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HIV JournalView
July/August 2005
Table of Contents
Choosing this month's articles to review was a challenge. The past 2 months in the world of HIV research have been productive, with the publication of many excellent reports that are sure to change HIV clinical practice. As occasionally happens, several reports described different aspects of the same problems. For instance, new information related to metabolic complications of HIV and its therapies were found in abundance in the major HIV/AIDS journals. In addition, a few novel antiretroviral treatment strategies were reported that are, at the least, thought provoking. Rounding out these themes is a reassuring paper regarding the use of the influenza vaccine among HIV-infected patients that arrives in time to prepare for flu season, as well as an article examining surrogate markers for CD4+ cell count in areas where such testing is inaccessible.
Metabolic Complications of HAART
Seaberg EC, Munoz A, Lu M, et al, for the Multicenter AIDS Cohort Study. Association between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003. AIDS. June 10, 2005;19(9):953-960.
Many of us have had a sneaking suspicion that combination antiretroviral therapy contributes to hypertension. Patients with normal blood pressure would start highly active antiretroviral therapy (HAART) and experience incremental increases into the hypertensive range soon thereafter. Later, with a switch in regimen, blood pressures would return toward normal. But, because these experiences have been anecdotal and the benefits of HAART are so striking, our concern regarding hypertension has not risen to the levels seen for hyperlipidemia or body shape changes.
Muddying the waters is the fact that hypertension becomes more prevalent with increasing age and weight -- both HAART byproducts. So, linking hypertension to HIV therapy has been tricky business. A few years ago, some reports began to trickle in regarding protease inhibitor (PI) therapy and hypertension. Hewitt et al described an association between indinavir (IDV, Crixivan) and elevated blood pressure in a retrospective review of a clinical cohort.1 This was followed by additional studies reporting results that have been conflicting -- possibly reflecting disparate research designs and populations scrutinized.2-3
An ideal way to address the question of the role of HIV therapy in blood pressure would be to look at trends in hypertension in a large cohort of HIV-infected patients who were evaluated with serial blood pressure measurements before and after the initiation of a variety of antiretrovirals. Better yet would be to compare these individuals to a group of HIV-uninfected controls who were similarly evaluated. This is exactly what Eric Seaberg and colleagues in the Multicenter AIDS Cohort Study (MACS) did.
MACS has been following a cohort of more than 5,500 gay men since 1984 in 4 U.S. cities (Baltimore/Washington, D.C.; Chicago; Los Angeles; Pittsburgh). The participants are seen regularly and blood pressure is obtained, along with treatment history and blood for laboratory analyses. Importantly, not all of the cohort is HIV infected; in fact, by 2003, the last year of data contributed for this study, 60% remained HIV uninfected. Almost all of the original MACS participants were available for the hypertension analysis.
To look at the baseline characteristics of the cohort is to look through a retrospect-o-scope back on the gay American man in the 1980s.
At baseline, the median age was 32 years old, 83% were Caucasian and almost 60% had a history of smoking, with about 40% current smokers. The median body mass index (BMI) was a trim 23 kg/m2 (25 kg/m2 is considered overweight and 30 kg/m2 is obese). Blood pressure in this young group of mostly lean men, "back in the day," was a median 120/80.
By 2003, the average BMI of the cohort increased to 26 kg/m2, but smoking declined to just 18% of these men. Among those participants who are HIV infected, the percentage who were taking HAART at any one of the semiannual study visits was approximately 37%, but varied considerably over time.
The prevalence of both systolic (>140 mmHg) and diastolic (>90 mmHg) hypertension at baseline was 5.9%. Men who were older than 50 years, are African American or had a BMI greater than 25 kg/m2, had a higher prevalence of hypertension. Over time, hypertension became more common, particularly among the groups listed above, as well as those taking HAART. Systolic hypertension was detected during 12% of the study visits made by the trial participants on HAART, while diastolic hypertension was registered during 9.2% of these visits. These rates were higher than those observed during the visits of the overall cohort (7.3% with systolic hypertension and 8.0% with diastolic hypertension).
Interestingly, the rate of diastolic hypertension during the first 5 years of HAART was no different than that observed among HIV-uninfected men. However, after 5 years, the rate shot up. For systolic hypertension, the rate was stable for the first 2 years of HAART and increased sharply after that.
Multiple regression analyses found some expected independent factors associated with hypertension, including greater age, African-American race, higher BMI and, for systolic hypertension alone, smoking. But, when looking at HIV therapy, the results were more surprising. Men who were HIV infected and were not on antiretrovirals or were on therapy that was not HAART (i.e., monotherapy or dual-nucleoside therapy), had a lower prevalence of hypertension than HIV-uninfected men. (Why this is, is not clear or discussed in the paper, although perhaps suboptimal HIV therapy is a marker of substance abuse, nonadherence or other characteristics that may lead to poor nutrition and overall health and a lower blood pressure.) Among those on HAART for less than 2 years, the prevalence of systolic hypertension was no different than that in HIV-uninfected men, though, as described above, it increased substantially thereafter. The risk of systolic hypertension was 51% higher after 2 years of HAART than for an HIV-uninfected man.
To see if PIs were the culprit, as has been suggested in some reports, exposure to the class, as well as to individual agents of the class, was examined. The results indicate that PIs (overall and specific agents) did not contribute to systolic hypertension above and beyond the other independent factors described above. The odds ratio for PI-containing HAART was exactly the same as for non-PI-containing HAART, 1.37 (P<.05). HAART was not independently associated with diastolic hypertension in the regression analysis, regardless of the duration of therapy.
The Bottom Line
The association of HAART with systolic hypertension is concerning because isolated systolic blood pressure elevation is linked in the Framingham Study to atherosclerotic disease, including myocardial infarction and stroke. Isolated systolic hypertension is usually a manifestation of decreased arterial compliance following deposition of atherosclerotic plaques and reduced aortic distensibility. Therefore, this finding fits with an emerging picture regarding the effect of HAART on arterial function. However, the study only included men, which has always been a limitation of MACS. Further, the cohort is largely Caucasian and affluent. As our clinic cohorts are increasingly exactly the opposite and comprised of more women, one should apply these findings broadly only with caution.
Clinicians should take from this report a heightened awareness of the role of HAART in blood pressure elevation. Specifically, in addition to the "no-brainer" risk factors for elevated blood pressure (age, increased weight, being African American and smoking), HAART (be it PI sparing or containing) is independently associated with an increased systolic blood pressure in men like those in MACS. Monitoring blood pressure and treating according to published guidelines makes good sense and good practice.4
Efavirenz Reduces Plasma Levels of Popular Statins
Gerber JG, Rosenkranz SL, Fichtenbaum CJ, et al, for the AIDS Clinical Trials Group A5108 Team. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr. July 1, 2005;39(3):307-312.
Managing the dyslipidemia that accompanies antiretroviral therapy is complicated by drug-drug interactions among several major HIV and lipid-lowering therapies. Further, some of the most lipid-offensive antiretrovirals are the most likely to influence the metabolism of the drugs used to reduce lipids, especially the HMG-CoA reductase inhibitors (more commonly known as statins).
In this report, John Gerber and colleagues in the AIDS Clinical Trials Group (ACTG) investigated the effect of the popular antiretroviral efavirenz (EFV, Sustiva, Stocrin) on 3 commonly used statins: simvastatin (Vytorin, Zocor), atorvastatin (Caduet, Lipitor) and pravastatin (Pravachol).
Fifty-two healthy, HIV-uninfected study participants were administered 1 of these statins for 3 days, during which the levels of the drug were checked over a 24-hour period. Efavirenz was then administered alone for 12 days and then together with the statin for an additional 3 days -- allowing for the levels of both drugs when co-administered to be compared with those obtained earlier in the study. The dosage for each statin was as follows: simvastatin 40 mg daily, atorvastatin 10 mg daily and pravastatin 40 mg daily.
Of those enrolled, 42 participants contributed to the final analyses. The remainder either discontinued due to side effects or had improper specimen collection. Of the study patients who remained in the trial, most were men and two thirds were Caucasian.
Co-administration of efavirenz with simvastatin led to a 58% decline in area under the curve (AUC) and a similar decline in the active metabolite HMG-CoA reductase AUC. For atorvastatin, there was a median 42.7% decline in the AUC of this drug and a 34.5% drop in levels of its active metabolites in the presence of efavirenz. Likewise, the pravastatin AUC was reduced by a median of 40.4% with efavirenz. Efavirenz concentration was unaffected by the statins.
To demonstrate that these changes in AUC are potentially clinically meaningful, the investigators examined the low-density lipoprotein (LDL) cholesterol levels of the participants after the first short course of their statin alone and after the statin with efavirenz. They found a trend toward attenuation of the lipid-lowering effect of the drugs.
The Bottom Line
This extremely helpful study defines an important and commonplace drug-drug interaction. Efavirenz can contribute to increases in lipids, therefore, the prospect of concomitant administration of this non-nucleoside reverse transcriptase inhibitor (NNRTI) and a statin is indeed real. As a potent inducer of the metabolism of these 3 statins, efavirenz (and probably nevirapine [NVP, Viramune], given its known induction of CYP3A4) can significantly reduce the levels of these drugs. As such, the dosing of the studied statins, when co-administered with efavirenz, will likely need to be increased to achieve a desired lipid-lowering effect. Clinicians can feel less anxious about initiating a higher dose of statin than usual (above the lowish starting doses we typically use) when NNRTIs are on board, but should continue to apply the proper side-effect surveillance.
