HIV Wellness Series: Ready, Set ... When?
Debate Continues Over When to Begin Treatment
These medications restore health to an extent that few could have imagined even months before the first triple-drug cocktails became available, but it is evident that there are costs in terms of the toxicity of therapies that are intended to be taken for decades. In the absence of definitive data to tell us exactly what to do, deciding when to start taking ART requires us to look carefully at not only where we have been, but also at recent research findings that can be linked to provide a reasonable approach to this old but increasingly relevant question.
Treatment guideline recommendations for initial HIV treatment are a barometer of the collective mood regarding ART. In response to the prevailing data and available therapeutic options, these guidelines have vacillated regarding what CD4 cell count should trigger the start of HIV therapy. Early in the epidemic, HIV was often treated much like any other infection, soon after the diagnosis. Unfortunately, therapy at that time was limited to just a single drug, zidovudine (ZDV or AZT), and in the days before viral loads and drug resistance testing, clinicians did not realize they were asking too much, often too late, of this one medication. Studies quickly showed that AZT alone had only a transient benefit and the demise of those who'd been prescribed the drug as a last ditch effort seared questions regarding the safety of HIV medications into the consciousness of the community.1,2
"The enthusiasm for early treatment of HIV was quickly tempered by the disturbing side effects these drugs were discovered to produce."
In the mid-1990s, of course, additional HIV medications became available and were combined to produce potent regimens. It is difficult to overemphasize the significance of this revolution in HIV care and the effect it had on the willingness to aggressively treat HIV. In the heady days of 1998, when hitting the virus hard with the new powerful drugs was going to be able to keep the HIV genie bottled for good, the U.S. Department of Health and Human Services (DHHS) guideline panel recommended HIV therapy for those with CD4 cell counts above 500/mm3.3 However, while the success of these regimens in restoring health was dramatic, the enthusiasm for early treatment of HIV was quickly tempered by the disturbing side effects these drugs were discovered to produce. Clinics accustomed to treating AIDS-related opportunistic infections soon found themselves dealing with lactic acidosis, fat accumulation, dyslipidemia, diabetes, and other "metabolic" disorders among their patients taking the new cocktails. Suboptimal adherence to these twice- or thrice-a-day dosing regimens led to the emergence of drug resistance, some of which was transmitted to others, further dimming the star of these drugs.
At the same time, observational cohort studies demonstrated clear benefits of HIV therapy when started before a fall in CD4 cell count to below 200/mm3 but less protection at higher counts.4,5 Guidelines responded to these data and the emergent suspicion of combination ART by advising a delay of HIV treatment until the CD4 reached 200/mm3.6 With additional cohort data showing benefits of HIV therapy when started between counts of 200 and 350/mm3, the starting line moved to 350/mm3 7,8 and a new standard of care was established -- one that some still remain attached to.
In late 2009, the DHHS guideline panel issued an update that recommended that ART be started in patients with CD4 cell counts between 350 and 500/mm3 after considering some of the data described below.9 The panel was divided on whether to recommend treatment at counts above 500/mm3 with half advocating for this recommendation and the other half considering treatment at above this count as optional.
New Data Influencing When to Start
The recent sea change in thinking about ART and its relative benefits and risks can be traced to the early termination of the SMART study, a large clinical trial among patients with high CD4 cell counts randomized to continuous ART versus a CD4 cell count-guided interruption of HIV therapy.10 With over 5,000 patients enrolled, the trial originally hypothesized that intermittent HIV therapy would protect patients from their adverse effects. However, the trial was stopped after it was found that interrupting therapy significantly increased the risk of opportunistic disease or death from any cause, compared with staying on ART. Additionally, conditions ascribed to ART, including cardiovascular, renal, and hepatic events, were more common in the study group stopping their HIV medications than in the group assigned to stay on their HIV therapy. Subsequent investigations to explain these unexpected findings suggest that the increased levels of HIV during periods of treatment interruptions can lead to activation of the immune system and an internal chemical cascade that produces a generalized inflammatory response.11 This inflammation, in turn, can damage organ systems, sometimes fatally.
On the heels of this important trial came the results of two large observational cohort studies that enroll and follow large numbers of people living with HIV. The first, the NA-ACCORD, enrolls HIV-positive patients in clinical care in the U.S. and Canada.12 To gauge the benefit of early HIV therapy, the study investigators examined the survival rates among over 9,000 patients who entered care with a CD4 cell count above 500/mm3, comparing the outcomes of patients who did and did not start HIV therapy. They found that those who initiated ART above this high CD4 cell count threshold suffered a significantly lower risk of dying than those who elected to wait to start therapy. Similar findings of a survival benefit with ART had been found in an earlier analysis focusing on the 8,000 or so patients with a CD4 cell count over 350/mm3 when they entered HIV care. So far, mortality data are available for only a subset of participants, but the leading causes of death were not from AIDS in these patients with generally high CD4 cell counts, but were non-HIV-related (such as hepatic, renal, and cardiovascular diseases and non-AIDS-defining cancers). Therefore, HIV therapy, even in people with what we would consider decent immune function, seemed protective against death, especially from diseases not typically linked to HIV infection.
A second observational study, the ART-CC, looked at a cohort of over 24,000 HIV-positive patients, mostly European, and found that deferring HIV therapy until a CD4 cell count of 251 to 350/mm3 was associated with higher rates of AIDS and death compared to starting therapy in the next highest range of 351 to 450/mm3.13 However, there was no significant benefit seen with starting therapy at CD4 cell counts above 450/mm3, although fewer participants with such high counts were enrolled, reducing the ability to detect differences between these and other CD4 cell groups.
