Elevated effector cell sensitivity to Treg-cell suppression that is not associated with reduced Th17-cell expression distinguishes HIV+ asymptomatic subjects from progressors.

Suppression mediated by Treg cells is a balance between Treg-cell suppressive potency versus sensitivity of effector cells to Treg-cell suppression. We assessed if this balance, along with Treg-cell number relative to the Treg-cell counter-regulatory cytokine IL-17, differs between asymptomatic HIV(+) subjects versus those who progress onto disease. Cross-over studies comparing Treg-cell potency, measured by effector cell proliferation or IFN-γ expression, from HIV-infected versus control subjects to suppress the proliferation of allogeneic control effector cells demonstrated increased sensitivity of CD4(+) CD25(-) effector cells from asymptomatic HIV(+) subjects to suppression, rather than an increase in the suppressive potential of their CD4(+) CD25(+) Treg cells. In contrast, HIV(+) progressors did not differ from controls in Treg-cell potency or effector cell sensitivity to Treg-cell suppression. Both CD4(+) CD25(+) Foxp3(+) Treg and effector IL-17 absolute cell numbers were significantly lower in all HIV(+) subjects tested and not restored by antiviral therapy. Thus, these novel data suggest that elevated Treg-cell-mediated suppression due to increased sensitivity of effectors to Treg cells may be a natural host response in chronic asymptomatic HIV infection, which is lost as disease progresses and that this feature of CD25(-) effector cells is not inextricably linked to reduced production of the Treg-cell counter-regulatory cytokine IL-17.

Lung infections in the HIV-infected adult.

PURPOSE OF REVIEW: This review describes current epidemiology, diagnosis, treatment and prevention of adult HIV-related lung infections using evidence published within the past 2 years. RECENT FINDINGS: Recent evidence has helped better determine the importance of early initiation of antiretroviral therapy in co-infected individuals with advanced immune suppression. Although this has led to a greatly reduced incidence of opportunistic infections in people with HIV, Pneumocystis pneumonia remains common. Pneumonia due to bacterial pathogens, such as Streptococcus pneumoniae, also causes considerable disease burden, but emerging evidence of the clinical efficacy of pneumococcal vaccination, especially conjugated vaccines, offers considerable promise. As HIV-infected populations become older, more emphasis should be given to the potential benefit of influenza prevention, particularly with vaccination, and encouraging smoking cessation. Co-infection with tuberculosis is still a huge problem worldwide, but the recent development and use of simple clinical algorithms based on symptoms and point-of-care testing for recognizing active disease offers great potential. SUMMARY: The lung remains an important site of disease in HIV-infected individuals. Increasing emphasis should be placed upon prevention of infection and modification of risk factors.

Re-boost immunizations with the peptide-based therapeutic HIV vaccine, Vacc-4x, restores geometric mean viral load set-point during treatment interruption.

BACKGROUND: Vacc-4x, a therapeutic HIV vaccine candidate has previously induced a significant reduction in viral load (VL) set-point compared to placebo upon interruption of combination anti-retroviral therapy (ART) (2007/1 study). This study, (2012/1), explored the potential to maintain Vacc-4x effect by re-boosting eligible 2007/1 study participants. METHODS: Participant inclusion required 2007/1 participants to have completed all Vacc-4x immunizations and interrupted ART for up to 26 weeks. At weeks (wk)0 and 2, participants received intradermal (i.d.) Vacc-4x booster immunizations (1.2mg) on ART with GM-CSF (60µg) i.d. as a local adjuvant. ART was interrupted for up to 16 weeks (wk12-wk28). Participants were then followed on ART until wk36. VL set-point, total proviral DNA (pvDNA) and immunogenicity assessed by IFN-γ ELISPOT, T-cell proliferation and delayed type hypersensitivity (DTH) reactions were compared to participants' values in the 2007/1 study where available. RESULTS: This open, multicenter, clinical study enrolled 33 participants from 9 clinical trial sites in the US and Europe. In the per-protocol (PP) population, the VL set-point geometric mean (GM) 18162 copies/mL was not significantly changed compared to the 2007/1 study (GM VL 22035 copies/mL), (p = 0.453, n = 18). For participants with available preART VL values, the VL set-point (GM 26279 copies/mL) remained significantly lower than the preART VL set-point (GM 74048 copies/mL, p = 0.021, n = 13). A statistically significant reduction in pvDNA (49%) from baseline to wk4 was observed (p = 0.03, n = 26). DTH responses (wk4) increased significantly from baseline (p = 0.006, n = 30) and compared to the 2007/1 study (p = 0.022, n = 29) whilst the proportion of participants with ELISPOT and T-cell proliferation responses was similar between the two studies. CONCLUSIONS: Vacc-4x booster immunizations safely maintained the mean VL set-point at that established following primary Vacc-4x therapeutic immunization. The reduction in pvDNA during ART supports the potential for Vacc-4x immunization to reduce HIV reservoirs and thereby contribute to combination HIV cure strategies.