Carotid Intima-Media Thickness Not Associated With Protease Inhibitor Use
Currier JS, Kendall MA, Zackin R, et al, for the AACTG 5078 Study Team. Carotid artery intima-media thickness and HIV infection: traditional risk factors overshadow impact of protease inhibitor exposure. AIDS. June 10, 2005;19(9):927-933.
Carotid intima-media thickness (CIMT), as assessed by ultrasonography, is a validated early marker of early atherosclerosis. Whether HAART, and PIs in particular, increase CIMT has been unclear, since different studies have reached opposing conclusions.5-10 To better evaluate the effect of PIs on CIMT, Judith Currier and colleagues conducted a carefully designed study in which 3 groups were enrolled:
A patient from each group was enrolled together as a triad and matched for age (+/- 5 years), race, sex, blood pressure status, smoking history and, for the few women in this study, menopause status. Patients with diabetes, obesity, family history of early myocardial infarction or a personal history of cardiovascular disease were excluded. CIMT was to be measured at baseline and at weeks 2, 24, 48, 72 and 96. A comparison of baseline characteristics and CIMT is presented in Currier et al's paper.
A total of 134 patients on 45 triads were enrolled (40 male and 5 female). Three quarters of the study patients were Caucasian; 55% had never smoked. There were some notable differences between the groups. The waist/hip ratio was higher among participants with a history of PI use. Similarly, the PI-exposed participants had higher total cholesterol and triglyceride levels. Compared to the PI-experienced patients, the other group of HIV-infected patients had a lower CD4+ cell count (481 cells/µL versus 530 cells/µL) and a lower proportion had a viral load less than 50 copies/mL (69% versus 75%).
CIMT at baseline was 0.690, 0.712 and 0.698 mm in groups 1, 2 and 3, respectively. There were no significant differences between groups, no matter which pair-wise comparison was made or when combining the HIV-infected groups. In a multivariable model, increases in CIMT were associated significantly with older age and increased BMI. High-density lipoprotein (HDL) cholesterol was protective, especially when triglyceride levels were high.
The Bottom Line
These results may be counterintuitive to many -- certainly, if the researchers had found that CIMT was associated with PI therapy, it would hardly have been shocking, given the contribution of this antiretroviral class to LDL cholesterol and triglyceride elevations. The authors state several possible explanations for the lack of an effect of PIs on CIMT, including one critical explanation: Perhaps PI-mediated atherosclerotic disease takes time to develop and the exposure (median 216 weeks) was too short in this study to see an effect on this particular artery. Also, the participants in this study were a bit more pristine than those in the average clinical cohort, since patients with major cardiovascular disease risk mediators, such as diabetes and personal or family history of heart disease, were excluded. The effect of PIs on CIMT may be more rapid and evident in such patients.
Furthermore, the site of action for PI-mediated cardiovascular disease may not be in the carotid intima, but elsewhere, and thus went undetected in this study. Lastly, and probably most convincingly, traditional risk factors for cardiovascular disease, which were controlled for in this study, may conceivably trump any effect of PIs (or any antiretroviral therapy) on subclinical atherosclerosis (e.g., HAART is a drop in the bucket compared to elevated blood pressure, smoking, etc.). This study is unlikely to be the final word on the CIMT story and results of the follow-up phase of this study will be of great interest; however, for the moment, redemption for the much-maligned PI is in the air.
Managing Dyslipidemias: Is It Better to Fight or Switch?
Calza L, Manfredi R, Colangeli V, et al. Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS. July 1, 2005;19(10):1051-1058.
When confronted with serious antiretroviral therapy-induced dyslipidemias, a clinician must choose between initiating lipid-lowering therapy and switching the medication(s) most likely to be the culprit. When a switch is desired, swapping a PI for an NNRTI has been the typical approach. But, in cases where there are limited options for a switch -- due to pre-existing resistance, a history of intolerance or, in many cases, when modifying the regimen is considered too risky -- lipid-lowering therapy is often prescribed.
In this clever study from Italy, patients on their first antiretroviral regimen, consisting of 2 nucleoside/tide reverse transcriptase inhibitors (NRTIs) and one or more PIs at baseline, had to have:
A total of 130 patients meeting the entry criteria enrolled. Of these, 78 were male. The mean baseline triglyceride and total cholesterol levels were 293 mg/dL and 267 mg/dL, respectively. One of the NRTIs being taken at baseline by 46% of the patients was stavudine (d4T, Zerit). Of the PIs, mostly lopinavir/ritonavir (LPV/r, Kaletra) (28%), nelfinavir (NFV, Viracept) (21.5%), or indinavir (IDV, Crixivan) (17%) were taken at baseline. The mean duration of PI-based HAART was 29 months.
Patients were randomized to 1 of the 4 arms:
All patients were advised to start a low-fat diet and to exercise. After 6 months, triglycerides fell 26% in the nevirapine arm, 9.8% in the efavirenz arm, 42% in the pravastatin arm and 47% in the fibrate arm. When combined and when considered individually, the lipid-lowering arms were significantly superior to both the switch arms taken together. Nevirapine was better than efavirenz, but no difference was seen between the statin and fibrate with regard to triglyceride reduction. These reductions were essentially unchanged at 12 months.
At 6 months, total cholesterol was reduced from baseline by 28% for nevirapine, 11% for efavirenz, 44% for pravastatin and 37% for the fibrate. LDL cholesterol declines were almost identical. For both total and LDL cholesterol, the statistically significant differences followed the same pattern as seen for triglyceride reduction (lipid-lowering therapy was better than the switch, nevirapine was better than efavirenz and pravastatin was as effective as the fibrate).
For HDL cholesterol, despite all the noise made about how NNRTIs increase this cholesterol fraction, the rise seen with these antiretrovirals was minimal (2-3%) compared to the increase seen with the fibrate (8%) and the statin (10%). All these changes persisted at 12 months of follow-up.
After a year, the rates of suppression of plasma HIV viremia were no different between the 4 arms; they ranged from 96.5% in the nevirapine arm to 100% in the pravastatin arm. There were no reports of treatment-limiting toxicity in any of the arms and lesser toxicities occurred at similar rates across the arms.
The Bottom Line
Although this study is relatively small, it is a wake-up call to stop futzing around with antiretroviral switches and start appropriate lipid-lowering therapies. Even trading to the drug nevirapine, purported to be a lipid-friendly agent, led to normalization of triglyceride and total cholesterol levels in only 31% and 9% of patients, respectively, whereas pravastatin, which is not an extremely potent statin, achieved a rate of triglyceride normalization of 44%. As expected, the fibrate performed well, with 58% of the patients who were assigned to this agent normalizing triglycerides.
Certainly, some switches make more sense than others, and few clinicians would advise patients who are experiencing dyslipidemia while taking stavudine to suck it up and start a statin rather than switch to a more lipid-favorable NRTI. And, with the advent of atazanavir (ATV, Reyataz), a strategy not studied here, switching older PIs to this agent has become attractive, especially given its convenient once-daily dosing. However, expecting a switch to ritonavir (RTV, Norvir)-boosted atazanavir to produce results that would best those seen with nevirapine is a stretch, despite whatever belief system regarding this boosted PI we are creating for ourselves.
When there are additional reasons (ease of dosing, other toxicities, low-level viremia) to prompt a treatment switch and a new prescription is undesirable (another co-pay, toxicity potential, pill burden), a switch can be justified. However, this study tells us not to expect too much from an antiretroviral switch by way of lipid changes. Clearly, when drastic lipid reductions are required, lipid-lowering therapy is the best option.
Exporting Lipodystrophy
Pujari SN, Dravid A, Naik E, et al. Lipodystrophy and dyslipidemia among patients taking first-line, World Health Organization-recommended highly active antiretroviral therapy regimens in western India. J Acquir Immune Defic Syndr. June 1, 2005;39(2)199-202.
This report was not unexpected. The heavy reliance on stavudine in much of the developing world has made such a study, detailing the toxicity of combination antiretroviral therapy in such locales, inevitable. This drug, now considered too toxic for use in the United States, has become one of the most popularly used antiretrovirals in Africa and Asia. Typically, stavudine is contained in a fixed-dose combination with two other antiretrovirals: lamivudine and nevirapine. Produced in India by Cipla LTD, this fixed-dose combination goes by the brand name Triomune. This is a cheap and potent antiretroviral combination -- too attractive for antiretroviral-starved HIV epidemic hot spots to disregard, despite its warts. Some hoped that the apparently higher prevalence of lipodystrophy (at least the body shape changes) in Caucasians taking stavudine would mean metabolic abnormalities would not be a significant problem when taken by those with darker skin color and disparate genetic backgrounds. But, this turns out not to be the case, as clinicians working in the Dominican Republic, India and Thailand can attest.
In this report from Pune, India, 180 consecutive patients receiving either stavudine/lamivudine/nevirapine (150 patients) or zidovudine (AZT, Retrovir)/lamivudine/nevirapine (30 patients) for a minimum of 1 year, were evaluated for body shape changes, dyslipidemia and hyperglycemia and compared to 126 HIV-infected, treatment-naive patients. To be included in the trial, the HIV-therapy-treated patients had to be considered adherent by self-report, laboratory results, clinical improvement and elevated MCV (mean corpuscular value) (for those on zidovudine).
