WHO 2013 guidelines: when the risk:benefit may not favour starting at CD4 count of 500
Simon Collins, HIV i-Base
There was overwhelming interest in the new and consolidated WHO 2013 guidelines when they were launched in a WHO satellite meeting prior to the opening of the 7th IAS conference – even though many of the key changes were already expected. 
One of the reasons why the guidelines generated so much discussion was the decision to recommend a higher CD4 threshold for starting HIV treatment. This modest increase on paper – moving from 350 to 500 cell/mm3 – is based on the hoped for merger of clinical, prevention and operational benefits of earlier treatment.
This even upstaged the preceding satellite session, launching the WHO evaluation and update on current global access that highlighted the much more significant news that close to 10 million people in low- and middle-income countries are now taking HIV treatment.  The two issues are closely connected though, because by raising the CD4 threshold, the number of people in need of treatment has risen from 16 million to 25 million.
The recommendation to raise the CD4 threshold to 500 is stated as “strong” and supported by a “moderate” level of evidence that many think errs on the generous side. Using PICO questions (Population Intervention Comparison Outcome) and the systematic data reviews required for the GRADE system for producing evidence-based guidelines, only two randomised clinical trials (SMART and HPTN052) were judged suitable to inform this question. Importantly, both used sub-analyses rather than primary endpoints, they most importantly compared earlier treatment to deferring to a CD4 count of 250 (and not 350), and neither study was primarily designed to look at the timing of when to start treatment.  This meant that cohort data was used to help answer the question of when to start and the contradictory results from these studies should have lowered the rating for the quality of evidence rather than increased it. 
This recommendation in the guidelines may therefore be based on higher quality evidence (from randomised studies) that ART reduces transmission. With this mix of individual and public benefits, the evidence from the public benefits is stronger and has driven the change. Another factor, perhaps even more important, is that it may have operational benefits by keeping people in care after testing.
This makes the guidelines aspirational. It also makes them political. Both of which are good things. They show a drive to lead global health that is activist in spirit. Wanting to narrow the gap between WHO guidelines and Western guidelines is also good, although it is important to recognise the greater size of the epidemics in the poorest countries such that “a public health” rather than “individual patient” approach is needed. Things change slowly in global health and if the data are not currently available to prove the benefit of starting treatment at 500 rather than 350, there is a good chance that it will be available in a couple of years. On this at least, WHO will be ahead of the game, although it could be difficult if the benefit from early ART is not as great as some people expect. It would just have been better if the guidelines stated this, instead of stating so emphatically that the clinical benefits are “firmly rooted in evidence”.
The detailed data set used to inform the guidelines – likely to run into several hundred pages – is due to be published in August. This limits the ability to look in detail at the evidence, process and methodology until then, by which time the mainstream media are likely to have lost interest.
When resources are limited – when are they not limited? – the guidelines state that people with a CD4 count <350 should have priority access to treatment. They also recommend that ART should be available universally irrespective of CD4 count (ie at counts higher than 500) for three important groups: pregnant women, children less than five years old, and HIV positive people in relationships where HIV transmission is a risk.
In this bold move, WHO are establishing the global urgency for broader access to treatment. They have produced an ideal rather than be restrained by settings with the most limited access. “WHO recommends earlier HIV treatment” was not a bad headline from global news agencies. [4, 5] This message could help lead to earlier testing and earlier access to treatment. It might also maintain pressure on governments to keep HIV as a high priority by setting a target by which national treatment programmes would be assessed.
The interesting history of the moving CD4 threshold is not discussed. In 1987, with the approval of AZT, the US DHHS guidelines recommended a CD4 threshold of 500. It stayed at 500 until 2000 when the threshold dropped first to 350 and then to 200 based on the side effects of early treatment, including d4T. As newer and better drugs became available, this increased back to 350 in 2007 and returned to 500 in 2009. In 2013 however, US guidelines recommended treatment irrespective of CD4 count, even when above 500, though acknowledging the evidence base was only “expert opinion”. Whether what has been proposed for the US will work in very different settings, with different access to drugs and monitoring will be the long-term test. It is worth noting however that even in the US, most people start treatment far later than 500 cells/mm3, and the aspirational aspect of the US guidelines was to encourage earlier and routine testing and so limit late diagnosis.
