Good News On Viral Resurgence

[MitchMiller]

After 6 years at undetectable, looks like if you're 100% adherent the possibility of a viral rebound is virtually nill.

http://www.natap.org/

Duration of Viral Suppression Strongly Modifies the
Adherence-Viral Rebound Relationship
 
 
     Reported by Jules Levin
5th IAS Capetown July 19-22 2009
 
Viviane Lima1, D Bangsberg2, PR Harrigan1, M Rosenblum3, S Deeks3, B Yip1, RS Hogg1, JS Montaner1
1 British Columbia Centre for Excellence in HIV/AIDS; 2 Harvard Medical School;
3 University of California, San Francisco (vlima@cfenet.ubc.ca)
 
"Viral rebound was less likely to occur among those with long duration of suppression This translates in an odds of viral rebound decrease of 8% per each month of continuous viral suppression across all adherence levels. Individuals with high levels of adherence (≥95%), the probability of failure was 0.12 (IQR: 0.08-0.45) after being suppressed for 12 months and 0.04 (IQR 0.03-0.07) after being suppressed for 72 months". Sustained & near perfect adherence increases probability of long-term viral suppression, this is particularly critical at the earliest stages after starting HAART. From Jules: High levels (95%) of adherence required during first year on HART to achieve best chances for long-term viral suppression.

[GNYC09]

"Lower levels of drug exposure are required to prevent viral rebound because the overall viral burden declines over time."  -- so doesn't this imply that we (hypothetically) can take lower doses of our meds after x years since there is less virus to fight?  

[Inchlingblue]

"Lower levels of drug exposure are required to prevent viral rebound because the overall viral burden declines over time."  -- so doesn't this imply that we (hypothetically) can take lower doses of our meds after x years since there is less virus to fight?  

That's a very good point but the thing is it would take many clinical trials to prove before they could set it into practice with actual recommendations.

There was a small study in which people were given Isentress and unboosted Reyataz after they were already suppressed with a triple combo and it worked at continuing suppression. The study was not large enough and was non-randomized but at least it showed that this kind of thing needs to be explored further.

Since all it takes to become resistant to some of the drugs is sometimes just one mutation (as with Isentress and Reyataz) it's best to have more hard data. Needless to say, it would be great to take fewer drugs or lower doses of the same drugs.

[MitchMiller]

GNY:  If you follow the original link that I posted, you'll see the correlation that the study determined between rates of viral resurgence vs adherence.

However, your idea is partially correct for some drugs.  More studies would probably be needed to demonstrate which drugs.  However, to be honest, I'm a bit afraid to skip my Sustiva doses because it has got a low threshold to resistance.  Here's a study that showed good results when some drugs were skipped on the weekends.  Other studies where patients took them every other day didn't perform so well (a couple years back).

Sorry, because a lot of the content is in an image, you'll need to follow the link to get all the details, then search the page for the article's title.
   
/http://www.natap.org/   
 
THE FOTOSTUDY
48 week Results to assess durability of the strategy of taking Efavirenz, Tenofovir and Emtricitabine Five-days-On, Two-days-Off each week in virologically suppressed patients
 
 
     Reported by Jules Levin
IAS Capetown July 19-22 2009
 
C. Cohen1, A. Colson1, G. Pierone2, E. Dejesus3, F. Kinder4, R. Elion5, D. Skiest6, A. Habel1, J. Jensen1, J. Garb7, H. Schrager1, D. Back81CRI New England, Boston, United States, 2AIDS Research and Treatment Center of the Treasure Coast, Fort Pierce, United States, 3Orlando Immunology Center, Orlando, United States, 4Kinder Medical Group, Miami, United States, 5Whitman-Walker Clinic, District of Columbia, United States, 6CRI New England, Springfield, United States, 7Baystate Medical Center, Springfield, United States, 8University of Liverpool, Liverpool, United Kingdom Community Research Initiative of New England, Boston USA
 
From Jules: One concern raised is regarding adherence, that patients get into a routine and stopping & starting ARTs as in this study might be difficult to maintain. Forgetting Monday's dose might be just enough to cause virologic failures. The study does not report if higher rates of AEs in the FOTO arm were due to stopping & starting and study doesn't report the types of AEs reported. In a clinical study like this it is easier to control patients while in the clinic it is much easier for patients to be non-adherent or not stick to such a strict protocol as in the FOTO arm.
 