Body shape changes were assessed by both patient and clinician report. Lipids and glucose levels were obtained after a 12-hour fast. The patients were mostly male and lean (BMI in the controls was 21.3 kg/m2, in the stavudine/lamivudine/nevirapine arm it was 22.7 kg/m2 and in the zidovudine/lamivudine/nevirapine arm it was 24.0 kg/m2). All cases had a CD4+ cell count less than 200 cells/µL prior to treatment, the mean duration of which at study entry was 19.5 months for the stavudine arm and 24.3 months for the zidovudine arm. At study entry, CD4+ cell counts were 407 cells/µL and 460 cells/µL in the stavudine and zidovudine groups, respectively, compared to 260 cells/µL in the control arm.
The overall prevalence of body shape change among the treated patients was 46%; lipoatrophy was documented in 27% of those who were taking stavudine and 10% of those receiving zidovudine (P = .08). On regression analysis, stavudine was significantly associated with lipoatrophy (OR = 3.3 [95% CI 1.3-11.3]). Fat accumulation was reported in 23% of the stavudine group and 17% of the zidovudine group (P =.57). A mixed picture of fat accumulation and wasting was observed among 10% and 7% of those taking stavudine and zidovudine, respectively (P = .8). Those on HIV therapy had higher total cholesterol, LDL cholesterol and fasting blood glucose than the untreated controls, although there were no differences between the study arms. The proportion of patients on stavudine with an LDL cholesterol of more than 130 mg/dL was 31% compared to 27% in the zidovudine arm and 4% among the controls. Likewise, triglyceride levels above 500 mg/dL were observed in 4% of the stavudine-treated patients, but none of the zidovudine or control patients. HDL cholesterol was higher in the treatment arms than the controls, as would be expected given the use of nevirapine.
The Bottom Line
This report has a number of limitations, including its low sample size, poor power to detect differences between stavudine and zidovudine-based treatment regimens, lack of objective measures of body shape and limited data regarding the weight of the patients receiving full-dose stavudine. However, the general results suggest that in this Asian clinic where stavudine-heavy World Health Organization (WHO)-recommended first line therapies are employed, metabolic complications are being experienced at a high rate. The trend for a greater prevalence of complications -- especially body shape abnormalities -- among those receiving stavudine signals the justified concern over the widespread application of this agent. The authors themselves call for increased access to alternative drugs such as abacavir (ABC, Ziagen) and tenofovir (TDF, Viread) at affordable prices.
It is certain that additional reports will emerge describing high rates of metabolic complications among patients in Africa and Asia who are receiving similar therapies. When the chorus becomes loud enough, the pictures of lipoatrophied faces become ever-present at large HIV conferences and the New York Times does a cover story on the reliance on cast-off therapies for the treatment of HIV in the developing world, then maybe there will be sufficient pressure to produce an alternative to the cheap stavudine-based regimens people in these regions have no choice but to swallow.
New Approaches to HIV Therapeutics
Lopinavir/Ritonavir PLUS Efavirenz -- Worthy or Wacky?
Allavena C, Ferre V, Brunet-Francois C, et al, and the Bitherapy Kaletra-Sustiva Study Group. Efficacy and tolerability of a nucleoside reverse transcriptase inhibitor-sparing combination of lopinavir/ritonavir and efavirenz in HIV-1-infected patients. J Acquir Immune Defic Syndr. July 1, 2005;39(3):300-306.
If efavirenz is the King Kong of the HIV therapy market, lopinavir/ritonavir has got to be the Godzilla. Both are big and powerful, and neither has been bested to this day in a head-to-head contest. Both drugs are listed in the U.S. Department of Health and Human Services antiretroviral guidelines11 as preferred regimen anchors. There has yet to be a direct comparison of these potent agents, and while that will be of intense interest (the ongoing ACTG study A5142 is performing such a comparison in naive patients), this report from France looks not to pit these behemoths against one another, but rather to make nice and team them up together in a nucleoside-sparing regimen.
In this pilot study, 65 antiretroviral-naive and 21 treatment-experienced patients received lopinavir/ritonavir (533/133 mg, 4 capsules) twice daily plus efavirenz (600 mg) once daily for 48 weeks. The treatment-experienced patients were all NNRTI naive and 12 had only received NRTIs previously. If they had prior PI exposure, they could not have more than 1 virologic failure on a PI-containing regimen and had to have less than 5 primary mutations that reduce susceptibility to lopinavir (LPV). Patients' median CD4+ cell count was 276 cells/µL and the median viral load was 4.87 log10 copies/mL.
During the 48-week study, 24% (21) of the patients discontinued study therapy. There were 7 adverse event-related discontinuations (see below), and 6 patients were lost to follow-up. Two trial participants experienced protocol-defined virologic failure. The other premature discontinuations were due to pregnancy, nonadherence, withdrawal of consent, protocol violation, psychiatric illness, tuberculosis and pruritus. At week 24, 69% of the patients had a viral load below 50 copies/mL. This persisted to week 48 by intent-to-treat analysis. There were no differences in viral suppression between patients who were naive to therapy and those who were not, or when patients were stratified by a baseline viral load of greater than or less than 100,000 copies/mL. The mean CD4+ cell count increase was 238 cells/µL at week 48.
Treatment-limiting adverse events attributed to study therapy included grade 3 central nervous system disturbances (in 3 patients), rash (in 3 patients) and grade 4 dyslipidemia (in 1 patient). Lipids seemed to increase in most patients, but the authors are a bit cagey about describing lipid details. Apparently, fasting cholesterol increased by about 60 mg/dL and triglycerides by 119 mg/dL -- changes which may not have been statistically significant. Mean HDL cholesterol did increase significantly at week 48, from 42 to 49 mg/dL. LDL cholesterol changes were not reported, although we are informed that an LDL cholesterol of more than 160 mg/dL was seen in 2% of antiretroviral-naive patients at baseline and 35% at week 48. Among the treatment-experienced subset of patients, 12% had an LDL of more than 160 mg/dL at baseline and this increased to 20% at week 48. Despite this, only 3 patients started lipid-lowering therapy.
Genotyping of retrieved virus from patients who failed therapy revealed only NNRTI resistance (K103N) and no new mutations in the protease region.
The Bottom Line
This pilot study provides early data on a novel combination that has some obvious advantages and disadvantages. Sparing NRTIs, especially during first-line therapy, may provide potent and convenient secondary treatment options and avoid NRTI-associated adverse effects. On the other hand, the study combination may not be the easiest regimen to adhere to and it risks the elevation of lipid levels.
This study suggests that the lipid elevations, even on the presumably rich French cuisine, are not as bad as one would have expected and that when failure occurs, PI resistance is unlikely. This last point jibes with the general clinical experience that resistance to ritonavir-boosted PIs is hard to come by.
This study is not the final word on this NNRTI-PI combination. As part of the large ACTG study comparing 2 NRTIs + efavirenz to 2 NRTIs + lopinavir/ritonavir in treatment-naive patients, there is a third arm being studied: lopinavir/ritonavir + efavirenz alone. So, in the not-too-distant future, we will have the opportunity to see just how well these antiretroviral giants perform against one another and judge whether this NRTI-sparing regimen is just as good as the 2 top NRTI-based regimens or just too much. Until then, this is a combination to be used only when necessary (i.e., when you have to).
Putting Atazanavir + Ritonavir on the Map
Johnson M, Grinsztejn B, Rodriguez C, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. April 29, 2005;19(7):685-694.
This study, the first to examine ritonavir-boosted atazanavir and one which helped the drug receive U.S. Food and Drug Administration approval, has been presented previously at a series of HIV conferences and has now finally been published. The study launched the current wave of boosted-atazanavir use even though, as described below, the setting in which it was studied was limited to patients who had prior antiretroviral experience and detectable HIV-RNA levels.
The open-label trial was designed to test 3 different treatment strategies:
plus tenofovir 300 mg daily and another NRTI choice based on phenotypic resistance testing at screening.
Trial participants were patients who had failed 2 or more HAART regimens that included 1 or more NRTIs, an NNRTI and a PI. However, participants had to have had a 1.0 log10 decline in viral load or suppression to less than 400 copies/mL on a prior HAART regimen. Also, their baseline HIV-RNA level had to be greater than 1,000 copies/mL and their CD4+ cell count more than 50 cells/µL.
The primary outcome was based on the time-averaged difference in the reduction of HIV RNA through week 48, with the proportion less than 50 and 400 copies/mL at week 48 seen as the secondary outcomes. This was a non-inferiority trial in which the study arms were compared to assess whether they are not inferior to the comparator (in this case the lopinavir/ritonavir arm). Keep in mind that, statistically speaking, not being inferior to something is different than being superior to it or even equal to it. It only means that you were (probably) not worse.
A total of 347 patients were enrolled to the 3 arms. Participants were about 80% male and 70% white. A third had a diagnosis of AIDS, 60% were on an NNRTI prior to entry and 34% were on a PI. The median number of baseline NNRTI mutations was 3 and to PIs was 2. The median baseline HIV-RNA level was about 4.44 log10 copies/mL and the median CD4+ cell count was approximately 300 cells/µL.
