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A Little Bit of Stupid
"Um, Cullen, can I ask you something?" Mike had grasped his neck with one hand, clearly a nervous gesture. Edward thought he looked like he WAS about to ask him out. He kept his face blank, in case the urge to laugh should well up in him again. The whole situation was bordering on the absurd.
1. Chapter 1
Rating 5/5 Word Count 1094 Review this Chapter
The innocuous thought intruded into Edward's mind in the middle of the physics exam. Everyone else in the room was thinking about the second law of Thermodynamics – which question Edward had answered about twenty minutes previous. But not Mike Newton. Mike was thinking about the same thing he was ALWAYS thinking about, though Edward wasn't sure yet exactly how his current thoughts related to the usual topic.
How angry can it make him, anyway? And I'm not afraid of him!
Edward scowled down at his paper, unconsciously looking – for the first time ever – like maybe he was having difficulty with one of the questions. He wasn't. He never did. He answered another question, suppressing a sigh, and forced himself not to look over at Mike.
What's so great about Cullen, anyway? Mike was asking himself sullenly. I mean, sure he's a pretty face and all, but - I did NOT just admit that Edward Cullen is pretty. Dammit, what question was I on?
Edward couldn't help it. His shoulders absolutely shook with laughter he wasn't allowed to voice. The teacher caught his eye at just that moment, a disapproving expression on his face, and Edward smiled down at his paper, trying to look properly chastised. He couldn't wait to tell Jasper about THIS one.
He probably wouldn't tell me anyway. He'll know why I'm asking.
This was true. Edward would know that WHATEVER it was that Mike wanted to know, he wanted to know it because of Bella. But so far, he hadn't been able to glean exactly what it was Mike was after. Which was annoying.
He finished the last question, and then shuffled his papers back to one of the middle pages, as if he was going back to work on something he'd skipped. Except that he hadn't skipped anything. He never did.
Maybe I can just get close enough to tell....knock his books out of his hands or something? No, that's stupid. He'll think I'm trying to ask HIM out.
Again, Edward had difficulty reigning in his amusement. He snorted, and then tried to cover it with a cough. But, of course, he hadn't actually coughed in decades. He hoped it sounded right. Mike was looking at him, now, but he kept his eyes on his paper. The teacher had already given him one dirty look. He was over his quota for the day.
By the time the exam ended, Mike had still not actually thought about what it was he wanted to know. And Edward was getting frustrated about it. He didn't want to be caught by surprise, but he resigned himself to the possibility as more and more people stood to turn in their tests.
When half the class had been to the teacher's desk, Edward took his test up and laid it in the pile with the others. He tried to avoid the teacher's eyes, not wanting to come across as gloating. He knew he'd aced it. He always did.
Four minutes later, when the bell rang, Edward didn't rush out of the room, as was his usual habit when Bella wasn't present.
Remember to say cologne, not perfume, he heard Mike reminding himself in his head. And it clicked. He FINALLY knew what Mike was planning to ask. He had to force himself not to laugh again. He finished gathering up his books and turned toward the door. Mike had just walked through. No. I can't. I just – can't.
Edward couldn't resist grinning as Mike abandoned his plan entirely, even though he was making himself as available as inhumanly possible. Even though Edward now WANTED him to ask, if only for the entertainment value. Jasper was going to laugh half the night over this. He passed Mike in the hallway and met his eyes, thinking to encourage him. No dice. Mike shivered, and Edward remembered, too late, to tone down his smile and show less teeth.
At the last second, just before he'd passed Mike by entirely, Edward fumbled his books on purpose, and they scattered all over the floor at his feet. He swore, trying not to sound amused. Predictably, when he bent to pick them up, good ole' Mike Newton helped him out.
They knelt there for a minute in the hallway, Mike trying to talk himself into saying it and Edward trying not to give away that he already knew the question, or that he'd already come up with an answer.
"Here," Mike said half-heartedly, handing Edward half his books as they both stood up.
"Thanks." Edward turned away, disappointed. It wasn't very often that anything truly entertaining happened when Bella wasn't around. The day had been remarkably dull aside from this.
"Um, Cullen, can I ask you something?" Mike had grasped his neck with one hand, clearly a nervous gesture. Edward thought he looked like he WAS about to ask him out. He kept his face blank, in case the urge to laugh should well up in him again. The whole situation was bordering on the absurd.
"Sure, Mike, what's up?"
"I was just wondering....do you – you know – have a favorite perf-cologne, I mean, that you wear?"
Edward raised an eyebrow, trying to act as if the question surprised him, but he could feel his lips turning up a little, and couldn't quite manage to force them back down. "I never wear anything but Drakkar Noir," he replied, winking. After all, what self-respecting vampire would wear anything else? he added silently, far more amused than he figured he really should be. Cologne. Of all the stupid things to ask.
"Thanks," he said again, gesturing to his books before continuing down the hall as if this wasn't the weirdest conversation he and Mike Newton had ever had.
The worst part was after, though. Mike stood in something of a trance in the middle of the hallway and watched him leave. Damn. If that's the look he gives her, no wonder she never looks away. Oh hell!
Edward started laughing in earnest at the whispered conversation that suddenly broke out behind him.
"Are you staring at Cullen's ass?" Eric Yorkie asked Mike gleefully. "You know he'll never go out with you, right?"
"Shut up! I was not. I was asking him a legitimate question!" Mike snapped in response. I'll never live this down.
Edward disappeared into the cafeteria as fast as he could without attracting notice, and went to sit with a very amused-looking Alice. She didn't comment, though, and he didn't offer to share his thoughts. He did, however, wonder just how strongly Mike Newton would smell of Drakkar when they got back to school the next day.


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Rising for the second day, the rupee today strenghtened by 12 paise to end at a three-week high of 62.1 against the dollar on capital inflows linked to rise in stocks and a weak American currency ahead of US retail sales.
The rupee traded in a tight range in otherwise listless trade as participants eyed domestic industrial production data and retail inflation figure, said forex traders.
After forex markets closed, the government said retail inflation dropped to 8.79 per cent in January versus 9.87 per cent in December. IIP contracted 0.6 per cent in December.
The rupee commenced higher at 62.08 a dollar from last close of 62.22 but immediately touched a low of 62.1750. Later, it recovered and rose to a high of 62.04. It finally concluded at 62.10, showing a rise of 12 paise or 0.19 per cent. Yesterday, it had gained 21 paise or 0.34 per cent.
Rupee's closing value of 62.10 against dollar is the highest since 61.93 on January 23, 2014.
Pramit Brahmbhatt, CEO, Alpari Financial Services (India) said: "Yesterday, dollar declined against its rivals after that country's major trade partner China reported stronger than expected exports growth in January. Taking cues from this, the rupee appreciated. The trading range for the spot rupee is expected to be within 61.80 to 63.20."
The dollar weakened against all but two of its 16 major peers on fears thaty US retail sales were sluggish last month.
The benchmark S&P BSE Sensex today improved further by 85.12 points or 0.42 per cent. As per stock exchange data, FIIs pumped in Rs 200 crore in equities today.
Forward dollar premiums softened further on sustained receipts by exporters. The benchmark six-month forward dollar premium payable in July declined to 241-243 paise from 242-246 paise and far forward contracts maturing in January also eased to 482.5-484.5 paise from 484.5-486.5 paise previously.
The RBI fixed the reference rate for the dollar at 62.1250 and for the euro at 84.7215.
The rupee fell back against the pound to end at 102.76 from 102.20. It rebounded to 84.58 per euro from 85.01 previously. It, however, improved further to 60.65 per 100 Japanese yen from 60.79.
Narendra Modi or Rahul Gandhi? Who will win the battle royale of the Lok Sabha Elections 2019?
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subset: commoncrawl


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Heavy Lift Crane - HLC
The Liebherr heavy lift crane series (HLC) is designed especially for the installation of wind farms and for the oil and gas as well as the decommissioning sector.
Liebherr heavy lift crane
The new heavy lift crane series is the biggest offshore crane Liebherr has developed so far.
Heavy lift crane series - lifting height
The new Liebherr HLC series has a lifting height in excess of 180 metres, 23 metres higher as the top of the world famous Cologne Cathedral.
HLC series - lifting capacity
The Liebherr heavy lift crane has a maximum lifting capacity of up to 5,000 tonnes at more than 30 metres outreach. The crane would be able to lift 9 fully loaded A380 airplanes in one go.
Heavy lift crane series - maximum radius
The maximum radius of the Liebherr HLC series is 160 meters! Even a football pitch seems small in comparison!
HLC series
|HLC series
|Overturning moment (max.)
|295,000 tm
|Main lift capacity (max.)
|5,000 t
|Main jib length (max.)
|160 m
Advantages at a glance
The well proven A-frame design enables large lifting capacities with a low total weight of the crane at the same time.
For the HLC series, the A-frame is available in a foldable version on customer request. This innovative feature allows passage under low bridges and reduces transit times.
The combination of swivel bearings, slewing mechanisms, winches and the Liebherr Litronic system ensures precise positioning as well as exact movement of the loads. Together with the powerful electro-hydraulic drive, this guarantees optimum control of the equipment in all operating situations.
The HLC can be deployed as a heavy duty crane for the assembly and maintenance of offshore installations. At a maximum of 5,000 tonnes, the enormous lifting capacity of the crane facilitates the installation of next generation wind turbines as well as loading and subsequent installation of heaviest foundations.
Next to this commissioning and decommissioning of offshore installations such as oil and gas platforms is another area of use.


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Beth Anne needed a new logo design and created a contest on 99designs.
A winner was selected from 228 designs submitted by 75 freelance designers.
Law Firm needs new logo to be used on its website banner and other marketing. If could be used on letterhead, business cards, etc., all the better. Hopefully, will look good when used in small size and larger size.
The name on the logo will be The TurleyLaw
Firm . We want it to be modern looking and
progressive, but not too over thetop. Will be
used on banner of new website and in other
marketing. We aremaritime lawyers
(representing people getting injured on boats
and ships) fromSan Diego, California. A
nautical inspired theme incorporated into
thedesign may be desirable. Thoughthis is
not a must. The logo must convey a
professional image.
- Colors- Marine Blue
- Light Blue
- Blue
- White
- Look should be Modern Progressive, perhaps with a modern looking font. Need to have the APLC included in the logo but does not have to be the same size font.
- no scales of justice
- no boats/ships in the logo
- no anchors
Find out how a design contest works or learn more about our logo design services.


