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Author Topic: Sustiva beats Kaletra (and I'm confused)...  (Read 2219 times)

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Offline Cliff

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Sustiva beats Kaletra (and I'm confused)...
« on: August 24, 2006, 08:48:51 AM »
I'm considering going on Sustiva and the news, (that Tim delivered in Montreal), seems to suggest this is a probably a good plan.  However, I'm reading the study summary and I don't understand part of it.  The summary states,
Quote
The time to treatment failure was shorter in the Kaletra/NRTIs group than in the Sustiva/NRTIs group. The percentage of patients who experienced treatment failure by week 96 of the study was 33% in the Kaletra/NRTIs group, compared to 24% in the Sustiva/NRTIs group and 27% in the Kaletra/Sustiva group. The comparison between the Sustiva/NRTIs group and the Kaletra/NRTIs group was statistically significant, meaning that the difference most likely was not due to chance.
So by week 96, 67% of those on Kaletra, 76% of those on Sustiva and 73% of those on Sustiva/Kaletra (dual-therapy) did not experience treatment failure.  Fine.  But then they go on to say...
Quote
Dr. Riddler also explained that, at week 96 of the study, the percentages of patients with viral loads less than 50 was 83% in the Kaletra/Sustiva group, 89% in the Sustiva/NRTIs group, and 77% in the Kaletra/NRTIs group. Here also the difference between the Sustiva/NRTIs group and the Kaletra/NRTIs group was statistically significant.
This is where I get lost.  How can one stat state that 89% of those on Sustiva have viral loads of less than 50, which means 11% had viral loads over 50 (by week 96) and yet in the previous stat, they state that 24% of those on Sustiva experienced treatment failure? 

How does the 24 and the 11 match up?  Can you have treatment failure and still have a viral load of less than 50?  Also, if side effects isn't the reason why Sustiva performed well, is there any way to tell why?  I thought Sustiva had a lower genetic barrier to resistance, which on paper would make it less potent than Kaletra.  I could understand Sustiva beating Kaletra if more people stopped Kaletra because of worse side effects, but the study seems to indicate that this wasn't the case.

The full summary:

Quote
IAC: Sustiva vs. Kaletra – ACTG Study Declares a Likely Winner

By Tim Horn, Senior Writer & Editor, AIDSmeds.com

The U.S. Department of Health and Human Services (DHHS) currently recommends either Sustiva® (efavirenz) or Kaletra® (lopinavir plus ritonavir) – in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) – for HIV-positive people starting treatment for the first time. But a central question has been lingering for several years: which of these medications is more effective? Long-awaited study results, reported yesterday at the International AIDS Conference (IAC) in Toronto, may help settle this question once and for all.

The study (A5142) was conducted by the AIDS Clinical Trials Group and was reported at IAC by Sharon Riddler, MD, of the University of Pittsburgh. It actually compared three drug regimens taken for almost two years: Kaletra plus two NRTIs, Sustiva plus NRTIs, and Kaletra plus Sustiva (without any NRTIs).

A5142, with an enrollment of 757 treatment-naive patients, is the first large study to compare Kaletra to Sustiva – the reigning standard-of-care options in the United States for HIV-positive people starting treatment for the first time.

Across the board, all of the treatment regimens were reported to be effective by Dr. Riddler. Among the three treatment groups, approximately 83% had viral loads below 50 after 96 weeks of treatment.

However, there was one key difference between the treatment groups. The time to treatment failure was shorter in the Kaletra/NRTIs group than in the Sustiva/NRTIs group. The percentage of patients who experienced treatment failure by week 96 of the study was 33% in the Kaletra/NRTIs group, compared to 24% in the Sustiva/NRTIs group and 27% in the Kaletra/Sustiva group. The comparison between the Sustiva/NRTIs group and the Kaletra/NRTIs group was statistically significant, meaning that the difference most likely was not due to chance.

Dr. Riddler also explained that, at week 96 of the study, the percentages of patients with viral loads less than 50 was 83% in the Kaletra/Sustiva group, 89% in the Sustiva/NRTIs group, and 77% in the Kaletra/NRTIs group. Here also the difference between the Sustiva/NRTIs group and the Kaletra/NRTIs group was statistically significant.