In the analysis used, boosted atazanavir was not found to be inferior to lopinavir/ritonavir; however, the atazanavir + saquinavir combo was inferior to lopinavir/ritonavir. Looking at more usual metrics of performance, the mean reduction in viral load was -1.93 log10 for the atazanavir + ritonavir arm, -1.55 log10 for the atazanavir + saquinavir arm and -1.87 log10 for lopinavir/ritonavir. The proportion of patients with a viral load less than 50 copies/mL was 46% for those on lopinavir/ritonavir, compared to 38% for those who were on boosted atazanavir and 26% for those on atazanavir + saquinavir.
The differences between the ritonavir-boosted atazanavir and lopinavir arms was not statistically significant (statistically, atazanavir + saquinavir tanked). Increased baseline resistance predicted muted response to the treatment assignment; this was most profound for the ill-fated atazanavir + saquinavir arm, which had low levels of response, with an accumulation of PI mutations.
CD4+ cell counts increased by 110, 121 and 72 cells/µL in the atazanavir + ritonavir, lopinavir/ritonavir and atazanavir + saquinavir arms, respectively.
Treatment-related adverse effects at a grade 2-4 level were reported by about a quarter of the patients in each arm and serious adverse events in approximately 10% of each arm. Jaundice was reported in 6% of the atazanavir + ritonavir patients and none of the lopinavir patients. In addition, 11% of the lopinavir-receiving patients had diarrhea, compared to 3% of the boosted-atazanavir patients. Total bilirubin increased, as expected, in the atazanavir + ritonavir arm. A total of 49% of the patients who were assigned to this arm experienced a grade 3-4 bilirubin elevation during the study. Liver transaminases increased in very few patients (4%) and were equal to that seen in the other study arms.
Lipid differences were what made headlines when this study first was presented and favored the atazanavir + ritonavir arm over the lopinavir/ritonavir arm. LDL cholesterol decreased 10% in the atazanavir + ritonavir arm and increased 1% in the lopinavir/ritonavir arm (P = NS). Likewise, fasting triglycerides dropped 4% in the atazanavir + ritonavir arm and rose 30% in the lopinavir/ritonavir arm (P<.005). Lipid-lowering therapy was initiated during the study in 14% of the patients taking lopinavir/ritonavir, but in only 3% of those who were on atazanavir + ritonavir.
The Bottom Line
This is an important study that showed boosted atazanavir could go toe-to-toe with lopinavir/ritonavir in patients with some, but not a lot, of PI resistance detected at baseline. The impressive responses seen with this new PI, and the lipid improvements after switching from NNRTI- (60%) and PI- (34%) based regimens, have led to considerable enthusiasm regarding the use of atazanavir with ritonavir in such patients. Although the jaundice and bilirubin abnormalities seen were significant, they did not lead to excess treatment discontinuation -- a finding that predicted clinical experience. An important caveat is to recognize that the improved lipids do not mean that boosted atazanavir is lipid neutral. There are no data describing the effects of ritonavir + atazanavir on the lipid levels of treatment-naive patients. It is likely that this combination does increase lipid levels, but to a lesser extent than that seen with lopinavir/ritonavir.
Induction-Maintenance With Zidovudine/Lamivudine/Abacavir
Markowitz M, Hill-Zabala C, Lang J, et al, for the ESS40013 Study Team. Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. July 1, 2005;39(3):257-264.
In the wake of ACTG Study 509512 and the finding of a suboptimal response to the fixed-dose combination of zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) compared to a regimen of efavirenz combined with either zidovudine/lamivudine (AZT/3TC, Combivir) or zidovudine/lamivudine/abacavir among treatment-naive patients, use of this triple NRTI alone has become rare. This interesting study, sponsored by the good people at GlaxoSmithKline, the maker of zidovudine/lamivudine/abacavir, aims to see if a prolonged induction treatment with a potent combination of zidovudine/lamivudine/abacavir + efavirenz can be followed by use of zidovudine/lamivudine/abacavir alone. The benefits of such a strategy are threefold: reduced exposure to efavirenz, and therefore removal of the adverse lipid effects and possibly persistent central nervous system disturbances of this agent; simplification of therapy; and lower expense of treatment.
Treatment-naive (less than 2 weeks of prior therapy) patients with an HIV-RNA level greater than 5,000 copies/mL were included in this study. All patients received zidovudine/lamivudine/abacavir + efavirenz at standard doses. Those with a viral load less than 50 copies/mL at weeks 36 and 44 were randomized at week 48 to continue or discontinue efavirenz.
A total of 448 patients were enrolled across the United States (~85% male, 50% non-white). The median HIV-RNA level was a little over 5 log10 copies/mL and the median CD4+ cell count was about 212 cells/µL. More than half of those enrolled had a viral load over 100,000 copies/mL at baseline. Of these initial patients, 166 (37%) discontinued study treatment during the first 48 weeks due to the following reasons: adverse events (33% of those discontinuing), withdrawn consent (20%), loss to follow-up (17%) and virologic failure (15%). Of those who entered the induction phase, 61% had a viral load less than 50 copies/mL at week 48 in an intent-to-treat analysis. This is not a stellar response and pales in comparison to the rates of viral suppression being seen in recent clinical trials of treatment-naive patients. The reason for the low rate of success at the end of the induction phase was mostly related to dropouts due to adverse effects and loss to follow-up. Seven percent of the patients experienced suspected abacavir hypersensitivity reactions and 2% experienced treatment-limiting rash. Of those who made it to week 48, however, 90% had a viral load less than 50 copies/mL.
A year after the randomization, 79% of those remaining on the quadruple therapy had suppression of their viral load to less than 50 copies/mL, as did 77% of those on zidovudine/lamivudine/abacavir alone (P =.7). Virologic failure after randomization occurred in 16 patients in the zidovudine/lamivudine/abacavir arm and in 8 patients in the quad therapy arm (P =.13). CD4+ cell count increased nicely in both arms to a median level of 425 cells/µL in the quad therapy arm and 453 cells/µL for the zidovudine/lamivudine/abacavir arm. There was a trend toward greater self-reported adherence among the zidovudine/lamivudine/abacavir alone arm than the quad therapy arm, 88.8% versus 79.6%, respectively (P =.057).
Of those who experienced virologic failure during the induction phase, the most common resistance detected was to efavirenz and/or lamivudine. Two patients had resistance to these plus zidovudine detected and, curiously, 2 additional patients selected for the K65R mutation (something zidovudine is supposed to prevent). During maintenance, the most common mutation detected was to lamivudine alone, although some patients did cultivate additional mutations, including thymidine analog and NNRTI resistance.
Lipids generally increased during induction, but dropped close to baseline in the zidovudine/lamivudine/abacavir-alone arm after randomization, while remaining elevated in the quad therapy arm.
The Bottom Line
The induction-maintenance concept is one that is attractive to clinicians familiar with the oncological therapy model. The idea is to hit hard and reduce viral burden to the point where suppression can be preserved with less-toxic and more-convenient therapy. Here, the problem was the somewhat surprising intolerance of the induction therapy. Zidovudine/lamivudine/abacavir + efavirenz has been administered in ACTG 5095 without anywhere near the 37% discontinuation rate seen here. In that study, only 7% of the overall participants discontinued therapy by week 32. Besides bad luck, it is hard to imagine a reason for the problems seen here in the first phase of the study -- although the high loss to follow-up/consent withdrawn rate may hint at some participant disgruntlement. It is important to note that of those who did make it to a year on induction therapy, almost all (90%) were undetectable. Furthermore, following the switch, persistence of viral suppression was comparable between the arms (77%-79%).
Is this approach ready for prime time? As a general strategy, not quite. Induction-maintenance for HIV infection has a checkered past. However, there are situations in which these results provide reassurance. Last week I saw an elderly woman who has been on zidovudine/lamivudine/abacavir + efavirenz for over 2 years, with viral loads uniformly less than 50 copies/mL and a CD4+ cell count that is now over 500 cells/µL. She complained of persistent dizziness since starting her regimen, which prevents her from tending her garden. She can pinpoint the start of her symptoms to the day she started her efavirenz. After reading this paper (and having a long discussion with her and her family), I decided to remove the efavirenz and continue the zidovudine/lamivudine/abacavir alone. In such cases, where success of the induction therapy has been made clear, discontinuation of the NNRTI seems more attractive, particularly when dealing with toxicity. In other cases, I would be hesitant to alter therapy.
Refining Treatment Strategies
Predicting CD4+ Cell Counts Where There Are None
Costello C, Nelson KE, Jamieson DJ, et al. Predictors of low CD4 count in resource-limited settings: based on an antiretroviral-naive heterosexual Thai population. J Acquir Immune Defic Syndr. June 1, 2005;39(2):242-248.
Can you imagine trying to manage HIV therapy without the benefit of HIV-RNA testing or even CD4+ cell counts? That is the circumstance that most clinicians in Africa and Asia find themselves working in. In some places, CD4+ cell counts are available, but cost more money than the patient can afford or rely on overworked machines and personnel. As HIV therapies penetrate into resource-poor regions, having a marker to assist in determining when to start therapy, to monitor response to treatment once started and to indicate when there is a need for prophylaxis for opportunistic infections will be essential. Recognizing the problem, the WHO has published alternative recommendations for the initiation of HIV therapy in places where CD4+ cell count testing is unavailable. Based on the correlation between CD4+ cell count and the total lymphocyte count (TLC),13 these guidelines are as follows:
To determine whether the addition of other readily available information can increase the sensitivity of the WHO recommendations, investigators from the U.S. Centers for Disease Control and Prevention examined data from a cohort of 839 patients participating in a clinical study in Thailand. The population studied was diverse with regard to age, gender and CD4+ cell count. All were antiretroviral naive.
