Biomedical subjects

Matthew Law

Publications and source records attributed to Matthew Law.

At least 19 recordsLinked to original sources

PubMed2007

Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and [corrected] hypoadiponectinemia.

OBJECTIVE: Metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes. Definitions exist to identify those "at risk." Treatment of HIV infection with highly active antiretroviral therapy can induce severe metabolic complications including lipodystrophy, dyslipidemia, and insulin resistance. The purpose of this study was to report the prevalence of metabolic syndrome in HIV-infected patients and compare insulin resistance and total body, limb, and visceral fat and adipokines in those with and without metabolic syndrome. RESEARCH DESIGN AND METHODS: This was an international cross-sectional study of a well-characterized cohort of 788 HIV-infected adults recruited at 32 centers. Metabolic syndrome prevalence was examined using International Diabetes Federation (IDF) and U.S. National Cholesterol Education Program Adult Treatment Panel III (ATPIII) criteria, relative to body composition (whole-body dual-energy X-ray absorptiometry and abdominal computed tomography), lipids, glycemic parameters, insulin resistance, leptin, adiponectin, and C-reactive protein (CRP). RESULTS: The prevalence of metabolic syndrome was 14% (n = 114; 83 men) by IDF criteria and 18% (n = 139; 118 men) by ATPIII criteria; the concordance was significant but only moderate (kappa = 0.46, P < 0.0001). Many patients (49%) had at least two features of metabolic syndrome but were not classified as having metabolic syndrome as their waist circumferences or waist-to-hip ratios were in the non-metabolic syndrome range. Metabolic syndrome was more common in those currently receiving protease inhibitors (P = 0.04). Type 2 diabetes prevalence was five- to ninefold higher in those with metabolic syndrome. With IDF criteria, subjects with metabolic syndrome showed disturbances in inflammation and adipokines: they had higher CRP (5.5 +/- 7.0 vs. 3.9 +/- 6.0 mg/l, P < 0.003) and leptin (9 +/- 9 vs. 4 +/- 6 ng/ml, P < 0.0001) and lower adiponectin (12 +/- 8 vs. 15 +/- 10 microg/ml, P < 0.0001) levels. By ATPIII criteria, those with metabolic syndrome had higher leptin (6 +/- 8 ng/ml, P = 0.006) and lower adiponectin (15 +/- 10 vs. 18 +/- 8 microg/ml, P < 0.0001) levels. CONCLUSIONS: Metabolic syndrome prevalence in HIV-positive adults was lower than that reported for the general population. Metabolic syndrome was associated with a substantially increased prevalence of type 2 diabetes in this specific cohort. Many subjects without metabolic syndrome had at least two metabolic syndrome components (particularly elevated lipid levels) but did not meet waist circumference or waist-to-hip ratio cutoff metabolic syndrome criteria in this group with high rates of body fat partitioning disturbances.

Adiponectin↗

PubMed2006

Cancer incidence before and after kidney transplantation.

CONTEXT: Immune suppression after organ transplantation is associated with a markedly increased risk of nonmelanoma skin cancer and a few virus-associated cancers. Although it is generally accepted that other cancers do not occur at increased rates, there have been few long-term population-based cohort studies performed. OBJECTIVE: To compare the incidence of cancer in patients receiving immune suppression after kidney transplantation with incidence in the same population in 2 periods before receipt of immune suppression: during dialysis and during end-stage kidney disease before renal replacement therapy (RRT). DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study of 28,855 patients with end-stage kidney disease who received RRT, with 273,407 person-years of follow-up. Incident cancers (1982-2003) were ascertained by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. MAIN OUTCOME MEASURE: Standardized incidence ratios (SIRs) of cancer, using age-specific, sex-specific, calendar year-specific, and state/territory-specific population cancer incidence rates. RESULTS: The overall incidence of cancer, excluding nonmelanoma skin cancer and those cancers known to frequently cause end-stage kidney disease, was markedly increased after transplantation (n = 1236; SIR, 3.27; 95% confidence interval [CI], 3.09-3.46). In contrast, cancer incidence was only slightly increased during dialysis (n = 870; SIR, 1.35; 95% CI, 1.27-1.45) and before RRT (n = 689; SIR, 1.16; 95% CI, 1.08-1.25). After transplantation, cancer occurred at significantly increased incidence at 25 sites, and risk exceeded 3-fold at 18 of these sites. Most of these cancers were of known or suspected viral etiology. CONCLUSIONS: Kidney transplantation is associated with a marked increase in cancer risk at a wide variety of sites. Because SIRs for most types of cancer were not increased before transplantation, immune suppression may be responsible for the increased risk. These data suggest a broader than previously appreciated role of the interaction between the immune system and common viral infections in the etiology of cancer.

