on switching to a new regimen if pre-existing drug resistance is not taken into account. We examined whether genotyping based on cellular HIV-1 DNA during controlled viraemia identifies resistance mutations detected in plasma HIV-1 RNA during treatment with previous antiretroviral regimens. PATIENTS AND METHODS: All 169 patients enrolled in the Agence Nationale de Recherche sur le SIDA (ANRS) 138-intEgrase inhibitor MK_0518 to Avoid Subcutaneous Injections of EnfuviRtide (EASIER) trial had already received three antiretroviral drug classes [nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)] and had plasma HIV-1 RNA<400 copies/ml at baseline. The results of previous resistance genotyping of plasma HIV-1 RNA in individual patients were compared with those of resistance genotyping of whole-blood HIV-1 DNA at randomization. RESULTS: A median of 4 plasma RNA genotypes were available for the 169 patients. The median numbers of resistance mutations in HIV-1 RNA and DNA were, respectively, 5 and 4 for NRTIs, 2 and 1 for NNRTIs, and 10 and 8 for PIs. The difference was significant for all three drug classes (P=0.001). Resistance to at least one antiretroviral drug was detected exclusively in HIV-1 RNA or in DNA in 63% and 13% of patients for NRTI, 47% and 1% of patients for NNRTI, and 50% and 7% of patients for PI, respectively. CONCLUSION: This study shows that, among highly treatment-experienced patients on effective highly active antiretroviral therapy, resistance genotyping of HIV-1 DNA detects fewer resistance mutations than previous analyses of HIV-1 RNA. These results have implications for patient management and for the design of switch studies.

Factors associated with a strictly undetectable viral load in HIV-1-infected patients.

OBJECTIVES: The aim of the study was to identify factors associated with a strictly undetectable viral load (VL) using a routine sensitive real-time polymerase chain reaction (RT-PCR) technology. METHODS: From a large prospective cohort, 1392 patients with a VL<50 HIV-1 RNA copies/mL while receiving a three-drug suppressive regimen for at least 1 year were included in a cross-sectional analysis. Patients were classified into three groups and compared by univariate and multivariate analysis: 479 patients with a strictly undetectable VL (group 1; 34%), 617 patients with detectable VL below the threshold of 20 copies/mL (group 2; 44%), and 296 patients with a VL of 20-50 copies/mL (group 3; 12%). RESULTS: Comparing groups 1 and 2, VL zenith<5 log(10) copies/mL [odds ratio (OR) 1.51; 95% confidence interval (CI) 1.15-1.99; P=0.003], current CD4 T-cell count<500 cells/µL (OR 1.44; 95% CI 1.08-1.92; P=0.01), and duration of viral suppression<50 copies/mL longer than 2 years (OR 2.32; 95% CI 1.20-4.54; P=0.01) were associated with undetectable VL. Comparing groups 1 and 3, VL zenith<5 log(10) copies/mL (OR 2.48; 95% CI 1.75-3.50; P<0.001), duration of viral suppression<50 copies/mL longer than 1 year (OR 3.33; 95% CI 1.66-6.66; P=0.0006), and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (OR 1.45; 95% CI 1.03-2.04; P=0.03) were associated with undetectable VL. No individual drug effect was found within NNRTI molecules. CONCLUSIONS: Longer duration of viral suppression<50 copies/mL, lower viral load zenith and NNRTI-based regimen were independently associated with a strictly undetectable viral load. This routinely used RT-PCR assay may prove to be a valuable tool in further large-scale studies.

Investigation of the significance of Oil Red O-positive macrophage excess in bronchoalveolar lavage fluid during HIV infection.

OBJECTIVE: To assess the significance of increased levels of Oil Red O-positive macrophages (ORO-PM) in bronchoalveolar lavage fluids (BALFs) from HIV-positive patients. METHODS: Cytological data for seventy BALF samples from 66 consecutive HIV-infected patients were analysed according to antiretroviral therapy regimen, presence of Pneumocystis jiroveci infection, blood CD4(+) T cell count, HIV-1 viral load and plasma lipid levels. Non-parametric tests were used to compare the values between groups. RESULTS: The percentages of ORO-PM were high in this group: 40% [6-80] (median [interquartile range]). They were positively correlated with the BALF total cell count, 21% [5-48.5] for <300 cells/mm(3) and 60% [26.5-80] for >300 cells/mm(3) (P<0.01) but inversely correlated with the percentage of BALF lymphocytes, 50% [20-80] for <15% lymphocytes and 11.5% [2-47] for ≥15% lymphocytes (P<0.01). Antiretroviral therapy with or without protease inhibitors, plasma lipid levels, HIV-1 viral load, blood CD4(+) T cell count or presence of a Pneumocystis jiroveci infection were not correlated with the ORO-PM status. CONCLUSION: Significantly increased numbers of ORO-PM were correlated with high total cell counts and low lymphocyte counts in BALF, irrespective of disease activity or treatment. Extended work on a larger series of patients needs to be conducted.