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redheards999 Senior Thursday 15/11/2012, 21:12
A guild for anyone that wants to rid Urban Rivals of the evil that lurks near. Join and help us fight for what is right. Must be active if u are gone for longer then 4 weeks u may be disband from the guild. Please use the guild board if u have any questions. There will be guild tournies once every two weeks or so. Got to the link if u would like to join and again all r welcomed http://www.urban-rivals.com/en/guilds/guild/?id=1857480
Shanks Guru Colossus E X C A L I B U R Friday 16/11/2012, 18:57


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This page contains questions about disclosure and discovery procedures under the rule amendments effective November 1, 2011 and the committee's answers to those questions. The answers are in the nature of committee notes. They have not been reviewed or approved by the Supreme Court, and they are not binding on any court. We hope that the reasoned and considered opinions they express are persuasive. Each link is a brief summary of the topic. Click on the link to read the full question and answer.
Depositions — Length of depositions.
Disclosures — Exclusion as sanction for failure to disclose
Discovery deadlines — Effect of later-added parties on discovery deadlines.
Discovery deadlines — Monitoring discovery deadlines.
Discovery deadlines — When to start discovery.
Discovery tiers — Definition of "damages" for designation of a discovery tier.
Discovery tiers — Designating a tier without specified damages.
Discovery tiers — Effect of discovery tier on limiting the judgment.
Discovery tiers — Effect of not designating a discovery tier.
Effective date of disclosure and discovery rules.
Expert discovery — Data relied upon by an expert.
Expert discovery — Effect of premature disclosure of expert witnesses.
Electronic filing — "3-day mailing" rule.
Expert discovery — Timing of disclosures, elections and extensions.
Extraordinary discovery — Reaching the limits of standard discovery.
Sharing discovery between aligned parties.


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Recipe Review: Watermelon-Cucumber Refresher Straight Up Cocktails and Spirits
Looking for a mouthwateringly good warm-weather cocktail with garden-fresh ingredients? How about a savory-sweet Watermelon-Cucumber Refresher?
I was leafing through DIY Cocktails when this summer sipper immediately caught my eye. A drink made from cool slabs of sweet watermelon and soothingly vegetal cucumber seemed like the perfect thing on a hot day. The curious thing about the recipe, though, was that all of its ingredients were listed in parts instead of the ounces found in most cocktail books. And its ingredients were each given a descriptive designation. Categories like "strong," "sweet," and "sour."
Turns out that "Ditch the Recipe, Use the Ratio," is the cheerful message of this engagingly instructive, encouragingly freewheeling cocktail book. Providing the thirsty reader with 10 basic recipe ratios, or templates, to work from, it opens the doors to creativity while making sure flavors stay beautifully balanced.
But let's get back to that deliciously cool watermelon-cucumber cocktail. One of many recipes in the "Life of the Party" section of the book, it sits alongside classic sours such as Margaritas, Sidecars, and Cosmopolitans. It uses a homemade watermelon-cucumber-mint juice as a base, combining it with something strong (vodka), something sweet (triple sec), and something sour (lime juice).
I gave the recipe a try and it truly was refreshing. The watermelon-cucumber-mint juice took a few extra minutes to make, but was well worth it (and the leftovers came in handy as you can see in my suggested riffs below).
Watermelon-Cucumber Refresher (adapted from DIY COCKTAILS: A Simple Guide to Creating Your Own Signature Drinks by Marcia Simmons & Jonas Halpren)
3 parts vodka (I used 1 1/2 ounces) [Note: tequila makes a great recipe variation too]
1 part (1/2 ounce) triple sec
1 part (1/2 ounce) watermelon-cucumber-mint juice*
1 part (1/2 ounce) fresh lime juice
Combine all ingredients in a cocktail shaker with ice. Shake and strain into a cocktail glass. Garnish with a watermelon and/or cucumber slice and/or a sprig of mint.
*Watermelon-Cucumber-Mint Juice
2 parts (I used 2 cups) diced, seeded watermelon flesh
1 part (1 cup) peeled, seeded cucumber
2 sprigs mint (10-12 leaves)
Whir all ingredients together in a blender. Strain through a fine-mesh strainer. Discard pulp.
Some Possible Riffs:
- Swap out vodka for tequila. I tried this one and found it made a great variation on a Margarita. (I haven't tested it yet, but would also like to try subbing in a slice or two of jalapeño for the mint.)
- Use the watermelon-cucumber-mint juice as the base for a highball. Add a shot of vodka, tequila, or mezcal; a squeeze of lime; some sugar if you'd like; and a healthy splash of club soda. A good way to use up leftover juice. So easy and so good.
- Make a non-alcoholic cocktail. I tried this one after a sweaty workout on a hot day. Skip the booze and simply add a squeeze of lime and a splash of club soda to the watermelon-cucumber-mint juice. Incredibly refreshing and restorative.
Buy the Book: DIY COCKTAILS: A Simple Guide to Creating Your Own Signature Drinks by Marcia Simmons & Jonas Halpren, Adams Media, 2011, $11 from Amazon.
Nora Maynard is a longtime home mixologist and an occasional instructor at NYC's Astor Center. She is a contributor to The Business of Food: Encyclopedia of the Food and Drink Industries and is the recipient of the American Egg Board Fellowship in culinary writing at the Writers' Colony at Dairy Hollow. She previously covered food and drink in film at The Kitchn in her weekly column, The Celluloid Pantry.
Related: How to Create Your Own Cocktail Recipes
(Images: Nora Maynard)


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|These little gems are in my shop !
|I'm stocked and ready to sell some ASCP!!
|These little gems are in my shop !
|I'm stocked and ready to sell some ASCP!!
Cute idea, Janet!
I have become such a big fan of those little trees! I put a forest around something every year for Christmas. This year it's Earl's grandmothers cottage teapot on a shelf. It looks like it is sitting in a little forest. I'm all for more glitter:>)
Great tip about the Diamond Dust; thanks for sharing. The little forest looks enchanting. I hope to try this if I can find some cute bottle brush trees.
Oh honey how I wish I were going to there for your show in Warrenton. I would love it.
Your trees are just the cutest and I love how you showed us how to capture the same look.
Have fun this weekend and if you get a chance to come by please do I am having a long over due giveaway
Love ya
You are really getting me into the Christmas spirit! I love your flocked tress. Mr. Snowman looks so cute peeking through his forest. Good luck with your open house and demonstration today! I wish I could be there.
That's lovely! Happy Holidays!
They are gorgeous!
neat idea! It looks so pretty! I love how you glued the crystal candle sticks on the bottom so clever!
Hello and happy holidays!
This is just such a fun tutorial. You have such darling and clever ideas! Thank you for sharing!
I can just hear Secret Agent now, "Honey, where is my tea cup? Oh and why is there a lovely snowy tree growing out of my slippers??"
I love them, and the bottle brushes are so unexpected! I'm going to try the Snowtex today for my secret ornament you helped me with!
Now this is just darling!!! This "Youngin" is LOVING this!!! Haha. I'm your newest follower and would love for you to follow me on your next visit!!!
Your newest bloggy friend,
Aimee from ItsOverflowing.com
holding the brush with your teeth, now that is dedication, lol. i love this, they are all so gorgeous and sparkly! great idea with the upside down wine glass, too.
Thanks for explaining so well. I bought some German glass glitter and LOVE it, but if there is something just as good for less, I'll be so happy to find it! I trip to Michaels is now in my plans for this week! :) I made some trees up for my Christmas table as well. I love them and love learning new ways and styles to create! :)
Just stopping by to let you know I featured this project on my Christmas tree craft collection.
Please grab a featured button from my side bar when you get a chance. Thanks
Love these trees! What wonderful little hostess or acquaintance gifts they would make. For a more expensive gift, how about putting them on the china cup that matches your friend's china pattern?


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Vintage Style Butterfly Entomology Locket Necklace GB
Handmade Cameo Locket Necklace Brand new in gift box. This gorgeous locket has one of our altered images set under a resin cabochon. The locket itself has a distressed antique goldtone plate and is patterned on both sides. The locket opens and has spaces for 2 photos. Under the back photo there's a small space a keepsake/lock of hair. The locket measures 47mm by 36mm and is hung on 30" matching chain. This is one of our handmade items


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The story of humble London businessman Quan (Chan), whose long-buried past erupts in a revenge-fueled vendetta when the only person left for him to love - his teenage daughter - is taken from him in a senseless act of politically-motivated terrorism. In his relentless search for the identity of the terrorists, Quan is forced into a cat- and-mouse conflict with a British government official (Brosnan), whose own past may hold clues to the identities of the elusive killers.
Director: Martin Campbell
Writer: David Marconi
Stars: Jackie Chan, Pierce Brosnan, Rufus Jones, Lia Williams
Interviews with Martin Cambell, Jackie Chan and Pierce Bronsan
Main Page


