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:
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.
|Table 1. Rationale and Evidence for Earlier Treatment|
|Study or Document||Summary Comment||Refs|
|Randomised clinical trials (RCTs)
This type of study provides the most reliable evidence based on both risks and benefits of an intervention.
|CIPRA HT-001 (Haiti) (2010)||Clear health and survival benefits were shown from starting at 200-350 vs waiting until less than 200.|||
|SMART (naive sub group) (2008)||Waiting until CD4 <250 had an increased risk of serious events compared to the early treatment group (median CD4 440).|||
|HPTN-052||Reduced risk of health events when starting at 350-550 compared to waiting until <250 (ie starting late). No difference in survival.|||
This type of study is used when RCT data is not available.It usually involves many more people than an RCT but the results are less reliable.This is because without randomisation it is impossible to adjust for the other things that make people who start treatment earlier different from people who start late.
|ART-CC(2009)||ART-CC showed combined health and survival benefit from starting at 350-450 compared to waiting until 250-350 but no significant difference in survival. No survival difference when starting at 450-550 compared to 350-450.|||
|NA-ACCORD(2009)||Starting at 350-500 reduced the risk of death compared to waiting until <350. Survival benefit reported when starting >500 compared to <500 but very small numbers of deaths so absolute impact of ART is not possible to estimate. The way this study analysed data has also been challenged.|||
|HIV CAUSAL(2011)||Estimated that starting at 350-500 has a reduced risk of an AIDS defining illness compared to <350. No difference seen in survival.|||
|CASCADE(2011)||No significant difference in illness or death starting at 350-500 compared to <350. No benefit in either health or survival from starting at 500-800.|||
|COHERE(2012)||Benefits in health outcomes including deaths were reduced as CD4 category increased. This included people starting at >500 but the paper notes that this is so small as to be of "little clinical relevance for most patients."|||
|Concern about inflammation||SMART (2008)ANRS (2009)||Growing awareness and concern with period of detectable viral load. Link to increased risk of serious "non-AIDS" events including heart, kidney, liver disease, neurological complications and some cancers. See the 2013 DHHS guidelines below for an excellent summary and discussion but the references (mainly from 113-127 in the when to start section E) outline basis for concern. Only two are from 2011 and most are significantly earlier.||[12,13]|
The guidelines help explain the complexity of the limited evidence.
It is important to read the text and not just the table summary recommendations.
All three guidelines come to different conclusions based on the same evidence.
|U.S. DHHS(2012)||Evidence base of clinical benefits is reduced as CD4 count gets higher. Strongest recommendation is for starting <350. Then for 350-500. The benefits for starting above 500 are based on expert opinion worried about the potential implications of keeping a detectable viral load. Prevention is discussed but clinical benefits are the main focus of these guidelines.|||
|IAS-USA(2012)||Recommendation to offer treatment to all patients at any CD4 count. Strongly influenced by the potential impact on reducing transmission. However the strength of evidence was highest for starting at <500. There was only moderate support for starting at >500, and this was based on the lowest rating for evidence.|||
|BHIVA(2012)||UK guidelines recommend starting at 350 or before CD4 count drops below 350. Based on lack of randomised data showing earlier benefit and conflicting results from observational studies.|||
|WHO(2009, 2012)||WHO treatment guidelines use 350 for clinical benefit based on moderate evidence for clinical benefit. In guidelines for serodifferent couples, ART use for prevention is supported by strong evidence.||[17,18]|
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