Adolescent↗

PubMed2006

Changes in body composition and mitochondrial nucleic acid content in patients switched from failed nucleoside analogue therapy to ritonavir-boosted indinavir and efavirenz.

BACKGROUND: Body composition changes complicate antiretroviral therapy. Improvements in lipoatrophy after a switch in nucleoside reverse-transcriptase inhibitors (NRTIs) have been demonstrated. We investigated 60 patients switching from failed NRTIs to ritonavir-boosted indinavir and efavirenz. METHODS: Body composition (assessed by dual-energy x-ray absorptiometry scan and by single-slice computed tomography of the abdomen through the level of the fourth lumbar vertebra [L4] and the mid-right thigh) and fasted metabolics were measured at the baseline time-point at switch and at weeks 48 and 96 thereafter. Mitochondrial DNA and RNA were extracted from right-thigh subcutaneous fat and peripheral-blood mononuclear cells (PBMCs) at weeks 0 and 48. The primary end point was the change in mean limb fat over 48 weeks. RESULTS: At week 96, we observed increases in mean (standard deviation [SD]) limb fat (+620 [974] g; P=.003), L4 subcutaneous adipose tissue (+20 [35] cm(2); P<.001), mid-thigh subcutaneous adipose tissue (+5 [10] cm(2); P<.001), and L4 visceral adipose tissue (+11 [34] cm(2); P=.01), but we also observed reduced lean limb mass (-831 [1,100] g; P=.3). Mean (SD) mtDNA content in subcutaneous fat and in PBMCs increased (+109 [274] and +45 [100] copies/cell, respectively). Improved virological control or immune recovery did not explain the results. Triglyceride, total cholesterol, estimated low-density lipoprotein cholesterol, ratio of total cholesterol to high-density lipoprotein cholesterol, and blood glucose levels deteriorated (i.e., had increased by 206%, 67%, 58%, 19%, and 6%, respectively, at week 96). CONCLUSIONS: This regimen was associated with statistically significant but clinically modest increases in peripheral fat, visceral fat, and mitochondrial nucleic acid content. A predominantly adverse metabolic profile developed.

Absorptiometry, Photon↗

PubMed2006

Is sensory urgency part of the same spectrum of bladder dysfunction as detrusor overactivity?

It has been suggested that the urogynecological diagnosis of sensory urgency is an early form of detrusor overactivity and may be just earlier in the spectrum of disease. The former term is generally defined as increased perceived bladder sensation during filling, a low first desire to void and low bladder capacity in the absence of recorded urinary tract infection (UTI) or detrusor overactivity. The aims of this study are to determine the prevalence and associations of sensory urgency in comparison with detrusor overactivity, and whether sensory urgency is shown to be in the same spectrum of bladder dysfunction as detrusor overactivity. Five hundred and ninety-two women attending for an initial urogynecological/urodynamic assessment took part in this prospective study. In addition to a full clinical assessment, all women underwent free uroflowmetry, residual urine volume measurement (by vaginal ultrasound) and multichannel filling and voiding cystometry. Data were separated into those having (1) sensory urgency or (2) detrusor overactivity. Apart from prevalence figures, comparative associations were sought for (3) age; (4) parity; (5) presenting symptoms; (6) presence of at least one (medically) documented UTI in the previous 12 months; (7) two or more (recurrent) documented UTIs in the previous 12 months; (8) prior hysterectomy; (9) prior continence surgery; (10) menopause; (11) menopause and HRT use; (12) sign of clinical stress leakage; (13) retroverted uterus; (14) anterior vaginal wall prolapse; (15) uterine prolapse; (16) posterior vaginal wall prolapse; (17) apical vaginal prolapse; (18, 19) maximum, average urine flow rate (MUFR, AUFR) centiles, Liverpool Nomograms; (20) median residual urine volume (RUV) in milliliters; (21, 22) voiding difficulty: VD1,VD2 (MUFR, AUFR under 10th centile Liverpool Nomogram and/or RUV >30 ml); (23) diagnosis of urodynamic stress incontinence and (24) diagnosis of uterine and/or vaginal prolapse (grade >0). The prevalence of sensory urgency was 13%. The only differences in the clinical and urodynamic profiles of it and detrusor overactivity were (1) significantly increased prevalence of the symptom of urge incontinence and (2) (by definition) abnormal detrusor contractions during filling cystometry in women with detrusor overactivity. Overall, sensory urgency and detrusor overactivity appear to be part of the same spectrum of bladder dysfunction.