[A case of Salmonella enterica serovar typhi with decreased susceptibility to ciprofloxacin]. / Salmonella enterica serovar Typhi de sensibilité diminuée à la ciprofloxacine.

The use of fluoroquinolone (FQ) as first line therapy for typhoid fever should be reconsidered because of the emergence of Salmonella Typhi and Paratyphi A strains with decreased susceptibility to FQ, mainly from Asia. Relapse can occur when ciprofloxacin MIC is over 0.12 mg/l, as illustrated by our case report. Azithromycin can be used successfully for patients infected with reduced ciprofloxacin susceptibility isolates. Literature review led us to suggest a new therapeutic strategy for uncomplicated typhoid fever, the antibiotic was chosen according to nalidixic acid susceptibility and ciprofloxacin MIC of the strain. High-dose intravenous ceftriaxone (4 g per day) is always efficient in first line therapy. Depending on FQ susceptibility testing results, it is relayed by oral therapy with a FQ (ciprofloxacin 500 mg bid for 7 days) if the isolate has maintained susceptibility, or azithromycin (1 g first day and 500 mg per day, 7 days) if the isolate is resistant to nalidixic acid or has a ciprofloxacin MIC superior to 0.12 mg/l.

[Impact of malaria on HIV infection]. / Impact du paludisme sur l'infection par le VIH.

Malaria and HIV are two major public health issues, especially in sub-Saharan Africa. HIV infection increases the incidence of clinical malaria, inversely correlated with the degree of immunodepression. The effect of malaria on HIV infection is not as well established. Malaria, when fever and parasitemia are high, may be associated with transient increases in HIV viral load. The effect of subclinical malaria on HIV viral load is uncertain. During pregnancy, placental malaria is associated with higher plasma and placental HIV viral loads, independently of the severity of immunodeficiency. However, the clinical impact of these transient increases of HIV viral load remains unknown. Although some data suggests that malaria might enhance sexual and mother-to-child transmissions, no clinical study has confirmed this. Nevertheless pregnant women and children with malaria-induced anemia are also exposed to HIV through blood transfusions. Integrated HIV and malaria control programs in the regions where both infections overlap are necessary.

Vaccination in adults with auto-immune disease and/or drug related immune deficiency: results of the GEVACCIM Delphi survey.

INTRODUCTION: There are insufficient data regarding the efficacy and safety of vaccination in patients with auto-immune disease (AID) and/or drug-related immune deficiency (DRID). The objective of this study was to obtain professional agreement on vaccine practices in these patients. METHODS: A Delphi survey was carried out with physicians recognised for their expertise in vaccinology and/or the caring for adult patients with AID and/or DRID. For each proposed vaccination practice, the experts' opinion and level of agreement were evaluated. RESULTS: The proposals relating to patients with AID specified: the absence of risk of AID relapse following vaccination; the possibility of administering live virus vaccines (LVV) to patients not receiving immunosuppressants; the pertinence of determining protective antibody titre before vaccination; the absence of need for specific monitoring following the vaccination. The proposals relating to patients with DRID specified that a 3-6 month delay is needed between the end of these treatments and the vaccination with LVV. There is no contraindication to administering LVV in patients receiving systemic corticosteroids prescribed for less than two weeks, regardless of their dose, or at a daily dose not exceeding 10mg of prednisone, if this involves prolonged treatment. Out of 14 proposals, the level of agreement between the experts was "very good" for eleven, and "good" for the remaining three. CONCLUSION: Proposals for vaccine practices in patients with AID and/or DRID should aid with decision-making in daily medical practice and provide better vaccine coverage for these patients.

[Hyperreactive malarial splenomegaly: three clinical cases and literature review]. / Splénomégalie palustre hyperimmune : à propos de trois cas cliniques et revue de la littérature.

Hyperreactive malarial splenomegaly (HMS) is the chronic stage of a long-term stimulation of the immune system secondary to plasmodial infections, more frequently in genetically predisposed patients. HMS is a leading cause of large tropical splenomegaly in endemic zones but has been described in immigrants from Africa and in some European expatriates living in endemic countries. Diagnostic criteria include: long-term stay in a endemic zone, often large splenomegaly, high IgM titer, high antiplasmodial antibody titer, regression by at least 40% of splenomegaly six months after curative antimalarial treatment. In tropical settings, B-cell lymphoma and splenic lymphoma are the main differential diagnoses, which may be identified by a clonality analysis. Recent studies suggest that HMS can be treated by a short-term antimalarial therapy as long as the patient resides out of a malarial endemic country.

[Quinquina and man]. / Du quinquina et des hommes.

Many great discoveries have been made by chance but some have been the result of human perseverance and ingenuity. A sterling example of the second case is quinquina that was discovered in Peru and is now produced in Java. Quinquina has gone through centuries without losing its medical efficacy that efficacy allowed the exploration and colonization of Africa and played a key role in the ability to conduct overseas military campaigns. Because of its strategic importance, it was a coveted resource. It led to the discovery of homeopathy and dyes, allowed the development of organic chemistry, and has been used to make alcoholic bitters and soft drinks.