No AIDS-Free Survival Benefit to Starting HIV Treatment at CD4s of 500 or More

[tednlou2]

October 11, 2011

Cohort Study: No AIDS-Free Survival Benefit to Starting HIV Treatment at CD4s of 500 or More




Starting antiretroviral (ARV) therapy with a CD4 count above 500 doesn’t decrease the risk of AIDS or death from any cause, according to a new report from a large cohort study published in the September 26 issue of Archives of Internal Medicine.

For people living with HIV with CD4s below 350, the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) study confirmed the clinical benefits of starting and remaining on ARV treatment. As for those with CD4s between 350 and 500, CASCADE indicated slower rates of disease progression associated with starting treatment, though there were too few new AIDS cases or deaths in this particular group during the study to yield firm conclusions. 

The question of when ARV therapy should be started has not yet been answered. Three large cohort studies indicate that people should not wait until their CD4s fall below 350 to start ARV therapy. As for waiting until the CD4 count falls below 500, one cohort—the NA-ACCORD study—suggested this is detrimental, whereas another did not; the third cohort only included patients with fewer than 500 CD4s, thus a detailed analysis was not possible. NA-ACCORD also pointed to disease-free survival advantages when therapy is started when the CD4 count is between 500 and 800.

Acting on the initial cohort findings, the U.S. Department of Health and Human Services changed its ARV treatment recommendations in 2009. Whereas the guidelines previously recommended treatment for all people living with HIV with CD4s below 350, the threshold was increased to below 500 in light of the important—but inconclusive—findings.

Some experts argue that the only way to know the absolute benefits and risks of starting therapy early—indeed, even immediately after HIV is diagnosed—is to examine the results of a randomized prospective study. The international Strategic Timing of Antiretroviral Treatment (START) trial is exploring this question, but data are unlikely to be available until 2015. Taking place at roughly 90 sites in nearly 30 countries, START is randomizing more than 4,000 antiretroviral-naive HIV-positive individuals with CD4s above 500 cells to either begin treatment immediately or defer treatment until their CD4s are less than 350 cells.

In the meantime, additional data are available from the CASCADE study, a large cohort consisting of 23 small cohort studies being conducted throughout Europe, Australia and Canada. The report published in Archives of Internal Medicine by Michele Jonsoon-Funk, PhD, of the University of North Carolina at Chapel Hill and her colleages is similar to a preliminary review of the data orally presented in July 2010 at the XVIII International AIDS Conference in Vienna.

Unlike other cohorts, which began following people from the time they started therapy, the new CASCADE analysis involved 9,455 people who were infected within the previous two years and followed them until they started ARV therapy. In other words, CASCADE researchers were in the unique position to document what happened to patients before they began treatment.

Between January 1996 and May 2009, the CASCADE researchers enrolled new patients every month, thereby created 161 small groups of patients for comparisons purposes. Patients were followed, on average, for nearly five years in the study. When ARV treatment was started, the investigators noted the patients’ CD4 counts. Where there were AIDS-defining conditions or deaths, the investigators noted how long they occurred after each patient joined the cohort.

The greatest benefits were seen among those who started therapy with immune systems that were clearly compromised. For example, those who started treatment as soon as their CD4 count fell below 50 were nearly 70 percent less likely to develop an AIDS-defining illness or die, compared with those who waited. Among those with CD4s between 50 and 200, starting therapy as quickly as possible reduced the risk of AIDS or death by 70 percent, compared with those who delayed treatment.

Of interest, the researchers reported a number-needed-to-treat (NNT) analysis for patients starting HIV treatment in each CD4 group. An NNT analysis is a relatively simple measure of effectiveness of a particular medical intervention, and it aims to determine the average number of people living with a disease who need to be treated to prevent one additional outcome. For example, the NNT analysis employed in CASCADE set out to determine the number of people living with HIV and a CD4 count within a particular range who need to be treated with ARV therapy to prevent one new AIDS case or death.

Not surprisingly, the NNT among patients starting with very low CD4s was also low—a total of three people living with HIV with CD4s below 50 needed to be treated with ARV therapy to prevent one AIDS case or death. Among those with CD4s between 50 and 100, the NNT was 7. The NNT for those with CD4s between 200 and 350 was 21.

