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Researchers recommend early ART following START trial results
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Recent data from the START trial showed that early ART initiation was associated with fewer AIDS-related events and non-AIDS–defining cancers, suggesting that all patients should receive therapy immediately after infection.
Although there were fewer events with early therapy, many patients still develop cardiovascular disease and many other non-AIDS events. Infectious Disease News asked several experts to address the promising results of the START trial and the implications they might have for the future of HIV care, as well as the challenges they continue to endure.
The following commentaries were excerpted from videos featured on Healio.com/ID.
Michael Saag, MD, University of Alabama at Birmingham
The issue about when to start ART goes back to 1987, when the AZT trials were first released. A placebo-controlled study showed benefit of starting [therapy] with a CD4 count of less than 200. To me, the bad legacy of that study is that it linked all of our thinking about when to start therapy to a CD4 count metric, to a number.
As we moved into the ’90s using AZT, monotherapy worked a little bit when the CD4 count was up to 500, but [the benefits] only lasted about 12 to 18 months. As the more modern era of ART came in around 1995 to 1996, the question resurfaced. We learned a lot about the biology of the virus, [and] that the virus replicates at 1 billion to 10 billion viruses a day, which [made us question] why we shouldn’t be treating everyone. [However], the studies were looking at a CD4 count of 350 or 200, and we were again stuck in this realm.
As better therapies came out [between] 2000 and 2010, the guidelines started to relax a little bit on CD4 count. Some randomized studies told us we should be starting [treatment] at 350, but the newer therapies were much more tolerable and people were able to [be treated] for a longer period of time.
A landmark study by the NA-ACCORD, led by Mari Kitahata, MD, and Richard Moore, MD, [looked] at people who came into care at or above a 500 [CD4 count] and either [received] therapy then or waited until their CD4 counts dropped below 500. By looking at that retrospective analysis, we were able to determine that the benefit of starting therapy, even above 500, gave a relative risk of about 1.9. There was almost a twofold benefit. Some of us at that time, myself included, said that based on the biology [and] the cohort data, we should be treating everyone regardless of their CD4 count. On the other end of the spectrum, there were people who said we needed a randomized trial. That trial was started in the late 2009 [to] 2011 era.
The START trial randomized people to starting [ART] with a higher CD4 count or waiting until the CD4 count [went down] to 350. [The results] showed that starting above 500, indeed, gave significant advantage clinically to people as opposed to waiting. Now we can say, unequivocally, the question has been answered.
What does that mean for the future? If we redouble our efforts to get people tested [and] get them into care now, we have a chance to catch them before their CD4 count drops below 500. [Then], ART has its best shot to stop this relentless replication of the virus and give them the best chance to live a full, meaningful life with regard to HIV.
David Wohl, MD, University of North Carolina at Chapel Hill
While the results may not be completely shocking [and] come after the field has already moved to treating earlier, it settles the issue once and for all. An important aspect of the START trial is for those who are really ambivalent. There are many of us, myself included, who are veterans of the HIV care wars. We know bad things can happen from HIV therapies, so some of us have been tempered in our enthusiasm for applying HIV medicines wholeheartedly in everyone who is infected. I understand completely the toxicity and complications of HIV therapy, but [I] also appreciate that newer therapies are cleaner than the medicines we used before. Thus, I feel starting therapy earlier trumps any concern because of the benefits that we see in the epidemiological cohort studies and now in actual clinical trials.
We know from other studies [that] HIV therapy reduces inflammation once it starts to reduce viremia, so there could be other subsequent downstream effects of ART that are beneficial. I hope these trials will motivate my colleagues to understand that ... the harm of the virus outweighs any toxicity or concerns for modern-day HIV therapy. The good news is that, reflecting the [the U.S. Department of Health and Human Services] guideline change from a few years ago, most [health care providers] are already thinking about HIV therapy, even in their patients who present with high CD4 cell count. Internationally, it’s going to be a little bit more tricky.
Alan J. Taege, MD, Cleveland Clinic
In the United States, we initiated therapy at counts of 500 or above, but there are global guidelines such as UNAIDS and WHO that have proposed to wait until CD4 counts drop lower. ... Despite people having their CD4 counts at 500 or higher, because of the therapy that they’re on, they still develop some of these non-AIDS–defining cancers, cardiovascular disease and other events. This then leads to further questions that need to be answered. Even though we have CD4 as our marker for quote success, it is an incomplete marker of immune function, which is something we’ve known for a long time. Additional studies [need to] find better markers of immune function and inflammation, which is driven by the virus.
Carl J. Fichtenbaum, MD, University of Cincinnati College of Medicine
The current belief is that HIV causes a level of inflammation that increases the risk of developing atherosclerosis or plaque. We really want to understand the driving force behind [inflammation]. One hypothesis is that you have ongoing replication, even though people [are] very well-controlled on their medications. We see activated cells called macrophages, which are very important in controlling HIV infection, but are also part of the problem in coronary artery disease. These cells tend to slip across the blood vessel border and lodge themselves just beneath the subendothelium. In this space, these activated macrophages fill up with cholesterol and fat and form plaque.
One of our most important advances is something called the REPRIEVE trial, which enrolled the first patient in March of this year. [REPRIEVE] is a randomized, prospective, blinded study comparing [Livalo (pitavastatin, Kowa Pharmaceuticals)] to placebo. Pitavastatin is a member of the statin class, or the HMG-coA-reductase inhibitors, that are known to lower cholesterol and have been proven to help prevent further problems from coronary artery disease when given to people who already have it. This has never been studied in people with HIV infection. We hope to find [that] if we give individuals who do not have any evidence of coronary artery disease or cardiovascular disease a statin like pitavastatin it lowers the rate of myocardial infarctions, stroke or the need for individuals to have interventions such as bypass surgery or a stent to relieve a blockage in a coronary artery.
One of the hardest things to figure out is the relationship between HIV; other known risk factors for coronary artery disease, such as cigarette smoking and genetic predisposition for heart disease [and] high blood pressure; and the medications for HIV. We’ve known for many years that these are probably risk factors. It’s hard to tease out which one is primary, and that’s why most of us believe it’s probably an aggregate of these risks that are leading to events.
[Over] the next few years, I expect to learn more about the relationship between inflammation, HIV, and coronary artery disease or cardiovascular events. It’s really important that health care providers who see individuals with HIV infection talk to them about their cardiovascular risk [and] help them prevent it.
Disclosures: Saag reports that his institution has received research funding from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare, but has not personally received any funding. Wohl reports serving on advisory boards for Gilead Sciences and Janssen Therapeutics and receiving research support through his university from Gilead Sciences, Janssen and Merck. He does not own any stock in pharmaceutical companies. Taege reports being on the speakers bureau for Gilead Sciences. Fichtenbaum reports that his institution receives research grants from Cubist Pharmaceuticals, Gilead Sciences, Pfizer and ViiV Healthcare.