Dual infection by chikungunya virus and other imported infectious agent in a traveller returning from India.

Chikungunya virus infection is a vector-borne self-limiting disease. Recent outbreaks in the Indian Ocean islands have drawn attention to the condition. Nevertheless, only a few reports of co-infection with other communicable agents have been reported. The case described now is of a traveller returning from India with concomitant documented chikungunya virus infection associated with systemic amoebiasis. This report highlights the multifaceted pathology that can be encountered with tropical infections.

Intermittent antiretroviral therapy in patients with controlled HIV infection.

BACKGROUND: To assess the safety of a drug-sparing treatment regimen in patients with high CD4 cell counts and controlled HIV replication under antiretroviral therapy. METHODS: An open-label, non-inferiority study involving 403 adults with CD4 cell counts of 450 x 10(6) cells/l or greater and plasma HIV-1-RNA levels less than 200 copies/ml, randomly assigned to switch to an 8-week off, 8-week on regimen or to continue their antiretroviral regimen. The primary endpoint was the proportion of patients reaching a confirmed CD4 cell count less than 300 x 10(6) cells/l. RESULTS: Over 96 weeks, the proportion of patients meeting this endpoint was non-inferior in the intermittent group (3.6 versus 1.5%, upper bound of the 95% confidence interval of the difference 5.6%). No AIDS-defining event and two non-HIV-related deaths (intermittent arm) were recorded. The median decrease from baseline in the CD4 cell count was greater in the intermittent arm (-155 versus -8 x 10(6) cells/l, P < 0.0001). Minor HIV-related events, mainly lymphadenopathy and mucosal candidiasis, were more frequent in the intermittent group (14 versus 7%, P = 0.04) as were thrombocytopenia. The incidence of grade 3-4 non-HIV-related events and laboratory abnormalities were not statistically different between the groups. At week 96, the proportion of patients with plasma HIV-1-RNA levels less than 400 copies/ml were 81 and 90% in the intermittent (8 weeks after treatment resumption) and continuous groups (P = 0.02), respectively, with similar patterns of HIV resistance genotypes. CONCLUSION: Despite some limitations, an 8-week off and on intermittent treatment regimen appeared clinically safe over 96 weeks while sparing half of the drug exposure.

Primary resistance to enfuvirtide (T20) in recently HIV-1 infected, antiretroviral-naive patients from the ANRS Aquitaine Cohort.

BACKGROUND: Transmission of HIV-1 variants with resistance to reverse transcriptase (RT) and protease inhibitors has been widely characterized in developed countries. However, no clear evidence of primary resistance to HIV-1 fusion inhibitors has been shown so far. We wished to investigate the possibility of genotypic resistance to enfuvirtide (T20) in a cohort of antiretroviral-naive, recently infected patients. METHODS: We included patients from the Aquitaine Cohort with an estimated date of seroconversion in 2004 and 2005, a plasma sample obtained less than 18 months after seroconversion and no prior history of antiretroviral therapy. RT, protease and gp41 sequences were determined by direct population sequencing from plasma samples and drug resistance mutations were reported. RESULTS: A total of 55 patients were included in the study. The overall prevalence of transmitted HIV-1 resistance was 20%. Two patients had viruses with resistance mutations to T20. The first case had an N42D mutation in the HR1 region of the gp41, along with transmitted resistance mutations in the protease (D30N, M361, N88D) and in the RT (M41L, L210W, T215D). The second case had a G36D HR1 mutation, with no evidence of other drug resistance mutations. CONCLUSION: We have shown the first cases of primary resistance to T20 in recently infected patients in southwestern France. Epidemiological surveillance of the transmission of drug-resistant HIV-1 should include the resistance to T20.

Tobacco addiction and HIV infection: toward the implementation of cessation programs. ANRS CO3 Aquitaine Cohort.

