Ian Woolley

Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993–2006

The aim of the study was to describe the prevalence of and risk factors for HIV‐associated sensory neuropathy (HIV‐SN) in 2006 [the era of stavudine, didanosine and zalcitabine (dNRTI)‐sparing highly active antiretroviral therapy (HAART)] and to compare our findings with data obtained in the same clinic in 1993 (pre‐HAART) and 2001 (frequent use of dNRTI‐containing HAART).

Low CD4 Count Is Associated With an Increased Risk of Fragility Fracture in HIV-Infected Patients

Background:Low bone mineral density in HIV-infected patients is an increasingly recognized clinical problem. The aim of this study was to determine the incidence, prevalence, and risk factors for development of low trauma or fragility fractures in an HIV-infected population. Methods:A 1:2 matched case-control study was performed of HIV-infected patients attending the Alfred Hospital between 1998 and 2009. Controls were matched on gender, age, and duration of HIV infection. Results:The overall fracture incidence rate was 0.53 per 100 person-years [95% confidence interval (CI): 0.43 to 0.65] and period prevalence of 3.34 per 100 patients (95% CI: 2.66 to 4.13). There were 73 low trauma fractures in 61 patients. Patients were predominantly male (89%) with a mean age of 49.8 years. Independent risk factors for fragility fracture were a CD4 cell count <200 cells per microliter odds ratio (OR): 4.91 (95% CI: 1.78 to 13.57, P = 0.002), corticosteroids OR: 8.96 (95% CI: 1.55 to 51.88, P = 0.014) and anti-epileptic medications OR: 8.88 (95% CI: 1.75 to 44.97, P = 0.008). There were no significant associations between HIV viremia (P = 0.18), use of or class of antiretroviral medication, and risk of fracture. Eighty-eight percent of patients with fracture had established osteopenia or osteoporosis. Conclusion:This is the largest clinical study to date of fragility fractures occurring in an HIV-infected population. The study found that risk of fracture was strongly associated with a low CD4 cell count, use of corticosteroids, and anti-epileptic medications. There were no associations between fracture risk and viral load, use of class, or duration of antiretroviral agent.

Guidelines for the prevention of sepsis in asplenic and hyposplenic patients

Asplenic or hyposplenic patients are at risk of fulminant sepsis. This entity has a mortality of up to 50%. The spectrum of causative organisms is evolving as are recommended preventive strategies, which include education, prophylactic and standby antibiotics, preventive immunizations, optimal antimalarial advice when visiting endemic countries and early management of animal bites. However, there is evidence that adherence to these strategies is poor. Consensus‐updated guidelines have been developed to help Australian and New Zealand clinicians and patients in the prevention of sepsis in asplenic and hyposplenic patients.

Splenectomy Associated Changes in IgM Memory B Cells in an Adult Spleen Registry Cohort

Asplenic patients have a lifelong risk of overwhelming post-splenectomy infection and have been reported to have low numbers of peripheral blood IgM memory B cells. The clinical value of quantitation of memory B cells as an indicator of splenic abnormality or risk of infection has been unclear. To assess changes in B cell sub-populations after splenectomy we studied patients recruited to a spleen registry (n = 591). A subset of 209 adult asplenic or hyposplenic subjects, and normal controls (n = 140) were tested for IgM memory B cells. We also determined a) changes in IgM memory B cells with time after splenectomy using the cross-sectional data from patients on the registry and b) the kinetics of changes in haematological markers associated with splenectomy(n = 45). Total B cells in splenectomy patients did not differ from controls, but memory B cells, IgM memory B cells and switched B cells were significantly (p<0.001) reduced. The reduction was similar for different indications for splenectomy. Changes of asplenia in routine blood films including presence of Howell-Jolly bodies (HJB), occurred early (median 25 days) and splenectomy associated thrombocytosis and lymphocytosis peaked by 50 days. There was a more gradual decrease in IgM memory B cells reaching a stable level within 6 months after splenectomy. IgM memory B cells as proportion of B cells was the best discriminator between splenectomized patients and normal controls and at the optimal cut-off of 4.53, showed a true positive rate of 95% and false positive rate of 20%. In a survey of 152 registry patients stratified by IgM memory B cells around this cut-off there was no association with minor infections and no registry patients experienced OPSI during the study. Despite significant changes after splenectomy, conventional measures of IgM memory cells have limited clinical utility in this population.

