Search

Pregnancy is known to be a time of increased susceptibility to acquiring to human immunodeficiency virus (HIV) infection and this increased maternal risk places the unborn child at risk of vertical transmission. Pre-exposure prophylaxis (PrEP) involves the provision of antiretroviral therapy to an HIV-negative individual with ongoing risk of HIV exposure to limit the likelihood of HIV transmission. The inclusion of PrEP as part of a comprehensive strategy is recognised as an effective and safe means of reducing HIV infection in serodiscordant couples, thereby reducing the risk of vertical transmission of HIV. Current data suggest that PrEP is safe to continue during pregnancy and breastfeeding in HIV-negative women who remain vulnerable to acquiring HIV. The recent Pharmaceutical Benefits Scheme subsidisation of PrEP has reduced the financial and practical obstacles of PrEP provision, and a subsequent increase in patient awareness and acceptance of PrEP is expected. The framework for appropriately identifying and managing at-risk pregnant and lactating women requiring PrEP is poorly defined and warrants further clarification to better support clinicians and this patient group. This review discusses the current recommendations highlighting the gaps in the guidelines and makes some recommendations for future guideline development.

Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.

Development of multiple sclerosis (MS) is frequently preceded by an acute or subacute neurological disturbance referred to as clinically isolated syndrome (CIS). The specific immunological disturbances present in CIS remain underexamined. This study analysed peripheral blood mononuclear cells from n=18 treatment-naive individuals with recently diagnosed CIS (

Non-Human Leukocyte Antigen (HLA) genes have concomitant, although modest, effects on multiple sclerosis (MS) susceptibility; however findings have varied in different populations. Here we present the results of an association study of 16 single nucleotide polymorphisms (SNPs) in 10 non-HLA genes (IL7R, IL2RA, CLEC-16A, TYK2, CD58, IRF5, STAT3, CTLA-4, APOE, ICAM-1) in a Western Australian cohort of 350 MS patients and 498 population control subjects. Our results indicate that in this population, SNPs in IL7R, TYK2, IRF5 and APOE have modifying effects on MS susceptibility. We also found evidence of interactive protective effects between polymorphisms in the IL7R/CD58, CLEC-16A/CTLA-4, and TYK2/IRF5 genes, which in some instances are restricted within HLA- or gender-defined groups.

Low vitamin D and insufficient sun exposure are additive independent risk factors for the development of multiple sclerosis (MS). The usual measure of vitamin D status, serum 25-hydroxy vitamin D [25(OH)D], is also a marker of recent exposure to the UVB rays of sunshine. The main evidence for a protective effect for MS development of higher 25(OH)D comes from observational studies, but this study design cannot separate out whether 25(OH)D is acting as a marker of vitamin D status, sun exposure, or both. In light of a lack of definitive outcomes in MS patients after trials of vitamin D supplementation and the ability of narrowband UVB to induce vitamin D, as well as other immune-regulatory molecules in skin, the Phototherapy for Clinically Isolated Syndrome (PhoCIS) trial was established to investigate the benefits of narrowband UVB, in addition to supplemented vitamin D, on MS development in individuals with Clinically Isolated Syndrome. We propose that the PhoCIS trial provides a fresh approach to re-defining the reported associations of 25(OH)D levels with MS development and progression.

Cellular immune responses during acute Hepatitis C virus (HCV) and HIV infection are a known correlate of infection outcome. Viral adaptation to these responses via mutation(s) within CD8+ T-cell epitopes allows these viruses to subvert host immune control. This study examined HCV evolution in 21 HCV genotype 1-infected subjects to characterise the level of viral adaptation during acute and early HCV infection. Of the total mutations observed 25% were within described CD8+ T-cell epitopes or at viral adaptation sites. Most mutations were maintained into the chronic phase of HCV infection (75%). The lack of reversion of adaptations and high proportion of silent substitutions suggests that HCV has structural and functional limitations that constrain evolution. These results were compared to the pattern of viral evolution observed in 98 subjects during a similar phase in HIV infection from a previous study. In contrast to HCV, evolution during acute HIV infection is marked by high levels of amino acid change relative to silent substitutions, including a higher proportion of adaptations, likely reflecting strong and continued CD8+ T-cell pressure combined with greater plasticity of the virus. Understanding viral escape dynamics for these two viruses is important for effective T cell vaccine design.

Mulloway Argyrosomus japonicus is a native fish species in Western Australia, for which aquaculture production has recently been developed. A single cohort was stocked in a cage offshore at Geraldton, Western Australia, at a water depth of 6 m. Fish appeared healthy before stocking. Routine histological analysis was carried out from 10 mo post stocking and until completion of harvest (about 2.5 yr post stocking). No gross pathology was evident. Microscopically, however, granulomatous lesions were present in the kidneys of almost 100% of the fish examined. Enclosed in the granuloma was an aggregate of organisms, 4.2 to 5.4 µm in diameter. Kidney granulomas appeared as multi-focal aggregates. Granulomas at different stages of formation and finally fibrosing granulomas were observed. Granulomas also appeared infrequently in other organs: a few granulomas were found in the liver and spleen and a single granuloma in the heart of one fish. Transmission electron microscopy (TEM) revealed that the organism was composed of 2 cells, an outer cell enclosing an inner cell. The inner cell was surrounded by a double membrane and the outer cell by a single membrane. Cellular material, presumably of parasitic nature, surrounded the outer cell. The organism contained primitive mitochondria and abundant free ribosomes. Small subunit ribosomal DNA (SSU rDNA) sequence obtained by PCR revealed an 84% sequence identity with the myxosporean Latyspora scomberomori. Based on TEM and preliminary molecular results, we suggest that the organism is the extrasporogonic developmental stage of a myxozoan parasite, which failed to form spores in the mulloway host.