Type 2 diabetes prevalence and its risk factors in HIV: A cross-sectional study.

BACKGROUND: Type 2 diabetes (T2D) has a reported greater prevalence and poorer treatment outcomes in people living with HIV (PLWH) than comparable HIV-uninfected cohorts. We conducted a cross-sectional study to delineate the factors driving T2D in PLWH in an ethnically diverse cohort, and additionally observed how these have changed over time. SETTING: We studied a diverse HIV cohort in London to determine the prevalence and risk factors for T2D, and compared them to a cohort studied 10 years previously. METHODS: Patients were classified as normoglycaemic (fasting glucose <6.0 mmol/l) or dysglycaemic (≥6.0 mmol/l). The relative contribution to dysglycaemia of modifiable and fixed factors, including demographics, anthropometrics, comorbidities, immune status, and HIV therapy, were analysed using univariate and logistic regression analyses. RESULTS: T2D prevalence was 15.1% in 2015 with a relative risk of 2.4 compared to the general population. The prevalence compared to 6.8% ten years earlier. The 2015 versus the 2005 cohort was significantly older (median age 49 (42-57) years versus 41 (IQR 35-47), p<0.001), had a higher BMI (27.4 (23.3-29.9) versus 24.9 (22.4-28.0) kg/m2 respectively, p = 0.019) and hypertensive (37.9% versus 19.6 respectively, p<0.001). The strongest predictors of dysglycaemia in the 2015 cohort were hepatic steatosis and hypertension, odds ratios (OR) and 95% confidence intervals (CI) 6.74 (3.48-13.03) and 2.92 (1.66-5.16) respectively, and also HIV-related factors of weight gain following antiretroviral initiation and longer known duration of HIV infection (OR 1.07 (1.04-1.11) and 1.06 (1.02-1.10) respectively). CONCLUSIONS: The alarmingly high prevalence of T2D in HIV requires improved screening, targeted to older patients and those with a longer duration of exposure to antiretrovirals. Effective diabetes prevention and management strategies are needed urgently to reduce this risk; such interventions should target both conventional risk factors, such as abdominal obesity, and HIV-specific risk factors such as weight gain following initiation of antiretrovirals.

Pharmacokinetics of two randomized trials evaluating the safety and efficacy of indinavir, saquinavir and lopinavir in combination with low-dose ritonavir: the MaxCmin1 and 2 trials.