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Parent Directory | Revision Log
|Links to HEAD:
|(view) (download) (annotate)
Check for earlier version, not different version (bug #519558 by kavol).
Add 340x device mask (bug #519314 by Joerg Neikes). Sort mask logic by version. Add braces to variables. List myself as maintainer.
Use readme.gentoo.eclass (bug #457594).
Check for lspci before use.
Update documentation URL.
Remove duplicate PCI ID.
simplify nvidia-driver-get-card(); tidy
Remove ebeep because newer nvidia-drivers have EAPI=4.
Actually make the mask print work. Yay for typos.
Update to support a new legacy series
fix random bugs in eclass documentation, and convert to new @AUTHOR tag
Forcibly lowercase the IDs scavenged from the nVidia documentation for 177 as they do not work otherwise. As pointed out by Kevin Bowling <firstname.lastname@example.com> in bug #228661.
Add 173 level masking for GeForce FX series cards, being discontinued in 177.
Chainsaw is taking over maintaining nvidia-drivers
add eclass docs for nvidia-drivers. bug #210027. patch provided by mren <email@example.com>
remove old style nvidia-driver version number since they're gone. this fixes bug #202104
update NVIDIA drivers mask messages for users
Apply whitespace checks from repoman to eclasses.
typo on my part. not versionator doc issue.
versionator seems to be documented backwards
it's version_compare, oops
check versions so we don't output the warning when they are emerging a proper version
Better link provided by email@example.com
Add some more notes and docs
Add new nvidia-driver eclass for determining nVidia card models that match driver versions
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Search by Body Style
Welcome to Lithia
New & Used Car Dealers
There's no two ways about it. We spend a lot of time in the car. Many of us with a two-hour, or longer, commute per day. Doesn't it stand to reason then, that instead of getting sucked into the same mundane routine, it would be better to upshift your ride with a new or used car from Lithia?
How will a new 2018-2019 model such as the Chrysler 300, Toyota Corolla, Honda Civic, Subaru Outback, Volkswagen Jetta, and Jeep Cherokee elevate your daily commute?
Well, for one: the peace of mind that comes with an impressive list of cutting-edge safety features. Additionally, there are a host of creature comforts. These come in the form of supportive seating, temperature control, a killer sound system and other A-list entertainment options. Everything about the new vehicles we supply - from their time-tested endurance to their fun-inspired performance - is designed to give you something to look forward to. If you're looking for a specific car manufacturer, visit our showroom page to find all the new vehicles from your favorite make, like Jeep, Toyota, and more.
Of course, at Lithia, you're not obligated to commit to new-car prices. We have carefully handpicked a truly reliable, like-new collection of used cars - made by Toyota, Jeep, Subaru, Hyundai and Honda as well as other best-selling brands. No matter where you call home, we also offer luxury brands too, and it's never been easier to browse from the comfort of your couch using our online showroom.
Ready to Drive Your Next Car Home?
Lithia is ready to discuss car loan and lease solutions
If you can already picture the vehicle you've had your eye on in your driveway, remember you can always ask Lithia for help. Our financing team is prepared to explain your car loan and lease options in detail after you've gone for a test drive. That way, you can know exactly what it will cost to get back behind the wheel and cruise the streets in style.
Lithia is also here to help you with your car service and maintenance. Our service and car repair centers are ready to help your vehicle live a long life with genuine OEM parts (which you can order for yourself as well).
Lithia Motors' new car inventory includes a variety of great models by many top automakers including the Volkswagen Passat, Honda HR-V, Toyota Camry, Kia Sorento, Subaru Forester, and Nissan Rogue. It doesn't end there! You will also discover new cars, trucks and SUVs like the Ram 1500 and Ford F-150.
New and Used BMW, Mercedes-Benz, Acura and Audi in Medford and Beyond
BMW, Mercedes-Benz, Acura and Audi are bringing a lot of exciting new luxury cars to our showrooms for the current model year. Come explore your favorite model's fresh new look, enhanced comfort and convenience, and updated safety features today. We're happy to share complete specs, compare models (including the Mercedes C-Class, BMW X5, Audi A4, and Acura MDX,) and arrange test drives.
It'll be hard to choose between the BMW 3 Series, Mercedes-Benz C-Class, Acura RDX, Porsche Macan, CADILLAC CTS or any of the highline models available through Lithia Motors luxury car dealerships.
Lithia Guarantees:
Pre-Owned Vehicle Warranties
Lithia's pre-owned vehicles are known for quality, and you can find a safe used car and a reliable truck at Lithia dealers. You can check on car trade-in value with Lithia's built-in Kelly Blue Book trade-in evaluation tool and used vehicles all come with vehicle history reports.
Vehicle Repair Service
Lithia Motor's factory trained auto mechanics and technicians provide quality vehicle service and auto repair (lube jobs, tire rotations, clutch, brakes & more) with Original Equipment Manufacturer (OEM) and accessories. You can locate a car repair and auto service shop near you and schedule a car repair online at any of the Lithia dealers' websites.
Auto Body and Paint Shops
Full service auto body and paint shops are in most Lithia markets. We hope you will never need our auto body shop services, but if you do, we are confident our highly trained staff will repair your vehicle "like it never happened". Locate a full service Lithia Body and Paint Shop near you.
About Lithia Motors
Lithia Motors, Inc. is one of the largest automotive retailers in the United States and is among the fastest growing companies in the Fortune 500 with 170+ stores in 18 states. We offer 30 brands of new vehicles and all brands of used vehicles in our stores and online at over 200 websites.
Find the Lithia dealership near you on the Store Locator Page, or learn more about Lithia Motors and our people at Lithialife.com. We also have Lithia and Lithia Life videos on YouTube - or check out mobu.com.
Stay Connected:
Facebook Twitter Instagram YouTube Wikipedia LinkedIn


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Maino & More Using I Am T-Pain Iphone Auto-Tune App! "F**K Hov Talkin Bout D.OA. Da F*ck Is Wrong With Him. Im Just Gettin Started"
T-pain pushing his new Auto Tune app on Itunes
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GJ's is an indoor/outdoor market selling all sorts from craft, to bric-a-brac, books, sewing supplies and much more. We are always looking for new stallholders for both inside and out.
Kiddiewinks, our children's market, is now a part of the GJ's weekend market which means that you can choose which Sunday to bring your child along to sell his or her goodies.
Space for children remains free of charge.
We are now open midweek, on a Wednesday as well as the usual Saturday and Sundays, and over time, hope to open 7 days.


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Welcome to our Website
Please contact us if you are having trouble finding what you are looking for.Home
Receive a 10% discount off the sale price on your first order. Cannot be combined with other promo codes.
Be the first to know about...
Additional Promo Code Discounts
New Product Design
Customer Comments
Signature Projects
*Promo code will be provided in e-mail confirmation


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Randolph Scott, Dorothy Malone and Forrest Tucker tell the tale of the mysterious stranger who tangles with evil ranchers and bank robbers.
Nevadan, The (1950)
CategoriesFree Classic Movies Westerns
Readers Comments (5)
i love westerns
I always enjoy Randolf Scott hope to see more of his movies. I sure appreciate this website. It is hard to find good classic action movies.
It has suddenly started to show up on left side of screen and stays as a tiny strip to play movie. what did I do wrong? I have been on here for over 3 years and it is never like this?
Love the nostalgic poster.
Brilliant touch!


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Revision as of 16:29, 9 February 2011 by Michael.obrien.oracle.com (Talk | contribs) (→Experimental)
bugzilla id: michael.obrien(at)oracle.com
committer id: mobrien
Location: Ottawa, Canada - Eastern Standard Time
- Committer on Eclipse Persistence Services project - EclipseLink
Profession: Overly enthusiastic and optimistic Enterprise Software Developer
Currently working with Oracle Corporation on their TopLink product and with the Eclipse Foundation on their EclipseLink product. Specializing in Application Server Container deployments, JMX and the Metamodel API in the latest JSR-317 JPA 2.0 API RI for the JEE6 specification.
- 1 References
- 1.1 Misc
- 1.2 EE Tutorial Pages
- 1.3 EclipseLink related Forums
- 1.4 Software References
- 1.5 Hardcover
- 1.6 Experimental
- 1.7 Activity
- 1.7.1 Official
- 1.7.2 Indirectly/Adjacent/Followup/Assist
- 1.7.3 Interest
- 1.7.4 UnOfficial
- 1.7.5 Deferred but Very Important
- 1.7.6 Pending
- 1.7.7 Raised
- 1.7.8 Bugs and Enhancements I am interested in
- 1.7.9 Experimental
- 1.7.10 To Review
- 1.8 Log
- EclipseLink Main | New Bug | 2010 Summit | Oracle Wiki | Eclipse.org Wiki | OTN | Design Docs
- EclipseLink bugs/Target FishEye
EE Tutorial Pages
- EclipseLink RT : Users : Dev
- Oracle TopLink/JPA : TopLink/EclipseLink : JPA with TL/EL : WebLogic Server - EJB : GlassFish : OTN TopLink/EclipseLink
Software References
- JPA Real World Hardware Integration
- External Technical Blogs
- Any EclipseLink Bugs or Enhancements I am currently working on can be viewed on my LED display board on my cubicle wall - In case I forget over the weekend. The bug numbers are automatically downloaded from an eclipse web query every 15 min and downloaded both to the display controller (an 8 core parallel processor - 1 core/line and the 5th core for USB comms) and a server-side Derby database via an EclipseLink JPA based SE network application.
- 20101231: continue work on the following issues (Note: bugs/enhancements that are prefixed with a ":" are usually raised by myself).
- P3:E:2.3 332953 Spring 3.0 JPA Tutorial
- P2:M:2.2 333336 GlassFish V3 JMX API findMBeanServer() requires security.AccessControlException handler - defer to JNDI for this platform
- P2:M:2.1.3 333160 JMX: ModuleName string extraction code does not handle -1 not found index in 3 of 5 cases
- P2:C:F 331094 PersistenceProviderResolverHolder is thread unsafe
- P2:N:F 326728 Computed root URL for META-INF/persistence.xml inside a war-file is wrong
- P2:C:F 307105 FileNotFoundException when using .JARs from remote Windows location
- eclipselink-users persistence.xml in standalone app and enterprise beans
- OTN forum post JPA delete involving @PrivateOwned, CascadeType, orphanRemoval
- TopLink/EclipseLink forum posts on OpenJPA 2140287 JPA 2.0 2150419 DDL generation
- eclipselink-users PDE/OSGI dependency issue with ANTLR in 333320
- Concurrency.acquire() hangs when toString() is overriden to print a lazy IndirectList with 3+ elements where the @OneToMany is LAZY and the owning side of the bidirectional relationship @ManyToOne is EAGER - Also verify not related to 312110 or 312462
- Expand on 3 scenarios for EclipseLink logging on WebLogic in http://wiki.eclipse.org/EclipseLink/Examples/JPA/Logging#Server_Logging
- Respond to 1 2 posts and expand WebLogic JPA 2.0 tutorial wikis for 310849
- Take care of updating all pending Oracle WebLogic 10.3.4 11gR1 PS3 outstanding code issues, tutorial content, bugs, wiki pages and newsgroup items that were on hold until WebLogic 10.3.4 released on 20110115
- Respond to SpringSource serialization issue with EclipseLink in http://forum.springsource.org/archive/index.php/t-59443.html
- http://dev.eclipse.org/mhonarc/lists/eclipselink-users/msg05724.html
- 333602: Amazon Elastic Compute Cloud ECC AMS instances running EclipseLink JPA as the ORM layer
- http://en.wikipedia.org/wiki/Technical_debt
Dynamic Persistence
- 332994 SQL query generated depends on the order of invocation of setSelectionCriteria() and addJoinAttribute() when using dynamic persistence
Architecture Aware Computing
SaaS | PaaS | IaaS
- EclipseLink MultiTenancy | Extensibility - Reviewing from Tom
- IaaS at Oracle
Concurrency Issues
- Investigate EJB 3.x equivalent to cascade=CascadeType.SAVE_UPDATE? Is MERGE better than PERSIST? - see https://forum.hibernate.org/viewtopic.php?f=9&t=963665&start=0 and http://forum.springsource.org/showthread.php?t=85108
- How can we use @PrivateOwned - discussed this with Guy - we need to managed the non-defaults for all CascadeType=, @OrphanRemoval=false and the opposite @PrivateOwned=false
- Then respond to http://forums.oracle.com/forums/thread.jspa?threadID=2152045&tstart=0
- What exactly are the differences between @EmbeddedId and @IdClass?
Deferred but Very Important
- I would like to get some scheduled time to finally resolve the remaining workarounds for WebLogic 10.3.3.0 and JPA 2.0 for EclipseLink, Hibernate and Spring in http://wiki.eclipse.org/EclipseLink/Development/JPA_2.0/weblogic#TODO
Bugs and Enhancements I am interested in
- The following have my interest, I may or may not be involved in the solution, or I may have the issue myself. Usually I add myself to the CC list on the Bug or ER.
- 336596: java.util.NoSuchElementException when using @ElementCollection for enum in Embeddable
- 336599: EclipseLink2.1.2: metadata processing: use of custom property annotaton causes: "Mapping annotations cannot be applied to fields or properties that have a @Transient specified."
- Distributed JPA application using multiple SE clients connected to a single EE server using various EJB/RMI, JMS, JAX-RS and WebServices technologies. Use this distributed framework to hammer the JTA container managed persistence context and observe how it handles concurrency contention.
- Concurrency
- Thread safety
- Mixed JSF/Spring/AJAX/EJB framework artifacts
To Review
- Extensibility - Dynamic Data Model (required before implementing Multi-Tenancy
- Multi-Tenancy or SaaS Features and eventually PaaS aka EC2 a quick google search will come up with Analysis work done by Frederick Chong, Gianpaolo Carraro, Roger Wolter and Paul Henry at Microsoft in 2006
- 2008 http://www.oracle.com/technetwork/articles/entarch/spring-096279.html
- 2006 http://www.oracle.com/technetwork/articles/entarch/jpa-spring-medrec-091875.html
- 20101231:3188
- 20100908: rewrite started at hit 2620