When it came to CD4 count (T cell count) increases, however, the Kaletra/NRTIs group came out slightly ahead of the Sustiva/NRTIs group. After 96 weeks of treatment, CD4 counts increased by 285 cells in the Kaletra group, compared to an increase of 241 in the Sustiva group. This difference was also statistically significant.

The medications were equally well tolerated when measured by the number of study volunteers who had to stop their treatment due to side effects. However, some of the side effects associated with symptoms (e.g., nausea, diarrhea, and headache) and blood test abnormalities (e.g., increased triglyceride levels) were more common in the Kaletra/Sustiva group compared to the Kaletra/NRTIs or Sustiva/NRTIs groups.

Dr. Riddler pointed out that the A5142 study team has much more data to analyze from this study. Detailed information regarding side effects including metabolic changes (cholesterol, blood sugar, and lipodystrophy), adherence, and resistance testing will be reviewed in the next few months.

Until firm conclusions can be drawn, Dr. Riddler indicated that when a primary goal of therapy is to keep viral load undetectable for as long as possible to prolong the benefits of treatment and reduce the risk of drug resistance, Sustiva plus two NRTIs appears to be a better bet than Kaletra plus two NRTIs.

Source:

Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infections – ACTG 5142 [Abstract THLB0204]. XVI International AIDS Conference, Toronto, 2006.
« Last Edit: August 24, 2006, 08:53:45 AM by Cliff »

Offline gerry

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #1 on: August 24, 2006, 09:32:50 AM »
Cliff:

I believe they do not equate "treatment failure" as not having achieved a viral load < 50.  I haven't seen the entire study or abstract but in other studies I've seen, treatment failure was defined by a higher viral load (e.g. >200).

Gerry

Offline newt

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #2 on: August 24, 2006, 09:58:28 AM »
Yeah the figs are balmy, it's a result of definitions, volumes and counting at various timepoints I guess. The second set of figs are on an intent-to-treat basis at week 96, ie the people still on the drugs then, meaning some people had dropped from the study nos since the previous count and report. Poor reporting really, the Aidsmap report is more informative.

Treatment faliure in this study was defined as a viral load above 200 copies/ml after week 32.

Tim's report don't say that, of people who "failed", nuke resistance was higher in the Sustiva arm than the PI arm and NNRTI v PI resistance much higher in the Sustiva arm (48% in the Sustiva+2 nukes arm of people "failing" here who were genotyped compared to 2/91 who "failed" in the PI arm).

Anyway, so what? I can show you studies that give reverse results, eg Kaletra better than Sustiva for treatment-naive people, at about the same level of statistical significance, plus studies that put them on level pegging. True, this is the first head-to-head study, but you gotta be careful with studies, easy for them to be sound & statistically significant but underpowered or underfactored or not especially informative when it comes to you taking the drugs.

Practically speaking 75% is about the same as 85% on a small clinical population like 300. I mean, you can't have/treat HALF a person. It's what works for you that counts.  Most good, modern combo regimes will score undetectable for between 2/3rds and 9/10ths effectiveness, depending on the study criteria, population, nukes used etc etc. 

The conclusion I draw from this study is, clinically speaking, as we already know, a good PI or a good NNRTI + 2 nukes is an effective first-line combo for 8/10 people, and that Sustiva/Kaletra, while strong, is a bugger on the lipids etc.

Plus (an aside really) participants got to choose 1 of the nukes, so it's not really a perfect head-to-head if they chose different, esp since AZT and d4T(!) were included, which as we all know, can be well nasty and disincline you to be adherent/incline you to change combo.

One study a market leader should not a combo make (but bet BMS love it).