In treated HIV-infected patients, mortality is now dominated by non-AIDS-related causes in which tobacco smoking is a predominant risk factor. The implementation of tobacco smoking cessation programs is therefore warranted to increase survival but should consider the specificities of this population to be successful. All outpatients consulting in May to June 2004 within the ANRS CO3 Aquitaine Cohort of HIV-infected patients were asked to complete a self-administered questionnaire including questions about tobacco and other drugs consumption, the Fagerström Test for Nicotine Dependence (FTND), a visual scale to estimate motivation to stop smoking and the Center for Epidemiologic Studies Depression (CESD) scale. Among 509 patients included, mean age was 44 years, 74% were men, 19% were infected through injection drug use, and 257 (51%) were regular smokers (at least one cigarette per day). Among them, 60% had a medium or strong nicotine dependence (FTND = 5), 40% were motivated to quit smoking and 70% had already tried at least once. An FTND of 5 or more was more frequently reported in the 146 smokers (62%) with depressive symptoms compared to other smokers (70% versus 48%). Fifty-five regular smokers (23%) were codependent on cannabis and 31 (12%) to alcohol. Overall, only 35 (14%) regular smokers were motivated, non-codependent, without depressive symptoms, and could be proposed a standard tobacco cessation program. Depressive symptoms were highly prevalent in this representative population of HIV-infected patients. To be successful, smoking cessation interventions should be specifically built to take into account depression and codependencies in addition to nicotine dependence and motivation.

Hepatitis B virus genotypes: a retrospective survey in Southwestern France, 1999-2004.

OBJECTIVE: To determine the prevalence of HBV genotypes in Southwestern France and the association between HBV genotypes and patients characteristics. METHODS: 194 HBsAg-positive patients (median age: 45 yrs, range: 7-77, male: 78%) followed in Bordeaux Hospital in 1999-2004 were included. HBV genotype, pre-core (PC) and core promoter (CP) mutations were determined by sequencing. RESULTS: Genotype distribution was A 51%, B 6.7%, C 5.7%, D 26.3%, E 7.7%, F 0.5%, G 2.1%. Among the 146 patients documented, 71.2% were Caucasians, 15.8% Africans, 13.0% Asians. Fifty-seven patients (36%) were HIV-infected. Eighty-two (42.3%) patients were HBeAg-positive. Genotype A was almost exclusively carried by Caucasians (96%), Africans were most frequent among genotype E (82%), and Asians were most prevalent among genotypes B and C (82% and 80%, respectively). Genotype A was associated with a higher prevalence of HBeAg than genotype D (53% versus 35.3%, P=0.03). PC variant was detected in 35% and CP variant in 43% of patients. PC variant was uncommon in genotype A patients (7.3%). CONCLUSION: Distribution of HBV genotypes differs according to ethnic origin, genotypes A and D being the most frequently found. Genotype A was more frequently associated with HBeAg-positivity and genotype D with HBeAg-negativity.

Neuro-muscular biopsy in Churg-Strauss syndrome: 24 cases.

Churg-Strauss syndrome (CSS) is a distinctive clinical entity in which systemic vasculitis, associated with eosinophilia, occurs almost exclusively in individuals with adult-onset asthma. The major complications of the condition result from damage to the lungs, heart, and peripheral nerves. Necrotizing vasculitis with eosinophils in the cellular infiltrate, vascular or perivascular infiltration by eosinophils in absence of vessel wall necrosis, extra-vascular eosinophil infiltrates, and vascular or extra-vascular granuloma are histopathological features supportive of CSS. As the peripheral nerve disease often dominates the clinical picture, the peripheral nerve biopsy may be decisive in establishing the diagnosis. In this retrospective study of neuro-muscular biopsies in 24 CSS cases, the authors give an extensive description of neuropathological lesions associated with this disorder. Fifteen patients (62.5%) exhibited eosinophils either in extra-vascular infiltrates or in vessel walls, and 6 of them (25%) had an associated necrotizing vasculitis. Granulomas were found in only 3 cases (12.5%). The clinical diagnosis of CSS was supported in 15 out of the 24 patients (62.5%), in the nerve in 2 cases (8.3%), in the muscle in 8 cases (33.3%), and in both nerve and muscle in 5 others (20.8%).

Virological responses to atazanavir-ritonavir-based regimens: resistance-substitutions score and pharmacokinetic parameters (Reyaphar study).

