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.

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.

Leber's hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus.

PURPOSE: To describe the clinical features of two cases of Leber's hereditary optic neuropathy (LHON) precipitated by antiretroviral treatment for human immunodeficiency virus (HIV) infection. METHODS: Two cases of LHON (from an expected four new cases a year throughout Australia) were identified in men on treatment for HIV infection. RESULTS: Two HIV-infected men were receiving combination antiretroviral therapy that included nucleoside analogues. Both patients carried the 14 484 mitochondrial DNA mutation and were distantly related (seventh cousins). Although both men presented with sequential visual loss typical of LHON and one had a known close relative affected by LHON, the correct diagnosis was delayed in both cases. The final visual outcome was profoundly reduced in both instances and cessation of antiretroviral therapy did not result in recovery of vision in one patient. CONCLUSION: Patients with a family history of LHON who require antiretroviral treatment should be warned of the high risk of severe visual loss. The underlying mechanism of antiretroviral side effects may help characterize the other trigger factors for LHON.

The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition.

OBJECTIVES: This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. METHODS: We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. RESULTS: According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis, LDP and LAP were significantly associated with stavudine (d4T) use, while LAP was also associated with zidovudine (ZDV) treatment. There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. CONCLUSIONS: The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible.

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.

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.

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.

Determinants of antibodies to Cryptosporidium infection among gay and bisexual men with HIV infection.

A cross-sectional serosurvey for markers of prior Cryptosporidium infection was conducted among homosexual or bisexual males infected with human immunodeficiency virus (HIV); of 262 individuals approached, 236 (90%) agreed to participate. Serological response to two Cryptosporidium antigens was measured using a Western blot assay. The intensity or detection of serological responses to two Cryptosporidium antigens was not associated with CD4 cell counts or tap water consumption. A number of sexual practices were related to increased serological response for only the 27-kDa marker, including having had sex within the past 2 years, having anal sex and having had a larger number of sex partners during the past 2 years. Attending a spa or sauna was related to serological response to both the 27-kDa and 17-kDa markers. Based on these results, activities related to sexual activity appear to be a significant risk factors for prior Cryptosporidium infection.

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.

Trends in incidence of AIDS illnesses in Australia from 1983 to 1994: the Australian AIDS cohort.

To assess time trends in incidence of AIDS illnesses in Australia, a retrospective cohort of people diagnosed with AIDS from January 1, 1983 to December 31, 1994 in three HIV medicine units in Sydney, Melbourne, and Perth was established. Data on initial and subsequent AIDS illnesses were available for 2580 AIDS cases, or 45% of Australian AIDS notifications over the study period. Males represented 97.2% of the cohort, and HIV exposure category was homosexual contact for 89.9%. Subcohorts were formed by interval of AIDS diagnosis: 1983 through 1987, 1988 through 1990, and 1991 through 1994, with estimation of cumulative risk for each AIDS illness by the Kaplan-Meier method. The cumulative risk declined for Pneumocystis carinii pneumonia (PCP) (p < 0.0001) and for Kaposi's sarcoma (KS) (p < 0.0001); PCP cumulative risk estimates 2 years following AIDS diagnosis were 70% for people diagnosed with AIDS in 1983 through 1987 and 48% in 1991 through 1994, and KS cumulative risk estimates 2 years following AIDS diagnosis were 44% in 1983 through 1987 and 32% in 1991 through 1994. In contrast, cumulative risk increased from 34% to 40% for cytomegalovirus (CMV) disease (p = 0.005), from 47% to 50% for Mycobacterium avium complex (MAC) (p < 0.0001), and from 26% to 33% for esophageal candidiasis (p < 0.0001). Corresponding to this changing spectrum of AIDS illness has been an increase in severity of immunodeficiency at AIDS, with median CD4 cell count declining from 54 cells/mm3 in 1983 through 1987 to 34/mm3 in 1991 through 1994 (p = 0.002).

Prognosis of Kaposi's sarcoma as an initial and later AIDS associated illness.

BACKGROUND: The natural history of Kaposi's sarcoma (KS) as a primary presentation of AIDS has been well defined, but little is known about the prognosis of KS following a different AIDS defining illness (ADI). PATIENTS AND METHODS: Retrospective review of 852 consecutive individuals diagnosed with AIDS at Fairfield Hospital between 1984 and 1994. Demographic data, year of diagnosis, CD4 cell counts, treatment for KS and PCP prophylaxis were included in the analysis. Survival following a diagnosis of KS was evaluated, adjusting for the effects of year of diagnosis, primary or secondary KS and degree of immunodeficiency. RESULTS: The overall cumulative incidence of KS by three years post ADI was 34%. Median survival for KS as an ADI (n = 130) was 20 months versus 9 months for KS subsequent to another ADI (n = 75, P < 0.001). Those with KS as an ADI had a higher CD4 count (median 90 vs. 11, P < 0.001), lower incidence of visceral disease (5 of 130 vs. 11 of 75, P = 0.032) and fewer associated AIDS related illnesses (1 vs. 2, P < 0.001). Poorer survival following diagnosis of KS was associated with a lower CD4 count at diagnosis of KS (P = 0.002), extensive cutaneous or visceral KS at diagnosis (P = 0.009 and P < 0.001 respectively) and with the number of associated AIDS related illnesses (P < 0.001). A multivariate analysis suggested that, after adjusting for these factors, there was no difference in survival between primary and secondary KS. CONCLUSION: We found no difference in survival between primary and secondary KS after adjusting for potential confounding factors. We cannot exclude, however, that the greater incidence of visceral disease identified in secondary KS reflects an inherently more aggressive biology.