- matt
« Last Edit: August 24, 2006, 10:43:29 AM by newt »
"The object is to be a well patient, not a good patient"

Offline newt

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #3 on: August 24, 2006, 10:51:45 AM »
Abstract:

http://www.aids2006.org/PAG/Abstracts.aspx?AID=50649

Okay from the results:

"Kaplan-Meier estimates of the proportions without VF by week 96 were 73%, 67% and 75% for L/E, LPV and EFV arms, respectively. At week 96, the percentages with HIV-1 RNA <50 copies/mL were 83%, 77%, and 89% for the L/E, LPV and EFV arms, respectively (p=0.003 LPV vs. EFV)..."

Now someone needs to explain the difference between the expected an actual results. 

Plus 89% = 222 people, compared to 77% =  195 people. Difference of 27, or perhaps less, since the intent to treat analysis excludes a few from the count, I think, for some (bad) reason.

- matt
« Last Edit: August 24, 2006, 12:24:57 PM by newt »
"The object is to be a well patient, not a good patient"

Offline Cliff

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #4 on: August 24, 2006, 10:56:48 AM »
ok, so the intent-to-treat numbers are higher.  At first I couldn't understand why they would show both stats (total population, versus only the intent-to-treat folks), but I guess some people may be interested in looking at the impact to those who did not meet the end-points.

Tim's report don't say that, of people who "failed", nuke resistance was higher in the Sustiva arm than the PI arm and NNRTI v PI resistance much higher in the Sustiva arm (48% in the Sustiva+2 nukes arm of people "failing" here who were genotyped compared to 2/91 who "failed" in the PI arm).

I'm not sure I understand this part.  If you achieve viral breakthrough of your primary drug, (for lack of better words), (be it a PI or a NNRTI), how could that not automatically lead to resistance to your backbone drugs (the nukes)?  I, maybe erroneously, assumed that once your virus breaksthrough your meds, it has broken through all the drugs you are on, or else you would still have an undetectable count.  

Said differently, can a virus break through one drug, then go on to show potent replication, (i.e., a non-undetectable viral load), and still have sensitivity to the other two drugs you are on?

Offline newt

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #5 on: August 24, 2006, 11:36:51 AM »
Re: resistance...

NNRTI resistance is kinda sudden when it happens, requiring only one mutation, whereas PI resistance requires several mutations and evolves slowly.  So no surprises that the proportion of people not achieving viral suppression on Sustiva ending up resistant to this drug was high.

The most common nuke mutation reported so far was (as probably expected) M184V. I am unclear from the info availale if this was present equally or differently in non-nuke and PI study subjects "failing" treatment.  M184V is the most common nuke mutation you get from incomplete viral suppression, but, given the frequent monitoring in this study, it may well have been present beforehand rather than a consequence of treatment not working (so far, we ain't been told).

From the Aidsmap report (about resistance and people who did not achieve viral suppression to under 50 copies):

"Resistance mutations in two drug classes - NRTI-associated (M184V) and NNRTI-associated (K103N) - were more common in the efavirenz [Sustiva] group plus NRTIs group than in Kaletra-treated patients, and primary protease inhibitor mutations were detected in only two of 91 patients who failed a Kaletra-containing regimen." 

I wanna stress right now, as far as the reports allow me to say,  that the vast majority of people in this study on any combo, achieved long-term viral suppression & therefore had no resistance issues.

- matt
« Last Edit: August 24, 2006, 11:56:48 AM by newt »
"The object is to be a well patient, not a good patient"

Offline Cliff

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #6 on: August 24, 2006, 01:53:45 PM »
"Resistance mutations in two drug classes - NRTI-associated (M184V) and NNRTI-associated (K103N) - were more common in the efavirenz [Sustiva] group plus NRTIs group than in Kaletra-treated patients, and primary protease inhibitor mutations were detected in only two of 91 patients who failed a Kaletra-containing regimen."
...still confused.  So when Sustiva fails, it more likely will result in resistance to Sustiva and a Nuke (3TC/FTC), but when a Kaletra combo fails, it usually just results in resistance to a nuke and not Kaletra itself.  But how can that be? 

How can a virus breakthrough a Kaletra regimen, (treatment failure), and yet still display no resistance to Kaletra?  Wouldn't the regimen not fail in the first place, if the virus was still suspectible to Kaletra (even if 3TC or the other drug failed)?  Wouldn't all three drugs have to fail before a virus can breakthrough a combo?

