Janine M. Trevillyan

Associations between surface markers on blood monocytes and carotid atherosclerosis in HIV-positive individuals

Chronic HIV infection is associated with increased risk of cardiovascular disease (CVD), including in patients with virological suppression. Persistent innate immune activation may contribute to the development of CVD via activation of monocytes in these patients. We investigated whether changes in monocyte phenotype predict subclinical atherosclerosis in virologically suppressed HIV‐positive individuals with low cardiovascular risk. We enroled 51 virologically suppressed HIV‐positive individuals not receiving protease inhibitors or statins and 49 age‐matched uninfected controls in this study. Carotid artery intima‐media thickness (cIMT) was used as a surrogate marker for CVD, and traditional risk factors, including Framingham risk scores, were recorded. Markers of monocyte activation (CD14, CD16, CCR2, CX3CR1, CD38, HLA‐DR and CD11b) were measured in whole‐blood samples by flow cytometry. Associations were assessed using univariate and multivariate median regressions. Median cIMT was similar between HIV‐positive and HIV‐negative participants (P=0.3), although HIV‐positive patients had significantly higher Framingham risk score (P=0.009) and systemic inflammation. Expression of two monocyte markers, CD11b and CX3CR1, independently predicted carotid artery thickness in HIV‐positive individuals after controlling for Framingham risk score (P=0.025 and 0.015, respectively). These markers were not predictive of carotid artery thickening in controls. Our study indicates that monocyte surface markers may serve as novel predictors of CVD in HIV‐positive individuals and is consistent with an important role for monocyte activation in the progression of HIV‐related cardiovascular pathology.

Fosfomycin for treatment of prostatitis: new tricks for old dogs

Treatment options for prostatitis caused by multidrug-resistant gram-negative bacilli are limited. We report two cases cured with oral fosfomycin and provide a pharmacokinetic analysis of fosfomycin predose concentrations during treatment.

Steroids control paradoxical worsening of Mycobacterium ulcerans infection following initiation of antibiotic therapy.

Lessons from Practice patients present outside endem by the long incubation period o BU is characterised by slowl with local necrosis, destruction ingly little systemic inflammatio infection is the result of its mycolactone, an immunomodu necrosis of host tissues and can responses and the recruitmen yc ca loc (BU). The M obacterium ulcerans infection is a geographilly restricted infection often referred to by its al name as Daintree, Buruli or Bairnsdale ulcer disease occurs in sub-Saharan Africa and within discrete regions of Australia, predominantly coastal Victoria and northern Queensland. Significant diagnostic delays, which place patients at risk of more extensive disease, are common. A recent review identified a mean duration of 42 days of symptoms before diagnosis (range, 2–270 days).3 These delays often occur when ic areas, a factor affected f 4–7 months.4 y progressive skin lesions of lipocytes and surprisn. This unusual pattern of unique virulence factor latory toxin that induces limit initiation of immune t of inflammatory cells.5 Following the increased use of antibiotics in BU, there have been descriptions of worsening clinical condition after an initial response to therapy.6 Such deteriorations (referred to as paradoxical reactions) are most common in patients with extensive disease and can take a variety of forms including increased ulcer size, ulceration of previously non-ulcerative papules or the development of new lesions not detectable before antibiotics.7 It is particularly important that paradoxical reactions are not misinterpreted as antibiotic failure, as the vast majority of lesions will resolve without a change in antibiotic regimen. Paradoxical reactions may be the result of antibioticinduced suppression of mycolactone synthesis, leading to decreased mycolactone concentrations and thus a reversal of macrophage and neutrophil dysfunction with renewed immune surveillance and response.7 There are many parallels to the paradoxical reactions described with Mycobacterium tuberculosis in HIV co-infected patients who initiate antiretroviral therapy. In that setting, the reaction likely represents an increased inflammatory response secondary to antiretroviral-induced immune reconstitution. As with M. tuberculosis, paradoxical reactions to BU commonly occur 4–8 weeks after therapy commences.7 In our case, the deterioration 4 weeks into therapy at the time that mycobacterial cultures became sterile indicates that this was not a failure of antibiotics but an unmasked immune phenomenon. Although our patient did receive a short course of intravenous antibiotics at the time of initiation of steroid therapy, the rapidity of his response and lack of identification of a new bacterial Clinical record

Abacavir exposure and cardiovascular risk factors in HIV-positive patients with coronary heart disease: A retrospective case-control study