This highlights a more serious issue with the WHO guidelines. The benefit from broader and earlier ART, is dependent on the quality and range of the drugs being used and related issues including drug supply and monitoring. But although the guidelines very clearly and emphatically call for better care – for example by phasing out d4T – they don’t go into details about how this affects the decision of when to start. They lack the same careful data-based analysis of the impact that commonly faced real-world factors – such as continued use of d4T – or the likelihood of a stock out – would have on the risk:benefit assessment. This data is readily available because it was used to draft earlier guidelines in countries when d4T was an acceptable standard of care in the West.
The operational benefits from expanding the criteria to access treatment are important. Once diagnosed, people who start treatment may be more likely to be retained in care – and current loss from care is a big concern. But from this perspective, WHO could have dropped the CD4 count criteria altogether. The threshold of 500 is as arbitrary as 350 and current studies are looking at immediate treatment (at any CD4 count) compared to waiting until 350. This would have been a bolder move – but then we’d be back to the difficult detail of the lack of evidence. Loss to care may be more directly reduced by decentralising health care and this is part of the challenge for countries moving to Option B+ for pregnant women.
|d4T used in first-line treatment.||Mitochondrial toxicity: peripheral neuropathy, facial lipoatrophy, lactic acidosis, pancreatitis.||The CD4 threshold for starting treatment in Western countries when d4T was standard of care was 200-350.For a person with CD4 counts <500 but >200 and certainly >350 the risk of HIV-related complications is considerably lower than the risk of debilitating and lifelong d4T-related side effects.The global move to replace d4T with tenofovir is likely to change local access with the next two years. On a lifetime balance, deferring treatment until non-d4T options are available is recommended, and is urgent.|
|If AZT is only option.||Anaemia, lactic acidosis, facial lipoatrophy.||Although AZT is still widely used in resource-limited settings, if this is the only first-line option, similar concerns to d4T are important. Facial lipoatrophy (loss of facial fat) is a side effect of AZT, albeit at a reduced rate. Similar concerns about the risk:benefit ratio apply for people with CD4 counts above 350. AZT is also currently more expensive than tenofovir.|
|Efavirenz side effects||Limited alternatives for people with serious intolerance.||The side effect profile for efavirenz is well described in Western settings where approximately 30% of people switch to an alternative. Even if severe psychiatric reactions effect <5% of people, this would be significant in population terms. In some settings (Option B+) have no alternative to efavirenz.|
|Stock-outs and NNRTI-based ART with some NTRIs.||Drug resistance following interruption of treatment.||Some combinations have a higher risk for developing resistance if treatment is stopped (all drugs at the same time). This especially concerns NNRTI-based combinations (including FDCs) with NRTIs that have shorter half-lives (ie twice-daily dosing). Stopping these combinations risks a period of NNRTI monotherapy when resistance can easily develop.The assessment of risk:benefit for earlier treatment in a setting where stock-outs are common and tenofovir is not available may make the risk of drug resistance during a drug interruption outweigh the benefit from earlier treatment.This will further depend on the likelihood of a stock-out (5%, 10%, 20% chance per year etc), the normal length of stock out (greater than a few days to a week will provide time for resistance), and whether alternative options are in place for stock-outs (for example, emergency supply of NRTIs for staggering time for stopping treatment or access to PI/r to cover the NNRTI pharmacologic “tail” etc).|
|Limited options for second-line and third-line therapy.||Need for treatment if first-line fails.||If second-line therapy is not readily available this has an implication for planning treatment. First-line treatment might not work for 5-10% of people, even with good adherence. This is not a reason not to use treatment on an individual level but on a population level needs to be included as a disadvantage of earlier treatment. In a setting where virological failure is unlikely to be detected early due to limited access to viral load testing, extensive resistance would develop on first-line treatment for little or no clinical benefit.|