There was also an appreciable benefit for those who started therapy as soon as their CD4s landed between 200 and 350, compared with those who delayed therapy—a 25 percent reduction in the risk of AIDS or death. However, Funk and her colleagues note, when treatment was started with CD4s in this range, “the benefits of treatment initiation become evident only beyond two years, suggesting that patients need to consider the long-term course of treatment, including the risk of adverse effects of [ARV therapy] during an extended period.”

Here the NNT was significantly higher—34 HIV-positive individuals with CD4s between 350 and 500 needed to be treated with ARV therapy to prevent a new AIDS case or death.

As for those with CD4s above 500, there was no advantage in terms of AIDS-free survival. Here, no NNT could be calculated in terms of preventing AIDS or death, though the researchers did suggest that 239 people living with HIV and high CD4 counts would need to be treated with ARV therapy to prevent a single death, from any cause.

A limitation of the CASCADE study is that it didn’t monitor participants for some of the non-AIDS-related health complications that are believed to be more common among people living with HIV. “Patient well-being is adversely affected my many serious non-AIDS-defining conditions,” Funk’s team writes. “For example, immunodeficiency and uncontrolled viremia have been implicated in the development of cardiovascular disease and non-AIDS-defining malignancies. Although CASCADE does not pool data on non-AIDS morbidity, this analysis reflects the most serious outcome (death) due to non-AIDS conditions.”

While awaiting the results of SMART, treatment decisions for those with CD4s above 350 “will need to be made based on the available evidence from observation cohorts,” Funk’s team concludes. “We used a novel approach applied to a unique cohort of seroconverters to reduce the potential for lead time bias. We found that treatment initiation and CD4 cell counts of 350 to 499 was associated with slower disease progression. We did not observe any benefit to treatment initiated at 500 to 799.”

http://www.poz.com/articles/hiv_cascade_start_761_21296.shtml

[spacebarsux]

Wow. Very interesting for me since I'm treatment naive with counts above 500 at the moment.

I think the more pertinent question is: Is there a 'net long term benefit'  in initiating therapy with CD4 counts > 500 as opposed to waiting until it drops to 350 ?

And that's precisely what the START study results should shed some light on.

You're not on therapy either, are you Ted?

Thanks for the article.

Edited for typo

[tednlou2]

Yep, still waiting.  I go back and forth on it.  I've decided to try and be in tune with my body so I'll know when is right....of course with regular labs.

[Mycen]

I started when I was diagnosed with HIV on HAART.  I am in the medical field and had already done some research on HIV.  After I was awaiting my results and right after I was officially diagnosed I really went overboard with researching HIV.  I found several articles in relevance to how HIV is not ever completely eradicated from your body and how it hordes itself in reservoirs in lymph nodes and other areas.  There were views for both sides that said if you started therapy earlier, then the amount of HIV locked in the reservoirs would be less.  My HIV Dr was of the same mind when we discussed whether or not I should go on HAART.  While my CD4 count didn't justify it, there was no definite research for or against it.  So I chose to er on the side of caution and start therapy.  I figure, if it stops or slows the progress of HIV becoming further rooted in the hiding places of my body...then one day when there is a cure, it might be that much easier to be completely through with it.  I'm fortunate to live in the county that I do, where my meds are paid for, as well as any other health concerns...I know this sounds crazy, but I have better health coverage now with HIV than I did before.

I'm curious to know what this research yields since my CD4 count was over 500.  It would be interesting to know the long term benefits or negatives.

[spacebarsux]

Mycen, that's the thing I don't really understand:- for someone with counts over 500, is that person erring  on the side of caution be starting therapy early or by waiting until his/her counts drop ?

The answer is not crystal clear and there is room for debate -until we get a clearer picture from the START study results.