BACKGROUND HIV-positive patients have an estimated twofold increased risk of acute myocardial infarction and coronary heart disease (CHD). While traditional cardiovascular risk factors and the effects of HIV and chronic inflammation all play a role, the contribution of long-term exposure to antiretroviral (ARV) agents is becoming clear. METHODS We performed a retrospective case-control study of HIV-positive patients seen from January 1996 to December 2009 to evaluate the impact of HIV suppression and exposure to specific ARVs on the incidence of CHD. RESULTS Cases (n=68) were HIV-positive with evidence of CHD. Two age- and sex-matched HIV-positive controls (n=136) without a diagnosis of CHD were assigned for each case. The cumulative incidence of CHD in the period covered by the study was 3.8%, with an incidence of 8.5 cases per 1000 patient-years of follow up. Cases had an increased likelihood of having hypertension (odds ratio (OR): 6.62, P<0.001), a family history of CHD (OR: 5.82, P<0.001), lower high-density lipoprotein levels (OR: 0.28, P=0.025) and higher Framingham risk scores compared with controls. Following adjustment for traditional cardiovascular risk factors, the presence of CHD was significantly associated with the current use of abacavir (OR: 2.10, P=0.03). Protease inhibitor therapy, HIV viral load and duration of known HIV infection were not predictive of CHD in our patient population. CONCLUSIONS Our data add to the evidence that abacavir use is associated with CHD in HIV-positive patients in Australia.

Plasma lipidomic profiling of treated HIV-positive individuals and the implications for cardiovascular risk prediction.

Background The increased risk of coronary artery disease in human immunodeficiency virus (HIV) positive patients is collectively contributed to by the human immunodeficiency virus and antiretroviral-associated dyslipidaemia. In this study, we investigate the characterisation of the plasma lipid profiles of treated HIV patients and the relationship of 316 plasma lipid species across multiple lipid classes with the risk of future cardiovascular events in HIV- positive patients. Methods In a retrospective case-control study, we analysed plasma lipid profiles of 113 subjects. Cases (n = 23) were HIV-positive individuals with a stored blood sample available 12 months prior to their diagnosis of coronary artery disease (CAD). They were age and sex matched to HIV-positive individuals without a diagnosis of CAD (n = 45) and with healthy HIV-negative volunteers (n = 45). Results Association of plasma lipid species and classes with HIV infection and cardiovascular risk in HIV were determined. In multiple logistic regression, we identified 83 lipids species and 7 lipid classes significantly associated with HIV infection and a further identified 74 lipid species and 8 lipid classes significantly associated with future cardiovascular events in HIV-positive subjects. Risk prediction models incorporating lipid species attained an area under the receiver operator characteristic curve (AUC) of 0.78 (0.775, 0.785)) and outperformed all other tested markers and risk scores in the identification of HIV-positive subjects with increased risk of cardiovascular events. Conclusions Our results demonstrate that HIV-positive patients have significant differences in their plasma lipid profiles compared with healthy HIV-negative controls and that numerous lipid species were significantly associated with elevated cardiovascular risk. This suggests a potential novel application for plasma lipids in cardiovascular risk screening of HIV-positive patients.

Locally extensive angio-invasive Scedosporium prolificans infection following resection for squamous cell lung carcinoma.

We report a case of Scedosporium prolificans infection in a patient following surgery for squamous cell lung carcinoma. Combination therapy with voriconazole and terbinafine was commenced for intrathoracic infection and mycotic vasculitis. In spite of antifungal treatment, he developed culture-positive sternal and rib osteomyelitis four months later. Scedosporiosis is not commonly reported in patients with solid organ malignancies, and this case highlights its aggressive nature and propensity for direct local invasion.

Successful treatment of Epstein-Barr virus encephalitis in the setting of HIV-associated neurocognitive disorder: a diagnostic and therapeutic challenge.

We report a challenging case of HIV-associated neurocognitive disorder with superimposed Epstein-Barr virus (EBV) encephalitis. The patient presented with an abnormal MRI brain scan, and EBV DNA that was detected in the cerebrospinal fluid and brain biopsy, which also demonstrated histopathological findings consistent with the diagnosis. This occurred on the background of a 12-month period of gradual cognitive decrease secondary to HIV-associated dementia. Invasive testing was required to reach the diagnosis in this case, highlighting the importance of thorough investigation of neurological impairment in HIV-positive patients. Clinicopathological recovery was achieved through optimization of antiretroviral therapy and use of valganciclovir.