Our objective was to identify possible differences in protease inhibitor plasma concentrations between and within three protease inhibitor regimens (indinavir, saquinavir and lopinavir all in combination with low-dose ritonavir) and to relate these differences to safety and efficacy. Data originated from pre-defined pharmacokinetic substudies within two randomized 48-week trials evaluating the safety and efficacy of three protease inhibitor regimens. At weeks 4 and 48, plasma was collected and minimum drug plasma concentrations, C(min), were obtained. Out of 656 randomized patients, 283 patients had available C(min) at week 4. Indinavir, saquinavir and lopinavir C(min) were high when combined with low-dose ritonavir. No significant difference in the proportion of patients experiencing treatment failure could be found according to the C(min) within any treatment arm. A saquinavir C(min) > 2000 ng/ml was associated with an increased risk of gastrointestinal grade 3 or 4 adverse events and higher total cholesterol. Overall, there were no changes in C(min) from week 4 to week 48 in patients who remained on therapy. No association between treatment failure and the C(min) could be demonstrated. Associations between high C(min) and toxicity were identified in the saquinavir arm; therefore, dose reductions may be appropriate in certain patients with C(min) several times above the minimum effective concentration.

Severe osteoporosis and multiple fractures in an AIDS patient treated with short-term steroids for lymphoma: a need for guidelines.

An HIV-1 infected patient on dual protease inhibitor treatment developed spontaneous vertebral fractures and avascular necrosis of the femoral bone after receiving combined chemotherapy for Burkitt's lymphoma including short-term prednisolone. The factors involved in the pathogenesis of osteopaenia and osteoporosis in this case are discussed and we propose the need for guidelines in order to reduce the incidence of such events in HIV-infected patients in the future.

Effect of heterosexual intercourse on mucosal alloimmunisation and resistance to HIV-1 infection.

BACKGROUND: Unprotected sexual intercourse between regular heterosexual partners could elicit alloimmune responses that might be associated with inhibition of in-vitro HIV-1 infectivity. We investigated this hypothesis in people practising unprotected sex and those using protection. METHODS: We recruited 82 participants from an outpatient genitourinary medicine clinic. 29 monogamous heterosexual couples having unprotected sex; and 15 women and 10 men having condom protected or no sex. We used the mixed leucocyte reaction (MLR), stimulating one partner's peripheral blood mononuclear cells (PBMC) with the other partner's irradiated PBMC and compared the resulting response with control PBMC. We studied resistance to HIV-1 infection by challenging activated CD4-positive T cells with CCR5-binding and CXCR4-binding HIV-1 strains, and comparing the infectivity in participants having unprotected sex with those practising protected sex. We used the correlation coefficient to establish the significance of the relation between MLR and HIV-1 infectivity. FINDINGS: We recorded a significant increase in the stimulation indices in PBMC from women whose cells were stimulated with irradiated PBMC (2%, 10%, or 50%) from their regular partners. The mean with 10% partner's cells was 8.6 (SD 7.7), compared with those from unrelated cells (4.7 [3.9], p=0.009). Significant alloimmune responses were also seen in corresponding male partners, but only with 50% stimulating cells (p=0.013). Dose-dependent inhibition of activated CD4-positive T cells to HIV-1 infection with both binding strains was noted in vitro in women practising unprotected intercourse, compared with those having protected sex or having no sex for more than 1 year. Highly significant differences were found for CCR5 (p=0.0001) and for CXCR4 (p=0.001) strains of HIV-1 at all four virus-concentrations. Male partners also showed in-vitro inhibition of HIV-1 but this was less than that in women. INTERPRETATION: Unprotected sexual intercourse might result in alloimmunisation stimulated by HLA antigens in seminal or cervicovaginal fluid. Mucosal alloimmunisation may reduce infection by HIV-1, and the role of such immunisation in preventive and therapeutic vaccination should be investigated.

Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion. A quantitative myocardial contrast echocardiography study.