OBJECTIVE: To assess the impact of baseline HIV-1 substitutions, individual pharmacokinetic (PK) parameters (Cmin, Cmax, area under the curve [AUC0-->24 h]) and genotype-inhibitory quotient (GIQ) on virological responses (VR) to atazanavir-ritonavir (300 mg/100 mg)-based highly active antiretroviral therapy (HAART) in 71 antiretroviral-experienced, atazanavir-naive patients in virological failure (VF) on HAART. METHODOLOGY: VR was defined as HIV RNA <1.7 log10 copies/ml at week 12 (W12). A clinically relevant genotype-substitutions score for atazanavir-ritonavir was developed and validated (Reyaphar substitutions score). Previously published substitutions scores were also tested. RESULTS: Patients had a median (Q1; O3) of 6 (3; 8) previous treatment lines during 9 (7; 11) years. Baseline (WO) values were as follows: 262 (187; 435) CD4+/microl, 3.9 (2.6; 4.9) log10 HIV-1 RNA copies/ml, 4 (2; 6) protease substitutions and 3 (1; 4) NRTI-related substitutions. Respective steady-state Cmin, Cmax and AUC0-->24 h were 300 (200; 700) ng/ml, 620 (430; 750) ng/ml and 78,000 (61,000; 94,000) ng.h/ml. At W12, 49% of the patients had VR with a median decrease of -1.2 (-0.5; -2.3) log10 HIV-1 RNA copies/ml. The Reyaphar score included 12 baseline protease substitutions from the International AIDS Society USA list that were associated with poorer VR: L10I/F/R/V, K20I/M/R, L241, M461/L, 154L/M/T/V, L63P, A71I/L/V/T, G73A/C/F/T, V771, V82A/F/S/T, 184V, L90M and the polymorphism substitution Q58E. Comparing <5 versus > or =5 Reyaphar substitutions, the W12-W0 HIV-1 RNA decrease was - 1.4 (-0.7; -2.3) versus -0.5 (-1.2; +0.5) log10 copies/ml (P=0.009) with VR in 63% versus 110% (P<10(-4)), respectively. This score predicted VF at W12 with 46% sensitivity, compared to 33% and 28% for the ANRS 2004 and 2005 scores. PK parameters alone were not associated with VR, but GIQ was associated with virological outcome (P=0.04). 150L, known to be correlated with atazanavir-specific resistance, emerged in 2 (8%) of the 24 failing patients with paired genotypes at WO and VF. CONCLUSIONS: These findings highlight the need to cross-validate genotype-based algorithms to interpret substitution impact on virological outcome using different patient databases before their implementation in routine clinical practice.

Antiretroviral efficacy and virological profile of a zidovudine/lamivudine/tenofovir disoproxil fumarate combination therapy in antiretroviral-naive patients.

OBJECTIVE: To study the antiviral efficacy and the mutations selected by a triple therapy with zidovudine (AZT), lamivudine (3TC) and tenofovir disoproxil fumarate (TDF). METHODS: Antiretroviral-naive patients received 300 mg AZT/150 mg 3TC twice a day plus 300 mg TDF once a day in an open pilot study. Follow-up was assessed at baseline therapy (MO) and at months 1, 3, 6, 9 and 12. Reverse transcriptase (RT) genotypic resistance analysis and in selected cases, a recombinant drug susceptibility and replication capacity assay were performed from plasma RNA at baseline and in case of virological failure (VF); that is, rebound of viral load >50 copies/microl on therapy. RESULTS: Twenty-four patients were included. At baseline, the median CD4+ T-cell count was 443 cells/microl and the median plasma viral load (VL) was 4.38 log10 copies/ml. RT resistance mutations were observed at MO in 4 patients. At M12, the proportion of patients with a VL <50 copies/ml reached 88% using an on-treatment analysis and 67% with an intent-to-treat analysis. The median increase in CD4+ T cells at M12 was 94 cells/microl. Four patients had a VF on therapy: two with wild-type viruses, one with selection of M184V and thymidine analogue mutations (TAMs) on a background of TAMs, and one with selection of K65R and M184V, with a replication capacity at 2.4%/o. CONCLUSION: The virological response in our study demonstrates the antiviral efficacy of the AZT/3TC/TDF combination therapy, which needs further evaluation. The moderate frequency of selection of K65R could be due to the presence of AZT in the regimen.

An additive/subtractive genotypic score as a determinant of the virological response to didanosine in HIV-1 infected patients.