|Treatment as prevention: reducing infectiousness.||Is HIV transmission a concern?||The recommendation to treat at 500 is based on reduced risk of transmission. If this does not affect you, this will change the weight of evidence recommending earlier treatment.For example: if you currently always use condoms, if your partner(s) are HIV positive (and drug resistance is not a concern), if you are not currently sexually active, etc.There may be clinical benefits from earlier treatment, but this is based on expert opinion rather than evidence from clinical studies.If treatment is being used to reduce infectiousness, guidelines (including WHO, US, UK and EACS) recommend ART can be used irrespective of CD4 count.|
|Stability of current CD4 count above 350 and “normal” levels.||Individual immune responses to HIV means 350-500 may be normal for some people.||This is a complex issue to integrate into public health guidelines but is an important detail. The reference range for a “normal” CD4 range is approximately 420 – 1600 cells/mm3, based on the 95% range but varies by test, laboratory and background population. This means a significant minority of people would fit the criteria to start treatment prior to any evidence of immune damage from HIV. This emphasises the importance of CD4 monitoring. As several research groups have recently proposed using 900 as a new target for “normal” levels, this issue will become more important. For someone with a “normal” CD4 count less than 500 it is difficult to see how ART could increase this further.|
Finally, two indications of the effectiveness of ART at a CD4 threshold of 350 cells/mm3, can perhaps minimise the urgency of this question. Firstly, studies reporting that ART normalises life expectancy for someone newly infected, albeit in uncomplicated cases – was based on a threshold of 350. 
Secondly, the START and TEMPRANO clinical trials, that will provide evidence from well powered randomised studies on both the risks and benefits of immediate treatment compared to waiting until 350, are both large studies requiring many years of follow-up. [8, 9]
START for example is expected to need to follow more than 4000 people for 3-6 years in order to see a difference between starting above 500 or waiting until 350. The guidelines explicitly mention the importance of both studies providing essential data to inform the decision on when to start treatment.
For settings where current standard of care does not match the US, a suggested appendix for when a CD4 threshold of 500 cells/mm3 may not be appropriate to start treatment is included in Table 1.
In the bigger picture, the move to broader ART access is a good thing and the profile of the 2013 WHO guidelines have already helped in this. The leading role they are taking for global health is real and important.
Access to earlier treatment on a global scale is probably more important than the detail of whether to start at 350 or 500 – or even whether there should be a CD4 threshold at all.
The guidelines should also take in to account the differences between well resourced and resource-limited settings and that the HIV epidemic is so much greater in the latter needing a public health not individual approach.
In the detail, people who decide to start treatment earlier in their infection should be able to do this based on a risk:benefit assessment of the treatment options available when they start. Otherwise, nothing will have been learnt from mistakes that Western guidelines have made in the past.
- World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. June 2013.
- World Health Organization. Global update on HIV treatment 2013: Results, impact and opportunities. June 2013.
- Easterbrook P. Deriving public health recommendations from a systematic review of evidence. WHO satellite meeting: Launch of the 2013 WHO Consolidated ARV Guidelines – What’s the Evidence? Session link includes slides and webcast.
- BMJ series 2008: Five articles introducing the GRADE system and explaining how it works.
- Dreaper J. HIV/Aids drugs: WHO to recommend earlier treatment. BBC news. (30 June 2013).
- Castillo M. World Health Organization: Start treatment for HIV earlier. CBS News. (1 July 2013).
- US Department for Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 1998-2013. Online and archived guidelines.
- The Antiretroviral Therapy Cohort Collaboration Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. The Lancet, Volume 372:293-299. (26 July 2008).
- Strategic Timing of AntiRetroviral Treatment (START) study.
- Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis Against Tuberculosis in HIV-infected Adults (ANRS 12136 TEMPRANO).