Objective: The identification of a vitamin D–responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1–associated MS risk. Methods: We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing. The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls. Results: The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group. Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles ( p = 10 −12 ) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles ( p −18 ). Conclusions: HLA-DRB1 groups corresponding to serologic HLA-DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11-fold range, suggesting functional relationships between risk-modifying HLA-DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D–dependent regulation of HLA-DR expression may still play an important role given that HLA-DRB1*04/*07/*09 (DR53) alleles that express the “nonresponsive” VDRE motif were associated with significantly reduced risk of MS.

AIMS: Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA-B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA-B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients. METHODS: We examined 23 patients referred with AH. RESULTS: Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian. CONCLUSIONS: Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol.

Background Epstein-Barr virus (EBV) infection represents a major environmental risk factor for multiple sclerosis (MS), with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1)-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome. Methods Sanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan) and candidates were evaluated for cross recognition with human brain proteins. Results EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off). In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes (‘AEG’: aa 481–496 and ‘MVF’: aa 562–577), and two putative epitopes between positions 502–543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis. Conclusions This study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach has identified a number of immunogenic regions of EBNA-1 as well as known and novel targets for autoreactive HLA-DRB1*15-restricted T cells within the central nervous system that could arise as a result of cross-reactivity with EBNA-1-specific immune responses.

High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E epsilon4 (APOE epsilon4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Abeta clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE epsilon4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE epsilon4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.

Obesity and overweight, well known risk factors for cardiovascular disease and type 2 diabetes, are now associated with Alzheimer's disease (AD). It remains to be determined if obesity and overweight contribute to the risk of developing AD through modulating levels of amyloid-beta (Abeta), a key molecule in AD pathogenesis. Thus, we investigated whether there were any associations between plasma Abeta levels and body mass index (BMI) or fat mass (FM) in a group of 18 healthy adults. A statistically significant correlation was found between BMI, FM, and plasma levels of Abeta42 (BMI r = 0.602, P = 0.008; FM r = 0.547, P = 0.019), the longer, more pathogenic form of Abeta, but not with plasma levels of the shorter, less pathogenic Abeta40. Although not significant, positive correlations between plasma levels of Abeta42 and levels of insulin and the inflammatory marker C-reactive protein (CRP), along with an inverse trend between plasma Abeta42 levels and levels of high density lipoprotein (HDL) were answered. These results suggest that proteins implicated in inflammation, cardiovascular disease and type 2 diabetes, which in turn are risk factors for AD, may contribute to the associations between BMI/FM and plasma Abeta42 levels. Longitudinal studies involving larger cohorts are required to determine if elevated body fat may predispose individuals to AD through increasing Abeta42 levels throughout early to late adulthood.

Variation in the host response to infection by pathogens including HIV-1 may be conferred by polymorphic genetic factors such as HLA and killer immunoglobulin-like receptors (KIR) genes. Here, we examined KIR and HLA genotype effects on pretreatment viral load, rate of CD4(+) T-cell decline and progression to AIDS among adult HIV-1-infected patients within the Western Australian HIV Study Cohort. In this study, carriage of KIR genes within the 'B' haplotype (eg KIR2DS2) was specifically associated with a more rapid CD4(+) T-cell decline over time and progression to AIDS. In contrast, KIR gene repertoire had no effect on pretreatment viral load while selected HLA alleles (eg HLA-B*5701, HLA-B*2705) demonstrated significant protective effects on viremia. Furthermore, interactions between specific HLA and KIR genes did appear to influence HIV disease progression. The results suggest that host genetic variation within the HLA and KIR gene complexes have clinically relevant effects on the course of HIV-1/AIDS, acting independently as well as synergistically to modify disease progression at multiple levels.

In the current era of HIV treatment, the toxicity profiles of antiretroviral drugs have increasingly emerged as a basis for selecting initial antiretroviral regimens as well as a reason for switching therapy in treatment-experienced patients. In this respect, an intensive research effort involving clinical research as well as basic science research over the past six years, has focused on the cluster of metabolic and body composition abnormalities that have come to be termed the 'lipodystrophy syndrome'. These data have now provided a clear and clinically relevant understanding of the individual profiles of drugs within the nucleoside analogue reverse transcriptase inhibitor , HIV protease inhibitor and non-nucleoside analogue reverse transcriptase inhibitor drug classes, and have provided a rational basis for assessing and monitoring these adverse effects in clinical practice. In this review, current and emerging drug toxicities are considered with an emphasis on lipodystrophy complications.

