The rate of bone loss slows after 1-2 years of initial antiretroviral therapy: final results of the Strategic Timing of Antiretroviral Therapy (START) bone mineral density substudy.

OBJECTIVES: Initial antiretroviral therapy (ART) causes loss of bone mineral density (BMD) over the first 1-2 years. Whether this loss continues with longer therapy is unclear. We determined changes in bone and spine BMD over 5 years in adults receiving immediate or deferred initial ART. METHODS: In the Strategic Timing of Antiretroviral Therapy (START) BMD substudy, ART-naïve adults with CD4 counts > 500 cells/µL were randomized to immediate or deferred ART. Deferred group participants not yet on ART were offered ART after May 2015. Mean per cent changes in total hip and lumbar spine BMD (measured annually by dual-energy X-ray absorptiometry) were compared between groups using longitudinal mixed models. Fracture rates were also compared between groups for all START participants. RESULTS: Substudy participants (immediate group, n = 201; deferred group, n = 210; median age 32 years; 80% non-white; 24% female) were followed for a mean 4.5 years until December 2016. In the immediate group, > 96% used ART throughout. In the deferred group, 16%, 58% and 94% used ART at years 1, 3 and 5, respectively. BMD decreased more in the immediate group initially; groups had converged by year 3 at the spine and year 4 at the hip by intent-to-treat (ITT). BMD changes after year 1 were similar in the immediate group and in those off ART in the deferred group [mean difference: spine, 0.03% per year; 95% confidence interval (CI) -0.4, 0.4; P = 0.88; hip, -0.2% per year; 95% CI -0.7, 0.3; P = 0.37]. Fracture incidence did not differ significantly between groups (immediate group, 0.86/100 person-years versus deferred group, 0.85/100 person-years; hazard ratio 1.01; 95% CI 0.76, 1.35; P = 0.98). CONCLUSIONS: Significant ART-induced bone loss slowed after the first year of ART and became similar to that in untreated HIV infection.

Porphyromonas gingivalis antibody levels and diagnosis of coronary artery disease in HIV-positive individuals.

BACKGROUND AND OBJECTIVE: Periodontal disease has been associated with cardiovascular disease in the general population. It is unknown whether IgG antibody levels for periodontal pathogens are associated with the diagnosis of coronary artery disease (CAD) in HIV-positive individuals. MATERIAL AND METHODS: Twenty-four HIV-positive individuals (cases) with stored plasma available in the 12 months before CAD diagnosis were age- and sex-matched 1:2 with 46 HIV-positive individuals without CAD (controls). Antibody levels to whole cell extracts from periodontal pathogens Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum, as well as markers of inflammation sCD14, CXCL10 and high-sensitivity C-reactive protein, were compared between cases and controls using enzyme-linked immunosorbent assays. RESULTS: P. gingivalis-specific IgG levels (µg/mL) were significantly higher in individuals with CAD (median 1.48 [IQR 1.06-2.05]) compared to controls (0.70 [IQR 0.35-1.24], P<.001), and remained significantly higher following adjustment for traditional cardiovascular risk factors and HIV viral load (OR 21.6 [95% CI 3.73-125.63] P=.001). There was a borderline association between A. actinomycetemcomitans IgG antibody levels (cases, median 3.86 [IQR 3.19-4.72]; controls, 3.34 [IQR 2.59-4.07], P=.050) and no association found between F. nucleatum antibody levels and CAD. sCD14 levels (µg/mL) were higher in cases compared with controls (median 3.45 [IQR 3.03-4.11] vs 2.65 [IQR 2.32-2.99] P<.001), while CXCL10 (median 127 pg/mL [IQR 88-157] vs 153 [IQR 90-244] P=.321) and high-sensitivity C-reactive protein (median 3.44 mg/L [1.98-5.32] vs 1.85 [1.13-6.88] P=.203) levels were not different between cases and controls. CONCLUSION: Periodontal bacteria may be contributing to CAD risk in HIV-positive individuals.

Decreased levels of platelet-derived soluble glycoprotein VI detected prior to the first diagnosis of coronary artery disease in HIV-positive individuals.

