Why the “when to start” question is complex and informed by limited evidence: a response to Dr Myron Cohen
Simon Collins, HIV i-Base
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 , 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:
- Overstating the evidence in the guidelines, understating the quality of that evidence and over-simplifying the final recommendations.
- Merging the health benefits of treatment with the impact on reducing transmission, rather than keeping these distinct.
- Suggesting that earlier treatment reduces deaths.
- Ignoring the broad range of individual immune responses to HIV.
- Creating an urgency that is not supported by the very low risks at high CD4 counts and using emotive language to scare people to use treatment.
Guidelines and evidence for the CD4 count at which to start treatment
The interview starts by saying that both the US 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 US move “to start people immediately” but missing that until 2001, the US 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, US 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.  Also, modelling studies report life-expectancy for HIV positive people normalising to HIV negative populations, were calculated based on starting treatment at 350.  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.
|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.
|US 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]|
Treatment as prevention and the risks of merging benefits
Even when reviewing the additional benefit from prevention, treatment guidelines are rooted in recommendations that are primarily focused on clinical need. [14, 15, 16]
But the impact of treatment on prevention is an area where new data is strong. Evidence includes several large and important randomised studies, showing a dramatic impact from treatment on reducing the risk of sexual transmission.
One of these studies was HTPN-052, for which Dr Cohen was the lead investigator. HPTN-052 proved clearly that ART dramatically reduces the risk of heterosexual transmission and that the magnitude of protection exceeded that reported by condom studies alone. For this it was ground-breaking. 
But on a population level, being HIV positive does not necessarily mean that you transmit HIV. On an individual level, you may not even be having sex. You may be having exclusively safe sex, either by the choice of activity or careful and consistent condom use. Or your partner may also be HIV positive, and HIV transmission is only an issue in the context of drug resistance.
In the context of informed choice, starting earlier treatment to reduce the risk to your sexual partner(s) can be important and can improve the quality of life for both HIV negative and positive people. WHO guidelines developed for resource-limited settings recommend ART at any CD4 count for serodifferent couples to reduce transmission.  It can reduce remaining anxiety for both partners and has given many people the peace of mind for improved sexual health. This comes from knowing that even with continued condom use, if a condom breaks, that passing on HIV is highly unlikely.
But the temptation to merge treatment benefits (probably tangible but slight at CD4 counts over 350) and prevention benefits (dramatically reduced for anyone with sustained viral suppression) needs to be resisted.
These are important caveats when considering a public health initiative to treat everyone on the premise that an HIV diagnosis equates to transmitting HIV.
Approximately 40% of ongoing transmissions may occur during primary infection (highly infectious) though this varies from approximately 10%-90% depending on the population being studied and the modelling. This is likely to disproportionately affect epidemics linked to higher number of sexual partners (such as MSM in the UK) and is likely to shift oral sex for gay men from a low to high risk. Another significant proportion of new infections relates undiagnosed chronic infection. The use of earlier treatment is unlikely to have a direct public health impact related to either of these key populations.
Dr Cohen states that in the context of heterosexual transmission “it becomes pretty clear that treatment renders them no longer contagious” but modifies this to “nearly 100% protection when adherent” to recognise that some transmissions still occur. This ignores concerns about drug levels in the genital tract, persistent shedding, lack of data, modelling problems, cost, adherence, the “inconvenient truth” about acute transmissions. These were just some of the reasons that Dr Cohen used to vociferously argue against “The Evangelical Test And Treat Movement” at the BHIVA conference in Autumn 2010. 
While that talk was an overly cautious and pessimistic review, it is difficult to see the volume of evidence since 2010 for such a rapid reversal in his views. Even the NA-ACCORD study – controversial in its methodology, but often referenced as observational cohort data supporting earlier treatment at CD4 >500 had been published 18 months earlier (in April 2009).
As supported in most guidelines, access to treatment to reduce transmission should be an option at any CD4 count. The reason for this use of treatment needs to be a clear patient choice.
Health benefits from earlier treatment: does this save lives?