The 'HIV lipodystrophy syndrome' consists of several distinct components, including lipoatrophy (pathological subcutaneous fat loss), lipohypertrophy (abdominal/visceral adiposity), and metabolic complications including insulin resistance and dyslipidemia. Lipoatrophy appears to represent an adipose tissue-specific form of mitochondrial toxicity associated strongly with stavudine NRTI therapy, whilst the 'metabolic syndrome' phenotype is associated with HIV protease inhibitor therapy. In this context, the role of uncoupling proteins (UCPs) in modulating resting energy expenditure in response to elevated fatty acid flux associated with the 'metabolic syndrome' is supported by clinical data as well as findings of elevated adipose tissue UCP expression. The role of UCPs in this syndrome therefore exemplifies the multifactorial nature of these antiretroviral therapy complications.

Background: The use of HIV protease inhibitors (PIs) as a component of combination antiretroviral therapy in HIV-infected patients has been associated with dyslipidaemia, but its significance as a risk factor for cardiovascular disease is unclear. Endothelial dysfunction is an early phase of atherogenesis that may be assessed non-invasively with ultrasonography in vivo. Aim: To evaluate vascular function and investigate potential determinants of endothelial dysfunction of the peripheral circulation in PI-treated, HIV-infected men with dyslipidaemia. Design: Observational, case-control study. Methods: We studied 24 HIV-infected, PI-treated men with dyslipidaemia and 24 normolipidaemic, healthy male controls matched for age and body mass index. Brachial artery endothelial function was studied using high-resolution ultrasound and computerized edge-detection software. This non-invasive technique measured post-ischaemic flow-mediated dilatation (FMD), and the endothelium-independent vasodilatory response to glyceryl trinitrate (GTN). Results: Within the HIV patient group, FMD was significantly associated with percentage of 'naive' CD4 + 45RA + T cells (p=0.03), while plasma lipid/lipoprotein and insulin levels, body mass, and smoking status did not correlate with endothelial function. FMD was not significantly different between the study group and the controls. Conclusions: The atherogenic potential of PI-associated dyslipidaemia may be attenuated in HIV-infected patients with decreased immune competence, reflecting a possible contribution of cell-mediated immune responses to the pathogenesis of atherosclerosis.

Objective: HIV-1 protease inhibitors (versus no protease inhibitors) and stavudine (versus zidovudine) are independently associated with a higher risk of lipoatrophy in HIV-infected patients. We sought to determine whether the revision of stavudine and/or protease inhibitor-containing regimens to combivir/abacavir would result in prevention and/or reversibility of lipoatrophy in HIV-1-infected patients. Design: The investigation was a prospective, randomized, controlled, open-label study. Subjects: The subjects included 37 HIV-1-infected individuals with stable undetectable HIV-1 loads who were taking a regimen containing either stavudine or zidovudine with lamivudine and a protease inhibitor. Intervention: Subjects were randomized to continue therapy or switch stavudine to zidovudine and protease inhibitor to abacavir, such that the universal switch regimen was combivir (zidovudine/lamivudine) and abacavir. Main Outcome Measures: Total body, leg, and arm fat mass was measured at baseline, 24 weeks, and 48 weeks using whole-body dual-energy x-ray absorptiometry. Single-cut L4 computed tomography and assays of multiple metabolic parameters were also performed. Results: There was an average gain in fat mass of 0.009 kg/(leg.mo) in switch patients versus a loss of 0.010 kg/(leg.mo) in controls (p =.04, on-treatment analysis) over 48 weeks. Significant arm fat restoration was observed in patients who switched regimens, with an average gain of 0.014 kg/(arm.mo) (p =.004), whereas controls did not have a significant change from baseline. Analyses of percentage changes in arm and leg fat masses showed similar findings. No significant effects on intraabdominal fat, blood lipid levels, glycemic indices, and lactate levels were detected, although most baseline mean values were normal in study subjects. Combivir/abacavir maintained virological control in all but one case, and three (13.6%) of 22 individuals had adverse reactions to abacavir therapy. Conclusions: A switch to combivir/abacavir therapy was associated with objective evidence of limb fat-sparing and fat restoration compared with continued treatment with stavudine and/or protease inhibitor.

Highlights are presented from this annual workshop, which was devoted to the investigation of adverse effects associated with antiretroviral therapy for HIV infection. Topics covered included the lipodystrophy syndrome, which encompasses body composition changes (subcutaneous fat wasting, visceral fat accumulation) and metabolic abnormalities (insulin resistance and dyslipidaemia). The relevance of HIV protease inhibitor-induced metabolic abnormalities to cardiovascular disease is discussed. Research in the areas of hyperlactataemia, abacavir hypersensitivity, and bone mineral density in the context of HIV infection is also briefly reviewed.

