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Biomedical subjects

Andrew Carr

Publications and source records attributed to Andrew Carr.

70 records · Page 4Linked to original sources
PubMed2002

A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor-associated hypertriglyceridaemia.

BACKGROUND: Hypertriglyceridaemia is common in patients with HIV, especially those taking protease inhibitors or with lipodystrophy, frequently observed at levels associated with accelerated cardiac disease. This study aimed to explore the efficacy and safety of gemfibrozil for hypertriglyceridemia in patients with HIV infection. METHODS: A 16-week, randomized, double-blind, comparative study of low saturated fat diet versus low saturated fat diet with gemfibrozil 600 mg twice daily in patients with triglycerides > or = 3mmol/l receiving protease inhibitor therapy. Following a 4-week period of dietary intervention alone, patients were randomized to gemfibrozil or matching placebo. The primary outcome was the difference in mean change in fasting triglycerides at week 16 between the two groups. RESULTS: 37 men were randomized (17 gemfibrozil, 20 placebo) with median fasting triglycerides 5.6 mmol/l. Mean changes in triglycerides from week 4 to week 16 were -1.22 mmol/l and +0.35 mmol/l for the gemfibrozil and placebo groups respectively (between-group mean difference of 1.57 mmol/l; 95% confidence interval, -6.7 to 3.5; = 0.08). Only one patient treated had triglycerides return to a desirable range (< or = 2.00 mmol/l). No significant changes in the other metabolic parameters were observed. Gemfibrozil was well tolerated, did not appear to induce additional protease inhibitor toxicity, and did not induce changes in CD4 lymphocyte counts or HIV RNA load. CONCLUSIONS: Gemfibrozil is safe and demonstrated at most, modest efficacy for hypertriglyceridemia in HIV-infected patients receiving protease inhibitors. Given the level of response, however, it is unclear whether these reductions will confer clinical benefit, at least in the presence of continued protease inhibitor use.

Diet↗
PubMed2002

Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.

OBJECTIVE: Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal body fat distribution have been recognized recently as frequent complications associated with HIV-1 infection and potent antiretroviral therapy, but limited data are available regarding the appropriate management of these disorders. These recommendations were developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy. PARTICIPANTS: A 12-member panel representing international expertise in HIV-1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society-USA, a not-for-profit physician education organization. Panel members met in closed meetings beginning in May 2000. All work was funded by the International AIDS Society-USA; the panel members are not compensated for their participation. EVIDENCE: The panel reviewed published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997 to 2002. The panel also considered studies of the pathophysiology and treatment of similar metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. PROCESS: For each metabolic complication, 1 or more member(s) reviewed and presented all available evidence to the panel, and then wrote a summary of the evidence and preliminary recommendations. Final recommendations were determined by full group consensus. The summaries were combined into a single working document and all panel members edited and approved all subsequent drafts. CONCLUSIONS: Carefully controlled studies to determine the incidence, etiology, risk factors, and most appropriate treatments for metabolic complications in HIV-1 infection are urgently needed. In the absence of these data, and to prevent acute illness and mitigate long-term risks, the panel recommends routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these complications are also recommended. Successful long-term antiretroviral therapy will require diligent monitoring and preemptive treatment of metabolic complications to optimize the risk-benefit ratio of antiretroviral therapies.

Adipose Tissue↗
PubMed2002

Clinical features of acute retroviral syndrome differ by route of infection but not by gender and age.

The rate of HIV disease progression is associated with the severity of the acute retroviral syndrome (ARS). We explored the clinical features of ARS by gender, age and route of infection among 378 individuals with documented ARS enrolled in 5 prospective cohort studies with similar enrollment criteria. No major differences were detected by gender or by age. Several symptoms were reported less frequently in the injecting drug users as compared with infection acquired through sexual contacts (either heterosexual or homosexual). This was observed in particular for fever (50% vs. 77%, p=.001), skin rash (21% vs. 51%, p=.001), pharyngitis (18% vs. 43%, p=.004), and myalgia (29% vs. 52%, p=.01). Genital ulcerations were present only in cases of sexual exposure to HIV. Injecting drug users had or reported symptoms associated with the ARS less frequently than persons acquiring HIV via sexual transmission.