Adolescent↗

PubMed2006

Has the true prevalence of voiding difficulty in urogynecology patients been underestimated?

Voiding difficulty has been relatively overlooked as a diagnosis. Previous estimates of its prevalence have generally been no more than 14% with one exception at 24%. The aim of this study is to determine the true prevalence and associations of voiding difficulty using a validated definition [urine flow rate under 10th centile of the Liverpool Nomograms and/or residual urine volume (by transvaginal ultrasound) more than 30 ml]. This study involved 592 women referred for an initial urogynecological assessment including urodynamics. Data were separated according to the presence or absence of voiding difficulty. The prevalence of voiding difficulty was 39%, far higher than previous estimates. It is the third most common urodynamic diagnosis behind urodynamic stress incontinence (USI-72%) and uterine/vaginal prolapse (61%) and ahead of the overactive bladder (13%). Voiding difficulty significantly increased in prevalence with age and increasing grades of all types of uterine/vaginal prolapse. Prolapse appeared to be the main factor in the age deterioration. Other significant positive relationships with voiding difficulty were prior hysterectomy and prior continence surgery, whilst USI and the symptom and sign of stress incontinence had significant inverse relationships.

Adolescent↗

PubMed2006

The role of hydroxyurea in enhancing the virologic control achieved through structured treatment interruption in primary HIV infection: final results from a randomized clinical trial (Pulse).

BACKGROUND: Structured treatment interruptions (STIs) have been postulated to improve virologic control in primary HIV infection (PHI) by stimulating HIV-specific T-lymphocyte immunity. The addition of hydroxyurea (HU) may reduce viral production from activated CD4 cells. METHODS: Patients with PHI received a standardized antiretroviral (ARV) regimen consisting of indinavir 800 mg twice daily (BID), ritonavir 100 mg BID, didanosine 400 mg (QD), and either stavudine 40 mg BID or lamivudine 150 mg BID, for up to 12 months and were randomized to HU 500 mg BID or not. If viral suppression (<50 copies/mL) was achieved, up to 3 STIs were undertaken. Two ARV cycles were allowed after each interruption if virologic rebound to more than 5000 RNA copies/mL occurred. Treatment success was defined as maintaining viral loads below 5000 copies/mL for 6 months after ARV interruption. RESULTS: Sixty-eight male homosexual patients were randomized: 35 to ARV + HU and 33 to ARV-alone. Median baseline HIV RNA was 5.73 log10 copies/mL, and median CD4 T-lymphocyte count was 517 cells/microL. Treatment success was not significantly different between those receiving and not receiving HU, with 9 (26%) and 9 (27%), respectively, maintaining viral load at less than 5000 copies/mL in each group (P = 0.88). Virologic control was achieved by 11 (19%) of 59 after 1 STI, 1 (2%) of 41 after 2 STIs, and 6 (17%) of 36 after the third STI. Serious adverse events were recorded for 9 (26%) of 35 of patients using HU and 3 (9%) of 33 in the ARV-only group (P = 0.28). CD4 cell increases were significantly blunted for the HU group compared to the ARV-alone group after the initial treatment phase (+101 cells vs. +196 cells, respectively, P = 0.006). CONCLUSIONS: Hydroxyurea was not found to be beneficial when used in association with STIs in patients during PHI.