OBJECTIVES: We assessed the effect of glycoprotein IIb/IIIa inhibition (GPI) on microvascular flow after coronary occlusion/reperfusion using quantitative myocardial contrast echocardiography (QMCE). BACKGROUND: Platelets may play a major role in the dissociation of epicardial artery recanalization and tissue-level reperfusion, referred to as the "no-reflow phenomenon." Therefore, GPI might improve myocardial reperfusion, distinct from its effects on epicardial patency.T METHOD: hree-hour occlusion of the left anterior descending coronary artery (LAD) was followed by 3-h reperfusion in 16 open-chest dogs: 8 controls and 8 given a continuous infusion of the GPI tirofiban, starting 45 min before LAD reopening. Perfusion of the LAD bed was quantified by the rate of intensity rise (b) by QMCE; myocardial blood flow (MBF) was assessed by fluorescent microspheres. RESULTS: No differences in b or MBF were observed within the risk area between the control and GPI groups at baseline or occlusion. However, b and MBF were higher in GPI dogs than in controls during reperfusion, despite similar epicardial flow (p < 0.05 at 30, 60, and 90 min; p = NS at 180 min). Infarct area size was significantly reduced in GPI dogs compared with non-treated dogs (26.9 +/- 10.5% vs. 49.0 +/- 11.1% of at-risk area, respectively). CONCLUSIONS: As demonstrated by QMCE, GPI improves microvascular flow and reduces the infarct area after coronary occlusion/reperfusion, independent of epicardial flow. These data demonstrate the usefulness of QMCE in assessing microvascular flow, provide novel evidence for the role of platelets in the early phase of reperfusion injury, and show that GPI is of value in preserving microvascular perfusion after coronary reperfusion.

Assessment of right ventricular perfusion after right coronary artery occlusion by myocardial contrast echocardiography.

OBJECTIVES: The purpose of this study was to examine the ability of myocardial contrast echocardiography (MCE) to assess right ventricular (RV) perfusion. BACKGROUND: Although MCE can readily assess left ventricular perfusion abnormalities, there are no data regarding the ability to assess RV perfusion abnormalities. METHODS: The right coronary artery (RCA) was occluded in 10 open-chest dogs. Myocardial contrast echocardiography was performed with 0.27 g/min Levovist infusion by harmonic power Doppler with electrocardiographically gated intermittent triggered imaging at pulsing intervals ranging from 1:1 to 1:20 at baseline and 90 min after RCA occlusion. Video-intensity of the RV wall was plotted against pulsing intervals and was fitted to an exponential function: y = A(1-exp(-bt)), where A is the plateau video-intensity and b is the rate of video-intensity rise. Myocardial contrast echocardiography and microsphere-derived myocardial blood flow (MBF) measurements were performed at baseline and 90 min after RCA occlusion. RESULTS: Because the severity of RV perfusion abnormalities assessed by MBF varied during RCA occlusion, diverse grades of patchy opacification defects were observed by MCE. The RV wall thickness decreased, and the RV dimension increased, after RCA occlusion in each dog. The correlation of occlusion to baseline MBF ratios in the RV wall was closer to the ratio of b (r = 0.897, p = 0.0004) than A (r = 0.767, p = 0.0097) and was the closest to the ratio of Axb (r = 0.935, p < 0.0001). CONCLUSIONS: The RCA occlusion is manifested by RV wall thinning and dilation as well as by perfusion abnormalities consisting of patchy opacification defects by MCE. Myocardial contrast echocardiography-derived refilling parameters can be applied to assess RV perfusion abnormalities produced by RCA occlusion.

Visualization of risk-area myocardium as a high-intensity, hyperenhanced "hot spot" by myocardial contrast echocardiography following coronary reperfusion: quantitative analysis.