OBJECTIVE: To assess the genotypic determinants of the virological response (VR) to didanosine (ddI) in nucleoside reverse transcriptase inhibitors (NRTI)-experienced patients. METHODS: Human immunodeficiency virus type 1 (HIV-1) genotype was determined at baseline in 74 ddI-naive-patients with baseline viral load >500 copies/ml and receiving ddI as part of a new regimen. VR was defined as a plasma HIV-1 RNA <50 copies/ml after three months on ddI. NRTI resistance mutations associated with higher or lower frequencies of VR with a p-value<0.25 were retained in different sets of mutations, where the mutations associated with a worse VR were added, whereas the mutations associated with a better VR were subtracted. The most significant mutation scores were then studied in a multivariate analysis. RESULTS: Changes at three codons (M41L, L210W, T215Y/F/D/C/E) were associated with a worse VR and three mutations (K70R, M184V, K219Q) with a better VR. The strongest association with the VR was obtained with the score M41L+L210W+T215Y/F/D/C/E-K70R-K219Q. The score was independently associated with the VR in the multivariate analysis. CONCLUSION: Taking into account the mutations associated with a better VR may improve genotypic resistance algorithms. Our results are of interest for the management of antiretroviral therapy in NRTI-experienced patients.

Occult hepatitis B virus infection in HIV-infected patients with isolated antibodies to hepatitis B core antigen: Aquitaine cohort, 2002-2003.

We prospectively assessed the prevalence of occult hepatitis B virus (HBV) infection by investigating HBV replication in 160 human immunodeficiency virus (HIV)-infected patients with isolated antibodies to hepatitis B core antigen. This prevalence was 0.6% (1 case/160 patients; 95% confidence interval, 0%-3.4%). A second serum sample was collected later from 52 of the patients. HBV DNA was once again undetectable in all patients, except for the sole patient who had previously been found to be HBV DNA positive.

Avascular necrosis in HIV-infected patients: a case-control study from the Aquitaine Cohort, 1997-2002, France.

Using a case-control study design, we studied the factors associated with HIV-related avascular necrosis (AN). During a 6-year period, 12 symptomatic AN cases were validated, and each case was individually matched with 3 control cases. A conditional logistic regression model showed that current alcohol consumption and a history of steroid use were the only factors associated with the occurrence of AN.

Clonal analysis of HIV-1 variants in proviral DNA during treatment interruption in patients with multiple therapy failures.

BACKGROUND: Treatment interruption (TI) in antiretroviral-treated patients on virological failure (VF) often results in a shift from resistant to wild-type HIV-1 in plasma. A clonal analysis was set out to determine the importance of archiving of resistant HIV-1 variants during TI and its relationship with the occurrence of a VF after treatment resumption. METHODS: A fragment of the pol gene was cloned and sequenced from peripheral blood mononuclear cells DNA sampled at the end of TI. Clonal sequences were compared to bulk plasma sequences determined before TI, after TI and at VF. RESULTS: Four patients were enrolled; all had a complete reversion to wild-type HIV-1 at the end of TI. In two patients with subsequent VF, archiving of minority resistant variants was detected in proviral DNA. Archived resistant variants were found to be phylogenetically linked to sequences detected before TI and at VF, suggesting the re-expansion of resistant HIV-1 from archived quasi-species. CONCLUSION: In patients having a TI in the context of VF, archiving of resistant HIV-1 variants in proviral DNA can be involved into the mechanisms of further VF after treatment resumption.

Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy.

Morphologic and metabolic changes associated with protease inhibitor (PI) therapy have been reported since the introduction of PIs for treatment of human immunodeficiency virus infection. These changes were measured 12-20 months after initiation of PI therapy in a cross-sectional study involving 614 patients from the Antiprotéases Cohorte (APROCO) Study (Agence Nationale de Recherches sur le Sida-EP11). The prevalence was 21% for isolated peripheral atrophy, 17% for isolated fat accumulation, 24% for mixed syndrome, 23% for glucose metabolism alterations, 28% for hypertriglyceridemia (triglyceride level, > or =2.2 mM), and 57% for hypercholesterolemia (cholesterol level, > or =5.5 mM). Age was significantly associated with different phenotypes of lipodystrophy and metabolic alterations, but body-mass index, CD4(+) cell count, and type of nucleoside reverse-transcriptase inhibitor or PI received were not constantly associated with these changes. Furthermore, in all models tested, exposure to stavudine was associated with lipoatrophy and exposure of ritonavir was associated with hypertriglyceridemia. Detection and management of these disorders should be implemented to prevent further complications.