Electronic Estimations of Renal Function Are Inaccurate in Solid-Organ Transplant Recipients and Can Result in Significant Underdosing of Prophylactic Valganciclovir

ABSTRACT In a prospective study of solid-organ transplant recipients (n = 22; 15 hepatic and 7 renal) receiving valganciclovir for cytomegalovirus (CMV) prophylaxis, electronic estimation of glomerular filtration rate (eGFR) underestimated the true GFR (24-h urine creatinine clearance) by >20% in 14/22 (63.6%). Its use was associated with inappropriate underdosing of valganciclovir, while the Cockroft-Gault equation was accurate in 21/22 patients (95.4%). Subtherapeutic ganciclovir levels (≤0.6 mg/liter) were common, occurring in 10/22 patients (45.4%); 7 had severely deficient levels (<0.3 mg/liter).

The location of Australian Buruli ulcer lesions—Implications for unravelling disease transmission

Background Buruli ulcer (BU), caused by Mycobacterium ulcerans, is increasing in incidence in Victoria, Australia. To improve understanding of disease transmission, we aimed to map the location of BU lesions on the human body. Methods Using notification data and clinical records review, we conducted a retrospective observational study of patients diagnosed with BU in Victoria from 1998–2015. We created electronic density maps of lesion locations using spatial analysis software and compared lesion distribution by age, gender, presence of multiple lesions and month of infection. Findings We examined 579 patients with 649 lesions; 32 (5.5%) patients had multiple lesions. Lesions were predominantly located on lower (70.0%) and upper (27.1%) limbs, and showed a non-random distribution with strong predilection for the ankles, elbows and calves. When stratified by gender, upper limb lesions were more common (OR 1·97, 95% CI 1·38–2·82, p<0·001) while lower limb lesions were less common in men than in women (OR 0·48, 95% CI 0·34–0·68, p<0·001). Patients aged ≥ 65 years (OR 3·13, 95% CI 1·52–6·43, p = 0·001) and those with a lesion on the ankle (OR 2·49, 95% CI 1·14–5·43, p = 0·02) were more likely to have multiple lesions. Most infections (71.3%) were likely acquired in the warmer 6 months of the year. Interpretation Comparison with published work in Cameroon, Africa, showed similar lesion distribution and suggests the mode of M. ulcerans transmission may be the same across the globe. Our findings also aid clinical diagnosis and provide quantitative background information for further research investigating disease transmission.

Effects of abacavir administration on structural and functional markers of platelet activation

Background:Current abacavir exposure has been reported to be associated with cardiovascular disease. Changes in platelet reactivity could plausibly explain the clinically observed pattern of association. Objective:To determine if platelet reactivity changed following abacavir exposure and whether this effect was reversible on cessation of the drug. Methods:In an open-label, interventional study abacavir, 600 mg daily, was added to a suppressive antiretroviral regimen in 20 adult HIV-positive men. Platelet function, estimated by the phosphorylated vasodilator-stimulated phosphoprotein (P-VASP) assay and through measurement of the expression and shedding of platelet-specific receptors, was assessed at baseline, following 15 days of abacavir and at completion of a 28-day washout period. Results:The VASP-index decreased significantly from 79.1% [interquartile range (IQR) 47.8–87.6] to 32.6% (IQR –11.5–51.0) following 15 days of abacavir administration (P = 0.010), and returned to baseline levels following the washout period (day 43 =76.3%; IQR 40.7–92.3). There was no change in resting (prostaglandin E1 alone) P-VASP but a slight increase in P-VASP within stimulated platelets (prostaglandin E1 and adenosine diphosphate). Integrin &bgr;3 levels decreased significantly [208.5 ng/ml (IQR 177.0–231.1) to 177.5 ng/ml (IQR 151.7–205) P < 0.001] and there was a nonsignificant trend towards decreased soluble glycoprotein VI levels [baseline; 72.5 ng/ml (95% CI 58.3–81.5) vs. day 15; 45.0 ng/ml (95% CI 33.0–98.2) P = 0.79]. Conclusion:Abacavir led to reversible changes in platelet function and structure. The clinical implications of these changes are uncertain; they may represent negative feedback mechanisms in response to an abacavir-associated prothrombotic state.