OBJECTIVES: We examined whether delayed post-injection imaging of a new ultrasound contrast agent (BR-14) could produce prolonged opacification and hyperenhancement of myocardium subjected to coronary occlusion/reperfusion. BACKGROUND: We hypothesized that ultrasound exposure destroyed BR-14 and eliminated visualization of sustained myocardial opacification from retained microbubbles. METHODS: We studied eight open-chest dogs with 3 h of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Myocardial contrast echocardiography (MCE) was performed before occlusion and 120 min after the onset of both occlusion and reperfusion. Ultrasound imaging was initiated 15 min after injection. Myocardial blood flow (MBF) was assessed by microspheres. RESULTS: Pre-occlusion images revealed uniform opacification of left ventricular myocardium greater than that of the cavity, with a mean intensity of the LAD bed of 8.66 +/- 1.38 dB. During occlusion, MCE resulted in the appearance of a perfusion defect in the LAD risk area (intensity 2.08 +/- 1.10 dB). After 120 min of reperfusion, the LAD risk-area myocardium manifested dense opacification of a higher intensity ("hot spot") than baseline (13.7 vs. 8.7 dB), but with reduced MBF consistent with accumulation of a high concentration of microbubbles. Increased MCE intensity was associated with a greater myeloperoxidase score. CONCLUSIONS: These data establish that contrast opacification by BR-14 may be selectively retained within the perfusion bed of a coronary artery subjected to occlusion/reperfusion. Such opacification exhibits defects with occlusion, manifests hyperenhanced intensity (hot spot) with reperfusion, is associated with the level of myeloperoxidase activity, and conforms to the area of myocardium subjected to altered flow.

Contrast echocardiography can assess risk area and infarct size during coronary occlusion and reperfusion: experimental validation.

OBJECTIVES: We sought to validate the ability of real-time myocardial contrast echocardiography (MCE) measures of opacification defect and contrast refilling parameters to estimate risk area (RA) and infarct area (IA) during coronary occlusion and reperfusion. BACKGROUND: No data exist establishing the accuracy of MCE in determining RA and IA size. We hypothesized that in the setting of coronary occlusion, MCE should identify RA as a perfusion defect early after bubble destruction, collateral flow to viable myocardium as opacification late during refilling and IA as absent opacification. METHODS: Three hours of coronary occlusion and reperfusion were each produced in 11 dogs in which real-time MCE was performed during intravenous infusion of Sonovue (Bracco). Real-time contrast echocardiography was performed at baseline, during occlusion and reperfusion. Early (BEGIN) and end (END) images from a FLASH refilling sequence were acquired, as well as late refilling images (LATE) 1 min after FLASH. Real-time contrast echocardiography defect size and quantitative refilling parameters were compared with RA and IA determined by tissue staining. RESULTS: During occlusion, defect size varied with refilling time; defects from BEGIN images correlated best to RA and those from LATE images to IA. Refilling parameters, but not LATE peak intensity, did not predict the IA size during occlusion. During reperfusion, defects from BEGIN images were well correlated to RA and END images to IA, whereas peak plateau intensity and refilling slope parameters predicted IA size. CONCLUSIONS: Real-time contrast echocardiography defect size varies throughout microbubble refilling. Appropriately selected defect sizes and refilling parameters provide estimates of RA and IA during coronary occlusion and reperfusion.

Dyslipidaemia and cardiovascular risk in HIV infection.

Cardiovascular disease is increasingly recognised as a consequence of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Dyslipidaemia is also a feature of HIV infection itself and the antiretroviral drugs from the protease inhibitor classes. Increased rates of atherosclerotic disease and diabetes have been associated with lipodystrophy and now from one of the major causes of morbidity in HIV and acquired immunodeficiency syndrome (AIDS).This review, based on a multi-database keyword search, summarises the lipid changes observed in the course of HIV infection and its treatment, and puts them into the context of other risk factors for cardiac disease, and other causes of cardiovascular disease in HIV.

Saquinavir/low-dose ritonavir: its use in HIV infection.

Exposure to saquinavir can be increased considerably by pharmacokinetic enhancement with ritonavir, without having a substantial impact on tolerability. Clinical trials indicate that both once-daily and twice-daily saquinavir/ritonavir treatment regimens, generally at dosages of 1,600 mg/100 mg once daily and 1,000 mg/100 mg twice daily, provide potent and sustained viral suppression and are well tolerated. In addition, data suggest that "double-boosting" strategies, including the combination of saquinavir with lopinavir/ritonavir, provide valuable treatment options in the salvage setting.