Comparison of 2 regimens that include interferon-alpha-2a plus ribavirin for treatment of chronic hepatitis C in human immunodeficiency virus-coinfected patients.

An open-label, randomized trial was conducted to compare the efficacy and safety of 2 regimens of interferon-alpha-2a (IFN-alpha-2a) plus ribavirin for management of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-coinfected patients. Sixty-eight patients were randomized to receive IFN-alpha-2a at a dosage of either (1) 6 MU given 3 times per week for 24 weeks, followed by 3 MU 3 times per week for an additional 24 weeks (group A; 31 patients); or (2) 9 MU per day for 2 weeks, followed by 3 MU per day for 22 weeks, followed by 3 MU 3 times per week for 24 weeks (group B; 37 patients). Ribavirin was added at week 16 of therapy if HCV RNA remained detectable at week 12. Sustained virological response was achieved in 10 patients (15%; 6 in group A and 4 in group B). HCV genotypes 2 or 3 and a decrease in the HCV load of >or=3 log(10) copies/mL between inclusion and week 4 were associated with virological response. In conclusion, the combination of conventional IFN-alpha-2a and ribavirin has poor virological efficacy in HCV-HIV-coinfected patients.

[The risk of rabies in France and the illegal importation of animals from rabid endemic countries]. / Risque de rage en France et importation illégale d'animaux en provenance de zones d'endémie rabique.

INTRODUCTION: Since October 2001, France has the status of a country free from rabies regarding warm-blooded animals. Nevertheless, the risk of rabies is ever present and related to the illegal importation of animals from countries in which rabies is considered to be endemic. OBSERVATION: In 2001, a puppy imported illegally from Morocco died from rabies in Gironde, requiring the prophylactic treatment of 21 persons exposed and the euthanasia of a contact animal, as well as the application of legal measures against the couple at the origin of the importation. CONCLUSION: Illegal importations of animal from areas of rabid enzootics are frequent. It is important to inform all the tourists who visit these countries on the sanitary risks involved, in terms of human and animal health, in bringing such animals back to their own country.

Molecular characterization of non-B HIV type 1 isolates from patients of a department of infectious diseases, University Hospital of Bordeaux, France, 1989-2009.

The molecular characterization of non-B HIV type 1 subtypes and the sociodemographic baseline characteristics have been studied for 114 non-B HIV-1-infected patients followed at the University Hospital of Bordeaux, France, and diagnosed as HIV infected between 1989 and 2009. Individuals enrolled in this study were mainly women with heterosexual transmission in West and Central Africa and who have been discovered to be HIV positive during pregnancy. Nevertheless, HIV acquisition among individuals born in France was significantly increasing. Recombinant form CRF02_AG was the most frequent subtype (38%) among a highly diverse viral background since 19 subtypes and CRFs have been characterized with a maximal diversity observed in the past decade.

Prevalence and predictors of deterioration of a trustful patient-provider relationship among HIV-infected persons treated with antiretroviral therapy.

OBJECTIVES: We studied the evolution of the patient-provider relationship (PPR) in HIV-infected patients who reported trustful relationships at highly active antiretroviral therapy (HAART) treatment initiation. METHODS: Psychosocial and clinical data were obtained from the French ANRS CO-8 cohort. Break of trust was defined using the question "How much do you trust the provider who usually treats you at this clinic?" Predictors of a possible break of trust during the 5 years after initiating treatment for those patients reporting a trustful PPR at month 0 were identified using a Cox model. RESULTS: During a total follow-up of 3,044 person-years, 68 (7%) patients reported having at least 1 break of trust in their PPR. Break of trust is independently associated with younger age, dissatisfaction with medical staff's explanations, cigarette smoking, and self-reported side effects and is independently inversely associated with severe HIV-related events and changes of treatment. CONCLUSIONS: A patient's break of trust in his provider is relatively infrequent. Accounting for the influence of immunologic status and psychosocial factors, self-reported side effects are shown to be detrimental to the PPR. Interestingly, clinical events and changes of treatment prevent a possible break of trust by reinforcing the provider's role. These results underline the importance of recognizing a patient's perceived secondary effects and developing appropriate care.