HIV-positive patients are at increased risk for coronary artery disease (CAD); changes in platelet activation may play a role. This study was performed to determine if levels of soluble glycoprotein VI (sGPVI), a platelet-specific marker of activation, were different in HIV-positive patients compared with HIV-negative controls and further if levels were predictive of CAD in HIV. Twenty-four HIV-positive individuals (HIV cases) with CAD were compared with 46 age- and sex-matched HIV-positive controls without CAD and 41 HIV-negative controls (healthy controls). Platelet activation (represented by sGPVI level) was compared 12 months and 1 month prior to CAD diagnosis. sGPVI was quantified by ELISA. sGPVI levels were higher in HIV-positive subjects (combined) than healthy controls (122.5 ng/mL [interquartile ranges (IQR) 90.3-160.5] versus 84.7 ng/mL [IQR 48.6-119.5], p <0.001). Twelve months before the event, there was no difference in sGPVI between HIV cases and HIV controls (113.4 ng/mL [IQR 85.6-141.65] versus 128.0 ng/mL [IQR 96.6-179.4], p = 0.369). One month prior to the event, sGPVI was significantly lower in HIV cases compared with HIV controls (109.0 ng/mL [IQR 79.4-123.4] versus 133.9 ng/mL [IQR 112.7-171.9], p = 0.010). These results remained significant following adjustment for possible confounders. This work demonstrates that HIV infection is associated with higher sGPVI levels. A fall in sGPVI immediately prior to first coronary artery event may reflect a loss of negative-feedback mechanism and be an important pathological step in the development of symptomatic CAD, but further work is needed to confirm these findings and determine their clinical impact.

A longitudinal cohort study of HIV 'treatment as prevention' in gay, bisexual and other men who have sex with men: the Treatment with Antiretrovirals and their Impact on Positive And Negative men (TAIPAN) study protocol.

BACKGROUND: Australia has increased coverage of antiretroviral treatment (ART) over the past decade, reaching 73% uptake in 2014. While ART reduces AIDS-related deaths, accumulating evidence suggests that it could also bolster prevention efforts by reducing the risk of HIV transmission ('treatment as prevention'). While promising, evidence of community-level impact of treatment as prevention on reducing HIV incidence among gay and bisexual men is limited. We describe a study protocol that aims to determine if scale up of testing and treatment for HIV leads to a reduction in community viraemia and, in turn, if this reduction is temporally associated with a reduction in HIV incidence among gay and bisexual men in Australia's two most populous states. METHODS: Over the period 2009 to 2017, we will establish two cohorts making use of clinical and laboratory data electronically extracted retrospectively and prospectively from 73 health services and laboratories in the states of New South Wales and Victoria. The 'positive cohort' will consist of approximately 13,000 gay and bisexual men (>90% of all people living with HIV). The 'negative cohort' will consist of at least 40,000 HIV-negative gay and bisexual men (approximately half of the total population). Within the negative cohort we will use standard repeat-testing methods to calculate annual HIV incidence. Community prevalence of viraemia will be defined as the proportion of men with a viral load ≥200RNA copies/mm3, which will combine viral load data from the positive cohort and viraemia estimates among those with an undiagnosed HIV infection. Using regression analyses and adjusting for behavioural and demographic factors associated with infection, we will assess the temporal association between the community prevalence of viraemia and the incidence of HIV infection. Further analyses will make use of these cohorts to assess incidence and predictors of treatment initiation, repeat HIV testing, and viral suppression. DISCUSSION: This study will provide important information on whether 'treatment as prevention' is associated with a reduction in HIV incidence at a community level among gay and bisexual men.

Immune-mediated cytopenias in human immunodeficiency virus: the first reported case of idiopathic aplastic anaemia successfully treated with immunosuppression.

Although isolated cytopenias are relatively common in human immunodeficiency virus (HIV), the incidence of aplastic anaemia is extremely rare. We report here the first case of a HIV-infected patient who developed severe idiopathic aplastic anaemia, and who was safely and effectively treated with anti-thymocyte globulin and cyclosporin. We briefly review immune-mediated cytopenias in HIV, including their frequency, pathophysiology and management strategies.

Nonoccupational post-exposure prophylaxis source tracing: is it really feasible in Australia?

OBJECTIVE: A Swiss nonoccupational post-exposure prophylaxis (NPEP) source-tracing study successfully reduced unnecessary NPEP prescriptions by recruiting and testing source partners of unknown HIV serostatus. The Victorian NPEP Service in Australia attempted to replicate this study with the addition of HIV rapid testing and a mobile service. METHODS: Patients presenting to two busy NPEP sites who reported a source partner of unknown HIV status were routinely asked if their source could be traced. If the exposed person indicated that their source partner was traceable they were asked to contact them and discuss the possibility of having an HIV test. RESULTS: No sources were enrolled and the study was terminated. CONCLUSION: We hypothesize that there are a number of differences between Australia and Switzerland that make source tracing unfeasible in Australia.

Insulin B chain functions as an effective competitor of antigen presentation via peptide homologies present in the thymus.