Offline gerry

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #7 on: August 24, 2006, 11:22:09 PM »
How can a virus breakthrough a Kaletra regimen, (treatment failure), and yet still display no resistance to Kaletra?  Wouldn't the regimen not fail in the first place, if the virus was still suspectible to Kaletra (even if 3TC or the other drug failed)?  Wouldn't all three drugs have to fail before a virus can breakthrough a combo?

Cliff:

Not all treatment failures (i.e., persistently detectable viral load) are accompanied by emergence of resistance mutations, especially as far as Kaletra is concerned.  Even in some Kaletra monotherapy studies, most those who fail to achieve undetectable VL during the study did not show evidence of Kaletra resistance.  Most of these patients went on to achieve undetectable viral loads when placed on conventional combo (i.e., adding 2 nukes) after failing on Kaletra alone.

Going back to the abstract (thanks for the link, Matt), I believe all the percentages presented were intent to treat.  If you read the methods section, it defines virologic failure as VL > 200 after 32 weeks.  So at the 96-wk mark, 33% in the Kaletra/NRTI group and 25% in the Sustiva/NRTI group met virologic failure criteria.  This is different from failing to achieve a VL of < 50 at the 96-wk mark, which was 23% for the Kaletra/NRTI group and 11% for the Sustiva/NRTI group.  This means that there are patients who had detectable viral loads but who did not quite fit the virologic failure definition (VL > 50 but < 200), which would account for the difference in the numbers.  Hope that makes mathematical and methodological sense (even though it does not necessarily make clinical sense).

Gerry

Offline Cliff

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #8 on: August 25, 2006, 06:11:38 AM »
Thanks Gerry!!!

That's interesting that you can be on Kaletra monotherapy, not achieve an undetectable VL, and still not have resistance to Kaletra.  I think the issue for me is that my understanding of resistance is too basic.  People are quick to explain it as the virus being able to reproduce while in the precense of your drugs, which renders your drugs useless.  But clearly it's not as simple as that.  So more researching for me to do...

Now, I've got to find how many people failed the Sustiva regimen and how many of those developed resistance to anything than 3TC/FTC and then I can decide what to do.  I think Matt has it up there somewhere.  I like Reyetaz, but I really want to try something else this time around.

Cliff

Offline jack

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #9 on: August 25, 2006, 07:16:24 AM »
and don't forget to take into account the sides of each drug. Maybe I have done so many drugs I am getting immune to sides, but Kaletra was pretty easy, for me. Sustiva was a nightmare in more ways than one.

Offline newt

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #10 on: August 25, 2006, 07:24:32 AM »
Cliff, 48% (say a maximum of 14 out of 28 people) who did not achieve a viral load of <200 copies had the defining mutation for NNRTI resistance (K103N). This is as expected I guess, since other studies support about half of people not achieveing virologic suppression on NNRTIs developing K103N.  Tis unfortunate that with Sustiva and Viramune, this single mutation generally confers high-level resistance, making the drug class wiped.

The other head-to-head study of note is this one: Zidovudine/Lamivudine Inferior as First-Line NRTI Backbone - a comparison of AZT/3TC or tenofovir/FTC + Sustiva as first-line therapy.  I post this because, in the context of this thread, the 96 week results in this study show a generally lower % achieiving a viral load of either under 400 copies or 50 copies than in A5142.  The AZT/3TC v tenofovir/FTC head-to-head has Sustiva+2 nukes showing figs closer to the Kaletra+2 nukes arm of A5142.  Making a direct comparison needs caution, but, as I said before, where you end up between 2/3rds and 9/10ths achieving viral load of less than 50 copies in a study of combos you already know work well depends on many factors.

- matt
« Last Edit: August 25, 2006, 07:27:10 AM by newt »
"The object is to be a well patient, not a good patient"

Offline gerry

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #11 on: August 26, 2006, 03:22:28 AM »
Cliff:

You may want to look at the data from the GS 903 trial, the original trial that compared TDF/3TC/EFV with d4T/3TC/EFV.  The entire article is available from JAMA but you need to register. 