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Ex-Nike exec is new Skullcandy President and CEO
Skullcandy, one of the leading global designers, marketers and distributors of performance audio and gaming headphones based in Park City has named Hoby Darling of Nike its new president and CEO effective immediately, according to a press release from Skullcandy.
Less than two months ago, Skullcandy announced former CEO Jeremy Andrus was stepping down to pursue a job with Massachusetts investment firm Solamere Capital, co-founded by Mitt Romney's son, Tagg.
According to a press release, Jeff Kearl, Chairman of the Board for Skullcandy spearheaded a search to replace Andrus. Focusing on candidates that could remedy the immediate initiatives outlined in last quarter's earnings.
"I am extremely excited to join the Skullcandy team at this early stage of the company's global growth cycle," Darling said in the release. "I have been admiring the brand's progress since Rick [Andrus] started the company 10 years ago, and I see tremendous potential to leverage the platform and culture that is already in place."
During his stint at Nike, Darling held the role of general manager of Nike Inc.'s digital sports division, a segment of the athletic gear and other tech-focused products. Prior to Nike, Darling served as an executive at the apparel-maker Volcom. Darling was also named to Sporting Goods Business' 40 under 40 in sports in 2010.
Reporting a dismal first-quarter in March, Darling has his work cut out for him in his early tenure. Despite notching impressive double-digit sales gains since going public in January of 2011, Skullcandy's 2012 10-K form suggests sales are expected to slump 30-percent in the current quarter.
"I can't be more pleased to welcome Hoby to the Skullcandy team," said Alden in a press release. "The board is acutely aware of the needs of this organization and has moved swiftly to find the greatest resource to meet those needs. Hoby's involvement with both emerging and global brands makes him the ideal person to lead the company."
Alden occupied the position until Darling was selected for the job. He launched Skullcandy in 2003, which quickly became one of the world's most distinct audio brands. The company, that first sold their product at Milo Snow & Skate in Park City, now distributes through a variety of channels in the U.S. and 80 countries worldwide.
Summit County and Park City leaders celebrate signing of renewable energy legislation
Summit County and Park City's elected leaders celebrated Earth Day by attending the signing of the Community Renewable Energy Act.


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SKY REPORTER: June 2011
by Steve Beyer on
Sky Data
During June the Sun reaches its highest annual elevation in our sky and summer returns to the northern hemisphere.
Wednesday June 1st, civil twilight begins at 4:54 a.m. and sunrise is at 5:27. That evening the sun sets at 8:21 p.m. and civil twilight concludes at 8:53. Earliest sunrises of the year, at 5:25 a.m., occur from Sunday June 5 until June 20th. The latest sunsets take place at 8:31 p.m. from Wednesday June 22 through the end of the month.
On the last day of June civil twilight begins at 4:54 with sunrise is at 5:28 a.m. That evening sunset occurs at 8:31 p.m. and civil twilight ends at 9:04.
Average overnight temperatures rise from 59 degrees Fahrenheit at the start of June to 67 degrees the night of June 30 - July 1.
Principal Phases of the Moon during this month are:
|New Moon
|June 1st
|First Quarter
|June 8th
|Full Moon (Strawberry Moon or Rose Moon)
|June 15th
|Last Quarter
|June 23rd
Sky Cast
On the evening of Saturday June 4th, the waxing crescent moon is low in the west-northwest among stars of the constellation Gemini, including the "Twins" Castor and Pollux.
At the start of June the only bright planet in the evening sky is Saturn. On the nights of June 9th and 10th the waxing gibbous Moon is in the constellation Virgo near Saturn. That planet currently is at visual magnitude 0.77, about the same as Spica, brightest star in Virgo.
During the second week of June Saturn is in proximity with renowned third magnitude double star Porrima, a.k.a. Gamma Virginis. Apparent separation between the star and Saturn that week is about half the diameter of the moon's disk. By the end of June Saturn, as it moves eastward through the zodiac, will have doubled its apparent distance from Porrima. Current separation between stellar components in the Gamma Virginis binary system is about one arcsecond. This dramatically compares to maximum separation of about six arcseconds, which last occurred during the 1920's. Seeing any gap between these components is currently a difficult task even when using rather large telescopes under excellent sky conditions.
At ten p.m. Thursday the ninth of June, brilliant star Arcturus is near the celestial meridian. This dividing line extends from north to south through the zenith, cleaving the sky into eastern and western halves. The meridian provides the "m" in our a.m. and p.m. designations of time. The designation a.m. ("ante" meridian) means the Sun has not yet reached the meridian and p.m. ("post" meridian) indicates the center of the Sun's disk has passed the meridian.
Here's a quick question: when do most people eat lunch? Around 12 am or 12 pm? The answer is neither! Midday is properly called 12 noon, and every new calendar date begins at 12midnight. However references to 12 a.m. and 12 p.m. are pervasive and use of these designations seems to be on the increase. Show astronomical awareness by encouraging use of more rational alternatives such as 12 mn for midnight and 12 nn for noon.
Jupiter, Mars, and Venus are all visible in the eastern sky during early morning hours throughout June. On Wednesday June 15th, the planets rise in turn at the following times: Jupiter at 2:42 a.m., Mars at 3:45 a.m., and Venus at 4:25 a.m., shortly before beginning of civil twilight.
At midnight, June 15-16, the Full Moon is in the constellation Sagittarius, very close to the direction of Milky Way Galaxy's center. That is nearly the same place in the sky where the Sun is located on the first day of winter—December 21st every year.
Among many magnificent objects in the sector of sky near this month's Full Moon is the nebula designated Messier 16. It has yielded some of the most spectacular Hubble telescope images. Although M16 has also long been called either the Eagle or Star Queen Nebula, due to Hubble's high resolution images and M16's role as an active site of star formation, the name "Pillars of Creation" is frequently used. The nebula's distance from the solar system is about 7,000 light years.
Nearly overhead around midnight during last weeks of June, the magnificent globular star cluster Messier 13 is well placed for viewing. Binoculars and telescopes reveal its presence when seen from dark sites far from urban centers. This nearly spherical grouping of about 100,000 stars spans 150 light years and is about 20,000 light years from us. It is believed to have formed over 12 billion years ago.
On Sunday June 21st at 1:16 p.m., the center of the Sun's disk is directly above Earth's surface on the Tropic of Cancer at a point between the Bahamas and Cuba. At that time summer begins in the northern hemisphere.
The early morning of Sunday June 26th at about four a.m., the Moon is five degrees of arc from Jupiter, which shines vividly at magnitude -2.3 in the constellation Aries.
Sky Lore
During June evenings look toward the eastern sky for stars Vega, Altair, and Deneb. They form the star pattern of the Summer Triangle. Each object is the brightest star in constellations Lyra, Aquila, and Cygnus. Vega is the brightest of the group with an apparent magnitude near zero, approximately the same as Arcturus, which on June evenings is not far from the meridian. Both stars are among the most vivid in our sky.
In the constellation Lyra, near Vega, observers with binoculars or small telescopes can detect an object called the "Double Double" star. More formally known as Epsilon Lyrae, small instruments show just two points of light, but with magnifications over 100 a total of four component stars may be visible.
Due to its great luminosity Deneb in Cygnus the Swan is one of the most distant stars we can see without optical assistance. It is prominent in our sky even at its tremendous distance of about 3,000 light years. By comparison, relatively close Vega is just 25 light years from us.
The third corner of the Summer Triangle is marked by first magnitude Altair in the constellation Aquila the Eagle. It and its immediately adjacent stars Alshain and Tarazed form a small asterism called the "Family of Aquila". Altair's distance from Earth is about 17 light years.