The B chain of mammalian insulins contains appropriately spaced amino acids that predict recognition by T cells. However, all T cell clones from an HLA-DR1, Dw6 diabetic donor recognize epitopes associated with the A chain, and the B chain was found to inhibit these responses. Effective intramolecular competition at the level of the APC, not a direct effect on the T cell, is responsible for the inhibition. Insulin B chain contains two clusters of amino acid homology with the TCR beta chain and B chain peptides lacking these clusters do not compete for antigen presentation. A hole in the repertoire for T cells that recognize this portion of the insulin molecule may arise in the thymus by deletion of T cells that recognize similar peptides.

Oral dapsone versus nebulized pentamidine for Pneumocystis carinii pneumonia prophylaxis: an open randomized prospective trial to assess efficacy and haematological toxicity.

OBJECTIVE: To compare the haematological toxicity and efficacy of oral dapsone and nebulized pentamidine as Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients receiving zidovudine. DESIGN: Randomized, prospective. SETTING: Infectious diseases hospital with participants drawn from both inpatient and outpatient departments. PATIENTS: Those eligible were starting treatment with zidovudine, needed PCP prophylaxis (CD4+ count < 200 x 10(6)/l or < 20% total lymphocyte count or previous episode of PCP), and had a normal glucose-6-phosphate dehydrogenase screen. Of the 98 patients enrolled, 96 returned for follow-up. INTERVENTIONS: Fifty patients received dapsone (100mg orally twice weekly) and 46 pentamidine (400 mg nebulized monthly). Follow-up was for a median of 18 months. MAIN OUTCOME MEASURES: The development of PCP, transfusion requirements, monthly complete blood cell counts, serious adverse reactions and death were recorded. RESULTS: Nine (18%) dapsone and eight (17%) pentamidine recipients developed PCP. There was no significant difference in number of patients transfused (12 dapsone and nine pentamidine recipients) or transfusion-free survival. At exit from the study, mean haemoglobin (11.7 versus 12.4 g/dl), white blood cell (3.9 versus 3.7 x 10(9)/l) and platelet (195 versus 184 x 10(9)/l) counts did not differ for the dapsone and pentamidine arms, respectively. There was no significant difference in the occurrence of serious adverse reactions (six in the dapsone and eight in the pentamidine arm). CONCLUSIONS: Dapsone can be recommended in preference to pentamidine as PCP prophylaxis on the basis of equivalent efficacy, absence of excessive haematological toxicity, low cost and ease of administration.

Declining incidence and later occurrence of Kaposi's sarcoma among persons with AIDS in Australia: the Australian AIDS cohort.

OBJECTIVE: To explore trends in cumulative incidence of Kaposi's sarcoma (KS) and the level of immunodeficiency at KS diagnosis among people with AIDS in Australia. SETTING: Three hospital-based HIV units. STUDY POPULATION: Retrospective cohort of 2580 people diagnosed with AIDS over the period 1983-1994, representing 45% of cases of AIDS in Australia over this period. METHODS: Data including date and CD4 T-lymphocyte count of KS diagnosis was abstracted from medical records. KS occurring as both an initial and subsequent AIDS illness was included. Three subcohorts were defined based on interval of AIDS diagnosis: 1983-1987, 1988-1990, 1991-1994. Cumulative risk estimates for KS development were calculated by the Kaplan-Meier method. RESULTS: KS was diagnosed in 716 people (27.8%), and in 451 (63%) of these as the initial AIDS illness. There was a decline over time in cumulative incidence of KS (P < 0.0005); the cumulative risk of KS at 1 year after AIDS diagnosis declined from 35% for those diagnosed with AIDS during 1983-1987 to 25% for 1991-1994. This decline was not due to a decline in homosexual HIV exposure category, and was independent of CD4 T-lymphocyte count at AIDS. In multivariate analysis independent risk factors for KS development were year of AIDS diagnosis (P = 0.003), male homosexuality (P = 0.003), and CD4 T-lymphocyte count at AIDS greater than 150 x 10(6)/l (P = 0.02). A decline in median CD4 T-lymphocyte count at KS diagnosis was seen, from 67 x 10(6)/l in 1984-1987 to 20 x 10(6)/l for 1991-1994 (P < 0.0005). CONCLUSION: The decline in incidence and later occurrence of KS suggest several hypotheses, including declining prevalence or reduced virulence of a KS cofactor.

Effects of high-dose oral acyclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double-blind, placebo-controlled study. European-Australian Acyclovir Study Group.