Abacavir does not affect circulating levels of inflammatory or coagulopathic biomarkers in suppressed HIV: A randomized clinical trial

Objective:The Simplification of antiretroviral therapy with Tenofovir-Emtricitabine or Abacavir-Lamivudine trial (STEAL) study randomized HIV participants to switch existing nucleoside reverse transcriptase inhibitors (NRTI) to either abacavir/lamivudine (ABC/3TC; n = 179) or tenofovir/emtricitabine (TDF/FTC; n = 178). An increased risk in cardiovascular disease (CVD) was reported (hazard ratio 7.7, P = 0.048) in ABC/3TC recipients compared with TDF/FTC in the STEAL study. The impact of ABC/3TC treatment on a range of CVD and inflammatory biomarkers was explored. Design and methods:Biomarkers were assessed at 0, 12, 24, and 48 weeks to examine: inflammation – high sensitive C-reactive protein, amyloid-P, amyloid-A, interleukin 6, interleukin 10, interferon α, and macrophage migration inhibitory factor; coagulation – D-dimer and fibrinogen; platelet function – soluble P-selectin; endothelial function – vascular cell adhesion molecule 1 and intercellular adhesion molecule 1; renal function – cystatin C. The primary endpoint was the difference between arms for mean change from baseline to week 12. Secondary analyses were differences between groups for mean change from baseline to weeks 24 and 48, time-weighted change from baseline to week 48, and changes to week 12 stratified by Framingham CVD risk score at baseline. Results:Sera were available from 330 (92%) of 357 participants. At baseline, all biomarkers were similar between treatment arms and when stratified for baseline NRTI exposure. There were no significant differences between treatment arms in the mean change from baseline to week 12 for any biomarkers. No consistent between-group differences were seen in the secondary analyses that could suggest one pathophysiological pathway. Conclusion:A thorough examination of selected biomarkers associated with cardiovascular morbidity and mortality did not reveal associations with the use of ABC/3TC relative to use of TDF/FTC.

Fragility Fractures in HIV-Infected Patients: Need for Better Understanding of Diagnosis and Management:

HIV infection, AIDS, and antiretroviral therapy (ART) have been associated with bone fragility fractures, although the prevalence and incidence are not well studied by researchers. In HIV and ART, osteopenia and osteoporosis are multifactorial, and health promotion or medical health maintenance should anticipate and prevent morbidity of bone fragility fractures.

HIV Replication Alters the Composition of Extrinsic Pathway Coagulation Factors and Increases Thrombin Generation

Background HIV infection leads to activation of coagulation, which may increase the risk for atherosclerosis and venous thromboembolic disease. We hypothesized that HIV replication increases coagulation potentially through alterations in extrinsic pathway factors. Methods and Results Extrinsic pathway factors were measured among a subset of HIV participants from the Strategies for Management of Anti‐Retroviral Therapy (SMART) trial. Thrombin generation was estimated using validated computational modeling based on factor composition. We characterized the effect of antiretroviral therapy (ART) treatment versus the untreated state (HIV replication) via 3 separate analyses: (1) a cross‐sectional comparison of those on and off ART (n=717); (2) a randomized comparison of deferring versus starting ART (n=217); and (3) a randomized comparison of stopping versus continuing ART (n=500). Compared with viral suppression, HIV replication consistently showed short‐term increases in some procoagulants (eg, 15% to 23% higher FVIII; P<0.001) and decreases in key anticoagulants (eg, 5% to 9% lower antithrombin [AT] and 6% to 10% lower protein C; P<0.01). The net effect of HIV replication was to increase coagulation potential (eg, 24% to 48% greater thrombin generation from computational models; P<0.01 for all). The pattern of changes from HIV replication was reversed with ART treatment and consistent across all 3 independent comparisons. Conclusions HIV replication leads to complex changes in extrinsic pathway factors, with the net effect of increasing coagulation potential to a degree that may be clinically relevant. The key influence of changes in FVIII and AT suggests that HIV‐related coagulation abnormalities may involve changes in hepatocyte function in the context of systemic inflammation. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00027352.