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Our Faculty
Professors at Cal Poly lead their students through the polytechnic process of learning by doing. Learn about deans at each of the six colleges here at Cal Poly.
Learn by Leading
Cal Poly professors blend advanced theoretical knowledge with advanced practical knowledge in the classroom, lab, studio, and field, leading their students through the polytechnic process of learning by doing. Academic personnel lead within one of six colleges (plus the Library and continuing education), each college is led by a dean, and the overall academic effort of the University is the primary charge of the Provost.
Search the Cal Poly Directory by name for a faculty member.
Meet our faculty by college or program:


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All Recipes
e bring you a large collection of Indian vegetarian recipes. The collection consists of variety of rotis, raitas, mixed veg. and much more. The recipes are sorted alphabetically. Browse through the section to find the guide to the real taste of Indian cuisine.
Garam Masala
Ginger lemon fizz
Green Mango Salad:
Green Pepper Curry
Grilled Paneer
Ground Nut Chatni
Gulab Jamun (Easy Method)
Indian Recipes
Top Recipes
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Gifts to India
India Calling Cards
Navratri Special
Tajonline Home
Paneer Tikka Masala
Allo Gobi Vegetable
Chili Potatoes
Pasta Salad
Falafel Sandwich
Advanced Search
online flower delivery in Bangalore
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Every Sunday, 9:30 a - 12:15 p, Room: GPC
CSM Theology Class
Theology Classes are for middle school and high school students who want to grow in their understanding of God. It is our hope that through these classes students will learn how to study the Bible, gain a desire to read the Word of God and develop their theology.
- High School: 9:30a - 10:45a, Game Plan Center
- Middle School: 11:00a - 12:15p, Game Plan Center


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Download of the Day: O&O DiskImage Express 4.1.47
Our Download of the Day today is O&O DiskImage Express 4.1.47.
O&O DiskImage Express is free software which enables you to image your entire computer and restore single drives.
Mounts image as a drive - if, for example, you've accidentally deleted just one important file, you can now select to restore this file only from the entire imageNew
Images all drives, including drive information and system partition - all your installed programs and their personal settings can be imaged and quickly restored when needed
Restores individual data drives
Saves space with incremental and differential images that save only changes - images only those files that have been changed or added after the last imaging. This saves time!
Displays imaging information - O&O DiskImage 4 Express Edition keeps you constantly informed
Easy to use and free - free data imaging developed by data professionals