Adult↗

PubMed2006

Cancer incidence among Australian nuclear industry workers.

To assess whether workers at Lucas Heights Science and Technology Centre (LHSTC) had different levels of cancer incidence from the New South Wales (NSW) population in Australia. A retrospective cohort study was undertaken at LHSTC. Data on 7,076 workers employed between 1957-98 were abstracted from personnel, dosimetry, and medical files. An inception cohort was defined which included 4,523 workers in employment between 1972-96 to examine cancer incidence. Cancer registrations in the inception cohort were identified to 1996 through electronic linkage of records with the NSW and the Australian national registers of cancer incidence. All-cancer incidence in workers at LHSTC was 15% below the NSW rates [SIR=0.85; 95% CI=(0.75, 0.95)]. Of 37 specific cancers and groups of cancers examined, statistically significant excesses relative to NSW rates were observed only for pleural cancer incidence [SIR=17.71; 95%=(7.96, 39.43)], and for incidence of cancer of the small intestine [SIR=4.34; 95% CI=(1.40, 13.46)]. This study gives little evidence of an increased risk of cancers associated with radiation exposure in a cohort of nuclear workers in Australia. The observed increase in the risk of cancer of the pleura was probably due to unmeasured exposures, given the lack of an established association with radiation exposure, and the strong link to asbestos exposure. Findings for cancers of the small intestine were based on small numbers and were likely to be due to chance.

Aged↗

PubMed2006

Evaluation of the HIV lipodystrophy case definition in a placebo-controlled, 144-week study in antiretroviral-naive adults.

OBJECTIVE: To compare three versions of the objective HIV-associated lipodystrophy (HIVLD) case definition (LDCD) and derived severity scale to spontaneous clinical LD assessment in adults initiating antiretroviral therapy. DESIGN AND MAIN OUTCOME MEASURES: The LDCD versions were the 'primary' LDCD [which includes dual-energy X-ray absorptiometry (DXA) and computerized tomography (CT)], a simpler 'central' LDCD that omits CT data, and a simpler but probably less accurate 'non-imaging' LDCD. Physician LD assessments were passively reported. Two of the 10 parameters in the primary LDCD were not collected and were imputed. Setting, participants and interventions: Retrospective analysis of a randomized, placebo-controlled, 144-week study of tenofovir DF or stavudine (d4T) in 600 antiretroviral-naive adults. RESULTS: Central LDCD and clinical assessment diagnosed LD in 27% and 19% of d4T recipients at week 144, respectively (P < 0.001), and 3% and 3% of tenofovir DF recipients, respectively (P = 0.248). The central LDCD performed at least as well as the primary LDCD; both were more sensitive than the non-imaging model. There was poor concordance between clinical and LDCD-based diagnosis (kappa 0.02-0.20); most clinical cases did not fulfill any LDCD. Using the central LDCD, most LD was grade 1; 6% of d4T recipients and no tenofovir DF recipient had grade 3-4 LD at week 144 (P = 0.007). Independent risk factors for LD using the central LDCD were d4T, increasing age, female sex and higher baseline triglycerides, whereas clinical assessment consistently identified only d4T. The LDCD score was more sensitive than DXA for assessing LD severity. CONCLUSIONS: In this prospective study of a first antiretroviral regimen, the LDCD was more sensitive for LD diagnosis and identified more lipodystrophy risk factors than spontaneous clinical assessment or DXA, and also objectively quantified LD severity. The central LDCD should make objective LD assessment cheaper and simpler. Spontaneous clinical LD assessment of is of limited value, even in placebo-controlled trials.

Absorptiometry, Photon↗

PubMed2005

Mucosally-administered human-simian immunodeficiency virus DNA and fowlpoxvirus-based recombinant vaccines reduce acute phase viral replication in macaques following vaginal challenge with CCR5-tropic SHIVSF162P3.