HIV protease inhibitors were introduced into clinical practice over 7 years ago as an important component of combination antiretroviral drug regimens which in many ways revolutionised the treatment of HIV infection. The significant improvements in prognosis that have resulted from the use of these regimens, combined with the need for lifelong treatment, have increasingly focused attention on the adverse effects of antiretroviral drugs and on the metabolic complications of HIV protease inhibitors in particular. In this review, the cluster of metabolic abnormalities characterised by triglyceride-rich dyslipidaemia and insulin resistance associated with HIV protease inhibitor therapy are considered, along with implications for cardiovascular risk in patients affected by these complications. Toxicity profiles of individual drugs within the HIV protease inhibitor class are examined, as there is an increased recognition of significant intra-class differences both in terms of absolute risk of metabolic complications as well as the particular metabolic phenotype associated with these drugs. Guidelines for clinical assessment and treatment are emphasised, along with pathophysiological mechanisms that may provide a rational basis for the treatment of metabolic complications. Finally, these drug-specific effects are considered within the context of HIV-specific effects on lipid metabolism as well as lifestyle factors that have contributed to a rapidly increasing incidence of similar metabolic syndromes in the general population. These data highlight the importance of individualising patient management in terms of choice of antiretroviral regimen, assessment of metabolic outcomes and use of therapeutic interventions, based on the assessment of baseline (pre-treatment) metabolic status as well as the presence of potentially modifiable cardiovascular risk factors.

ObjectivesIt has been proposed that the contribution of nucleoside-analogue reverse transcriptase inhibitor (NRTI) therapy to subcutaneous fat wasting involves adipose tissue-specific mitochondrial DNA toxicity. We have investigated the relationships between NRTI therapy, adipocyte mitochondrial DNA content, evidence of toxicity in adipose tissue and fat wasting in Caucasian male Western Australian HIV Cohort study participants. Methods: Longitudinal mixed effects analysis of fat wasting was undertaken in individuals receiving initial stavudine- or zidovudine-containing highly active anti-retroviral therapy (HAART) ( n=49, 149 DEXA measurements). Adipocyte mitochondrial DNA (mtDNA) depletion was also assessed according to current NRTI therapy in 92 subcutaneous fat biopsies from 69 HIV-positive individuals and seven healthy controls, and results were correlated with fat wasting among a subset of patients with biopsy data receiving initial stavudine-or zidovudine-containing HAART ( n=22, 103 DEXA measurements). Confocal microscopy was performed in 22 biopsy samples obtained before and after initiating/switching NRTI therapy.ResultsStavudine therapy was associated with more severe adipocyte mitochondrial DNA depletion ( PConclusionsSeverity of subcutaneous fat wasting is primarily determined by choice of NRTI therapy (stavudine versus zidovudine) and by duration of exposure to the relevant NRTI. At the cellular level, evidence is provided that this effect manifests through NRTI-induced mitochondrial DNA depletion.

It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (≤14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (≥27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS.

There is now abundant evidence that HIV protease inhibitors (PI) as a class make a powerful independent contribution to the 'metabolic syndrome' that accompanies the long-term use of highly active antiretroviral therapy (HAART) regimens. Clinical studies have demonstrated that PI therapy is strongly associated with the development of dyslipidemia and insulin resistance [1-6], and that short-term use of PI is sufficient to cause these abnormalities even in the absence of body composition changes associated with the 'lipodystrophy syndrome'[7]. Two published studies involving HIV-seronegative individuals have also shown that HIV infection is not a prerequisite condition for the effects of PI on lipid and glucose metabolism [8,9]. However, there are a number of critical questions that remain unresolved at this time. Firstly, what is the relationship between PI therapy and the three components of the 'metabolic syndrome' - dyslipidemia, insulin resistance, and visceral adiposity - and which of these interrelated outcomes is the primary pathogenic event? Secondly, how do PI, or the metabolic syndrome they cause, interact with nucleoside analogue reverse transcriptase inhibitors (NRTI) in the pathogenesis of subcutaneous fat wasting in individuals with lipodystrophy? The answers to these questions are fundamental to an understanding of the pathogenesis of the HIV lipodystrophy syndrome. In this setting, the study presented by Kosmiski et al. in this issue of AIDS[10] provides some welcome insights.

The introduction of highly active antiretroviral therapy (also known as combination therapy) has transformed the nature of HIV infection from a severe and ultimately fatal disease to that of a manageable chronic condition. HIV drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir and nevirapine therapy. This article discusses the issues of pharmacogenetic screening, in the light of the strong genetic association of the HLA-B*5701 allele and the susceptibility to developing abacavir HSRs. It also presents the screening's impact on clinical practice and discusses the practical considerations that influence the introduction and cost-effectiveness of such screening.

HIV/AIDS HIV, the wily virus that causes AIDS, is able to outwit any number of host immune defenses that it encounters during infection. However, as Nolan, James and Mallal discuss in their Perspective, there is increasing evidence that small pockets of individuals are relatively protected against HIV infection, and also experience less aggressive HIV disease progression, due to a fortuitous genetic barrier. The Perspective authors discuss the finding that a low copy number of the gene encoding CCL3L1, a ligand for CCR5 (the coreceptor that HIV must bind to for invasion of human T cells to proceed), can markedly alter HIV disease outcomes. The authors discuss the need to take into account genetic barriers like the CCR5-CCL3L1 network when developing vaccines against HIV.