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New Developments in HIV Drug Resistance and Options for Treatment-Experienced Patients
Coverage of the 4th European HIV Drug Resistance Workshop and the 12th Annual Conference of the British HIV Association
May 15, 2006
IntroductionThe emergence of drug resistant HIV in patients failing therapy is a result of two processes: the emergence of pre-existing genetic variants and the selection of drug-resistant virus as a result of selective pressure. There are a multitude of reasons for HIV's enormous genetic variability -- not only is the HIV reverse transcriptase (RT) error-prone, but there is also an absence of any enzymatic proofreading activity and a high rate of HIV replication in vivo. In patients who are maintained on a failing regimen, the insufficient potency of the treatment means viral replication is ongoing. This risks the accumulation of additional mutations as well as increasing cross-resistance.
Resistance continues to have substantial clinical relevance. Among viremic patients in the United States, 50% are estimated to harbor resistance to two classes of drugs and 13% to three.1 Thus we are left with the challenge of assembling an active regimen for HIV-infected patients with varying degrees of resistance. Fortunately, the treatment landscape has been somewhat transformed in the last few years with the approval of enfuvirtide (T-20, Fuzeon), which belongs to the new fusion inhibitor class of HIV drugs, and the approval in the summer of 2005 of tipranavir (TPV, Aptivus), a potent protease inhibitor (PI) active in many patients with resistance to PIs.
In addition, at the 13th Conference on Retroviruses and Opportunistic Infections (CROI 2006) as well as the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment (IAS 2005), a multitude of agents in various stages of development were showcased. In the pipeline are not only new agents from existing drug classes -- such as TMC125 (etravirine), TMC114 (darunavir), TMC278, vicriviroc (SCH 417690, SCH-D) and maraviroc (UK-427,857) -- that are active in multidrug-resistant patients, but agents from a new class altogether -- the integrase inhibitors MK-0518 and GS 9137.
Keeping track of all the investigational HIV antiretroviral agents is a tall order for the busy practicing clinician. With new, improved agents being developed in currently approved drug classes and exciting compounds with novel mechanisms of action working toward U.S. Food and Drug Administration (FDA) approval, clinicians are struggling to see how these new drugs will best serve patients.
The greatest urgency is, of course, to find solutions for heavily treatment-experienced patients. Reviews of all the resistance data for drugs in advanced clinical development will help to identify new options for these patients. Additionally, a greater understanding of the interpretation of resistance assay results for recently improved drugs has relevance for routine clinical practice and will help refine the use of some of the more recently introduced antiretrovirals.
This article will review presentations from the 4th European HIV Drug Resistance Workshop, which took place on March 29-31, 2006 in Monaco. Among the highlights of this conference was research looking at ongoing issues regarding the understanding of resistance, particularly in the context of new drugs such as tipranavir and TMC114. The Workshop provided important additional detail on much of the new data presented at CROI 2006. Also reviewed here are presentations from the 12th Annual Conference of the British HIV Association, which took place on March 29 - April 1, 2006 in the United Kingdom.
Epidemiology of HIV ResistanceSurveillance data on drug resistance in treatment-experienced patients reveals a lot about not only the prevalence of resistance, but also the reasons behind the resistance. In France, a nationwide study by Dominique Costagliola and colleagues, samples were taken from HIV-infected patients in 28 specialized centers in France and one in Switzerland.
To be included in the study, patients were required to have an HIV RNA viral load greater than 1,000 copies/mL and to be currently on antiretroviral therapy or on a treatment interruption of less than a month. In 2004, when this study was conducted, 80.3% of patients followed in French hospitals were receiving antiretroviral therapy and 21.3% were found to have viral loads of more than 1,000 copies/mL.
Patients had been exposed to a median of nine antiretrovirals (range: 6-12) with 12% having received enfuvirtide. A median of four nucleoside/tide reverse transcriptase inhibitor (NRTI) mutations, four PI mutations and zero non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations were detected.
Resistance was observed to at least one antiretroviral in 88% of patients, to at least one NRTI in 77%, to one PI in 66%, to one NNRTI in 50% and to enfuvirtide in 7%. Overall, 19% of the patients had virus that retained susceptibility to only a single drug class. NRTI resistance occurred with the most frequency, suggesting that most of the patients had begun therapy years ago with NRTI monotherapy or dual therapy.2
These data are a sad reminder of the consequences of the era before HAART (highly-active antiretroviral therapy) when fewer than three potent drugs were combined. Although combination therapy is now the standard of care, it must be remembered that the principles of resistance remain the same. Patients who are left on a regimen with only one to two active drugs, or who are switched to a new regimen that includes drugs that are no longer active, are in effect being treated with only one to two agents and will suffer the same consequence as if they were taking monotherapy or dual therapy -- namely high-level cross-resistance.
Predicting Treatment Response Based on Resistance ScoresWith up to 50% of treated patients estimated by some studies1 to have HIV drug resistance, the use of genotype resistance testing to guide treatment decisions is becoming increasingly more important, especially for patients who are failing first- or second-line therapy.
Genotypic resistance results need to be interpreted in terms of the clinical impact of the mutations.3,4 As such, many algorithms -- or genotypic resistance scores -- have been developed to help clinicians with such interpretation, thereby enabling clinicians to predict how well a patient may respond to a particular agent in a salvage setting. Freely accessible examples include the Stanford University HIV Drug Resistance Database and the French ANRS.
Unfortunately, even as new drugs become available to clinicians, the resistance data for them is often incomplete -- in part due to a need for the FDA to move these drugs quickly through the approval process so that HIV-infected patients with few treatment options can receive them in a timely manner.
Although preliminary resistance data are now included in the labeling of recently approved drugs, more data, and a better understanding of that data, is necessary. Only as larger and more diverse patient populations receive these drugs, and correlates of baseline resistance and virologic response are elucidated, can we fine-tune our ability to interpret resistance to these key antiretrovirals. A number of presentations at the 4th European HIV Drug Resistance Workshop offered improved insight into our ability to interpret resistance to some of these commonly used drugs.
Refinement of the Genotypic Resistance Score for TipranavirFor a genotypic resistance score to be clinically valid, baseline genotypes must be correlated with the virologic response to treatment. Given that the FDA only recently approved tipranavir in July 2005, researchers are still figuring out which mutations will affect treatment response.
Since there was only a limited number of samples collected during these trials, there is a need to improve the ability of the genotypic score to predict the response to tipranavir treatment. To this end, Eoin Coakley and colleagues performed phenotype and genotype assays on an independent set of clinical isolates obtained from the Monogram Biosciences database.5 Their results were presented at the 4th European HIV Drug Resistance Workshop.
By analyzing a total of 1,411 new clinical isolates, Coakley and colleagues determined that the tipranavir mutation score derived from the RESIST data modestly correlated with the mean fold change (FC) in tipranavir susceptibility (linear regression coefficient: 0.51; P < .0001). Moreover, the researchers identified several additional mutations not included in the original mutation score that influenced phenotypic susceptibility to tipranavir.
Figure 1
Slide by Eoin Coakley et al; reprinted with permission.
Although the revised tipranavir genotype algorithm might more accurately predict the response to tipranavir in heavily treatment-experienced patients, the algorithm is quite complex and does not fully capture the impact of all mutations affecting in vitro tipranavir susceptibility. Indeed, since it may be unclear what FC cutoff should be used to indicate decreased susceptibility, a clinical validation of this new score will be needed in order to assess its real usefulness.
Larger and more diverse populations must be studied to further improve our understanding of tipranavir resistance. Studies that include patients with a great variety of baseline genotypes and phenotypes and well documented virologic response data must be analyzed using appropriate statistical techniques. Once new genotypic scores and phenotypic cutoffs are derived, different datasets will be required to cross-validate these findings. Hopefully, efforts on both sides of the Atlantic will lead to these improved and validated interpretation scores.
The Value of Discussing Resistance Test Results With HIV Resistance ExpertsAs the case of the tipranavir resistance mutation score demonstrates, interpreting an HIV resistance test in light of various genotypic resistance algorithms can be a significant challenge, especially for clinicians who are not well versed in the importance of certain resistance mutations. A more accurate interpretation of genotypic, phenotypic and virtual phenotypic resistance tests might be had if an HIV resistance expert is consulted about the results, and it might ultimately lead to a better treatment decision, particularly in the case of salvage therapy.
To test the validity of this assumption, Joseph Llibre and colleagues conducted a multi-center, prospective study in which clinicians and HIV resistance experts partook in a conference call every six weeks to discuss suitable salvage therapy for 10 treatment-experienced patients each week. The final regimen chosen was based on their genotype and virtual phenotype test results, antiretroviral history, adherence to therapy and hepatitis B/C coinfection status.6
A total of 115 patients were discussed during conference calls throughout the study. These patients had been infected with HIV for a median of 10 years, had been on antiretroviral therapy for a median of eight years, and had received a median of 5.9 prior regimens of antiretroviral therapy.
Overall, 60% of all patients in this study harbored five or more resistance mutations within the HIV RT sequence, 67% harbored five or more resistance mutations within the HIV protease sequence and the majority of patients were resistant to NNRTIs (74%). In addition to the specific NRTIs, NNRTIs and PIs recommended as salvage therapy for these patients, the expert panel recommended that 65% receive enfuvirtide and that 11% undergo a treatment interruption.
Nearly 75% of all patients were administered the advised salvage regimen. The remaining quarter did not take the advised regimen largely due to the burden of a complex treatment schedule or reluctance to inject enfuvirtide. After 24 weeks of treatment, 42% of the patients had a viral load below 50 copies/mL and 59% had a viral load below 400 copies/mL, which is impressive considering that the patients were very treatment-experienced and harbored multidrug-resistant virus.
In this study, consultation between clinicians and HIV resistance experts achieved a high rate of viral suppression among a very heavily treatment-experienced population. Indeed, there was a considerable educational benefit to everyone hearing all the cases discussed during the conference calls: It provided all the participants with considerable training and updating.
Although we don't know how these patients would have fared without the expert consultation, since there was no control group, and even though "experts" in resistance can disagree, previous studies have shown that expert advice improves outcome.3 Needless to say, the vast majority of providers would probably welcome discussion before deciding on treatment for their multidrug-resistant patients.
Interpreting Genotype Results for Patients With Low Viral LoadTradeoffs exist when a clinician considers ordering a resistance test when HIV RNA levels are still very low (in the 50 - 1,000 copy range). Although we strive to detect and manage resistance as early as possible, technical and statistical limitations have challenged performing testing at very low viral loads. By increasing sample volume and optimizing the assay being used, many laboratories can now technically perform resistance testing at these very low levels. The question remains: To what degree do the results truly reflect a patient's viral population? The answer may not be clear cut.
Stone and colleagues showed that when HIV from paired blood samples is amplified and sequenced from patients with a viral load below 200 copies/mL, the sequences from the sample pairs are typically identical.7 However, in some instances (2/11; 18%), the researchers observed significant genetic differences between the sequences, likely corresponding to HIV variants present in the host. Because differences can be detected in paired extractions in a minority of patients with a very low viral load, the finding of wild-type virus does not mean that there is not a mutant virus hidden, so interpretation should be undertaken with care.
Clinical Implications of HIV Drug Resistance to Therapy With Approved Antiretrovirals
AtazanavirAtazanavir (ATV, Reyataz) is now widely used in PI-naive patients due to both its convenient dosing and reduced lipid-related toxicity. Although ritonavir-boosted atazanavir has been shown to have activity in patients harboring mild to moderate PI resistance, data suggest this is not the drug of choice for patients with significant PI resistance.
So the question remains: Just how much PI resistance can boosted atazanavir safely overcome? This has been the focus of much research in recent years since, although clinicians are eager to use a convenient and less toxic PI, above a certain threshold of resistance, other more potent PIs with higher genetic barriers might make better choices.
Significantly more patients who received boosted atazanavir achieved a viral load below 500 copies/mL versus those who received unboosted atazanavir -- 85% versus 63% at 48 weeks. Similarly, patients on boosted atazanavir achieved a CD4+ cell count increase of 97 cells/mm3 versus an increase of only 20 cells/mm3 for those on atazanavir alone. In addition, the boosted-atazanavir group had a significantly shorter time to virologic response than the unboosted-atazanavir group -- with a median time to virologic response of eight weeks versus 13 weeks for the unboosted-atazanavir group.