In response Dr Cal Cohen sent me an email -
As you know - adherence can be difficult for some people to maintain when given meds every day - challenges to maintaining adherence are not unique to the FOTO strategy of course. We found a very strong pt preference for the FOTO and preference in general correlates with adherence (see poster pix). While I agree that adherence to FOTO was likely optimal in our study population - it is also possible that there might be other non-study pts who might similarly do better on this schedule than they now do on daily medication. If daily med adherence was perfect for everyone our study would only be addressing cost savings - but we did see strong pt preference for this indicating this has additional merit. He also said that on the poster they reported that about 10% of pts did occasionally miss a Monday dose (e.g. took three days off) and there was no failure even with a 3-day holiday in the small number who did so. Agreed it could happen but we did not see any, and referred to Dybul/Fauci study a few years ago where they did a week on/week off and did not see viral rebound so a third day off may not lead to failure based on their study. We did report all AEs in the poster - anything that was considered at least mild related to the study procedure was reported. These were all patients in the study who were tolerating Atripla - so the control arm had no AEs in 24 weeks as they were all OK to start with. And you summarized the few events that occurred all on the FOTO arm - 3 people reported some sleep insomnia and 2 resolved by the next study visit without any Rx - one person started on a med Rx. There were only 2 other AEs noted - one night sweats, and one feeling intoxicated both of which were mild/transient. The cost saving issue - which is not trivial - if Atripla is 20000 per year and as FOTO saves about 5500 per year - for every 100 people who did FOTO instead of daily - there would be a savings of 550,000 - and I am pretty convinced that more than one hundred people would do well on this schedule. Indeed, if just 200 people do it successfully - over one million dollars now spent on drug could be spent on something else.
 
From Jules:
- 60 patients on Atripla with HIV RNA <75 for at least 90 days, <50 at screening were randomized equally to FOTO regimen 5 days on ART, 2 days off or to daily regimen. This poster reported adherence data (self-reported) and there appeared to be no difference between the 2 groups.
 
- Authors report at week 24 100% (n=25) As -Treated analysis <50 c/ml in FOTO, 86% (n=28) <50 c/ml on DAILY. No subject on either arm who continued experienced virologic failure during the entire 48 week study. Extension Phase 48 wks: week 36 90% on FOTO, week 48 90% on FOTO <50 c/ml.
 
- The EFV drug concentrations were higher in the daily vs FOTO: EFV >1000 ng/ml on FOTO (mean 60 hrs post last dose) 48%, while 90% on daily (mean 12 hrs post last dose) had >1000 ng/ml. Authors reported - PK: while nearly half of the trough concentrations were below the standard MEC used for EFV, there was no virologic rebound observed.
 
- In slide 12 authors report missed 1 or more doses in 5 day period on FOTO: 3/29 (1%) at week 4, 4/26 (15%) at week 12, and 2/25 (8%) at week 24; on DAILY: 5/30 (17%) at week 4, 2/28 (7%) at week 12, 3/28 (11%) at week 24
 
- At week 24 25/30 on FOTO completed (5 discontinued), while on daily 28/30 completed week 24 (2 discontinued): that's 17% vs 8% discontinued, although this is a small study. Of those 25 continuing to week 48 on FOTO 23 completed and on daily 27/28 completed.
 
- Reasons for discontinuation (n=10): 5 lost to follow-up, 4 withdrew consent, 1 pregnancy (n=5 on FOTO, n=4 on daily).
 
- ADVERSE EVENTS judged at least possibly related to study intervention: no AEs on daily through week 24; on FOTO: n=5 through 48 weeks, 'all mild in severity', n=3 with sleep related AEs: all resolved with one month (1 additional Rx), 1 night sweats, 1 with intoxicated feeling for 1 day. (from Jules: the higher number of AEs reported on FOTO could be due to stopping & starting).
 
- % who took 1 extra day dose during 2 days off: 3/29 at week 4 (10%) , 1/26 at week 12 (4%), 2/24 (8%) at week 24
 
- COST SAVINGS: the authors concluded: This strategy has the potential to conserve 28% of the cost of this three-drug regimen

image002.gif

image004.gif

image006.gif

image008.gif

image010.gif

image012.gif

image014.gif

image016.gif

image018.gif

image020.gif

image022.gif

image024.gif
 
   
 

[GNYC09]

You're right.  I had skimmed the article and missed a few key statements.