Further advances are required in understanding protection from AIDS by T cell immunity across mucosal sites of virus transmission. We analysed a set of multigenic HIV and SHIV DNA and Fowlpoxvirus (FPV) prime and boost vaccines for immunogenicity and protective efficacy in outbred pigtail macaques when delivered via mucosal surfaces (intranasally or intrarectally). Intranasally delivered DNA, even when adjuvanted and given as a fine droplet spray, was neither immunogenic nor protective in macaques. Some protection from acute infection with a pathogenic vaginal SHIVSF162P3 challenge was, however, observed with a regimen involving intramuscular DNA vaccine priming followed by either intranasally or intrarectally delivered rFPV boosting. Interestingly, animals boosted with rFPV vaccine via either of these mucosal routes had poor circulating T cell responses prior to challenge with SHIV compared to those boosted via the intramuscular route. Nevertheless, the mucosally-vaccinated animals generated equivalent anamnestic mucosal and systemic SHIV-specific CD4 and CD8 T cell responses following SHIV administration, with significant reduction in acute plasma viremia against this vaginal challenge. Our data suggest strategies for effective priming of partial immunity to mucosal HIV-1 exposure utilizing systemic prime and mucosal boost vaccination strategies.

Administration, Intranasal↗

PubMed2005

Buffalo hump seen in HIV-associated lipodystrophy is associated with hyperinsulinemia but not dyslipidemia.

Accumulation of dorsocervical fat, or a "buffalo hump" (BH), is commonly reported in adults with HIV-associated lipodystrophy (HIVLD). The pathogenesis underlying this aspect of a syndrome characterized by loss of subcutaneous fat from other body sites is poorly understood. We aimed to identify risk factors for a BH in HIV-infected adults in cross-sectional analyses of 2 HIV-infected ambulatory populations. The first group (Australian Lipodystrophy Prevalence Survey [APS]) consisted of 1348 Australian HIV-infected adults (95% male) irrespective of changes in body composition. The second group (Lipodystrophy Case Definition [LDCD] study) comprised 417 subjects (83% male) with at least 1 reported moderate or severe feature of HIVLD. A BH was reported in 24 (2%) APS subjects and 79 (19%) LDCD study subjects. A BH was not an isolated finding. Patients with a BH had a high prevalence of other features of HIVLD, similar to lipodystrophic patients without a BH, such as facial lipoatrophy reported in 100% and 61% BH-positive subjects from the APS and LDCD study, respectively. In both groups, those with a BH had higher fasting insulin (P<or=0.007), a higher body mass index (P<or=0.003), a higher waist/hip ratio (P<or=0.001), higher limb fat (P<or=0.003), and higher systolic blood pressure (P<0.05). On multivariate analysis, higher serum insulin, systolic blood pressure, age, and duration of exposure to ritonavir were independently associated with a BH in the APS group. In the LDCD group, higher insulin, diastolic blood pressure, and duration of exposure to zidovudine were independently associated with a BH. There was no association between a BH and hyperlipidemia. These data show that a BH is associated with other physical features of the lipodystrophy phenotype and suggest that hyperinsulinemia, a feature common to HIVLD, obesity, and hypercortisolism, is an important component of this phenotype, thus warranting closer monitoring of BH-positive patients for glucose intolerance and diabetes.

Adult↗

PubMed2005

Mortality among prisoners: how accurate is the Australian National Death Index?

OBJECTIVE: The effectiveness of the National Death Index (NDI) in identifying deaths among different populations has been studied before. Prisoners represent a segment of the population that might be expected to be difficult to link. The objective of this research was to evaluate the accuracy of the Australian NDI to ascertain the mortality status of prisoners in New South Wales, Australia. METHODS: Data on 311 inmates who had died in custody between January 1988 and March 2003, and on 7,558 inmates known to be alive at the end of May 2003, were matched to the NDI database. Matching was undertaken using a probabilistic linkage method followed by a clerical review. The underlying causes of death reported by the NDI were compared against those reported by the NSW Coroner and held at the Legal Branch of the Department of Corrective Services. RESULTS: Linkage correctly identified 275 of the 311 known deaths (sensitivity: 88.4%). Of the 7,558 prisoners known to be alive in custody at the end of May 2003, linkage to the NDI incorrectly identified 23 as dead (specificity: 99.7%). Cause of death was accurately reported by the NDI for 95.5% of deaths identified by the linkage. CONCLUSION: The results of this study show that the NDI is an accurate and feasible means for evaluating mortality among prisoners. The nature of the prisoner population makes the linkage a difficult task for the NDI. The success of the data linkage depends on the extent and accuracy of information contained in the index file and type and quality of information available.