Not surprisingly, patients who received the boosted regimen had a better chance of attaining viral suppression according to multivariate analysis. Factors predicting a poor virologic response to atazanavir included more advanced disease (U.S. Centers for Disease Control and Prevention stage C), a higher baseline viral load and more extensive exposure to PIs.
A median of 7.5 PI mutations correlated with virologic failure among those taking boosted atazanavir, whereas a median of only five PI mutations correlated with failure in those receiving the unboosted drug. Perhaps of most interest, the 69M mutation, which is a novel protease mutation potentially associated with PI resistance, significantly predicted a two-fold increased chance of virologic success (adjusted hazard ratio: 1.98; 95% confidence interval: 1.14-3.17).
Figure 3
Slide by Ada Bertoli et al; reprinted with permission.
Click to enlarge
Tenofovir (TDF, Viread) has gained widespread use in both treatment-naive and treatment-experienced patients. This agent has had excellent success when combined with agents from other drug classes, although there have been disappointing results when it has been used in particular NRTI-only combinations. In terms of tenofovir resistance, it is an evolving story. We still don't know the answers to the following questions: What are all the resistance pathways to the drug? How prevalent are they and to what degree do mutations selected by tenofovir affect other NRTIs? An example is the effect of mutation L74V on tenofovir. As this is a signature mutation for didanosine (ddI, Videx) and abacavir (ABC, Ziagen), its effect on tenofovir is of major interest. The data have been somewhat conflicting, with laboratory studies showing no effect on tenofovir susceptibility, but statistical analyses linking the presence of L74V with a poorer response to tenofovir. A number of studies at the 4th European HIV Drug Resistance Workshop provided additional insight into tenofovir resistance.
Although prior analyses have shown that K65R and certain thymidine analog mutations (TAMs) can reduce the response to tenofovir, McColl and colleagues performed a more in-depth analysis of the specific mutations affecting the response to tenofovir.9
Twelve mutations within the HIV RT, including L74V, were significantly associated (P < .05) with a diminished viral response to tenofovir. In an adjusted multivariate analysis, four TAMs -- M41L, D67N, L210W and T215Y -- and the L74V mutation significantly and independently predicted a poor response to tenofovir.
The correlation between L74V and a diminished virologic response is surprising considering that this mutation is completely susceptible to tenofovir in vitro. However, the researchers noted that the presence of the L74V mutation was usually accompanied by the K65R mutation and multiple TAMs -- mutations known to decrease the response to tenofovir.
Figure 4
Slide by D. McColl et al; reprinted with permission.
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K65R development was rare, with a frequency of only 2.6% among all patients. Of potential importance, the M184V mutation correlated with a significantly improved response to tenofovir (P = .004). These results support the use of lamivudine (3TC, Epivir) in a salvage regimen, even if M184V is present, because its maintenance will increase the activity of tenofovir in this setting. It is important to highlight that L74V alone will not have much impact on the antiviral activity of tenofovir. In these studies, L74V was always accompanied by TAMs or K65R.
The use of tenofovir/emtricitabine (TDF/FTC, Truvada) has been widely accepted in initial first-line therapy. These data on the apparent positive impact of the mutation M184V on tenofovir activity provide additional support for the use of tenofovir/emtricitabine in the salvage setting as well.
Although clearly all drug resistance should be avoided, data are accumulating to suggest that once the M184V mutation has been selected and the virological activity of the very potent NRTI lamivudine and emtricitabine (FTC, Emtriva) regrettably lost, some clinical benefit can apparently still be derived by continued use of these drugs. This, of course, has been suggested for many years for zidovudine (AZT, Retrovir), and now we see the data mounting for tenofovir as well.
In vitro data clearly show the presence of mutation M184V mitigating the effect of TAMs on tenofovir susceptibility, and now the clinical evidence appears to be accumulating as well. Since maintaining M184V requires lamivudine or emtricitabine to be continued in the regimen, the use of tenofovir/emtricitabine in the salvage setting to improve tenofovir activity may often be an acceptable choice.
There is a need to assess if this pathway is selected more according to the HIV subtype. Although not commonly encountered, it is prudent to monitor for this mutation and to consider it when evaluating resistance to tenofovir. As more data accumulate, interpretation algorithms may need to consider this mutation when determining resistance to tenofovir.
The Impact of Emerging Resistance Mutations on Treatment ResponseIn highly treatment-experienced patients there is the risk of developing K65R and therefore a possibility of a reduced response to tenofovir in patients harboring the L74V mutation. However, these observations cannot be extrapolated to treatment-naive patients who are experiencing their first confirmed virologic failure with the L74V mutation. Descamps and colleagues11 examined whether the K65R mutation was present as a minority variant where L74V was the major variant selected upon virologic failure of first-line abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa)-based HAART approaches.
The results of this study show that the selection of K65R minor viral variants is not a common phenomenon in abacavir/lamivudine-containing HAART. Indeed, they have demonstrated that the M184V mutation alone or in association with the L74V mutation remains the signature resistance pathway of abacavir/lamivudine-based therapies. These findings are important because they tell us that in treatment-naive patients, those failing abacavir/lamivudine might be rescued with tenofovir + zidovudine-based approaches.
The Impact of New Antiretrovirals on Treatment Options for Multidrug-Resistant PatientsThe magnitude and duration of virologic responses to currently approved antiretroviral agents are significantly reduced in treatment-experienced patients in comparison with treatment-naive patients. As such, agents that are highly potent against drug-resistant HIV and that can confer long-term viral suppression while still being tolerable represent ideal salvage therapies for treatment-experienced patients. Major conferences in late 2005 and early 2006, including CROI 2006, cast a spotlight on an encouragingly large number of such agents in the development pipeline.12 Several studies presented at the 4th European HIV Drug Resistance Workshop and the 12th Annual Conference of the British HIV Association provided a closer look at two of these drugs in particular: TMC114 and TMC125. In addition to presenting safety and efficacy data, these studies also delved more deeply into how the extent of baseline and developing resistance mutations can impinge on the response to novel and approved antiretrovirals.
TMC114In the summer of 2006, TMC114 may become the newest PI approved in the United States. Given its demonstrated activity in treatment-experienced patients, there is a great amount of interest not only in the extent of the drug's efficacy and safety, but in its resistance profile as well -- particularly in comparison to other recently approved PIs. Several recent studies attempted to elucidate these issues.
Further Positive Results for TMC114: The POWER 3 Study at Week 24
In 2005, three presentations on the POWER (Performance Of TMC114/r When Evaluated in triple-class-experienced patients with PI Resistance) 1 and 2 studies documented the intrinsic activity of TMC114 in PI-experienced patients.13-15 Based on the dramatic, positive results of these studies, the single-arm POWER 3 study16 was opened up for additional participants to receive the highest study dose of TMC114 -- 600 mg twice daily (with 100 mg twice daily of ritonavir) -- in combination with an optimized background regimen.
Twenty-four week data from POWER 3, conducted by Jean-Michel Molina and colleagues, were presented at the 12th Annual Conference of the British HIV Association. In all, 327 patients were enrolled in POWER 3, of whom 303 were newly recruited to receive TMC114, while 24 patients entered after being on the control arms of the POWER 1 and 2 trials. These were all triple-class-experienced patients with an extensive prior treatment history. Interestingly, 31% of the POWER 3 patients had already received tipranavir. Similar to POWER 2, 30% of the patients had previously received enfuvirtide. Patients had high-level PI resistance, reporting a median of three primary PI mutations and a median of nine PI-associated mutations at entry.
Results for POWER 3 confirm what was reported in the POWER 2 study results. At week 24, 65% of the patients maintained a viral load at least 1 log copies/mL below baseline, and there was a corresponding mean CD4+ cell count increase of 80 cells/mm3.
Also interesting is the breakdown of patients who achieved maximal viral suppression to below 50 copies. In total, 40% of the POWER 3 patients achieved maximal suppression at week 24 -- and the single best predictor of this response was the degree of baseline phenotypic resistance to TMC114. For example, 50% of trial participants with a phenotype of less than 10 fold at baseline achieved maximal suppression, as compared to a 17% response for those with a more than 40-fold resistance at baseline.
Fortunately, 170 of the 238 patients (about 71%) entering this study had a FC below 10 fold, suggesting that many triple-class-experienced patients will still show a response to TMC114. The study authors also noted that phenotype was more predictive of virologic response than the number of PI mutations.
Table 1
Safety results for this study were similar to those noted in prior reports on this drug. There was new onset of diarrhea (14%) and nausea (10%); 75% of the adverse events reported were graded mild/moderate. Among the most common grade 3 or 4 lab abnormalities was increased amylase, which was reported in 7% of the participants. Elevated lipase was only seen in 3% of participants, however. Grade 3 or 4 elevated liver function tests were seen in only 2% of participants.
There were minimal changes reported in lipid fractions compared to baseline, with the exception of a drop in triglycerides for those who entered while taking lopinavir/ritonavir (LPV/r, Kaletra). There was a very low rate of treatment discontinuation due to adverse events (2%). POWER 3 had no control arm, so no comparison of adverse effects is possible.
This study confirms the exciting results reported from the POWER 1 and 2 studies. It is reasonable to anticipate that a majority of drug-resistant patients -- even those with triple-class experience -- could receive some benefit from TMC114, especially when the drug is combined with other active antivirals. The safety profile of TMC114 continues to be reassuring as well, with no new adverse events observed in this study as compared to the earlier, smaller POWER 1 and 2 studies.
Who Can Benefit Most From TMC114 + Ritonavir? Examining the Genotypic and Phenotypic Data
A key challenge for clinicians faced with new treatment options is a precise understanding of which patients are most likely to benefit, and which factors contribute to ensuring the best activity from a novel compound. Anton Pozniak and colleagues combined data from the POWER 1, 2 and 3 studies to assess which baseline factors could predict which patients would have the greatest (or least) likelihood of virologic success when starting a regimen containing TMC114.17 Several interesting lessons came out of this look at the data, which were presented at the 12th Annual Conference of the British HIV Association.
In POWER 1, 2 and 3, there were a total of 458 patients who received TMC114 and 124 control patients. Previous analyses13-15 of the four doses tested in POWER 1 and 2 demonstrated that the best response was to the 600-mg, twice-daily dose; those who received only this dose were the focus of this analysis.
The multivariate analysis of response showed that the baseline phenotypic FC to TMC114 was the single best predictor of virologic response (defined as a viral load below 50 copies/mL). A FC below 10 was associated with a 50% response, compared to a 25% response rate for a FC of 10 to 40, and 13% for a FC of more than 40. (It was also noted that a FC of more than 10 was associated with having 10 or more PI-resistance mutations.)
Fortunately, 255 of 366 patients (about 70%) for whom FC data were available had a FC below 10. As noted in the POWER 3 analysis above, this finding suggests that the majority of triple-class-experienced patients have the potential to receive the most benefit from TMC114.
Another factor predicting virologic response was the number of other active antivirals in the regimen. For example, only 26% of all POWER study participants achieved a viral load of less than 50 copies/mL if the regimen contained no active antivirals, whereas 46% achieved a viral load of less than 50 if they had at least one other active antiviral.
One additional interesting finding noted that if someone was on a nucleoside that resistance testing predicted to be active, he or she had a slightly greater virologic response rate (51%) compared to patients who had no active NRTIs but instead used enfuvirtide (43%). However, this analysis did not control for degrees of baseline TMC114 resistance, which could reasonably be expected to differ in these two populations and could thus account for the observed disparity in virologic success.
It is worth adding that, among the subset of patients who had both an active NRTI(s) and enfuvirtide, the rate of suppression was 53% -- a similar rate to that of patients who had an active NRTI but did not receive enfuvirtide.
These data reassure and inform practitioners as to which patients can be predicted to have the best response to TMC114. The authors concluded that 600 mg TMC114 + 100 mg ritonavir twice daily was consistently more active than any control PI used by this PI-experienced cohort, regardless of the predicted susceptibility to another PI. They noted that baseline phenotype was the best predictor of response, though other factors were also important, including having at least one other active drug in the regimen. It is surprising that some NRTIs could have retained activity in this heavily-pretreated population, but that was confirmed by resistance testing to be the case for 165 of the participants who used TMC114 without enfuvirtide.