[vaguesbleues]

I had a similar view to that of "Mycen."  I didn't want to give the virus any opportunity to establish latent viral reservoirs in my body, nor do a lot of the initial GI damage that is common right after infection.  Furthermore, while my T-cell count at the time of starting therapy was over 1100, my viral load had started to go up compared to the initial undetectable, and I was very sick with CMV symptoms.  Getting this under control, even when the current guidelines would not automatically recommend therapy, was my primary goal.  Also, to each their own in regards to when to start therapy.  My doctor was comfortable having me wait, but let me make a lot of the decisions after covering all options available. 

And I agree, getting the results from the START study will hopefully shed some light on the benefits on whether or not to wait to being treatment.

[surf18]

i guess my thoughts on this was to weigh hiv running rampent in my body or get rid of as much as possible of it with drugs and deal with drugs. i just thought it was better to get rid of as much hiv as possible. though i had a count in the mid two's when i was dx'd so it really wasnt an option for me but if i had a high tcell count i would have proably went on them any ways.

[Mycen]

Mycen, that's the thing I don't really understand:- for someone with counts over 500, is that person erring  on the side of caution be starting therapy early or by waiting until his/her counts drop ?

One yields to caution when there is no right answer.  To medicate or not to medicate?  When taking meds might help, where as not taking meds would simply mean starting meds early and having to deal with them now.  In my case, it was not only just that my CD4 count was above 500, but I was diagnosed with HIV 3 months after I came in contact with it.  The research that I had come across wasn't in regards to CD4 counts greater or less than 500, but how soon one should start therapy from when they come into contact with HIV.  In this regards its hard to find people who have just come into contact with HIV to study since many are not diagnosed until years later when they begin to have other health problems as a result of HIV.

But, even though my initial reasoning for getting on therapy wasn't about CD4 counts being below 500, I'd still be very interested to know the results of this study.  And should there be a study that has definitive results on if starting therapy early from becoming in contact with HIV, I'd like to learn more about that as well!   

[mecch]

Bizarrely, I wouldn't want to be in your shoes.  Wondering when to start.
I get that its also a position that has advantages.  But always wondering when, would weigh on me, I can imagine.

[elf]

I had no choice really, diagnosed with CD4 of 353 three years ago, and started therapy on the next day.

[spacebarsux]

Mycen, I meant we don't really know for sure right now, 'which side' is erring on the side of caution. 

If, for example, the START study results indicate that there is 'no long term benefit' in initiating HAART with counts > 500 then the way I see it, starting meds sooner was not in anyway erring on the  side of caution cause one would have been putting chemicals into their body with no benefit. In fact, it would be erring on the side of caution to not have started meds (in retrospect).

Of course, everything should become clear with those study results.

[John2038]

As soon as the virus enter the body, it attack it.
I don't see the point, beside side effect and or meds toxicity, of waiting. Just my personal point of view.

[mecch]

As soon as the virus enter the body, it attack it.
I don't see the point, beside side effect and or meds toxicity, of waiting. Just my personal point of view.

??
As soon as HIV enters the body??? From where?
If you are HIV+, the virus is in you already.

[mbpoz6]

As soon as the virus enter the body, it attack it.
I don't see the point, beside side effect and or meds toxicity, of waiting. Just my personal point of view.

I agree 100%.

The way I saw it was that, the longer the wait to start meds, the bigger the reservoir gets overtime, the more the damage to my immune system (regardless of t-cell counts, high or low), the harder it will be to eradicate/purge/attack the reservoir when the time comes. Staying as healthy with as little virus in me as possible, thanks to meds is what I'm focusing on.

I think Dr. Fauci (or was it Dr. Deeks?... can't remember...) said the patients with the smallest established viral reservoirs will be best/easiest candidates to treat in the future of course as well having have been UD/having low viral count the longest, thanks to current potent treatments. It wasn't mandatory for me to start meds, but personally, I didn't see much hurt in starting now, or why I should just sit here and wait while the virus has a party in my body. I'm kinda seeing things more-so towards the future benefit of things. I'd rather be on medication and let them do whatever they do to me (good or bad, but of course its more good than bad), than the virus itself.

Luckily, so far I haven't really experienced any side effects, or toxicities anyway and I'm tolerating them extremely well. But that's just me. Everyone is different.