There was a high correlation between CD4+ cell count and TLC among men and women. The latest WHO guidelines indicating that a TLC of less than 1,200 predicted a CD4+ cell count of less than 200 cells/µL had a sensitivity of 34% in men and 32% in women, and a specificity of 90% for men and 86% for women. The authors found that with their real-life data, establishing a TLC of less than 1,500 as predictive of a CD4+ cell count of less than 200 cells/µL increased the sensitivity with minimal loss of specificity. The result is that more than twice as many patients with a CD4+ cell count of less than 200 cells/µL would be identified as individuals for whom HIV therapy would be recommended than would have been discovered with the lower cutoff. Similarly, for a CD4+ cell count of less than 350 cells/µL, increasing the TLC to 1,800 increased sensitivity without modification of specificity from that associated with the recommended 1,500 TLC.
Furthermore, the presence of anemia (defined as hemoglobin less than 12 g/dL for men and less than 11 g/dL for women), highly prevalent in this cohort, also predicted a CD4+ cell count less than 200 cells/µL. Adding it to the algorithm for both CD4+ cell counts less than 200 cells/µL and less than 350 cells/µL doubled the sensitivity above the current guidelines. Adding WHO stage II HIV infection classification to the CD4+ cell count less than 200 cells/µL model added further sensitivity. Therefore, the authors propose that the following guidelines be used when CD4+ cell testing is unavailable:
The Bottom Line
It is likely that data available even in places with poor healthcare infrastructure can be applied to provide improved surrogates for CD4+ cell counts. This analysis primarily adds the presence of anemia to the mix to increase the yield of slightly modified TLC cutoffs. The end result is fewer misclassified patients who, the current guidelines would suggest, are not eligible for HIV therapy although they have a CD4+ cell count less than 200 cells/µL.
Further testing of this helpful algorithm in other settings (e.g., Africa and China) is needed prior to broad application, but the results highlight the deficiencies of the current recommendations and the need to refine them based on available information.
Efficacy of Influenza Vaccine in HIV-Infected Patients
Yamanaka H, Teruya K, Tanaka M, et al, and the HIV/Influenza Vaccine Study Team. Efficacy and immunologic responses to influenza vaccine in HIV-1-infected patients. J Acquir Immune Defic Syndr. June 1, 2005;39(2):167-173.
If I added all the time I spend each winter trying to convince HIV-infected people to take the influenza shot, I wonder how much time I would have. A week? A day? Enough time to run down to employee health to get a shot myself? Maybe a more important question is whether all that time is worth it, even if I could cajole enough of the needle-phobic to roll up their sleeves or could help patients put aside urban myths about the influenza vaccine causing the flu. Does the vaccine really work?
In this study, researchers in Japan gave the influenza vaccine (the trivalent shot used in 2002 in Japan) to 262 HIV-infected patients who agreed to participate. Their responses and influenza rates were compared to 66 patients who declined vaccination. Three quarters of the patients in each group were on HAART; the median CD4+ cell count was 380 cells/µL and the median viral load was 2.5 log10 copies/mL (these were almost identical between arms).
During the influenza season, one of the worst of the decade, 30 participants had documented influenza infection -- 16/252 were in the vaccinated group while 14/66 were in the non-vaccinated group (P<.001). The relative risk of influenza in the vaccinated group was 0.29 (CI: 0.14-0.55); therefore, they had a risk of infection that was 29% lower than participants who were not vaccinated. In other words, the vaccine worked.
Of those who were vaccinated and became infected, 3 had a CD4+ cell count less than 200 cells/µL. Two of the unvaccinated patients with influenza had a low CD4+ cell count.
Looking at the immune responses to the vaccination, the researchers found that among patients without baseline antibody responses to the vaccine, immune responses to vaccination were more robust among those whose CD4+ cell count was greater than 200 cells/µL. Of those patients who had antibodies present at baseline (~30%), responses to the vaccine were excellent, regardless of CD4+ cell count. As expected, the patients who became infected with the virus despite vaccination mostly had suboptimal responses. Those patients who were on HAART had better specific CD4+ cell responses to influenza antigen.
The Bottom Line
The bottom line is that influenza vaccination is effective in preventing flu among HIV-infected individuals. These results suggest annual vaccination is worthwhile. The observed differences in response to the vaccine based on the presence of influenza antibodies likely reflect preserved immune responses. Patients who continue to produce antibodies respond briskly, whereas other patients who do not continue to produce antibodies respond only when their CD4+ cell count is high. This is interesting, but of minimal clinical value since such testing is not feasible. The point is that the majority of patients will respond, and this message needs to be communicated to patients.
This article was provided by TheBodyPRO. It is a part of the publication HIV JournalView.


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media poll
Arizona Wildcats
Coach: Sean Miller, fourth year (69-35)
Last year: 23-12 (12-6), fourth in the Pac-12
Preseason AP ranking: 12
Key player(s): Solomon Hill was a key player on the Wildcats' Elite Eight team two seasons ago and is now one of the best seniors in the nation and a Pac-12 player of the year candidate.
Rumble with the Buffs: Jan. 3 in Tucson and Feb. 14 in Boulder.
Marquee nonconference game(s): Dec. 15 vs. No. 10 Florida.
Outlook: The Wildcats, a team that blends a battle-tested core with the country's No. 1 recruiting class, are the preseason favorites to win the conference.
Coach speak: "I don't know if anybody in this conference, maybe even in college basketball, deserves to have a great senior year more than Solomon (Hill). He's paid the price," Miller said.
UCLA Bruins
Coach: Ben Howland, 10th year (208-97)
Last year: 19-14 (11-7), fifth (tied) in the Pac-12
Preseason AP ranking: 13
Key player(s): The Bruins' loaded roster includes potentially dominant big men (David and Travis Wear and Josh Smith) and two of the most highly touted freshmen guards (Kyle Anderson and Shabazz Muhammad) in the country.
Rumble with the Buffs: Jan. 12 in Boulder (CU doesn't travel to Los Angeles this season).
Marquee nonconference game(s): Nov. 19 vs. Georgetown, Dec. 1 vs. No. 20 San Diego State, Dec. 28 vs. No. 15 Missouri.
Outlook: UCLA, back in a renovated Pauley Pavilion this season, has the talent to win the conference and make a run at another Final Four if Howland can find the right chemistry.
Coach speak: "That's nice, but it really doesn't mean a whole lot. Bottom line is how you finish," Howland on the high preseson expectations for the Bruins.
Cal Bears
Coach: Mike Montgomery, fifth year (88-47)
Last year: 24-10 (13-5), second (tied) in the Pac-12
Preseason AP ranking: Unranked
Key player(s): Allen Crabbe, a first-team All-Pac-12 selection last season, is one of the best guards in the country. The 6-6 junior averaged 15.2 points and 5.7 rebounds for the Bears a year ago.
Rumble with the Buffs: Jan. 27 in Boulder and March 2 in Berkeley.
Marquee nonconference game(s): Dec. 2 at No. 23 Wisconsin, Dec. 9 vs. No. 18 UNLV, Dec. 15 vs. No. 16 Creighton.
Outlook: The Bears lose Pac-12 player of the year Jorge Gutierrez, but Montgomery has guided the program to a top-four finish in the conference in each of his four seasons in Berkeley.
Coach speak: "We were a little disappointed to be so close last year and have it in our grasp and not be able to sustain it down at the end and win it. I really value conference championships. I know how hard they are," Montgomery on Washington seizing the regular-season crown in March.
Stanford Cardinal
Coach: Johnny Dawkins, fifth year (75-59)
Last year: 26-11 (10-8), seventh in the Pac-12
Preseason AP ranking: Unranked
Key player(s): Aaron Bright and Chasson Randle are one of the best backcourt tandems West of the Mississippi.
Rumble with the Buffs: Jan. 24 in Boulder and Feb. 27 in Palo Alto.
Marquee nonconference game(s): Nov. 22 vs. No. 15 Missouri, Dec. 18 at No. 6 North Carolina State.
Outlook: The jury is out on the Cardinal. Will the team perform like it did in winning the NIT or underachieve during conference play again? The Buffs are certainly happy that Josh Owens graduated.
Coach speak: "Definitely I think the momentum will carry over this year. Towards the end of last year I think guys ... we just knew our roles and we just wanted to play in the postseason," Bright said of Stanford's impressive run to the NIT championship.
Washington Huskies
Coach: Lorenzo Romar, 11th year (219-113)
Last year: 24-11 (14-4), first in the Pac-12
Preseason AP ranking: Unranked
Key player(s): Romar recruits at a high level and has an outstanding backcourt (Abdul Gaddy and C.J. Wilcox) and a standout 7-foot center (Aziz N'Diaye).
Rumble with the Buffs: Jan. 16 in Seattle (the Huskies don't make the trip to Boulder this season).
Marquee nonconference game(s): Nov. 24 vs. Saint Louis, Nov. 29 at Connecticut.
Outlook: It will be difficult for the Huskies to repeat after losing Terrence Ross and Tony Wroten to the first round of the NBA Draft. Washington still has a dominant home-court advantage.
Coach speak: "I think Hec Edmundson Pavilion was there when Abraham Lincoln was president. It's been there a long time," Romar on Washington's famous home venue.