Acute Disease↗
PubMed2002

Comparison of clinical and patient-based measures to assess medium-term outcomes following shoulder surgery for disorders of the rotator cuff.

OBJECTIVE: To compare different assessments following shoulder surgery for impingement syndrome with or without rotator cuff tear or repair. METHODS: A prospective study of 93 patients was conducted. Standard assessments were performed before, at 6 months, and at 4 years following shoulder surgery using the patient-based Oxford Shoulder Score (OSS), the Medical Outcomes Study Short Form-36 (SF-36) questionnaire, and a surgeon-assessed Constant Shoulder Score. Patients were categorized according to the surgery received in relation to the presence of cuff tears: full repair, partial repair, cuff tear/no repair, no tear/no repair. RESULTS: Most patients (57%) received subacromial decompression for impingement with no cuff tear. This group had the fewest pre- and postoperative symptoms. The category of patients who received only partial repair of a cuff tear had worse scores on all outcome assessments compared with other groups. Patient-based measures were more stable over time than the Constant. CONCLUSION: The shoulder-specific measures had greater sensitivity than the SF-36 in registering significant differences in outcomes between comparison groups at 6 months and 4 years.

Adult↗
PubMed2002

Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial.

CONTEXT: Peripheral lipoatrophy may complicate antiretroviral therapy of human immunodeficiency virus (HIV) infection, often related to duration and type of nucleoside analog therapy, and may have a mitochondrial pathogenesis. No proven therapy exists for lipoatrophy, but abacavir is a nucleoside analog that may be less toxic to mitochondria. OBJECTIVE: To determine if substitution of stavudine or zidovudine with abacavir improves HIV lipoatrophy without affecting control of HIV replication. DESIGN: Randomized, open-label 24-week study. SETTING: Seventeen hospital HIV outpatient clinics and primary care centers in Australia and England, with randomization from June 2000 through January 2001. PARTICIPANTS: A total of 111 adults (109 men) with moderate or severe lipoatrophy who were receiving stavudine (n = 85) or zidovudine (n = 26) and had stable plasma HIV RNA levels below 400 copies/mL and no prior abacavir therapy. INTERVENTION: Patients were randomly assigned to switch from stavudine or zidovudine to abacavir, 300 mg twice per day, while continuing all other antiretroviral therapy (n = 54) or to continue all antiretroviral therapy (n = 57). MAIN OUTCOME MEASURES: The primary end point was limb fat mass, measured by dual-energy x-ray absorptiometry; key secondary end points were plasma HIV RNA levels, adverse events, physician-assessed (via subjective measures) lipodystrophy severity, total and central fat mass, and fasting metabolic (lipid, glycemic, and lactate) levels. RESULTS: There was a significant increase in limb fat in the abacavir group relative to the stavudine/zidovudine group (0.39 vs 0.08 kg; mean difference, 0.31; 95% confidence interval [CI], 0.06-0.57 kg), as well as significant relative increases in subcutaneous thigh (P =.01), arm (P<.001), and abdominal (P =.001) fat areas on computed tomography. Switching had no significant effect on secondary end points, including plasma HIV RNA (for unadjusted comparison between groups at week 24, odds ratio, 1.38; 95% CI, 0.48-3.96). Change in limb fat mass at week 24 did not correlate with change in subjectively determined perceived lipoatrophy severity (r = -0.06; P =.53 by Spearman correlation). Hypersensitivity to abacavir was seen in 5 patients (10%). CONCLUSIONS: In this sample of lipoatrophic HIV-infected adults, switching from stavudine or zidovudine to abacavir for 24 weeks led to significant, albeit modest, objectively measured increases in limb fat. Clinical lipoatrophy, as assessed subjectively, did not resolve, however, and at the rate of increase observed may take years to resolve with use of this strategy. Longer-term follow-up is needed.

Absorptiometry, Photon↗
PubMed2002

Finer linkage mapping of primary hip osteoarthritis susceptibility on chromosome 11q in a cohort of affected female sibling pairs.