Dr Cohen states that the HPTN-052 study had a “fairly big impact on health and survival”, merging very different endpoints.
Although earlier treatment was not associated with harm, the clinical benefits were far less dramatic:
- People in HTPN-052 were starting treatment at a CD4 count of 250 compared to 350-550. So any benefits could be driven by the low start threshold and not the benefit of treating above 350.
- There was no statistical difference in the number of deaths between the two groups (out of nearly 900 people in each group there were 10 deaths in the early treatment group vs 13 in the group that waited until 250), with a p-value of 0.5 showing no difference and no hint of a trend.
- There was no difference in serious “non-AIDS” events such as major organ complications and some cancers that would be expected from reducing viral load and related immune inflammation/activation.
- Higher events were driven by extrapulmonary TB at two study sites in India, with no difference in pulmonary TB. (An important note is that in high TB settings, earlier HIV treatment may reduce the risk of new TB infections).
Survival is a life and death matter. It is clearly important to doctors and patients. Anyone saying that “immediate” treatment for everyone upon diagnosis will reduce deaths, needs evidence to show this. Merging clinical benefits (less sickness – that is relatively minor and treatable) and survival benefits (less deaths) into a combined endpoint in this context is not helpful.
Combining survival and better health is common in studies. Better health is clearly important. But earlier treatment improved health by not getting some symptoms. Earlier treatment, in nearly all the studies in Table 1, did not reduce deaths.
Individual responses to HIV
Dr Cohen recognises that widely different HIV progression rates highlight a downside to universal treatment on diagnosis, but he is happy to treat people who don’t need treatment, when this is for the public good.
So while one-third of people progress rapidly, with a CD4 count dropping below 350 within two years of infection, 25% of people maintain CD4 counts higher than 500 for at lest five years and some for considerably longer.  A much smaller percentage, called “elite controllers” also have an undetectable viral load without treatment.
This wide diversity of responses to HIV does not argue for the urgency of “immediate” treatment for everyone. The most significant assault from HIV on the immune system probably occurs within the first weeks of infection. The burst of viraemia, commonly above 1 millon copies/mL is highly infectious and decimates CD4 cells based in the gut. Despite this, most people then generate an immune response that holds HIV at bay for many years. While viraemia during chronic infection is not a good thing, and is a valid concern supporting earlier treatment, quantifying the associated risk has still to be determined.
Earlier treatment clearly maintains higher CD4 counts. But the example of starting at 440 compared to 220 is too easy. The context of immediate treatment needs to aim higher, and with confidence. What about starting at 1100 compared to 900. Or 900 compared to 700. After 15 years experience with ART, the best cohort studies struggle to find consistent evidence for 700 compared to 500.
Similarly, the benefits of treatment may reach a stable ceiling after five or ten years. If this is the case, then the argument that over a lifetime there is little difference between 35 or 40 years on treatment becomes flawed. With no clinical urgency for treatment, this might become a difference of between 25 or 40 years, which is significantly different.
Side effects vs untreated HIV
The effective management of side effects is acknowledged as a caution to wider use of treatment, but the data do not exist to weigh the risks and benefits. Randomised studies have not been completed and observational cohorts don’t collect this data. As examples of risks, all combinations seem to reduce bone density, some people commit suicide on efavirenz, and the mechanism for fat accumulation is still unknown.
Dr Cohen notes that there “may be adverse events (side effects) at higher CD4 counts” but says this will be balanced by the “clinical benefit […] of protecting organs”.
This issue is important – the SMART study showed that people on treatment had fewer serious major organ complications (heart, liver, kidney) and reduced risk of some cancers, if they had a suppressed viral load on treatment, compared to people who interrupted treatment, even at CD4 counts over 350. SMART showed treatment to be far safer than was originally realised, and its results have driven a whole field of research into the implications of untreated HIV.
Damage from ongoing viral replication off-treatment is quite possible, or even plausible. Some studies have shown biomarker differences between even elite controllers and HIV negative people. But this is currently a research hypothesis and we are talking about lifelong treatment, for possible “subtle” differences.