Rat-bite fever septic arthritis: illustrative case and literature review

Rat-bite fever is a rare zoonotic infection caused by Streptobacillus moniliformis or Spirillum minus, which is characterised by fever, rash and arthritis. The arthritis has previously been described as non-suppurative and isolation of the organism from synovial fluid as very uncommon. This article reports a case of septic arthritis diagnosed as rat-bite fever when the organism was cultured from synovial fluid and reviews another 15 cases of S. moniliformis septic arthritis reported in the worldwide literature since 1985. Articles were included in this review if S. moniliformis was cultured from synovial fluid. Of the published cases, 88% presented with polyarthritis, affecting small and large joints although two had monoarticular hip sepsis. Fever was present in 88%, rash in 25% and 56% had extra-articular features. Synovial fluid analysis revealed high cell counts in all cases (mean 51,000 × 109/l) with a predominance of polymorphonuclear leucocytes, and organisms were found on Gram stain in only 50%. Penicillin was used for treatment in 56% of cases and surgery was required in 30%. All patients recovered. Rat-bite fever arthritis can be suppurative and attempts should be made to isolate the organism from synovial fluid. The diagnosis should be considered when there is arthritis and a high synovial fluid cell count but no apparent organism, especially when the patient has had contact with rats.

Trends in detectable viral load by calendar year in the Australian HIV observational database

BackgroundRecent papers have suggested that expanded combination antiretroviral treatment (cART) through lower viral load may be a strategy to reduce HIV transmission at a population level. We assessed calendar trends in detectable viral load in patients recruited to the Australian HIV Observational Database who were receiving cART.MethodsPatients were included in analyses if they had started cART (defined as three or more antiretrovirals) and had at least one viral load assessment after 1 January 1997. We analyzed detectable viral load (>400 copies/ml) in the first and second six months of each calendar year while receiving cART. Repeated measures logistic regression methods were used to account for within and between patient variability. Rates of detectable viral load were predicted allowing for patients lost to follow up.ResultsAnalyses were based on 2439 patients and 31,339 viral load assessments between 1 January 1997 and 31 March 2009. Observed detectable viral load in patients receiving cART declined to 5.3% in the first half of 2009. Predicted detectable viral load based on multivariate models, allowing for patient loss to follow up, also declined over time, but at higher levels, to 13.8% in 2009.ConclusionsPredicted detectable viral load in Australian HIV Observational Database patients receiving cART declined over calendar time, albeit at higher levels than observed. However, over this period, HIV diagnoses and estimated HIV incidence increased in Australia.

Duffy Antigen Polymorphisms Do Not Alter Progression of HIV in African Americans in the MACS Cohort

Data in this manuscript were collected by the MACS, with centers (Principal Investigators) at the Johns Hopkins University Bloomberg School of Public Health (Joseph B. Margolick, Lisa Jacobson); Howard Brown Health Center and Northwestern University Medical School (John Phair); University of California, Los Angeles (Roger Detels, Beth Jamieson); and University of Pittsburgh (Charles Rinaldo). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute. UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041. The website is located at http://www.statepi.jhsph.edu/macs/macs.html. I.J.W. is funded by the Covance Fellowship of the Royal Australasian College of Physicians.