Overall, both of these cohort studies point to an expectation of better clinical outcomes with earlier therapy. However, there are major limitations to observational studies and critics warn that there can be important, unmeasured factors, aside from ART, that could be associated with a reduced risk of adverse clinical events. For example, in NA-ACCORD, those with higher CD4 cell counts initiating ART could be different in some way than those who deferred therapy in terms of healthy lifestyle behaviors, potentially confounding the results. Further, while the relative risk of negative events was higher with the deferral of HIV therapy compared to early treatment, the absolute risk, that is, the excess number of people who actually suffered a worse fate with a delay in therapy, was low, as were the total number of events (deaths and/or progression to AIDS) in these studies.
Randomized, controlled trials, in which participants are assigned to treatment by chance, is considered a more rigorous study design than that of observational cohorts, as they minimize the influence of confounding factors. In a sufficiently large trial, potential influencing factors such as age, gender, socioeconomic status, healthy- and non-healthy lifestyles, should be balanced between study groups with randomization of participants to the study arms. At present, no randomized trial of early versus delayed ART has been completed, although one study (the START trial), enrolling patients with a CD4 cell count above 500/mm3 has recently opened to enrollment.
One randomized trial, albeit looking at those with lower CD4 cell counts, can shed some light on the when to start question. CIPRA HT001 was a trial conducted in Haiti that recruited 816 patients with CD4 cell counts between 200 and 350/mm3 who were randomized to immediate ART versus ART deferral until a CD4 cell count below 200/mm3 or development of an AIDS-defining condition.14 This was yet another study that was stopped early when it quickly became apparent that delaying therapy was associated with a significantly higher risk of death -- six in the treatment arm and 23 in the deferral arm. In addition, early ART appeared to be protective against tuberculosis. This study, although conducted in a developing nation and among those with CD4 cell counts below 350/mm3, provides another data point that, when viewed with others, makes a case for earlier being better when it comes to HIV therapy.
Putting It Together: Viremia, Inflammation and Nadir CD4 Cell Counts
The clinical research studies suggest a consequence of uncontrolled HIV, even at higher CD4 cell counts, possibly mediated by immune activation and subsequent inflammation and organ damage. This is a hypothesis and additional data are needed to confirm that this is the case, but a number of small studies do serve as backup to the tune being sung by the large cohort studies and clinical trials.
"HIV therapy does not necessarily turn the clock completely back to the time before infection, and the point at which ART is started may influence how well it can reverse damage inflicted by HIV."
It is well known that HIV therapy reduces the levels of HIV in the blood and other compartments of the body and, therefore, the immune system's activation, or level of activity in response to the viral invader. A similar decrease in measures of inflammation are also being seen with ART. In ART treatment trials among patients who had never taken HIV medications, levels of markers of inflammation in the blood, including C-reactive protein (CRP) and a chemical messenger used by cells to trigger inflammation called interleukin-6 (IL-6), were found to fall with the start of HIV therapy.15,16 A study conducted by the federally funded AIDS Clinical Trials Group (ACTG) comparing three different ART combinations measured the health of the endothelium of arteries -- the inner lining of the blood vessel that not only serves as a barrier but also is very active in sending signals that, among other things, control the size of the artery and its response to stress.16 Outside of HIV, abnormal function of the endothelium is associated with the development of atherosclerosis. Using a test called flow mediated dilatation (FMD) that looks with ultrasound at the response of an artery in the arm after blood flow is temporarily shut down with a blood pressure cuff, researchers observed that endothelial function improved over the first six months after the start of any of the three regimens studied. Therefore, in these studies, HIV treatment, regardless of type, led to decreases in the markers associated with risk of heart and other organ disease, suggesting that control of HIV leads to improvements in these measures.
However, HIV therapy does not necessarily turn the clock completely back to the time before infection, and the point at which ART is started may influence how well it can reverse damage inflicted by HIV. One recently presented study measuring arterial stiffness (having stiff arteries is not a good thing) among 80 HIV-positive men on ART with undetectable viral loads, found that having had a previous CD4 cell count below 350/mm3 was associated with having stiffer arteries.17 Other factors for arterial stiffness included older age, higher blood pressure, and diabetes -- well known risks for cardiovascular disease. Another study of over 1,500 HIV-positive patients, using complex testing, looked at cognitive disorders. This study found high rates of cognitive impairment, typically mild, but having a higher nadir (lowest ever) CD4 cell count was protective.18 These studies share a pattern in which nadir CD4 cell count was associated with less of a benefit of ART compared with earlier treatment of HIV.
An increasing number of studies point in the direction of favoring earlier HIV therapy. However, there remain concerns. Truly long-term data regarding the safety of most HIV regimens is lacking, and there are legitimate worries about the effects of these medications on long-term health. Recent studies suggest accumulated effects of ART on bone density, renal function, and cardiovascular disease. However, the question may come down to which is worse, HIV or its therapies. For many clinicians and researchers, the adverse effects of this virus trump those of present-day ART. The SMART trial and other studies are making it clearer that HIV itself does some nasty things to the body and the typically prolonged period from the time of infection to eventual treatment may be when lasting damage occurs -- damage that later threatens health and shortens survival. Now that ART has been recognized to be a potent HIV prevention measure there are also public health arguments for more widespread use of HIV therapy.
We do not have a "homerun" of a study that tells us for certain when is the perfect time to start HIV medications. Until we do, those deciding when to start ART can only look to the data we have and connect the dots to see if what emerges is a case for starting HIV medications now or too many questions to do anything else but wait.
Dr. Wohl is an Associate Professor of Infectious Diseases and Co-Director of the AIDS Clinical Trials Unit at the University of North Carolina. Metabolic complications associated with HIV infection and the nexus between HIV and incarceration are his major areas of research interest. His e-mail address is firstname.lastname@example.org.
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