Global health is only briefly touched on in the interview, but this is important given that in most countries most patients have access to fewer treatment choices. Simplifying the benefits of earlier treatment irrespective of the setting has specific risks.
Concern that WHO guidelines might increase the threshold for treatment from 350 to 500 was the focus of a review in the last issue of HTB.  These concerns are not about restricting access to treatment: WHO guidelines already recommend access to treatment for prevention at any CD4 count for serodifferent couples. They are about the risk of harm, in settings where access to resources and choices are dramatically reduced.
Wealthy settings have over 20 commonly used drugs from at six drug classes. Most countries base treatment on less than six drugs from two, or perhaps three classes. Access to second-line treatment is often extremely limited and is more expensive. Second-line treatment is also less effective because lack of viral load and resistance monitoring means people usually have far higher rates of drug resistance. In many countries, third-line treatment is even more rare.
Perhaps 50% of HIV positive people globally still use d4T (stavudine). The benefits of d4T-based treatment will not outweigh the risks of using it in a combination on diagnosis, at 500 or even 350. When this was the option in Western countries, the side effects were so severe that we set our guidelines at 200. When d4T is not in the combination, then 350 has the strongest evidence.
Treatment stock-outs are still common and are likely to pose a much greater safety concern than risks from HIV in someone with a high CD4 count. [22, 23, 24]
HIV positive people taking treatment for clear clinical benefits are most likely to have their treatment fail because of a break in their drug supply. No matter how perfect their adherence to taking meds, if there is a stock out and you are forced to stop treatment, you risk developing drug resistance as drugs levels in your blood fall during the first weeks off treatment. Restarting treatment when the supply returns will have only limited benefit for people in who resistance developed. It is difficult to see uninterrupted lifelong treatment be guaranteed when minimum financial targets for the Global Fund are missed year on year.
In the context of priority, in public health, in lives saved and health maintained, treatment above 350 for clinical benefit is not even on the radar in most resource-limited countries.
Patient choice and the decision to start
To further emphasise the urgency of immediate treatment, Dr Cohen says that the concept of a person being “ready to start” treatment suggests that a doctor-patient discussion to arrive at this position might project “a false sense of security” that “all is well”.
This central tenet of treatment guidelines – readiness to start – is one that activists have demanded and supported because of a high risk of failure when the need for treatment and how to use it is not understood. Whether someone is starting treatment on diagnosis, using a CD4 threshold of 500, 350 or 200 – for their personal health or to reduce the risk to their partner – it needs to be an informed choice.
Throughout the interview, language is used that increases anxiety, rather than providing information for an informed choice. This includes the “urgency” discussed above, but also emphasises the fear of the unknown. An HIV diagnosis is still traumatic for most people. It is a life-changing event. The decision to start treatment is similarly important.
Scaring people into the decision, whether for future health risks or on a public health agenda, will help no-one.
The plausibility of potential benefits of treatment on diagnosis has been argued since AZT monotherapy. No virus is better than virus. But at high CD4 counts there is too little evidence to know whether lifelong treatment is better than asymptomatic HIV.
Currently, the evidence (and expert interpretation of the same evidence in different guidelines) still supports equipoise for many people on the question of whether benefits outweigh the risks of earlier treatment at CD4 counts above 350. Results from the START study, expected in 2016, will provide the strongest real data to inform this question. 
This doesn’t mean nothing can be done until then, but guessing the results – or worst still, pretending the evidence already exists – has a serious risk for being wrong.
HIV positive people should have the option to start treatment at any CD4 count, especially to reduce the risk of transmission to sexual partners. But to be an informed choice, this needs to acknowledge that the evidence for personal health benefits at high CD4 counts has plausibility, but limited data.
Until 2016, a wide range of studies suggest both a low absolute risk from starting earlier treatment if this is an individual’s choice and a low absolute risk from deferring until 350 if that is an individual’s choice. This is especially important to remember for people enrolled in the START study, who will ultimately help settle this key question.
Simon Collins is a member of the Community Advisory Board for the INSIGHT group that is currently running the START study. This article was based on a previous weblog.  Thanks to the HTB editorial board for support and comments.
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