OBJECTIVE: To determine the efficacy of high-dose oral acyclovir in preventing cytomegalovirus (CMV) and other herpesvirus disease in patients with advanced HIV disease and to evaluate its effect on patient survival. DESIGN: Double-blind, placebo-controlled randomized trial of up to 1 year's therapy. SETTING: Outpatient clinics in 16 hospitals in Europe and Australia. PARTICIPANTS: A total of 302 patients with Centers for Disease Control and Prevention stage IV HIV disease, seropositive for CMV and with CD4+ lymphocyte counts < or = 150 x 10(6)/l. INTERVENTIONS: Oral acyclovir (800 mg, four times daily) or matching placebo for 48 weeks. MAIN OUTCOME MEASURES: Time to development of CMV and other herpesvirus disease. Following the results of another study, the protocol was amended to make survival a second major endpoint. RESULTS: Acyclovir failed to reduce the incidence of CMV disease: the probability of developing CMV disease at 1 year was 0.24 and 0.23 in the placebo and acyclovir groups, respectively (P = 0.53). However, acyclovir significantly reduced the probability of dying at 1 year of follow-up (from 0.39 to 0.23; P = 0.018). As expected, acyclovir significantly reduced the incidence and frequency of herpes simplex virus disease. There were no notable differences between treatment groups in clinically adverse experiences and no changes in haematological parameters to indicate clinically significant drug-induced toxicity. CONCLUSIONS: High-dose acyclovir failed to reduce the incidence of CMV disease, but significantly reduced the probability of dying at 1 year of follow-up.

Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons.

Infection with the human immunodeficiency virus (HIV) results in progressive depletion of the CD4 subset T-lymphocytes and the development of opportunistic infections and certain malignancies. Charts were reviewed for 185 HIV-infected individuals with 265 AIDS-defining illnesses (ADIs) who had T-lymphocyte subset analyses performed within 2 months prior to or 1 month following the diagnosis. Also included were 22 HIV-infected patients with oral candidiasis and 20 with asymptomatic infection. Significant differences in CD4 lymphocyte numbers were observed between the 12 ADIs, oral candidiasis, and asymptomatic infection, allowing them to be grouped into five general categories, based on mean CD4 count: (a) asymptomatic infection, CD4 greater than 500/mm3; (b) oral candidiasis and tuberculosis, range 250-500/mm3; (c) Kaposi's sarcoma, lymphoma, and cryptosporidiosis, range 150-200/mm3; (d) Pneumocystis carinii pneumonitis, disseminated Mycobacterium avium complex, herpes simplex ulceration, toxoplasmosis, cryptococcosis, and esophageal candidiasis, range 75-125/mm3; (e) cytomegalovirus retinitis, less than 50/mm3. Our data concur with clinical impressions and provide a basis for interim treatment and prophylaxis recommendations.

Mycobacterium fortuitum bacteremia in patients with cancer and long-term venous catheters.

Primary bacteremia due to Mycobacterium fortuitum is an uncommon occurrence. Four cases of M. fortuitum bacteremia in patients with cancer, one of whom was neutropenic, are presented. None of the patients had evidence of disseminated disease or endocarditis, and there was no mortality directly associated with this infection. Two patients had polymicrobial sepsis with skin commensal organisms. The infection was related to the use of long-term central venous catheters or recent instrumentation in all patients. M. fortuitum should be added to the growing list of organisms causing catheter-related infections.

Is the recommendation for pneumococcal vaccination of HIV patients evidence based?

BACKGROUND: both the current NHMRC guidelines of Australia and the USPHS/IDSA guidelines recommend pneumococcal vaccine be given to all patients with HIV infection despite a paucity of data to support these recommendations. OBJECTIVES: the aim of this study was to assess the incidence of invasive pneumococcal disease and use of pneumococcal vaccine in HIV-infected patients at The Alfred Hospital, Melbourne, Australia, and to review the evidence for the current recommendations. STUDY DESIGN: a case record review of all HIV-infected patients followed at The Alfred Hospital diagnosed with pneumonia between 1 June 1996 and 1 June 2000 was performed. Main outcome measures were the incidence of invasive pneumococcal disease and the proportion of these individuals who received pneumococcal vaccination. RESULTS: Invasive pneumococcal disease was a relatively infrequent event with an incidence of 1.9 per 1000 person years. This rate is lower than the 8.2 per 1000 person years reported for confirmed disease by CDC. Of the 34 patients with either definite invasive, presumptive or possible pneumococcal disease, 16 (47%) had received pneumococcal vaccine, seven of these within 5 years prior to the episode of pneumonia. In 15 cases, the vaccine was administered when the CD4 cell count was <500 per microl. CONCLUSION: lack of efficacy data, rarity of invasive disease plus evidence of infrequent administration delivered predominantly to those who are least likely to benefit, has prompted us to question the value of routinely vaccinating all our HIV-infected patients with pneumococcal vaccine. Review of the published literature provides conflicting data in support of the current recommendations for administration of pneumococcal vaccine in HIV patients. It may be more cost-effective to concentrate efforts on strategies to improve adherence to ARV therapy, as this has unequivocally been shown to be associated with a reduction in the incidence of pneumococcal disease.