Genetic (human leukocyte antigen), disease-related and demographic risk factors for nevirapine reactions were examined in a nevirapine-exposed cohort. Cases involving combinations of hepatitis, fever or rash were associated with an interaction between HLA-DRB1*0101 and the percentage of CD4, whereas no associations were detected for isolated rash. These data suggest that HLA-DRB1*0101 and the CD4 status may determine susceptibility to nevirapine hypersensitivity, consistent with a CD4 T-cell-dependent immune response to nevirapine-specific antigens.

Type I interferons (IFNs) exert anti-viral effects through the induction of numerous IFN-stimulated genes and an immunomodulatory effect on innate and adaptive immune responses. This is beneficial in controlling virus infections but prolonged IFN-α activity in persistent virus infections, such as HIV infection, may contribute to immune activation and have a detrimental effect on the function of monocytes and T and B lymphocytes. Activation of monocytes, associated with increased IFN-α activity, contributes to atherosclerotic vascular disease, brain disease and other ‘age-related diseases’ in HIV patients treated with long-term antiretroviral therapy (ART). In HIV patients receiving ART, the anti-viral effects of IFN-α therapy have the potential to contribute to eradication of HIV infection while IFN-α inhibitor therapy is under investigation for the treatment of immune activation. The management of HIV patients receiving ART will be improved by understanding more about the opposing effects of IFN-α on HIV infection and disease and by developing methods to assess IFN-α activity in clinical practice.

We describe the first reported cases of phenytoin-related drug-induced hypersensitivity syndrome in unrelated Indigenous Australians with the same HLA-B*56:02 allele. These patients shared common clinical and pathological features, and all three were found to have the otherwise rare HLA-B allele, which might represent a novel genetic susceptibility factor for this syndrome.

Background: In Australia, temporary visa holders are ineligible for Medicare and subsidised antiretroviral drugs. Additionally, HIV testing is not mandatory for visas unless applicants seek work in the health sector. We sought to understand the impact of HIV and issues of access and adherence to antiretroviral therapy (ART) in people holding temporary visas and permanent residents. Methods: Data were gathered from interviews with 22 participants. Information concerning medication adherence, side effects, CD4 T-cell count, viral load and rate of response to generic drugs were collected. Results: The mean age was 33.4 years (±s.d. = 6.0), 21 out of 22 were from HIV-prevalent areas in East Africa and Asia, 14 out of 22 were on temporary visas, 12 were ineligible for Medicare, 14 out of 22 were diagnosed during health screening, 19 out of 22 risk exposures were in country of origin, 8 out of 17 were taking generic ART at an average cost of $180 per month, adherence was excellent and self-reported side-effects were relatively infrequent. Participants applying for visa continuations and permanent residency were fearful, believing their HIV serostatus would prejudice their applications. Patients cited belief in ART efficacy, were motivated to maintain therapy and were anxious about lack of access to treatment in their countries of origin. Conclusion: Adherence to antiretroviral drugs in Medicare-ineligible HIV-infected individuals is excellent despite limited access to treatment. The threat of visa non-renewal and the likely failure of applications for permanent residency result in considerable anxiety and confidentiality concerns.

Self-report questionnaires on alcohol, nicotine and other drugs were administered to assess the current prevalence of alcohol, drug and nicotine use in our tertiary HIV service and inform the establishment of effective interventions. Many respondents reported use of alcohol over the preceding month (111 out of 152, 73%), and recent drug use (48 out of 137, 35%) and frequently both. Sessional alcohol consumption was prevalent among drinkers (52 out of 111, 47%), and correlated with both early treatment phase (P = 0.009) and non-adherence (P = 0.03). Encouraged by a notable proportion of patients expressing interest in clinic-based smoking cessation counselling, we recommend a targeted education strategy to motivate patients in health-seeking behaviours.

This study aimed to investigate the pathogenesis of a sub-acute progressive asymmetric pancerebellar syndrome in a 54-year-old man with associated mood disturbance, mild cognitive impairment and weight loss. Examination revealed a cachectic man with a reactive, teary and dysthymic affect and mild cognitive impairment. Neurological assessment revealed an asymmetric pancerebellar syndrome with no long-tract signs. An MRI of the brain showed T2-weighted hyperintensity with subtle patchy enhancement in the transverse fibres of the pons, the superior and middle cerebellar peduncles with involvement of the cerebellar white matter. Other investigations including autoimmune, vasculitic and infectious serological screening, and antineuronal antibodies were normal. Paraneoplastic screening was negative. Cererbrospinal fluid (CSF) analysis showed and elevated protein 1.14 g/l, glucose 2.2 and leucocytes