Efficacy and Safety of Tenofovir DF vs Stavudine in Combination Therapy in Antiretroviral-Naive Patients

Here's a summary of the resistance data from that trial with the TDF/3TC/EFV arm through week 144 of the study:

Total # of patients: 299
Virologic failure: 47 (3 patients turned out to have baseline EFV resistance prior to treatment and went on to develop more EFV mutations on treatment)

Any EFV resistance mutations: 26 (K103N was the most common EFV resistance mutation)
   EFV resistance alone: 7
   + M184V/I: 10
   + K65R: 3
   + K65R + M184V/I: 5
   + other NRTI resistance: 1

Any M184V/I mutation: 18

M184V/I alone: 3

Any K65R mutation: 8

K65R mutation alone: 0

Wild type or same as baseline: 18



So in this study, roughly 60% of patients who had virologic failure on treatment developed drug resistant mutations (mostly to EFV and 3TC).  Hope this helps some.

Gerry
« Last Edit: August 26, 2006, 03:29:28 AM by gerry »

Offline Cliff

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #12 on: August 26, 2006, 05:42:47 AM »
Thanks Gerry.  This helps.  For the moment I ignored resistance to Nukes.  But looking at the two studies (the one you just discussed and the original one), it appears that roughly 84-89% of those on Sustiva will have a successful regimen for an extended period of time and that roughly 90+% will not develop resistance to Sustiva (either because it is a successful combo for them or even if they do fail it they don't go on to develop resistance to Sustiva).  For the PI (Kaletra), while the overall success rate is lower, there is virtually minimal risk of developing resistance to the PI (99%+ will either have a successful combo or even if they do fail it they don't do on to develop resistance to the PI).  So it's roughly comparing 90 to 99%.

I ignored Nuke resistance, because I don't see the numbers for the first study discussed above.  The aidsmap report says,
Quote
Resistance mutations in two drug classes - NRTI-associated (M184V) and NNRTI-associated (K103N) - were more common in the efavirenz group plus NRTIs group than in Kaletra-treated patients, and primary protease inhibitor mutations were detected in only two of 91 patients who failed a Kaletra-containing regimen.
But it doesn't have any numbers to compare, nor does it state whether this difference, (Nuke resistance), between the two groups was significant.

Of course, much of this depends on how well those resistance tests are (I think).  If there is resistance there that isn't being picked up by the tests, (from the groups of people who failed the regimen but showed no resistance to Sustiva or Kaletra), then the analysis is flawed.

Offline gerry

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Re: Sustiva beats Kaletra (and I'm confused)...
« Reply #13 on: August 26, 2006, 11:45:54 AM »
Cliff:

You probably won't get much more detailed information on the resistance numbers in the current study until the study gets published.  But your overall assessment is what experts generally agree on.  That is, EFV/TDF/3TC is very effective in majority of patients who have no baseline drug resistant mutations and who can tolerate the combo well.  The effectiveness also seems to be durable.  In this group, resistance does not generally become an issue, assuming good adherence.  For the few in which the treatment is not successful, resistance becomes a real issue.  There is also some amount of predictability as to which mutations happen first, with K103N (selected by EFV) and M184V (selected by 3TC) happening more commonly, followed by the more dreaded K65R (selected by TDF).  But the GS 903 trial showed that the K65R did not happen here too commonly even in the subgroup that had virologic failure (8/47 = 20%) when compared, for instance, to the disastrous results of some triple NRTI combo.

I think I can understand your apprehension, because should you consider this treatment, you don't know exactly if you would fall in the 90% good responders (i.e, tolerated meds and achieved VL<50), in which case you don't have to really worry about resistance; or if you would fall in the 10% virologic failure, in which case resistance becomes a real issue in a relatively short period of time.  Unfortunately, that is part of the risk for any NNRTI-based regimen, which is probably not the case for boosted-PI based ones.

Gerry

 


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