Quantification of mitochondrial DNA in peripheral blood mononuclear cells and subcutaneous fat using real-time polymerase chain reaction.

BACKGROUND: With decreased rates of HIV mortality and disease progression attributable to treatment with nucleoside analogue reverse transcriptase inhibitors (NRTIs), attention has now become focused on the toxicities of these forms of treatment. It is believed NRTIs cause a decrease in mitochondrial DNA (mtDNA) synthesis due to their inhibition of DNA polymerase gamma. This hypothesis is supported by in vitro data from muscle biopsies and human lymphoblastic cell lines. The resulting mitochondrial toxicity is thought to manifest itself in a variety of clinical symptoms including fatigue, fat wasting and peripheral neuropathy. A non-invasive test of mitochondrial toxicity is needed to assess toxicity and optimise HIV treatment strategies. Peripheral blood mononuclear cells (PBMC) and subcutaneous fat could be ideal and accessible sources of mtDNA for examining toxicity. OBJECTIVES: The objectives of this study were (a) to develop an assay to quantify the mtDNA copy number of PBMC and obtain reproducible results and (b) to establish the utility of subcutaneous fat as a source of mtDNA for quantification. STUDY DESIGN: PBMC were isolated from blood by centrifugation over Ficoll-Paque and subcutaneous fat was obtained from two 3 mm punch skin biopsies. Following DNA extraction, the mtDNA copy number in each sample was quantified by real-time polymerase chain reaction (PCR). RESULTS: The real-time PCR assay was found to generate consistent and reproducible results with replicates of samples undertaken within the same run, and in two or more different runs, having a mean coefficient of variation of 11.3 and 17.2%, respectively. PBMC and subcutaneous fat contained 409+/-148 and 2042+/-391 copies of mtDNA per cell, respectively. CONCLUSIONS: From the work carried out it can be concluded that firstly, the real-time PCR assay generates consistent and reproducible results, and secondly that mtDNA can be extracted and quantified from PBMC and subcutaneous fat.

Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial.

The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.

Psychosocial factors are associated with prolonged hospitalization in a population with advanced HIV.

Our aim was to define a subgroup of patients with HIV at risk of adverse outcomes in terms of psychosocial factors in order to improve the targeting of hospital resources. The International Classification of Diseases, 9th Revision (ICD-9) coded discharges of all inpatients with HIV discharged from a tertiary hospital between July 1996 and March 1999 were matched against variables in the HIV/AIDS database. A 'prolonged hospitalization' subgroup was defined as those patients whose cumulative length of stay exceeded 90 days in the 33-month period. There were 2778 non-day stay discharges (n=757 patients) constituting 21,286 bed-days. The prolonged hospitalization group (n=62) accounted for 44.3% of the bed-days. Psychosocial co-diagnoses were associated with prolonged hospitalization in both crude and adjusted logistic analyses. These included psychiatric diagnoses such as mania, psychosis and anxiety, HIV dementia, housing issues and the need for social work interventions. In conclusion, a small group of individuals at risk of adverse outcomes has been defined by markers of psychosocial dysfunction. Increased understanding of this group should enable the development of programmes directed at morbidity and mortality.

Non-occupational post-exposure prophylaxis in Victoria, Australia: responding to high rates of re-presentation and low rates of follow-up.

In Australia, the non-occupational post-exposure prophylaxis service in Victoria (VNPEPS) maintains a database of non-occupational post-exposure prophylaxis (NPEP) use throughout the state. Through the database the service can monitor and respond to patterns of NPEP presentation, re-presentation and follow-up as well as those who test positive for HIV. We describe a cohort of NPEP individuals from the commencement of the service to 31 December 2009. During this time, 1864 individuals presented for NPEP on 2396 occasions. The majority (85%) were men who have sex with men (MSM) presenting after receptive anal intercourse (56.1%). Repeat NPEP presentations were high (17.5%) and follow-up testing at week 12 post-NPEP was low (34%). Twenty-two patients (1.2%) tested positive for HIV at baseline presentation and six patients seroconverted to HIV during follow-up. The VNPEPS has initiated strategies to encourage behaviour change for those who re-present for NPEP, and to improve rates of week 12 follow-up.