Why the "When to Start" Question Is Complex and Informed by Limited Evidence: A Response to Dr. Myron Cohen
This article was prompted by contributions to the "when to start" debate that avoid both it's complexity and the lack of evidence for benefits at higher CD4 counts. This issue has broad concern for HIV positive people, doctors and health workers, and public health policy.
While this is principally a response to an online interview with the respected researcher Dr. Myron Cohen,1 many of the points are similar to other presentations and articles about earlier treatment.
In such examples, a dramatic change in policy -- a public health approach of universal treatment on diagnosis -- is presented as self-evident based on plausible benefits. Neither the lack of evidence to make it possible to evaluate the risk in relation to the benefits, nor the contradictory evidence (generally from large cohort studies) is discussed in detail. This response is to emphasise the need for greater transparency in the evidence for this change in policy, without which HIV positive people and their treatment providers will be unable to make accurately informed choices.
Dr. Cohen's interview included interesting ideas about other aspects of treatment: including that we have a wide range of effective drugs, that doctor experience is important to get the best results; and that cure research and pipeline drugs may make today's treatment unrecognisable in ten years time. But the main areas of concern for treatment at high CD4 counts include:
Guidelines and Evidence for the CD4 Count at Which to Start Treatment
The interview starts by saying that both the U.S. DHHS and IAS-USA guidelines recommend "immediate" treatment irrespective of CD4 count. Dr. Cohen states: "This is a pretty big change, and it represents the accrued benefits, which are very, very strong."
Clearly something major has happened in the guidelines -- which is true. However, the implication that this is due to incredibly certain benefits that outweigh the risks is far less clear. There is an emphasis on urgency with "immediate" treatment. We learn that "earlier treatment is better" and that "this is pretty much written in stone."
The context of guideline changes is then presented as a simple linear progression from 200, through 350 and 500 to the U.S. move "to start people immediately" but missing that until 2001, the U.S. guidelines recommended a CD4 threshold of 500, even with AZT monotherapy, noting plausible benefits from starting higher. The reality of side effects and drug resistance dropped the CD4 threshold to 200, with limited use at 200-350 and the improved safety and efficacy of more recent drugs weighted the risk:benefit balance towards earlier treatment. Also, although there are other considerations for starting treatment (hepatitis coinfection, pregnancy, age etc) the focus on CD4 count is helpful for this main discussion.
Even with the best intentions, guidelines produced by experts, can be wrong when adequate data is not available. This lesson should have been learned: we don't yet have the data for risks when CD4 counts are highest. Even less complex, healthier, motivated patients in a clinical trial on the latest combinations fall short of 100% efficacy by 10-30% leading to drug resistance and evidence of harm.
Although few studies since 2009 provide evidence of the benefits and risks of ART at high CD4 counts, U.S. guidelines (ie for an advanced wealthy setting) have switched from 350 to 500 and now to treatment on diagnosis. An example of why the differences between starting at 350 or above 500 are likely to be so slight, is that the large international randomised START study is expected to need to follow more than 4000 patients for six years to see a difference.2 Also, modelling studies report life-expectancy for HIV positive people normalising to HIV negative populations, were calculated based on starting treatment at 350.3 Some of the complexities this produces for resource-limited settings are also discussed below.
Table 1 includes the most significant studies and guidelines relating to when to start treatment. Most of the studies struggle to find evidence for benefits at CD4 counts over 500 and most of the guidelines note the limited evidence on which their recommendations are made and the low quality of the evidence. Not all studies are equal and guidelines recognise the vulnerability of recommending treatment at high CD4 counts by grading the strength of the recommendation low because, this is largely based on expert opinion. Every time the recommendation to start treatment at high CD4 counts is stated, it is misleading not to also state that the level of evidence for this is low.
This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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