L.W. is a 48-year-old right handed female with a scleroderma overlap syndrome (scleromyositis) manifested by systemic sclerosis (skin and gastrointestinal involvement) with a predominantly proximal necrotizing myositis. It is likely that this is a rare polymyositis/scleroderma overlap or anti-synthetase syndrome. She is persistently antibody negative for U1RNP, PmScl, Ro, La, Jo-1 and Ku antibodies. Antibodies to smooth muscle and skeletal muscle are also negative. Her symptoms were treatment resistant to immunosuppression until B cell depletion with rituximab. We discuss her course and prognosis. The patient presented in 2008 with progressive gastrointestinal symptoms with malabsorption, eventually requiring total parenteral nutrition. Total parenteral nutrition resulted in improved general condition with weight gain. She was being treated with combination of methotrexate and prednisolone when she developed insidiously progressive proximal weakness, with parallel progression of skin thickening. Peak creatine kinase (CK) was recorded at 1800 u/L. There was no improvement in muscle strength with steroid reduction. Electromyogram in 2010 suggested a proximal predominant necrotizing myositis. We postulate she has a scleroderma overlap syndrome. She was treated with rituximab in January 2012. L.W. was monitored clinically with CK levels. B cell depletion was confirmed with CD20 count of

Lipoatrophy and metabolic complications of treatment of human immunodeficiency virus (HIV) infection may share common associations with adipose tissue pathology and inflammation. To investigate these relationships, we undertook a large-scale study of adipose tissue, body composition, and metabolic outcomes among HIV-infected adult men at a tertiary hospital HIV cohort during the period 2001-2007. Methods. Assessments included adipose biopsies (np211) for investigation of adipocyte mitochondrial DNA content, adipocytokine expression, and adipose macrophage content; and whole-body dual-energy X-ray absorptiometry (DEXA) scans (np225) for objective body composition changes; 138 individuals contributed both biopsy and DEXA data. Results. Compared with 78 treatment-naive control subjects, 98 zidovudine recipients (48%) and 49 stavudine recipients (67%) had leg fat measures

Objectives To describe hospitalization rates, risk factors and associated diagnoses in people with HIV in Australia between 1999 and 2007. Design Retrospective cohort study of people with HIV (n = 842) using data linkage between the Australian HIV Observational Database and administrative hospital morbidity data collections. Methods Incidence rate ratios with 95% confidence intervals were estimated using Poisson regression models to assess risk factors for hospitalization. Predictors of length of stay were assessed using generalized mixed models. The association between hospitalization and mortality was assessed using Cox regression. Results In 4519 person-years of observation, there were 2667 hospital admissions; incidence rate of 59 per 100 person-years. Hospitalization rates were 50–300% higher in this cohort than comparable age and sex strata in the general population. Older age (incidence rate ratio 1.46, 95% confidence interval 1.28–1.65 per 10-year increase) and prior AIDS (incidence rate ratio 1.71, 95% confidence interval 1.24–2.35) were significantly associated with hospitalization. Other predictors of hospitalization included lower CD4 cell counts, higher HIV RNA, longer duration of HIV infection and experience with more drug classes. Lower CD4 cell counts, older age and hepatitis C virus antibody positivity were independently associated with longer hospital stay. Non-AIDS diseases were the principle reason for admission in the majority of cases. Mortality was associated with more frequent hospitalization during the study period. Conclusion Hospitalization rates are higher in people with HIV than the general population in Australia and are associated with markers of advanced HIV disease despite the widespread use of combination antiretroviral therapy.

PURPOSE OF REVIEW Adipose tissue pathology plays a central role in lipodystrophy. This review discusses the mechanisms by which adipose tissue responses to specific antiretroviral therapy determine clinical outcomes, and key recent data are examined that can inform the successful avoidance or management of such toxicities. RECENT FINDINGS Changes in body composition and hyperlipidaemia that occur with the use of certain thymidine analogues and protease inhibitors are accompanied by profound alterations in adipose tissue. Drug toxicity in adipocytes affects the homeostatic regulation of adipocytokines secreted from adipose tissue that mediate proinflammatory and metabolic effects, both locally and in peripheral tissue. The inflammatory component of adipose pathology may also explain slow gains in fat after switching from toxic therapies. SUMMARY Lipodystrophy can be avoided by selecting therapies with benign effects on adipose tissue. Switching from certain HIV protease inhibitors may normalize the metabolic profile fairly rapidly. For individuals living with an ongoing burden of lipoatrophy, however, reversal of pathology appears slow, and the systemic implications of adipose pathology per se as a risk factor for cardiovascular disease should be considered. Further investigation of adipose pathology for disease in the HIV community is warranted, with the potential for explorations in therapeutic intervention.