A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection.

OBJECTIVES: To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. DESIGN: This was a pilot, open-label, three-arm prospective phase 1 study. METHODS: We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4 T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation. RESULTS: One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1ß - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1ß, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced. CONCLUSION: Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.

The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to < 400 copies/ml.

OBJECTIVES: To determine the prevalence and prognostic significance of intermittent viraemia (IV) in patients who attained an undetectable viral load (VL) < 400 copies/ml within 6 months on highly active antiretroviral therapy (HAART). METHODS: Retrospective analysis of viral load rebound > or = 400 copies/ml and CD4 cell counts rise for 765 patients followed for > or = 12 months following initial VL undetectability, comparing the 226 (29.5%) who maintained an undetectable VL for > 1 year from initiation of HAART and 122 (15.9%) who had one or more episodes of IV. Genotypic resistance was evaluated at the time of the first episode of IV > or = 2000 copies/ml. RESULTS: Patients with IV had a threefold higher rate of sustained virological rebound [hazards ratio (HR), 3.15; 95% confidence interval (CI), 1.72-5.77; P < 0.001). For patients with and without IV, the Kaplan-Meier estimates at 24 and 36 months after initiation of HAART were 19.3% (95% CI, 8.9-21.5) versus 7.7% (95% CI, 4.5-13.0) and 31.6% (95% CI, 21.8-44.2) versus 12.9% (95% CI, 7.5-21.5), respectively (P < 0.001). The median CD4 cell count rise at 18 and 24 months was significantly lower in those with IV than in those without: 138 [interquartile range (IQR), 58-221] versus 224 x 10(6) cells/l (IQR, 119-357) (P = 0.0001) and 200 (IQR, 89-294) versus 260 x 10(6) cells/l (IQR, 125-384) (P = 0.003), respectively. In a subgroup of 16 patients, genotypic resistance mutations were found in the reverse transcriptase gene for five (31%) and in the protease gene in one. A probable contributing factor/event was identified for most patients with IV, such as poor adherence (42.6%), intercurrent infection (26.2%) or drug interaction (6.8%). CONCLUSIONS: Patients with IV > 400 copies/ml are three times more likely to experience sustained viral rebound and to have an impaired CD4 cell rise relative to those who maintain undetectable VL. This supports the adoption of a more pro-active approach to treatment intensification and the need for caution with structured treatment interruptions.

Mutations in HIV-1 reverse transcriptase during therapy with abacavir, lamivudine and zidovudine in HIV-1-infected adults with no prior antiretroviral therapy.

OBJECTIVE: To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy. METHODS: In a randomized, double-blind study, 173 antiretroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) > 400 copies/ml could add other antiretrovirals. From weeks 11 to 48, samples with vRNA > 400 copies/ml were collected for genotyping and phenotyping. RESULTS: At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was > 400 copies/ml in seven of 72 (10% patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone (n = 3 cases), WT (n = 3) and M184V plus thymidine analogue mutations (TAMs) (n = 1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone (n = 37), WT ( n= 1) and M184V plus TAMs (n = 3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA < 400 copies/ml (intent-to-treat with missing = failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1-2 log,10 below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively. CONCLUSIONS: Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options.

Difference of optimal dose of contrast agent between gray-scale and power Doppler imaging in assessing graded coronary stenosis by myocardial contrast echocardiography.