Cause of Death↗

PubMed2005

Mortality rates among nuclear industry workers at Lucas Heights Science and Technology Centre.

OBJECTIVES: To assess whether workers at Lucas Heights Science and Technology Centre (LHSTC) have different levels of mortality from the New South Wales (NSW) and Australian populations. METHODS: A retrospective cohort study was undertaken at LHSTC. Data on 7,076 workers employed between 1957-98 were abstracted from personnel, dosimetry, and medical files. Deaths registrations in the cohort were identified to 1998 through electronic linkage of records with NSW and national registers of cancer incidence and mortality. Two inception cohorts were defined as including 4,717 and 3,543 workers in employment between 1972-98 and 1980-98, to examine cancer mortality and all-cause mortality respectively. RESULTS: All-cause mortality was 31% lower than the national rates; all-cancer mortality was 19% below the NSW rate. Of 37 specific cancers and groups of cancers examined, statistically significant excesses relative to NSW rates were observed only for pleural cancer mortality (SMR = 21.11; 95% Cl 8.79-50.72). CONCLUSIONS: The observed increase in the risk of cancer of the pleura was probably due to unmeasured exposures, given the lack of an established association with radiation exposure and the strong link to asbestos exposure.

Cohort Studies↗

PubMed2004

Evaluation in macaques of HIV-1 DNA vaccines containing primate CpG motifs and fowlpoxvirus vaccines co-expressing IFNgamma or IL-12.

Induction of HIV-specific T-cell responses by vaccines may facilitate efficient control of HIV. Plasmid DNA vaccines and recombinant fowlpoxvirus (rFPV) vaccines are promising HIV-1 vaccine candidates, although either vaccine alone may be insufficient to protect against HIV-1. A consecutive immunisation strategy involving priming with DNA and boosting with rFPV vaccines encoding multiple common HIV-1 antigens was further evaluated in 30 macaques. The DNA vaccine vector included CpG immunostimulatory molecules, and rFPV vaccines were compared with rFPV vaccines co-expressing the pro-T cell cytokines IFNgamma or IL-12. Vaccines expressed multiple HIV-1 genes, mutated to remove active sites of the HIV proteins. The vaccines were well tolerated, and a significant enhancement of DNA-vaccine primed HIV-1 specific T lymphocyte responses was observed following rFPV boosting. Co-expression of IFNgamma or IL-12 by the rFPV vaccines did not further enhance immune responses. Non-sterilising protection from a non-pathogenic HIV-1 challenge was observed. This study provides evidence of a safe, optimised, strategy for the generation of T-cell mediated immunity to HIV-1.

AIDS Vaccines↗

PubMed2004

The CpG island methylator phenotype is not associated with a personal or family history of cancer.

Colorectal cancers with widespread CpG island methylation display a number of distinct clinicopathological features, and it has been suggested that the condition has an inheritable genetic component. To address this possibility, histories of cancer were obtained from 562 individuals undergoing curative surgery for unselected colorectal cancer at one institution. Microsatellite status and methylation at p16, MINT1, 2, 12, and 31 loci were determined on fresh tumor tissue using standard methods. Fifty-five of 562 probands in this study provided a personal history of at least one other colorectal cancer, 10 reported at least one extracolonic cancer of hereditary nonpolyposis colorectal cancer type, and 84 individuals had another type of cancer. Age was strongly associated with the risk of multiple cancers, but there was no evidence that microsatellite instability or the CpG island methylator phenotype were independent risk factors for their development, either in the colorectum or elsewhere. Of the 547 individuals with knowledge of their family history, 80 (14.6%) reported a family history of colorectal cancer in a first-degree relative, and 60% of individuals reported a history of any cancer in a first-degree relative. Neither tumor CpG island methylator phenotype status nor microsatellite instability was predictive of a positive history of cancer in first- or second-degree relatives. The probability of a positive family or personal history of cancer did not increase with increasing number of methylated loci. Epigenetic silencing of multiple genes seen in some tumors is at best rarely the result of an inherited defect in the methylation apparatus. There is no justification for altering the personal or family cancer screening recommendations on the basis of tumor CpG island methylator phenotype status.