OBJECTIVE: To finer linkage-map a primary osteoarthritis (OA) susceptibility locus as a prerequisite to linkage disequilibrium/association analysis. METHODS: A 50-cM interval of chromosome 11q that we had previously identified as harboring susceptibility to hip OA in a female sibling-pair cohort was subjected to finer linkage mapping. Thirty-five microsatellite markers with a mean marker interval of 1.4 cM were genotyped in 146 families containing female sibling pairs who were concordant for hip OA, as ascertained by total hip replacement. RESULTS: Two-point and multipoint linkage analysis revealed 2 distinct regions of linkage within the 50-cM interval. The first locus had a linkage interval of 11.9 cM and was centered at 81.5 cM from the 11p telomere, with a maximum multipoint logarithm of odds (LOD) score of 2.4. The second region had a linkage interval of 6.5 cM and was centered at 93.1 cM from the 11p telomere, with a maximum multipoint LOD score of 1.8. CONCLUSION: Dense linkage mapping has highlighted the presence of 2 loci on chromosome 11q, each conferring susceptibility to hip OA. Both loci are sufficiently narrow for association analysis to be undertaken.

Chromosome Mapping↗
PubMed2002

HIV-associated lipodystrophy: description, pathogenesis, and molecular pathways.

HIV-infected individuals taking antiretroviral medications may experience changes in body shape and metabolism, commonly known as HIV-associated lipodystrophy (HIVLD). In vitro and in vivo research have revealed numerous effects of both protease inhibitors and nucleoside reverse transcriptase inhibitors on the function of various organs--most importantly adipose tissue, liver, and muscle. The metabolic abnormalities could result in an increased risk of cardiovascular disease in this vulnerable and relatively young population. Treatment strategies, normally successful in the general population, have generally been less effective in this group of people, in which the detrimental effects of the antiretroviral medications are ongoing.

Adipocytes↗
PubMed2002

Altered myocellular and abdominal fat partitioning predict disturbance in insulin action in HIV protease inhibitor-related lipodystrophy.

HIV protease inhibitor-related lipodystrophy is characterized by peripheral fat loss, hyperlipidemia, and insulin resistance. Increased availability of lipid to muscle may be one of the mechanisms that induce insulin resistance. Regional fat, intramyocellular lipid (by (1)H-magnetic resonance spectroscopy), serum lipids, and insulin-stimulated glucose disposal (by hyperinsulinemic-euglycemic clamp) were quantified in 10 men who had HIV-1 infection with moderate to severe lipodystrophy and a control group of 10 nonlipodystrophic men who had HIV-1 infection and were naïve to protease inhibitors to examine the effects of lipodystrophy on glucose and lipid metabolism. Lipodystrophic subjects showed lower insulin-stimulated glucose disposal than control subjects (P = 0.001) and had increased serum triglycerides (P = 0.03), less limb fat (P = 0.02), increased visceral fat as a proportion of total abdominal fat (P = 0.003), and increased intramyocellular lipid (1.90 +/- 0.15 vs. 1.23 +/- 0.16% of water resonance peak area; P = 0.007). In both groups combined, visceral fat related strongly to intramyocellular lipid (r = 0.83, P < 0.0001) and intramyocellular lipid related negatively to insulin-stimulated glucose disposal (r = -0.71, P = 0.0005). Fasting serum cholesterol and triglycerides related positively to intramyocellular lipid and visceral fat in lipodystrophic subjects only. The data indicate that lipodystrophy is associated with increased lipid content in muscle accompanying impaired insulin action. The results do not establish causation but emphasize the interrelationships among visceral fat, myocyte lipid, and insulin action.

Absorptiometry, Photon↗
PubMedDate not supplied

Progression of lipodystrophy (LD) with continued thymidine analogue usage: long-term follow-up from a randomized clinical trial (the PIILR study).