Colorado Buffaloes
Coach: Tad Boyle, third year (48-26)
Last year: 24-12 (11-7), fifth (tied) in the Pac-12
Preseason AP ranking: Unranked
Key player(s): Andre Roberson is the conference's reigning rebounding king and has also led the Buffs in steals the last two seasons. True freshman Josh Scott will have a major impact in the paint with sophomores Askia Booker and Spencer Dinwiddie expected to take the next step in the backcourt.
Marquee nonconference game(s): Dec. 5 vs. Colorado State, Dec. 8 at No. 7 Kansas.
Outlook: CU only has one senior but Boyle has assembled one of the most talented rosters in program history. The Buffs should get better each month and will be a tough out at the pac-12 Tournament again.
Coach speak: "It's a great time in our lives to be Colorado Buffaloes ... there's a lot of excitement around our program right now," Boyle said.
Oregon Ducks
Coach: Dana Altman, third year (45-28)
Last year: 24-10 (13-5), second (tied) in the Pac-12
Preseason AP ranking: Unranked
Key player(s): E.J. Singler is the clear-cut leader of the Ducks. The 6-6 senior forward averaged 13.6 points and shot 46.7 percent from the field last season.
Rumble with the Buffs: Feb. 7 in Eugene and March 7 in Boulder.
Marquee nonconference game(s): Nov. 16 vs. Vanderbilt, Nov. 23 at No. 18 UNLV.
Outlook: Altman will have to retool the roster with the loss of Devoe Joseph and the addition of six freshmen. The Ducks might have to settle for the NIT yet again.
Coach speak: "I think a number of the freshmen will progress at different rates throughout the season, but I hope (Dominic Artis and Damvean Dotson) can step up and help us right away," Altman on what newcomers have impressed him during preseason workouts.
Oregon State Beavers
Coach: Craig Robinson, fifth year (64-71)
Last year: 21-15 (7-11), eighth (tied) in the Pac-12
Preseason AP ranking: Unranked
Key player(s): The Beavers have a deep rotation filled with solid veteran players like guard Ahmad Starks and forwards Joe Burton, Eric Moreland and Devon Collier.
Rumble with the Buffs: Feb. 10 in Corvallis and March 9 in Boulder.
Marquee nonconference game(s): Nov. 15 vs. Alabama and Nov. 30 at No. 7 Kansas.
Outlook: The loss of Jared Cunningham a year early to the NBA probably makes the talented Beavers a middle-of-the-pack team instead of a true title contender.
Coach speak: "Even without Jared Cunningham I'm pretty excited. He'll be a tough guy to replace, but I'm confident and positive that every single player coming back knows how tough that is and has raised the bar for themselves," Robinson said.
USC Trojans
Coach: Kevin O'Neill, fourth year (41-55)
Last year: 6-26 (1-17), 12th in the Pac-12
Preseason AP ranking: Unranked
Key player(s): The Trojans are counting on three key players -- point guard Jio Fontan, forward Aaron Fuller and center Dedmon Dewayne -- who were lost to injuries during a disastrous 2011-12 campaign.
Rumble with the Buffs: Jan. 10 in Boulder (CU does not travel to Los Angeles this season).
Marquee nonconference game(s): Nov. 19-21 at Maui Invitational, Dec. 5 at New Mexico.
Outlook: The Trojans will be a surprise team in the conference this season and should have a chance to play in the postseason. There are some quality players on a roster that was ravaged by injuries a year ago.
Coach speak: "I think we're a team that is going to play with a chip in its shoulder," O'Neill said.
Washington State
Coach: Ken Bone, fourth year (57-46)
Last year: 19-18 (7-11), eighth (tied) in the Pac-12
Preseason AP ranking: Unranked
Key player(s): Brock Motum is one of the best players in the conference. The senior forward averaged 18.0 points last season and could win the scoring title again this season.
Rumble with the Buffs: Jan. 19 at Pullman (the Cougars don't make the trip to Boulder this season).
Marquee nonconference game(s): Nov. 19 at No. 7 Kansas, Dec. 5 vs. No. 21 Gonzaga.
Outlook: Bone has dismissed starting point guard Reggie Moore for "violating team rules," which is going to make it difficult for Washington State to climb the ladder in a deeper Pac-12.
Coach speak: "Just looking to accomplish a lot more wins than last season. I think if I can score more points than last year and that helps us win more games, then I'll do that," Motum said.
Arizona State Sun Devils
Coach: Herb Sendek, sixth year (88-75)
Last year: 12-19 (4-14), 10th in the Pac-12
Preseason AP ranking: Unranked
Key player(s): Carrick Felix, a versatile 6-6 guard/forward, is a potential all-conference selection. Jahii Carson, who redshirted last season, is a dynamic freshman guard.
Rumble with the Buffs: Jan. 6 in Tempe and Feb. 16 in Boulder.
Marquee nonconference game(s): Nov. 23 vs. Arkansas, Nov. 24 vs. No. 23 Wisconsin or No. 16 Creighton.
Outlook: The Sun Devils, like USC, should be moving up the standings this season. Felix and Carson, if nothing else, are going to create a lot more interest in the program.
Coach speak: "I assure you when (Carson) comes out (for the opener), he's going to be wearing a Arizona State shirt and he won't be wearing an 'S' and a cape," Sendek said.
Utah Utes
Coach: Larry Krystkowiak, second year (6-25)
Last year: 6-25 (3-15), 11th in the Pac-12
Preseason AP ranking: Unranked
Key player(s): Jason Washburn (6-10 center) is poised for a strong senior season and Jordan Loveridge (6-6 forward) could be a program-changing freshman for Krystkowiak.
Rumble with the Buffs: Feb. 2 in Salt Lake City and Feb. 21 in Boulder.
Marquee nonconference game(s): Dec. 8 at BYU.
Outlook: The Utes are going to win a lot more games this season due to a weak non-conference schedule. But this program is several years away from competing for the upper half of the Pac-12.
Coach speak: "A lot of people like to ask me, 'Why did you stay?' I believe in Utah, I believe in coach K, I believe that we're heading in the right direction. I like my team this year," Washburn said.

subset: commoncrawl


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Go to Austin City Limits' new blog at austincitylimits.org/blog for details about ticket giveaways for Them Crooked Vultures taping on 9/30, Mos Def followed by K'naan taping on 10/1 and Pearl Jam simulcast party on 10/3.
ACL Q&A in honor of Rock Hall designation
RSVP for 11 a.m. panel discussion here
RSVP for 1 p.m. panel discussion here
The Rock and Roll Hall of Fame and Museum will officially designate the Austin City Limits studio as a rock and roll landmark with an historic marker unveiling and educational programs at the KLRU-TV's Studio 6A on Thursday, October 1. In honor of this distinction, on Friday, Oct. 2, KLRU, ACL and the Rock Hall will host two 75 minute educational discussion panels moderated by Dr. Lauren Onkey, vice president of education and public programs at the Rock and Roll Hall of Fame and Museum, to spotlight the impact that ACL has on American culture. Both panels will take place in KLRU's Austin City Limits studio 6A.
The first panel will feature seasoned members of ACL's staff who will talk about the history and evolution of America's best known music television series. Doors will open at 10:30 a.m. and the discussion will start at 11 a.m. RSVP here for this panel
The 11 a.m. discussion will lay the groundwork for the second panel beginning at 1 p.m. which will feature artists Alejandro Escovedo, Patty Griffin and Martie Maguire talking about ACL's impact on music in general. Jim Henke, vice president of exhibitions and curatorial affairs at the Rock and Roll Hall of Fame and Museum will also join the panel to provide a historical perspective. Doors will open at 12:30 p.m. and the discussion will start at 1 p.m. RSVP here for this panel
Rock and Roll Hall of Fame press conference
Austin City Limits and Rock and Roll Hall of Fame press conference Aug 10th, 2009 from klru tv on Vimeo.
The Austin American-Statesman wrote an editorial about Austin City Limits in the 8/13 issue. Read it at statesman.com
ACL to be recognized as official Rock and Roll landmark
CLEVELAND (August 10, 2009) The Rock and Roll Hall of Fame and Museum today announced that Austin City Limits will be officially designated an historic rock and roll site as a part of the Museum's Landmark Series this coming October.
Terry Stewart, President and CEO of the Rock and Roll Hall of Fame and Museum, and Terry Lickona, Executive Producer of Austin City Limits, made the announcement at the KLRU-TV studio, home of the groundbreaking Austin City Limits series now in its 35th season.
ACL taping giveaway: M. Ward
KLRU will be taping a performance by M. Ward on Wednesday, August 5, at 8 p.m. Please visit the blog at austincitylimits.org for more details and to register for Space Available tickets.
Sneak preview of ACL with Willie and The Wheel
Program: Austin City Limits with Willie Nelson and Asleep at the Wheel
Time: 7 p.m.
Date: Sunday, August 2
Viewers in Austin will get an early look at a very special new episode of AUSTIN CITY LIMITS featuring Willie Nelson and Asleep at the Wheel, which was taped earlier this year for ACL's 35th anniversary season. The new episode marks the first time the two recording legends have shared the ACL stage, though both have performed many times separately in the show's 35-year history. The sneak peek event will air on KLRU-TV in Austin on August 2 at 7:00 pm as part of the PBS channel's summer pledge drive. It's the only chance to see the broadcast until it airs nationally on November 14.
