Antiretroviral therapy initiation in an Australian cohort: implications for increased use of antiretroviral therapy.

Human immunodeficiency virus (HIV) management is entering a "universal test and treat" phase, although the benefits from this approach in developed world scenarios are uncertain. We analyzed 79 combination anti-retroviral therapy (cART)-naïve HIV-positive individuals who were intensively prospectively followed from 2004 to 2013. We studied HIV-related illnesses, potential HIV transmissions, impact on sexual behavior, and factors impeding earlier cART initiation. Sixty-eight (86 %) subjects commenced cART at a mean of 6.0 years after diagnosis: 71 % with a CD4 T-cell count <350 cells/µl. A significant minority of subjects (29 %) resisted initiation of cART despite physician recommendation for a mean of 18 months. Only one HIV-related illness occurred in a patient who had not previously recorded a CD4 T-cell count <500 cell/µl, totaling 195 person-years of observation. A 40 % increase in sexually transmitted infections (STIs) occurred after commencing cART. We detected six HIV transmissions in our cohort, all of which were before initiating cART and 5 of them had a prior CD4 T-cell count <500 cells/µl. Illnesses related to cART deferral were rare and most HIV transmissions we detected occurred in people with a prior CD4 T-cell count <500 cells/µl. Our study raises concerns about increasing STI rates after cART initiation. Focusing resources on cART initiation among patients with CD4 T-cell counts <500 cells/µl and enhancing safe sexual practices should remain a priority.

Candidaemia in an Australian teaching hospital: relationship to central line and TPN use.

We performed a retrospective review of patient case records to identify risk factors for candidaemia and to assess incidence, management and outcome of candidaemia in an Australian teaching hospital. Between January 1994 and June 1996, 38 cases of candidaemia were identified. The incidence was 0.74 per 1000 admissions of 24 h duration, and 1.54 per 1000 admissions of 5 days or more. The mortality rate was 34%, with eight of 13 (62%) of these deaths attributable to candidaemia. Risk factors included underlying gastrointestinal disease (66%) and recent abdominal surgery (61%), while recent broad spectrum antibiotic use was a contributing factor in 95%. Twenty-nine patients (76%) had a vascular access device in situ at time of detection. This was the apparent source of candidaemia in 28 (97%). Twenty-six (90%) were being used for TPN administration. Of patients receiving TPN, 5.2% developed candidaemia. Standard central venous catheters (CVC) were present in 21 patients (55%), having been in situ for an average of 12.7 days. Eighteen (86%) had been in situ for 7 days or more. Management involved removal of any implicated intravascular device. Thirty of 33 early survivors received antifungal chemotherapy. Therapy with amphotericin B, fluconazole alone or amphotericin B followed by fluconazole was equally effective. Concurrent corticosteroid use and neutropaenia contributed to increased mortality. Candidaemia is not benign. Policies regarding regular changing of central lines, especially in the setting of TPN administration and control of broad spectrum antibiotic use are appropriate measures aimed to reduce incidence. Management involves removal of implicated lines and antifungal chemotherapy. Pre-emptive therapy for candida infection should be considered in selected patients with the likelihood of TPN-related central line sepsis. Fluconazole is an effective alternative to amphotericin B in non-neutropenic patients.

Role of monocytes in mediating HIV-specific antibody-dependent cellular cytotoxicity.

Antibodies (Abs) that mediate antibody-dependent cellular cytotoxicity (ADCC) activity against HIV-1 are of major interest. A widely used method to measure ADCC Abs is the rapid and fluorometric antibody-dependent cellular cytotoxicity (RFADCC) assay. Antibody-dependent killing of a labelled target cell line by PBMC is assessed by loss of intracellular CFSE but retention of membrane dye PKH26 (CFSE-PKH26+). Cells of this phenotype are assumed to be derived from CFSE+PKH26+ target cells killed by NK cells. We assessed the effector cells that mediate ADCC in this assay. Backgating analysis and phenotyping of CFSE-PKH26+ revealed that the RFADCC assay's readout mainly represents CD3-CD14+ monocytes taking up the PKH26 dye. This was confirmed for 53 HIV+plasma-purified IgG samples when co-cultured with PBMC from three separate healthy donors. Emergence of the CFSE-PKH26+ monocyte population was observed upon co-culture of targets with purified monocytes but not with purified NK cells. Image flow cytometry and microscopy showed a monocyte-specific interaction with target cells without typical morphological changes associated with phagocytosis, suggesting a monocyte-mediated ADCC process. We conclude that the RFADCC assay primarily reflects Ab-mediated monocyte function. Further studies on the immunological importance of HIV-specific monocyte-mediated ADCC are warranted.

Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia.

Enterovirus 71 (EV71) causes epidemics of hand, foot, and mouth disease associated with neurological complications in young children. We report an outbreak of EV71-associated neurological disease that occurred from February through September 1999 in Perth, Western Australia. Fourteen children with culture-proven, EV71-induced neurological disease were identified. Nine patients (64%) developed severe neurological disease; 4 of these patients developed long-term neurological sequelae. Neurological syndromes included aseptic meningitis, Guillain-Barré syndrome, acute transverse myelitis, acute cerebellar ataxia, opso-myoclonus syndrome, benign intracranial hypertension, and a febrile convulsion. Clinical and magnetic resonance imaging data indicated that immunopathology was a major factor in the pathogenesis of neurological disease in this outbreak. This finding is in contrast to reports of previous EV71 epidemics, in which virus-induced damage to gray matter was the most frequent cause of neurological disease.

Management of Aspergillus osteomyelitis: report of failure of liposomal amphotericin B and response to voriconazole in an immunocompetent host and literature review.

Presented here is a case of Aspergillus osteomyelitis in an immunocompetent patient that progressed despite surgery and prolonged treatment with liposomal amphotericin B; the report is followed by a review of the literature. The review of this case and 41 similar cases found an overall cure rate of 69%. The importance of surgery when amphotericin B is used as first-line therapy is indicated by a 14% cure rate when amphotericin B is used alone compared to 75% when combined with surgery. When therapy is failing or surgery is contraindicated, dose escalation using a lipid formulation was not effective. On review, the addition of another agent, in particular 5-fluorocytosine, appears to be more beneficial. The patient reported here responded rapidly to voriconazole, a promising new antifungal agent for Aspergillus infections.

Efficacy of DNA and fowlpox virus priming/boosting vaccines for simian/human immunodeficiency virus.

Further advances are required in understanding protection from AIDS by T-cell immunity. We analyzed a set of multigenic simian/human immunodeficiency virus (SHIV) DNA and fowlpox virus priming and boosting vaccines for immunogenicity and protective efficacy in outbred pigtail macaques. The number of vaccinations required, the effect of DNA vaccination alone, and the effect of cytokine (gamma interferon) coexpression by the fowlpox virus boost was also studied. A coordinated induction of high levels of broadly reactive CD4 and CD8 T-cell immune responses was induced by sequential DNA and fowlpox virus vaccination. The immunogenicity of regimens utilizing fowlpox virus coexpressing gamma interferon, a single DNA priming vaccination, or DNA vaccines alone was inferior. Significant control of a virulent SHIV challenge was observed despite a loss of SHIV-specific proliferating T cells. The outcome of challenge with virulent SHIV(mn229) correlated with vaccine immunogenicity except that DNA vaccination alone primed for protection almost as effectively as the DNA/fowlpox virus regimen despite negligible immunogenicity by standard assays. These studies suggest that priming of immunity with DNA and fowlpox virus vaccines could delay AIDS in humans.