PURPOSE: During the 24-week PIILR study of protease inhibitor (PI) withdrawal, improved lipids and reduction in intraabdominal visceral fat was seen, however, there was also a loss of subcutaneous limb fat in patients with HIV-lipodystrophy (LD). It was hypothesized that overall improvement in LD may require a longer period of time off PIs. METHOD: Follow-up of patients randomized to stop or continue PI-based therapy for 24 weeks, in a multicenter study, was continued for up to 120 weeks. Biochemistry and lipid parameters were assessed every 3 months. DEXA and CT scans were performed annually. Limb fat, visceral adipose tissue, and the lipodystrophy case definition score (LCDS) were used as indicators of LD severity. RESULTS: Forty-five male patients with baseline and week 120 body composition data were assessed. There were no significant changes in the limb fat or visceral adipose tissue (VAT) components of LD, with the exception of the LCDS (change from baseline +5.79, p < .001). Control of viral replication was maintained and lipid and glycemic parameters were unchanged over the 120-week follow-up. Linear regression analysis showed on-study usage of stavudine was independently and significantly correlated with both decreased limb fat mass and a higher LCDS. CONCLUSION: Body composition or metabolic features of LD did not improve over 2 years of observation in patients remaining on predominantly PI-sparing therapy. LD was adversely influenced by continued stavudine use.

Abdomen↗
PubMedDate not supplied

Randomized, open-label, comparative trial to evaluate the efficacy and safety of three antiretroviral drug combinations including two nucleoside analogues and nevirapine for previously untreated HIV-1 Infection: the OzCombo 2 study.

PURPOSE: To assess and compare the efficacy and safety of three triple combination antiretroviral therapies in HIV-1-infected treatment-naive patients. METHOD: Seventy treatment-naive HIV-infected adults with CD4+ T-cell counts >50/microL were randomized to receive either zidovudine + lamivudine + nevirapine (AZT + 3TC + NVP), stavudine + didanosine + nevirapine (d4T+ddI+NVP), or stavudine + lamivudine + nevirapine (d4T+3TC+NVP) for 52 weeks. Patient assessments were conducted monthly and included measurement of plasma HIV RNA levels and CD4+ T-cell counts and evaluations for drug toxicity. RESULTS: The mean time-weighted reductions in plasma HIV RNA in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 1.29, 2.13, and 1.78 log(10) copies/mL, respectively (p =.389). The proportions of patients with HIV RNA <50 copies/mL in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 73%, 68%, and 80%, respectively (p =.71). The mean time-weighted increases in CD4+ T-cell counts in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 139, 113, and 174 cells/microL, respectively (p =.30). Three patients ceased assigned treatment due to rash (one from each treatment arm), and 5 of the 45 patients on d4T (3 from the d4T+3TC+NVP arm and 2 from the d4T+ddI+NVP arm) ceased assigned treatment due to neuropathy. CONCLUSION: All three-drug combinations were equally effective at suppressing viral load and increasing CD4+ T-cell counts. No significant differences were detected between the treatment groups in virological or immunological response or cessation of study drugs due to adverse events, although it is possible that the study was underpowered to detect differences. NVP was safe and efficacious in this setting, and efficacy was not influenced by nucleoside reverse transcriptase inhibitor backbone.

Adult↗
PubMedDate not supplied

Centralized assessment of dual-energy X-ray absorptiometry (DEXA) in multicenter studies of HIV-associated lipodystrophy.

BACKGROUND: The accurate measurement of total body and subcutaneous fat is essential if therapeutic interventions, aimed at preventing or reversing lipodystrophy syndrome, are to be adequately assessed. The aim of this study was to investigate the variability of dual-energy X-ray absorptiometry (DEXA) scans analysis performed at local sites compared to central analysis in a multicenter clinical trial. METHOD: The PIILR study was a multicenter randomized clinical trial in which 80 HIV-infected patients with physician-documented lipodystrophy had serial measurements of body composition performed with Lunar DEXA scans. Scans were analyzed at local sites and then were reanalyzed centrally. RESULTS: DEXA scans from 73 patients who completed 24 weeks study were compared. Greater variation in the locally analyzed results than in the centrally reanalyzed data was noted, with arm, leg, and combined limb fat being most divergent between the local and centralized assessments (ratio of local to central standard deviation was 1.28, 1.31, and 1.35, respectively). The magnitude of this variance was enough to alter statistically relevant differences between study populations. CONCLUSION: Quality assurance is an important issue in the use of DEXA scans to determine body fat composition in multicenter research studies. A central quality assurance site should be incorporated to reduce variability in results.

Absorptiometry, Photon↗