Streptococcus canis infections in humans: retrospective study of 54 patients.

This 5-year retrospective study reports 54 patients with infection, caused by Streptococcus canis, a pyogenic Lancefield group G streptococcus initially isolated from various animal sources. During 1997-2002, Streptococcus canis accounted for 1% of all streptococci isolated. The clinical signs, outcome and bacteriological characteristics were reviewed. All except eight were symptomatic. Clinical manifestations were: soft tissue infection (n=35), bacteremia (n=5), urinary infection (n=3), bone infection (n=2) and pneumonia (n=1). The course was favorable in 52 cases while two died from sepsis. Cultures were often polymicrobial (n=42, 77.8%) apart from hemocultures. The isolates were sensitive to most antibiotics. Presence of the bacteria did not always signify infection owing to the possible occurrence of colonization. The frequency of S. canis infections is rare and likely underestimated owing to the fact that streptococci are sought only on the basis of the Lancefield classification. The search for S. canis is recommended whenever patients present with symptoms evocative of exposure to a potentially contaminated animal.

Prevalence of and factors associated with hepatic steatosis in patients coinfected with hepatitis C virus and HIV: Agence Nationale pour la Recherche contre le SIDA et les hépatites virales CO3 Aquitaine Cohort.

BACKGROUND: Hepatic steatosis is a common feature in liver biopsies from patients with chronic hepatitis C and is associated with fibrosis progression. Patients with HIV infection and hepatitis C virus (HCV) coinfection have more rapid progression of liver fibrosis than patients with HCV infection alone. The prevalence and factors associated with hepatic steatosis are not well defined in HCV-HIV-coinfected patients. METHODS: Steatosis was assessed among 148 HCV-HIV-coinfected patients of the Aquitaine Cohort. Steatosis was graded as follows: none, mild (1%-10% of hepatocytes), moderate (11%-30%), severe (31%-60%), and massive (more than 60%). Epidemiologic, clinical, biologic, and therapeutic data were retrieved from the cohort database to investigate the risk factors. RESULTS: Steatosis was present in 67% of patients (95% confidence interval [CI]: 59% to 74%) and was at least moderate in 30% (95% CI: 23% to 38%). Steatosis was macrovesicular or mixed (macro- and microvesicular) in 40.5% and 52.8% of patients, respectively. Necroinflammatory activity was the only factor independent of steatosis (adjusted odds ratio = 5.3, 95% CI: 1.6 to 17.9). When necroinflammatory activity was removed from the model, HCV genotype 3 and body mass index (BMI) were significantly associated with steatosis. CONCLUSIONS: Liver inflammation, HCV genotype 3, and BMI are associated with steatosis, a common finding in HCV-HIV-coinfected patients.

Drug-drug interactions with systemic antifungals in clinical practice.

PURPOSE: We describe drug-drug interactions (DDIs) encountered with antifungals in clinical practice. METHODS: Retrospective observational study of hospitalized adults receiving systemic antifungal treatment in the intensive care unit (ICU) and in the infectious diseases unit (IDU) of the University Hospital of Bordeaux, France between 1996 and 2001. All treatment episodes with antifungal agent were examined and all prescribed concomitant medication identified for potential drug-drug interactions (PDDI)-serious events occurring during treatment were adjudicated for clinical DDI. RESULTS: There were 150 treatment episodes with antifungal agent in 105 patients. Fluconazole was used in 48% of the treatment episodes, amphotericin B in 46%, itraconazole in 4.7% and flucytosine in 1.3%. One hundred and sixteen PDDIs were identified related to the use of amphotericin B (81.0%), fluconazole (17.2%) or itraconazole (1.7%). Of these, 22 were associated with a clinical evidence of adverse interaction (hypokalemia, increased creatininemia or nephrotoxicity). All these clinical drug-drug interactions (CDDIs) were with amphotericin B. They were due to furosemide (36.4%), cyclosporine (31.8%) and hydrocortisone (18.2%). PDDIs were mostly associated with leukaemia (40.4%), HIV infection (24.6%) and cancer (10.5%). CONCLUSIONS: In ICU and IDU, systemic antifungal treatments lead to many PDDIs, mainly related to the type of antifungal used and to the pathology treated. Clinical DDI seem more common with amphotericin.