Longtime fans of the show might recall that Willie Nelson appeared on the original pilot episode for AUSTIN CITY LIMITS, recorded in October 1974, and Asleep at the Wheel appeared on the first episode of the first official season in 1976. This new episode finds Nelson and Asleep at the Wheel performing songs from their recently released Willie and The Wheel (**** Rolling Stone) as well as classics like "On the Road Again" and "Always on my Mind."
Viewers making a pledge during the special August 2 broadcast between 7:00 and 9:30 pm will receive Willie Nelson and Asleep at the Wheel thank you gifts, including a limited number of ticket packages to see Asleep at the Wheel at the famed Lukenbach Dance Hall on August 8th.
Additionally KLRU-TV is giving away 100 pairs of tickets to a special simulcast of the August 10 AUSTIN CITY LIMITS taping featuring the Dave Matthews Band. Anyone pledging a gift of $100 or more during the first weekend of the pledge drive will be automatically entered for a chance to receive two tickets.
The 35th anniversary season of AUSTIN CITY LIMITS premieres nationally on October 3 with Dave Matthews Band. Other performers in the new season include Kenny Chesney, Pearl Jam, Elvis Costello, Ben Harper and Relentless7 and more.
ACL Space Available ticket giveaway
Austin's Heartless Bastards will tape an episode of Austin City Limits on Wednesday, June 3, at 8 p.m. KLRU will be giving away 75 pair (150 total) of Space Available tickets. Submit your name and email between now and noon Tuesday, June 2. Winners will receive 2 tickets each and be chosen through a random drawing. Please be in Austin or the surrounding community. These tickets do NOT guarantee admission. Space Available ticket recipients will receive an email notification with details about the taping. Register for your chance to get tickets on the Austin City Limits blog here
ACL chat with PBS
PBS Engage hosted a live web chat with ACL Producer Terry Lickona on March 16 as part of the SXSW Festival. You can read the transcript of that discussion and many others on the PBS Engage Web site.
Review: Austin City Limits Sarah McLachlan/Duffy
Austin City Limits "Sarah McLachlan followed by Duffy"
Saturday, Feb. 14, at 7 p.m.
Additional air dates: Wednesday, Feb. 18, at 10 p.m.; Friday, Feb. 20, at 11 p.m.
Preview the show at austincitylimits.org
For fans of intelligent, passionate songcraft, Sarah McLachlan hardly needs any introduction. The Canadian singer/songwriter has been an award-winning, critically-acclaimed, multi-platinum artist for two decades. Her 1987 debut album Touch launched the classically-trained Nova Scotia native as a star in the Great White North; subsequent albums Solace, Fumbling Towards Ectsasy and the Grammy-winning Surfacing made her an international sensation. Hits like "Possession," "Into the Fire," "Fallen" and "Building a Mystery" remain staples of adult album alternative radio. In addition to creating her own music, she's recorded numerous songs for soundtracks, including the Oscar-nominated "When She Loved Me" from Toy Story 2, curated the Lilith Fair music festival, launched a children's choir and percussion ensemble as part of a Vancouver-based outreach program and supported or established various charities around the world. Now, in support of her recently-released greatest hits album Closer: The Best of Sarah McLachlan and its single "U Want Me 2," she comes to studio 6A for her long-awaited debut episode of Austin City Limits.
Review: Austin City Limits with Foo Fighters
Program: Austin City Limits
Date: Saturday, Jan. 17
Time: 7 p.m.
Also Airs: Wednesday, Jan. 21, at 10 p.m.; Friday, Jan. 23
Preview the show: AustinCityLimits.org
Few bands striding the modern rock landscape can match the mix of mainstream popularity and critical credibility as the Grammy-laden Foo Fighters . Bandleader Dave Grohl had been quietly amassing a catalog of songs while still drumming for alt.rock kingpins Nirvana. When Nirvana dissolved following Kurt Cobain's suicide, Grohl began recording his tunes in earnest. After his demo tape sparked an industry bidding war, Grohl signed to Capitol and released the self-titled debut Foo Fighters. Grohl formed a band to tour the record and, barring a few personnel changes, has been making albums and hitting the road ever since. Acclaimed bestsellers like In Your Honor, There is Nothing Left to Lose and The Colour and the Shape sprinkled the radio with hits "Big Me," "Monkey Wrench," "This is a Call," "Best of You," "My Hero," "Learn to Fly" and more. Now the band brings its smooth blend of loud/soft dynamics and hard-rocking melodies to Austin City Limits' studio 6A in support of its Grammy-winning latest album Echoes, Silence, Patience & Grace, featuring the hits "Long Road to Ruin," "Let It Die" and "The Pretender."
– Michael Toland
About the Reviewer: Michael Toland is manager of national productions for KLRU and contributes music reviews to several online and print publications.


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Men should cut back on red meat, while young women should eat more of it, according to new national dietary guidelines.
The guidelines, produced by the National Health and Medical Research Council, are similar to the last version, released a decade ago.
But the council says since the last guidelines were released, the evidence has strengthened on the health benefits of breastfeeding, fruit and non-starchy vegetables, wholegrain cereals and milk, and on the link between sugar-sweetened drinks and weight gain.
The council says 60 per cent of Australian adults and 25 per cent of children are overweight or obese, and if trends continue, by 2025, 83 per cent of men and 75 per cent of women over the age of 20 will be overweight or obese.
The council says Australians are not eating enough vegetables, legumes and fruit, fish, seafood, poultry, eggs, nuts and seeds. According to the guidelines Australians should eat more wholegrain foods, such as wholegrain breakfast cereals and wholemeal bread, but reduce our intake of refined cereal foods, such as white bread.
It says we should consume more reduced fat milk, yoghurt and cheese, and lower our intake of high and medium fat dairy products.
It says we are eating too many ''energy-dense and/or nutrient-poor foods and drinks'', which are high in saturated fat, added sugars and added salt such as fried foods, cakes and biscuits, chocolate, lollies and chips.
The council says we should replace high fat foods that contain mainly saturated fats such as butter and cream with foods containing predominantly polyunsaturated and monounsaturated fats such as oils, nut butters and avocado, and limit our intake of salt and alcohol.
To revise the guidelines, the council modelled about 100 dietary patterns and looked at more than 55,000 pieces of peer-reviewed scientific research.


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Chris F wrote:And if none of these work - I'm going to see if there's a wave first light Wednesday?
Poo Stance wrote:I wanna see photos within the hour or I'm spambotting this forum to hell
Poo Stance wrote:You have till 8pm tonight or I'm creating a user for every 30mins that pass after that
You must have something on you now you can sort me out with? Just a wee phone pic, anything... I'm desperate man...
roberdy wrote:Poo Stance wrote:I wanna see photos within the hour or I'm spambotting this forum to hell
heh, they're on their way, took about 800 photos while away, couple of hours of GoPro footage although barely any decent stuff from surfing all from snrokelling and scuba! To be honest the waves were not epic for me, WA was a bit on the big and fricken scary side, Vic was good but slack at Bells and the only place I had really good waves the battery on the GoPro died after two waves, serve me for not charging it properly the night before. Anyway, there's some ok pics to put up, I need to go through them and load to flickr and then link on here, tedious ! Will get on some of it tonight for you Mr Stance
Chris F wrote:Agent Smith was down beach at 6am btw and said it was shite, so I got up and came straight to office. Plus Haar was in - in mid fucking August!!!!!
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A burst of flame from a J-2X Powerpack test-firing lights up the sky on Dec. 5, 2012 at NASA's Stennis Space Center in Mississippi. For the first time, the Space Launch System team invited Twitter followers behind-the-scenes for an all-day Tweet Chat, allowing the public to track test day activities and ask questions during this 1,286-second test.
The J-2X engine, built by Pratt & Whitney Rocketdyne of Canoga Park, Calif., will power the upper stage of NASA's Space Launch System, managed at the Marshall Space Flight Center in Huntsville, Ala. The new heavy-lift rocket system will launch the Orion spacecraft and enable humans to explore new destinations beyond low Earth orbit.


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How to Find the Best Office Printer
Whether you specifically own a business or company or you just want to make sure that your office has the best equipment, shopping for printers is a huge task. Whether it's a printer for small business or one for a large corporation, these business printers need to do lots of jobs, including printing in many different ways, scanning and working as office photocopiers. Some office printers are also in charge of sending faxes. When it comes to finding the best office printer for your office, use the following guidelines.
Top Microsoft Office 2010 Tips
Still using Microsoft Office 2010? It's hard to blame you. With the high cost to upgrade to a new version but the 2010 version still working, a lot of consumers are hanging onto the version of Office that came with their PCs. If you plan to stick it out with Office 2010, check out these tips to improve your experience.
Why Automation in IT Management Is Becoming More Pervasive
IT management is becoming more complex and sophisticated than ever. Simply having the right IT monitoring platform and IT monitoring software isn't enough to curb costs and achieve ideal productivity. Good network administrators demand high salaries and have many responsibilities, so automation is an effective way of maximizing that time and the employer's investment.
Microsoft Office 2007
Microsoft Office 2007 continues to reign as one of the most-used versions of the popular Office productivity suite. Despite its age, the software remains compatible with practically every email client and software package. Though other Microsoft products such as Office 365 have become widely available, many individual and business users prefer to buy and use the older version. Here, you will discover why.