RATIONALE AND OBJECTIVES: In myocardial contrast echocardiography (MCE), power Doppler imaging is more sensitive to contrast agent (microbubble) than gray-scale B-mode imaging; however, no data exist regarding the optimal contrast dose in power Doppler imaging. This study examined the optimal dose of contrast agent for power Doppler in assessing coronary stenosis. METHODS: Three grades of coronary stenosis were produced in 6 open-chest dogs. MCE was performed with gray-scale and power Doppler during continuous infusion of 0.2 mL/min FS-069. Thereafter, MCE was repeated with power Doppler during continuous infusion of 0.1 mL/min FS-069. RESULTS: Although the videointensity in the stenosed bed with power Doppler (214 +/- 14) was greater than gray scale (35 +/- 17) during 0.2 mL/min FS-069 infusion (P < 0.0001), power Doppler failed to identify milder coronary stenoses because videointensity in stenosed bed was quickly saturated with contrast agent. The videointensity in the stenosed bed with power Doppler (127 +/- 49) during 0.1 mL/min FS-069 infusion was greater than gray scale (35 +/- 17) during 0.2 mL/min FS-069 infusion (P < 0.0001), and all levels of stenosis were identified with power Doppler, even though the dose of contrast agent was half of that of gray scale imaging. The correlation between videointensity and myocardial blood flow was better in the case of power Doppler at 0.1 mL/min FS-069 infusion (r = 0.77, P < 0.0001) than in the case of gray scale imaging at 0.2 mL/min FS-069 infusion (r = 0.66, P < 0.01). CONCLUSIONS: These data support the need for a lower dose of contrast agent for power Doppler than for gray scale to detect milder coronary stenosis and avoid saturation of imaging fields.

Comparison of open- and closed-chest canine model for quantification of coronary stenosis severity by myocardial contrast echocardiography.

RATIONALE AND OBJECTIVES: The objective of the present study was to compare the data regarding the ability of real-time myocardial contrast echocardiography (MCE) to assess altered myocardial blood flow produced by graded coronary stenoses between open- and closed-chest canine models. MATERIALS AND METHODS: Three grades of left anterior descending coronary artery stenosis and occlusion were created in 6 open- and 6 closed-chest canine models. MCE used FS-069 infusion and real-time imaging. Myocardial signal intensity versus time plots were fitted to a 1-exponential function to obtain the peak signal intensity (A) and rate of signal intensity rise (b) for quantification of myocardial blood flow. RESULTS: The value of b obtained from closed-chest canine models (without stenosis = 0.995 +/- 0.087, mild stenosis = 0.968 +/- 0.076, moderate stenosis = 0.569 +/- 0.077, severe stenosis = 0.288 +/- 0.032, occlusion = 0.085 +/- 0.031) was not significantly different from that obtained from open-chest canine models (without stenosis = 1.028 +/- 0.107, mild stenosis = 0.998 +/- 0.098, moderate stenosis = 0.601 +/- 0.055, severe stenosis = 0.321 +/- 0.029, occlusion = 0.079 +/- 0.028) at any grade of stenosis (P = 0.09, 0.08, 0.44, 0.11, 0.74, respectively). CONCLUSIONS: In myocardial regions where attenuation of the ultrasound beam and artifacts produced by the chest wall are minimal, the data from transthoracic MCE in the closed-chest model may show values similar to those from MCE in the open-chest model.

Assessment of adenosine-induced coronary steal in the setting of coronary occlusion based on the extent of opacification defects by myocardial contrast echocardiography.

The authors examined the ability of real-time myocardial contrast echocardiography (MCE) to assess adenosine-induced coronary steal in the setting of coronary artery occlusion. The left anterior descending (LAD) coronary artery was occluded in 8 open-chest dogs. Real-time MCE was performed during LAD occlusion, and the extent of opacification defects from MCE was measured without and with adenosine infusion. Microsphere-derived myocardial blood flow (MBF) was measured in the LAD and left circumflex (LCx) coronary artery beds, and the LAD/LCx ratio of MBF was calculated. The LAD/LCx ratio of MBF decreased in response to adenosine administration (without adenosine: 0.66, with adenosine: 0.43, p < 0.01). The extent of opacification defects from MCE increased in response to adenosine administration (without adenosine: 18%, with adenosine: 22%, p < 0.01). Thus, real-time MCE allows for the detection of adenosine-induced coronary steal as changes in the extent of opacification defects in the setting of occlusion of 1 coronary artery accompanying another normally patent coronary artery.