UNLABELLED: The efficacy of specifically targeted anti-viral therapy for hepatitis C virus (HCV) (STAT-C), including HCV protease and polymerase inhibitors, is limited by the presence of drug-specific viral resistance mutations within the targeted proteins. Genetic diversity within these viral proteins also evolves under selective pressures provided by host human leukocyte antigen (HLA)-restricted immune responses, which may therefore influence STAT-C treatment response. Here, the prevalence of drug resistance mutations relevant to 27 developmental STAT-C drugs, and the potential for drug and immune selective pressures to intersect at sites along the HCV genome, is explored. HCV nonstructural (NS) 3 protease or NS5B polymerase sequences and HLA assignment were obtained from study populations from Australia, Switzerland, and the United Kingdom. Four hundred five treatment-naïve individuals with chronic HCV infection were considered (259 genotype 1, 146 genotype 3), of which 38.5% were coinfected with human immunodeficiency virus (HIV). We identified preexisting STAT-C drug resistance mutations in sequences from this large cohort. The frequency of the variations varied according to individual STAT-C drug and HCV genotype/subtype. Of individuals infected with subtype 1a, 21.5% exhibited genetic variation at a known drug resistance site. Furthermore, we identified areas in HCV protease and polymerase that are under both potential HLA-driven pressure and therapy selection and identified six HLA-associated polymorphisms (P

(See the editorial commentary by Hadigan, on pages 1729–31.) Background. Treatment of human immunodeficiency virus (HIV)–1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor (PPAR [PPARG gene]) . Rosiglitazone (RSG), a PPAR agonist, improves congenital lipoatrophy but not HIV lipoatrophy. Methods. Serial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied. Results. Subjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid– binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass. Conclusions. These data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials. Highly active antiretroviral therapies (HAART) used to treat HIV-1 infection are associated with metabolic

Background: Tissue mitochondrial DNA (mtDNA) levels have been proposed as a marker of nucleoside analouge reverse transcriptase inhibitor (NRTI) toxicity. However, clinical studies have yielded conflicting data regarding possible associations with mtDNA levels. This study examined mtDNA levels in matched samples of peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from a large Australian cohort to examine treatment, clinical, and demographic associations with mtDNA depletion. Methods: mtDNA was quantified by real-time polymerase chain reaction. Results were compared across patient treatment and demographic details using linear mixed models. Results: One hundred sixty-three PBMCs and 161 fat samples were available from 61 individuals. Current NRTI exposure was the major determinant of mtDNA levels. Both ddI (didanosine) and d4T (stavudine) exposures were associated with mtDNA depletion in fat (P

Lipoatrophy is perhaps the most visibly recognisable component of antiretroviral-therapy-associated lipodystrophy due to the rarity of this form of body composition change in the general population. In this respect, it is apparent that lipoatrophy represents a form of drug toxicity specifically involving the subcutaneous fat tissue, resulting in pathological fat loss that preferentially affects the limbs and face. It is now clear that the choice and duration of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy (stavudine > zidovudine) is the dominant risk factor for clinical lipoatrophy, as well as for the pathological changes to adipose tissue that underlie the clinical syndrome. Host factors have also emerged as important modulators of lipoatrophy severity in patients receiving these NRTI drugs, including age, racial origin, and severity of immune deficiency. On the other hand, the use of selected HIV protease inhibitor drugs is more closely associated with metabolic complications such as dyslipidemia and insulin resistance and has not been convincingly linked to lipoatrophy. This review examines the clinical and pathological manifestations of lipoatrophy, and also presents information regarding the safety profile of alternative NRTI drugs, such as tenofovir and abacavir, that have not been associated with lipoatrophy risk. With increasing knowledge of lipoatrophy pathogenesis, it is likely that moderate and severe forms of this complication can now be considered a preventable complication of HIV treatment. However, it is also important to recognise that there is an ongoing burden of disease in patients who have been affected by lipoatrophy over the past six years, and that therapeutic management of established lipoatrophy will remain a challenge into the future.

Lipodystrophy complications, including lipoatrophy (pathological fat loss) and metabolic complications, have emerged as important long-term toxicities associated with antiretroviral therapy in the current era. The wealth of data that has accumulated over the past 6 years has now clarified the contribution of specific antiretroviral drugs to the risk of these clinical endpoints, with evidence that lipoatrophy is strongly associated with the choice of nucleoside reverse transcriptase inhibitor therapy (specifically, stavudine and to a lesser extent zidovudine). The aetiological basis of metabolic complications of antiretroviral therapy has proven to be complex, in that the risk appears to be modulated by a number of lifestyle factors that have made the metabolic syndrome highly prevalent in the general population, with additional contributions from HIV disease status itself, as well as from individual drugs within the HIV protease inhibitor class. The currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, efavirenz and nevirapine, have been proven to have a favourable safety profile in terms of lipodystrophy complications. However, it must be noted that NNRTI drugs also have individual toxicity profiles that must be accounted for when considering and/or monitoring their use in the treatment of HIV infection.

The availability of durable, effective antiretroviral therapy for HIV-infected patients has fundamentally altered the prognosis of this disease and has also increased awareness that long-term drug toxicities have the potential to cause significant morbidity and even mortality in this patient population. The long-term use of nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs has been associated with a number of clinically relevant toxicities including hyperlactataemia and lactic acidosis, neuropathy, pancreatitis and, more recently, a syndrome of pathological loss of subcutaneous fat tissue (lipoatrophy). Importantly, the toxicity profile of each NRTI drug within this class is unique in terms of the overall risk of long-term complications, as well as the tissue specificity of its toxic effects. In this review, the clinical manifestations, risk factors and pathological basis for NRTI-associated toxicity syndromes are explored, with an emphasis on clinical assessment and management.