Improve Your Windows 7 Experience With These Tips
Windows 7 is an operating system that is incredibly popular around the world. You can buy Windows 7 online for great prices if you find a special promotion. You can also purchase Windows 7 Professional version that is great for small and large businesses. There are a few tips you can follow to get the most out of Windows 7.
The New And Improved Microsoft Office 2010
Let's face it. Today, most of us use computers on a daily basis. Whether you're a student, professional, or homemaker, chances are you find the need to prepare documents as part of your daily life. However, if you're using an older version of Microsoft to complete these tasks, there's a new and improved one that contains a number of exciting features, and there are a few notable reasons why you should buy Microsoft Office 2010 today.
How Security Guard Management Software Can Save You Money
The security industry is thriving but it's also competitive and long-standing companies might face threats from newer companies if they aren't prepared to compete. Security guard management software is playing an increasingly central role in the security industry, but some companies haven't yet adopted all this software has to offer. Here are a few of the ways security software can save your company money.
4 Reasons Why Real Estate Agents Need CRM
Real estate agents who want to succeed in the industry and continue to grow as a professional can take advantage of Real Estate CRM. The tool is increasing in popularity and offers a variety of benefits to agents to improve their workflow. When you want to understand the benefits of Real Estate CRM Software, there are a few advantages to consider to boost your productivity.
Windows 10.1
Summary: Windows 10.1
Windows 10
Summary: Windows 10


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CLERMONT, Fla.—Day three of the NTC Classic proved to be a rough going for UMass Boston Softball (2-4), as the Beacons fell 7-0 to SUNY Geneseo (4-4) and 4-0 to UW Eau-Claire (6-1), in a pair of contests at the NTC Main Complex.
The Beacons struggled offensively all afternoon, as they mustered just nine hits against two dominant out-of-region pitchers.
Junior Erika Vecchiet (Pequannock, N.J.) led the Beacons with three hits and some stellar defense split between first and second base, while senior third baseman Kelsey Souza (Braintree, Mass.) added two hits and made several diving stabs at the hot corner.
Sophomore left fielder Kristina Bove (Medford, Mass.) recorded one of UMass Boston's two extra-base hits on the day with a triple to right field, while Natalia Bouyea (East Longmeadow, Mass.), Taryn Asta (Marshfield, Mass.) and Emily Gray (New Bedford, Mass.) all added singles on the day.
GAME ONE: SUNY GENESEO 7, UMass Boston 0
After a mostly even first two innings, SUNY Geneseo put across three runs apiece in the third and fourth frames, thanks to six Beacons errors. The offensive explosion would be more than enough, as UMB mustered just six baserunners in the contest.
Errors would be the story of the game, as six of the seven Knights runs that came across were unearned.
Gray did all she could to keep the team in the game, allowing one earned run over seven innings in her third career complete-game, but couldn't overcome the early 7-0 deficit.
Offensively, Vecchiet reached base three times with two singles and a walk, while Bouyea, Bove and Gray accounted for the Beacons final three hits.
The Beacons put multiple baserunners on in just two of the seven innings, but failed to connect with a runner in scoring position.
GAME TWO: UW EAU-CLAIRE 4, UMass Boston 0
The Beacons would put up a much better effort in Game Two, but once again struggled to get themselves out of an early hole.
UW Eau-Claire struck for one run in the first inning and three more in the second, before the Beacons shut down the BlueGolds for the final four frames.
Sophomore pitcher Michelle Zullo (Everett, Mass.) recovered from a slow start to allow just five hits and three earned runs over six innings of work. Zullo struggled with her command for the second straight start, issuing five free passes, but also added four strikeouts.
Souza led the Beacons with two of their four base hits, including a double, while Asta and Vecchiet chipped in for the final two singles.


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Revealing The Leopard
series: Nature
air date: 8/02/13 3:00 AM
Leopards are the ultimate cat. They are the ultimate cat. They are the most feline, the most intelligent, the most dangerous, and, until recently, one of the least understood. Leopards hunt from South Africa to Siberia, from Arabia to Sri Lanka, and are the most widespread predator of their size on land. A leopard is a cat that walks by itself, unseen, secretively. They are the beautiful killers that live in the shadows. This film accumulates the evidence and puts together a psychological profile of this extraordinarily cunning cat. We learn how these cats rarely move without a completely premeditated strategy.
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Results 1 to 5 of 5
#1 Are Cell Phones Roasting Your Sperm
- Join Date
- Aug 2005
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- 22,891
As if the invisible spectre of cancer weren't enough, now you might need to worry a bit about what cellphones are doing to your testicle. A new study in the Journal of Andrology says phones might be ruining your sperm.
The report combines a variety of prior studies, concluding some rather disconcerting stuff for those of us with testicles, or for those of you with testicled loved ones:
Altogether the results of these studies show that RF-EMR decreases sperm count and motility, and increases the oxidative stress..... In human beings, two different experimental approaches have been followed, one has explored the effects of RF-EMR directly on spermatozoa and the other has evaluated the sperm parameters in men using or not mobile phones...... The results show that human spermatozoa exposed to RF-EMR have decreased motility, morphometric abnormalities, and increased oxidative stress, whereas men using mobile phones have decreased sperm concentration, motility (particularly the rapid progressive one), normal morphology, and viability..... These abnormalities seem to be directly related with the length of mobile phone use.
Cell Phone Maxium RF Power levels
The rate at which radiation is absorbed by the human body is measured by the Specific Absorption Rate (SAR), and its maximum levels for modern handsets have been set by governmental regulating agencies in many countries. In the USA, the Federal Communications Commission (FCC) has set a SAR limit of 1.6 W/kg, averaged over a volume of 1 gram of tissue, for the head. In Europe, the limit is 2 W/kg, averaged over a volume of 10 grams of tissue.
In the USA, the Federal Communications Commission (FCC) has set a SAR limit of 1.6 W/kg, averaged over a volume of 1 gram of tissue, for the head. In Europe, the limit is 2 W/kg, averaged over a volume of 10 grams of tissue. SAR values are heavily dependent on the size of the averaging volume. Without information about the averaging volume used, comparisons between different measurements cannot be made. Thus, the European 10-gram ratings should be compared among themselves, and the American 1-gram ratings should only be compared among themselves
One well-understood effect of microwave radiation is dielectric heating, in which any dielectric material (such as living tissue) is heated by rotations of polar molecules induced by the electromagnetic field. In the case of a person using a cell phone, most of the heating effect will occur at the surface of the head, causing its temperature to increase by a fraction of a degree. In this case, the level of temperature increase is an order of magnitude less than that obtained during the exposure of the head to direct sunlight. The brain's blood circulation is capable of disposing of excess heat by increasing local blood flow .
The 10 smartphones with the highest radiation
T-Mobile MyTouch 3G (1.55 W/kg)
Blackberry Curve 8330 (1.54 W/kg)
Palm Treo 600 (1.53 W/kg)
T-Mobile Shadow (1.53 W/kg)
Palm Treo 650 (1.51 W/kg)
Blackberry Curve 8300 (1.51 W/kg)
Blackberry Bold 9000 (1.51 W/kg)
Sony Ericsson P910a (1.50 W/kg)
HTC SMT 5800 (1.49 W/kg)
BlackBerry Pearl 8120/8130 (1.48 W/kg)
The T-Mobile MyTouch 3G, an HTC smartphone powered by Google Android that debuted to lots of fanfare this summer, topped the list of the worst radiation offenders. However, other popular smartphones dominated the list as well, especially BlackBerries and Treos. The BlackBerry Curve, the best-selling smartphone on the market in 2009, was a close second on the list, and it was joined in the top 10 by its cousins, the BlackBerry Pearl and the BlackBerry Bold.
The 10 smartphones with lowest radiation
Nokia 9300i (0.21 W/kg)
Nokia 7710 (0.22 W/kg)
T-Mobile MDA Wiza200 (0.28 W/kg)
Samsung Impression SGH-a877 (0.35 W/kg)
Nokia 9300 (0.44 W/kg)
Samsung Propel Pro SGH-i627 (0.47 W/kg)
Samsung Gravity SGH-t459 (0.49 W/kg)
BlackBerry Storm 9530 (0.57 W/kg)
Nokia E90 (0.59 W/kg)
Nokia N96 (0.68 W/kg)
Nokia, with five models in this top 10, and Samsung with three, were clearly the winners in terms of smartphones that emit the least amount of radiation. Its also interesting to note that although both of these companies produce dozens of different models, neither of them had a single model that made the list of the worst radiation offenders. The surprising member of the low-radiation club was the BlackBerry Storm (RIMs first touchscreen device) since so many of the other popular BlackBerries were on the high-emitters list.
If theres another phone youd like to look up, here is the full list......
Also, when seriously evaluating any smartphone on any of these lists, make sure you click through and look at the EWG page with the details of the phones radiation emissions using different connections and doing different activities. The number listed is the maximum radiation rating, but it can be deceiving in some cases until you look at the whole picture.
Only if you keep your cell phone in the pocket next to your nuts. Of course, some guys do that, and set their phones on vibrate and eagerly anticipate phone calls. :D--Odysseus
Sic Hacer Pace, Para Bellum.
Before you can do things for people, you must be the kind of man who can get things done. But to get things done, you must love the doing, not the people!
- Join Date
- Aug 2005
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08-22-2011, 10:48 AM--Odysseus
Sic Hacer Pace, Para Bellum.
Before you can do things for people, you must be the kind of man who can get things done. But to get things done, you must love the doing, not the people!
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