Adaptor Proteins, Signal Transducing↗

PubMed2004

No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lipodystrophy commonly complicates antiretroviral therapy of HIV-1 infection. Thiazolidinediones such as rosiglitazone promote subcutaneous fat growth in type 2 diabetics and adults with congenital lipodystrophy, and can prevent HIV-1 protease inhibitor toxicity to adipocytes in vitro. We postulated that rosiglitazone would improve HIV lipoatrophy. METHODS: 108 HIV-1-infected lipoatrophic adults on antiretroviral therapy were randomised to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks. The study had 80% power to detect a 0.5 kg difference in changes in limb fat (using dual-energy X-ray absorptiometry) between groups at week 48 by intention-to-treat analysis, and a 0.7 kg difference within each protease inhibitor stratum. FINDINGS: Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (mean difference -0.04 kg [95%CI -0.29 to 0.21]; p=0.74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4.2 mmol/L [102%]; p<0.0001) and in three markers of insulin sensitivity (p=0.01 to 0.02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0.9 mmol/L at week 48; p=0.04) and hypercholesterolaemia (1.5 mmol/L; p=0.001). INTERPRETATION: Rosiglitazone for 48 weeks did not improve lipoatrophy in HIV-1-infected adults receiving antiretroviral therapy. Use of less toxic antiretroviral treatment is necessary to prevent lipoatrophy.

Anemia↗

PubMed2004

Changes in hematologic parameters and efficacy of thymidine analogue-based, highly active antiretroviral therapy: a meta-analysis of six prospective, randomized, comparative studies.

BACKGROUND: Hematologic changes that occur with HIV infection and antiretroviral therapy may impact the quality of life of patients and have been associated with morbidity and mortality. The management of anemia and neutropenia has improved survival in persons with HIV. OBJECTIVES: This meta-analysis was performed to assess the changes in hemoglobin (Hb) levels and neutrophil counts that occur during thymidine analogue-based triple therapy and to establish whether different regimens of triple therapy are similar in efficacy based on CD4(+) T-cell count and viral load changes. METHODS: This was a meta-analysis of the impact of zidovudine (AZT) compared with stavudine (d4T) in triple therapy regimens in HIV patients with regard to hematologic parameters and efficacy markers. The peer-reviewed literature was searched with use of MEDLINE, PubMed, EMBASE, and the Cochrane database of systematic reviews (key terms: HIV, antiretroviral therapy, CD4, viral load, three, triple, and highly active antiretroviral therapy [HAART]). Searches were initially not limited by publication type, study design, date, or language but subsequently were sorted to include only studies performed in treatment-naive adult patients; randomized; and comparative of a regimen that included d4T with a regimen that included AZT; to involve regimens that included a minimum of 3 drugs each; and to include hematologic outcomes data. Outcomes were CD4(+), viral load, and hematologic parameters. RESULTS: This meta-analysis included 6 studies. Treatment efficacy as measured by changes in CD4(+) T-cell counts and viral load did not differ significantly between regimens. Hb levels decreased with AZT treatment by a mean (SE) 0.4 (0.05) g/dL and 0.2 (0.06) g/dL at weeks 24 and 48, respectively, but increased with d4T treatment by 0.45 (0.03) g/dL and 0.58 (0.04) g/dL, respectively. All grades of anemia and neutropenia events were consistently more common with AZT-based regimens relative to d4T-based therapy. CONCLUSIONS: AZT-based HAART has a greater negative impact on hematologic parameters relative to d4T-based regimens. AZT recipients are more likely than d4T recipients to experience anemia and neutropenia events of any grade, and AZT is associated with a net decrease in Hb level relative to a net increase with d4T. These factors may influence the choice of drug used in the treatment of certain patient populations.