Research into the effects of host genetics on HIV disease susceptibility and progression, and on the efficacy and toxicity of drug treatment, occupies a particular position in the landscape of HIV research...

The effect of TNF polymorphisms on the time-to-onset of lipodystrophy was investigated in 191 Caucasian participants in the western Australian HIV cohort. Carriage of the TNF-α-238G/A polymorphism was found in 13.1% of the cohort, and was associated with an earlier onset of lipodystrophy. The presence of TNF-α-238G/A was associated with lipodystrophy progression in Cox proportional hazards regression analyses, without influencing the relative risk and significance of other predictive host and treatment-related variables.

Background and objectives: To determine the factors contributing to changes in bone mineral density (BMD) over time in HIV-infected patients receiving highly active antiretroviral therapy (HAART). Methods: Analyses of lumbar spine BMD in 183 male Caucasian participants in the Western Australian HIV Cohort study, comprising a longitudinal analysis of data from 54 patients on stable HAART regimens, and a cross-sectional analysis comparing data from 131 protease inhibitor (PI)-treated patients and 52 PI-naive (including 28 antiretroviral treatment-naive) patients. Results: Average lumbar spine BMD remained stable or increased over the time frame considered. Although there was no evidence of a change of average BMD over time in patients receiving nelfinavir (P = 0.92), there was evidence of increasing bone density in the indinavir group (average increase, 0.31 z-score per year;P < 0.001). Lower initial z-scores in the longitudinal analysis were significantly associated with lower pre-HAART BMI (P = 0.003), consistent with results of the cross-sectional analysis in which lowest BMI prior to initial dual X-ray absorptiometry scan was associated with decreased BMD (P = 0.02, overall group). Although PI therapy was also associated with decreased BMD in a univariate analysis of the cross-sectional data (P = 0.04), this effect was abrogated in a multiple linear regression analysis (P = 0.11) with lowest BMI remaining significant (P = 0.04). Conclusions: We found no evidence, overall, of accelerated bone loss in patients treated with nelfinavir- or indinavir-containing HAART regimens, and propose that indinavir therapy may be associated with an increase in bone mineral density over time. Pre-HAART BMI was an independent and powerful determinant of an individual's initial z-score in the longitudinal analysis, and adjustment for this effect in a cross-sectional analysis abrogated the association between PI therapy and decreased lumbar spine z-score.

Objective: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. Design: A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. Results: In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. Conclusions: Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.

The abortion debate is rarely straightforward. Much of the discussion is coloured with irreconcilable differences between those who accept the availability of abortion and those who do not. Morals, ethics, religious beliefs, rights and a whole list of other variables are used to justify one or another position. The ‘right’ of the male partner to have a say in the decision whether or not to abort an unwanted pregnancy emerges periodically in the debate — and almost invariably in the context of forcing a woman to continue a pregnancy she does not want.

International audience; BACKGROUND: The health-related quality of life (HRQL) of people living with HIV infection is an important consideration in HIV management. The PROQOL-HIV psychometric instrument was recently developed internationally as a contemporary, discriminating HIV-HRQL measure incorporating influential emotional dimensions such as stigma. Here we present the first within-country results of PROQOL-HIV using qualitative and quantitative data collected from a West Australian cohort who participated in the development and validation of PROQOL-HIV, and provide a comprehensive picture of HRQL in our setting. METHODS: We carried out a secondary analysis of data from Australian patients who participated in the international study: 15 in-depth interviews were conducted and 102 HRQL surveys using the PROQOL-HIV instrument and a symptom questionnaire were administered. We employed qualitative methods to extract description from the interview data and linear regression for exploration of the composite and sub-scale scores derived from the survey. RESULTS: Interviews revealed the long-standing difficulties of living with HIV, particularly in the domains of intimate relationships, perceived stigma, and chronic ill health. The novel PROQOL-HIV instrument discriminated impact of treatment via symptomatology, pill burden and treatment duration. Patients demonstrated lower HRQL if they were: newly diagnosed (p=0.001); naive to anti-retroviral treatment (p=0.009); reporting depression, unemployment or a high frequency of adverse symptoms, (all p

Background Most HIV-infected persons are cytomegalovirus (CMV) seropositive and retain latent virus that can be reactivated by immune activation. Their T cell populations express markers reflecting a late stage of differentiation, but the contributions of HIV and CMV to this profile are unclear. We investigated the immunological “footprint” of CMV in HIV patients who had a history of extreme immunodeficiency but were now stable on antiretroviral therapy (ART). Results Twenty CMV seropositive HIV patients >50 years old with nadir CD4 T-cell counts 12 years on ART. 16 CMV seropositive and 9 CMV seronegative healthy controls were included. CMV antibody titres were higher in HIV patients than controls (P 12 years on ART. Age and presence of CMV disease influenced CD8 T-cell phenotypes. Elevated levels of sBAFF may be a consequence of HIV disease and contribute to high titres of CMV antibody. Electronic supplementary material The online version of this article (doi:10.1186/s12979-015-0041-0) contains supplementary material, which is available to authorized users.