Among the 215 patients assessed, the number of PI-resistance mutations present at baseline was eight. The baseline TMC114 FC emerged as the strongest predictor for virologic response. Patients with a TMC114 FC less than 10 demonstrated a much better virologic response than those with a FC above 10, which was strongly associated with the presence of 10 or more PI-resistance mutations. Moreover, the presence of the V11I, V32I, I47V or I54L/M mutations at baseline also correlated with a poorer virologic response, although the response was still higher than that observed in control patients who did not receive TMC114. Interestingly, isolates containing these mutations tended to contain more PI-resistance mutations overall than isolates without these mutations. Not surprisingly, the development of some of these mutations during treatment -- V32I, I47V and I54L -- in addition to other mutations -- L33F and L88V -- also compromised patients' virologic response and were implicated in at least 10% of all failures. Patients experiencing virologic rebound displayed a median TMC114 FC increase of 8.14-fold.
Despite the diminished response to treatment in a subset of patients -- mostly those harboring 10 or more PI-resistance mutations -- all isolates from patients experiencing virologic rebound that were found to be sensitive to tipranavir at baseline remained so.
Indeed, related data presented at the 4th European HIV Drug Resistance Workshop by DeMeyer and colleagues, also representing the manufacturer of TMC114, found that more than half (53%) of the nearly 600 isolates with decreased sensitivity to TMC114 included in their genotypic and phenotypic profiling analysis remained sensitive to tipranavir.19 By contrast, only 0.5% of these isolates remained susceptible to lopinavir (LPV). On the flip side, 77% of the isolates resistant to lopinavir and 70% resistant to tipranavir remained susceptible to TMC114.
Figure 5
Slide by S. DeMeyer et al; reprinted with permission.
Comparison of TMC114 + Ritonavir and Tipranavir
Any examination that involves both TMC114 and tipranavir cannot help but raise a larger question: Which of the two would make a better choice for salvage therapy? As both of these drugs have been developed for a similar use -- the suppression of HIV in patients with a history of PI resistance -- it is inevitable that clinicians will attempt to compare these two compounds on several measures.
In the absence of a randomized, head-to-head comparison study, one must use other means to assess the relative strengths and weaknesses of these two PIs. The most obvious way to do so is to directly compare the data from available studies on each drug -- in this case, the POWER 1 and 2 studies (for TMC114) and the RESIST 1 and 2 studies20 (for tipranavir). As these studies had many overlapping enrollment criteria, Andrew Hill and Graeme Moyle decided to conduct this analysis,21 which is the first formal effort to assess, from the available data, both the similarities and differences that there may be when comparing TMC114 and tipranavir. Their analysis, presented at the 12th Annual Conference of the British HIV Association, compared the week-24 virologic response across all four studies using publicly available data.
In all four studies, an optimized background regimen was constructed, with the optional use of enfuvirtide. NNRTIs were allowed in the RESIST studies (and used in 17% of the patients), while they were excluded from the POWER studies.
The baseline demographics were very similar across all four studies, as were the baseline HIV RNA data (4.6 log copies/mL in the POWER studies; 4.8 log copies/mL in the RESIST studies). Median CD4+ cell counts at baseline were also similar (153 cells/mm3 in POWER; 155 cells/mm3 in RESIST).
The level of treatment experience among patients was also well-matched between the POWER and RESIST studies. In both groups there was a median of four prior PIs used, and similar numbers of patients had prior experience with enfuvirtide (17% POWER; 12% RESIST). At baseline, there was a median of three PI mutations seen in both series of studies. By phenotype, again there were similarities: For example, there was a more than 79-fold resistance to lopinavir in the POWER studies, compared to an 87-fold resistance in the RESIST studies. There were similarities when comparing the FC to that of the other PIs as well, including tipranavir (1.8 POWER; 1.7 RESIST). As there were differences in the percentage of patients using enfuvirtide both overall and for the first use, Hill and Moyle conducted one subset analysis to compare the results while controlling for enfuvirtide use.
The POWER studies compared four doses of TMC114, but only one dose -- 600 mg with 100 mg ritonavir twice daily -- is being developed in phase 3 studies. Thus, this twice-daily dose was used for comparison against the results from the RESIST studies of tipranavir, in which 500 mg tipranavir was administered with 200 mg ritonavir twice daily.
In both series of studies, the newer PIs (i.e., tipranavir and TMC114) showed a significant activity advantage over the comparator PI arm. Hill and Moyle also noted that the response to the control or comparator PI arm was found to be extremely similar between POWER and RESIST -- regardless of whether virologic response was measured using the percentage of patients with:
For example, 19% of the patients in the POWER studies and 16% in the RESIST studies had their viral load fall below 400 copies/mL on the comparator PI arm; 21% of the patients in the POWER studies and 18% in the RESIST studies had at least a 1-log copies/mL reduction in viral load compared to baseline by week 24. This comparison serves to strengthen the authors' contention that these two cohorts were sufficiently similar at baseline as to make it reasonable to compare the responses of patients to each of the newer PIs.
Accordingly, Hill and Moyle presented several analyses of the response to tipranavir versus TMC114. In these analyses, TMC114 appeared to have greater activity based on several outcome measures. For example, TMC114 patients experienced a 1.9-log copies/mL decline in viral load from baseline, versus a 0.8-log copies/mL drop in viral load among the tipranavir patients.
Other analyses showed consistent differences, all of which appeared to favor TMC114. For instance, 48% of the patients in the POWER studies experienced a viral load reduction to less than 50 copies/mL, compared to 23% of patients in the RESIST trials.
Table 2
Hill and Moyle conclude that the data show statistically greater activity of TMC114 than tipranavir when each drug is pitted against a comparator PI. This suggests that TMC114 may be a more active agent than tipranavir in treatment-experienced patients, since the magnitude of the benefit of the newer PI versus the comparator arm consistently favored TMC114. This trend was seen even when controlling for the use of enfuvirtide.
The authors argue that their approach to comparing TMC114 and tipranavir was valid, as the inclusion criteria and design were similar between the POWER and RESIST studies, as were the baseline characteristics on several important measures, including predictors of response other than the PI used. However, there are always limitations to the strength of the conclusions one can make when comparing across trials. One analysis not done here that would also be of interest is a comparison of outcomes when both drugs were predicted to have activity, rather than looking at overall outcomes. It is certainly possible that there is greater retained activity to TMC114 given a broad spectrum of highly PI-resistant virus. However, there also may be greater similarity in the response rates for TMC114 and tipranavir when each drug is used "appropriately" -- i.e., in those predicted to have susceptible virus to that PI.
As a result of this research (as well as that by Eoin Coakley,5 summarized earlier in this article), more refined algorithms have been developed in order to predict which patients are most likely to respond virologically to TMC114 or tipranavir. While the FC to tipranavir was similar at baseline in the POWER and RESIST studies, it is possible that there were greater numbers of patients enrolled in the RESIST trials for which current algorithms would suggest reduced activity from tipranavir. Because the criteria to determine such thresholds were in part identified as a result of these studies, it is clear that the question posed by this analysis can only be rigorously and fairly answered by future randomized, comparison studies that directly compare TMC114 and tipranavir in PI-experienced patients whose resistance profile predicts that both PIs are fully active at study entry.
TMC125There is a critical need for a second-generation NNRTI that has the dosing simplicity of currently available NNRTIs and that can be used in sequence. The NNRTI TMC125, which has been engineered to have a high genetic barrier to resistance, is one such candidate -- in fact, it is the only candidate currently in phase 3 clinical trials.
TMC125 Effective Against NNRTI Resistance Through 48 Weeks: Study TMC125-C223
Data documenting the activity of TMC125 for at least 24 weeks were first presented at the 10th European AIDS Conference in Dublin, Ireland, in November 2005.22,23 However, due to concerns about the durability of response for a new NNRTI in NNRTI-resistant patients, there has been interest in ensuring that any initial activity observed would endure. Data from a study documenting the preserved activity of TMC125 in combination with a variety of background regimens were presented at the 12th Annual Conference of the British HIV Association.24
To participate in this study, patients were required to have NNRTI resistance and at least three primary PI mutations. This is a group of patients for whom new treatment options are particularly critical given their broad cross-resistance. The study design was somewhat distinct, based in part on the known pharmacokinetic (PK) interactions at the time the study was underway.
In all, 159 people were randomized to one of the two TMC125 doses, and 40 were randomized to the control. The median baseline CD4+ cell count was about 100 in all arms, and the median baseline HIV viral load was about 4.7 log copies/mL. The results at week 48 validate what had previously been observed at week 24. In fact, 88% of those who had a viral load of less than 50 copies/mL at week 24 in this study maintained this degree of suppression at week 48.
Patients in this study had significant cross-resistance to current treatments, as demonstrated by the fact that, in the control arm, median viral load had only dropped by 0.14 log copies/mL at week 48. However, patients in the arm taking the 800-mg, twice-daily dose of TMC125 had a viral load that was 1.01-log copies/mL lower at week 48, and patients in the arm taking the 400-mg, twice-daily dose of TMC125 had a viral load that was 0.88-log copies/mL lower. At week 48, 22% of the patients on the higher dose of TMC125 had a viral load of less than 50 copies/mL, compared to none on the control -- a highly significant difference.
Figure 6
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This is an interesting finding: It is consistent with the concept of a better genetic barrier to resistance for TMC125, and suggests that there can be a durable response to this NNRTI even if the remainder of the regimen is minimally active. Not surprisingly, there was a significantly better CD4+ cell increase (about 60 cells/mm3) at week 48 in patients on the TMC125 arms, compared to a 13 cells/mm3 increase for patients on the control arm.
Figure 7
Slide by Cal Cohen et al; reprinted with permission.
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In terms of safety issues, one way to examine these data is to compare the rates of specific events and note which were more frequent on the TMC125 arms versus the control arm, rather than only noting how often a specific adverse event was observed. However, this comparison gets complicated when one takes into account that patients spent much more time overall on the TMC125 arms than on the control arm (given that 78% of all control patients discontinued treatment by week 48 due to virologic failure, versus 9% of TMC125 patients). As a result, patients on the TMC125 arms also had more time to develop side effects.
Nonetheless, in this all-grade summary, there was a higher rate of many adverse events in the TMC125 arms compared to the control arm.
Table 3
In sum, TMC125 has documented durable activity in patients who have clear NNRTI resistance, and has a reasonable safety profile as well. Although the three currently approved NNRTIs (delavirdine [DLV, Rescriptor], efavirenz [EFV, Sustiva, Stocrin] and nevirapine [NVP, Viramune]) have no validated approach to successful "sequencing," it is clear that TMC125 will have preserved activity despite NNRTI resistance.
Effect of Baseline Resistance on TMC125 Response
The 79 patients included in the analysis harbored a median of four PI-resistance mutations and two NNRTI-resistance mutations. Only 17% of the patients showed some phenotypic susceptibility to a PI, and the median FC to efavirenz and nevirapine was 41 and 61, respectively.
Figure 8
Slide by Johan Vingerhoets et al; reprinted with permission.
Table 4
Figure 9
Slide by Johan Vingerhoets et al; reprinted with permission.
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However, based on these and other data, it is now critical to consider interrupting NNRTI-containing regimens at the time of virologic failure in order to minimize the risk of selecting for a greater number of NNRTI mutations, which appears to undermine the activity of this new compound. Phase 3 studies are well underway and will further characterize the future role of this new antiviral.
Conclusion/Closing CommentsThe treatment of drug-experienced patients -- many of whom started therapy in the pre-HAART era -- remains one of the key challenges for clinicians. Our hope for durable HIV RNA suppression lies in newer drugs and drug classes with improved resistance characteristics. Although studies of recently approved and investigational agents have shown greatly improved results in this patient population, clearly not all have benefited equally from these new therapies. It is urgent that we define the resistance characteristics of these drugs; determine clinically relevant genotypic and phenotypic patterns and levels; and compare these with other drugs of the same class.
The 4th European HIV Drug Resistance Workshop and the 12th Annual Conference of the British HIV Association were two important venues where recently generated data on such issues were presented and discussed. Refinement of our understanding of important salvage drugs such as tipranavir and tenofovir, and insight into the resistance of drugs in advanced clinical development such as TMC125 and TMC114 were presented. Mechanisms and early reports on resistance to investigational new drug classes such as the CCR5 and integrase inhibitors were also discussed and there were examinations of updates on new resistance technologies and epidemiology studies and their clinical relevance.
But many questions remain unanswered. Can we really extrapolate data from different studies in attempt to compare tipranavir and TMC114 -- or have we learned that this is an unwise practice and that we require true comparative studies? Which and how many NNRTI mutations will preclude or substantially reduce any durable response from TMC125 in NNRTI-experienced patients? What will be the incidence and clinical impact of resistance to CCR5 inhibitor therapy?
Hopefully future meetings will address these important questions.
Copyright © 2006 Body Health Resources Corporation. All rights reserved.
Wall Street Journal Examines So-Called "Salvage Therapy" for People With AIDS Whose Illness Is Not Responding to Treatment Options
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