Anemia↗

PubMed2004

Estimates of chronic hepatitis B virus infection in Australia, 2000.

OBJECTIVES: To estimate the prevalence of chronic hepatitis B virus (HBV) infection in Australia and attributable proportions associated with specific demographic groups at higher risk of infection. METHODS: Two methods were used to estimate prevalence of HBV surface antigen (HBsAg): (1) Population-based: results of a national serosurvey using sera collected opportunistically from laboratories across Australia were used for 1-59 year olds, with the HBsAg prevalence for 50-59 years extrapolated to the population aged 60 years and over; (2) Risk group-based: estimates for selected high-risk groups (injecting drug users, homosexual men, Indigenous Australians and people born in high-prevalence countries), using source data from antenatal HBV screening in central Sydney, HBV prevalence studies, and estimates for low-risk groups (first-time blood donors) were combined proportionally to their representation in the population. RESULTS: Prevalence of HBsAg in the national serosurvey increased, with age, from 0.0% for 1-4 and 5-9 year olds to 1.3-1.8% for the 40-49 year age group. Australian population HBsAg prevalence based on minimum and adjusted estimates from this serosurvey were 91,500 (0.49%) and 163,000 (0.87%) infections, respectively. The risk group method estimated an Australian HBsAg prevalence of 88,000 infections (0.47%). Approximately 50% of people with chronic HBV infection were estimated to be immigrants from either South-East Asia (33.3%) or North-East Asia (16.2%). CONCLUSION: The range of estimates for chronic HBV infection in Australia is broad, reflecting the uncertainty in source data. A national blood survey encompassing a large and representative population sample may help to provide more accurate estimates. A large proportion of people with chronic HBV infection are Asian born.

Adolescent↗

PubMed2003

An objective lipodystrophy severity grading scale derived from the lipodystrophy case definition score.

HIV lipodystrophy can be objectively diagnosed using a score derived from the 10 parameters in the HIV lipodystrophy case definition (LDCD). Lipodystrophy severity remains subjectively determined by physical examination and patient assessment. Regional dual-energy x-ray absorptiometry (DEXA) and single-slice abdominal computed tomography (CT) scanning are objective but are gender-dependent body composition measures. The LDCD score may provide a means of generating an objective and lipodystrophy grading/severity scale applicable to both men and women. Total and regional clinical lipodystrophy severity scores (generated using the HIV Outpatient Study [HOPS] scale: nil (0), mild (1), moderate (2), and severe (3) lipoatrophy or fat accumulation in 8 body regions) were correlated with objective measures of LD (LDCD score, DEXA, abdominal CT) and metabolic (lipid, glycemic, acid-base) parameters known to correlate significantly with lipodystrophy severity. Analysis was based on 417 lipodystrophic adults and 371 controls recruited to the HIV LDCD study. Correlation coefficients were used to compare physician and patient assessments (rPhysician, rPatient) with objective LD measures and metabolic parameters. The strongest objective correlate of total clinical lipodystrophy severity was the LDCD score (rPhysician = 0.641 [95% CI, 0.584-0.698]; rPatient = 0.620 [95% CI, 0.561-0.678]), whereas the strongest imaging correlate (trunk:limb fat ratio on DEXA) was significantly lower (rPhysician = 0.483 [95% CI, 0.420-0.546]; rPatient = 0.475 [95% CI, 0.412-0.538]; P < 0.001). The LDCD score also yielded significantly greater correlations with 7 of the 8 metabolic parameters than did clinical lipodystrophy severity scores. Based on quartiles of physician-rated severity, the LDCD scores were categorized to allow for rating of lipodystrophy as absent (LDCD score < 0), grade 1 (0-9.9), grade 2 (10-14.9), grade 3 (15-22.9), and grade 4 (>or=23). In conclusion, the LDCD score is the best objective measure of lipodystrophy severity and, in contrast to DEXA and CT, it is also gender independent. Subjective assessment of lipodystrophy severity could possibly be abandoned in cross-sectional studies. The LDCD score and its derived lipodystrophy grading scale merit prospective evaluation.

Adult↗