Issues That Divide Expert Opinion: When to Start, HIV and Aging and the Impact of HIV on Life Expectancy
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The Glasgow programme included overviews of three key aspects of HIV that still divides experts. This included when to begin ART, the overlapping complexity of HIV and ageing and the impact of both these issues on life expectancy.
The range of views held on each subject can make these discussions an unsettling experience for a patient who just wants to do the best thing for their health and who is faced with conflicting expert opinions.
If this is confusing for people diagnosed early when their CD4 count is still high and who have good access to treatment, it is more confusing for people with more complex histories. These questions are more than just an academic debate and the overlapping connections between these three subjects made for interesting discussions at the conference.
A few years ago, when the international START study was being planned, feedback from UK doctors argued for the CD4 threshold for early treatment to be 450 as there was a concern that setting this at 500 would be make the study impossible to enrol. Even 450 was expected to be a challenge given the consensus to defer until treatment was "really needed."
A lot has changed since then. There has been increasing attention given to concerns from unsuppressed viraemia and the associated immune inflammation. There is also greater confidence that ART is protective of serious non-AIDS events including cardiovascular, renal and hepatic disease and some cancers, rather than driving morbidity due to side effects. Finally, the reduced infectiousness demonstrated in HPTN-052 proves the potential of ART to reduce onward transmission.
In Glasgow, one of the first sessions included a debate on the timing of ART on a population level, with the extreme viewpoints of either universal treatment on diagnosis compared to deferring until the CD4 count reaches 350 cells/mm3.
Michael Saag, from University of Alabama, (and a member of the U.S. DHHS guideline panel) argued that the above benefits are sufficient in themselves to move to a policy of treatment after diagnosis, irrespective of CD4 count.1
This is broadly recommended in the U.S. DHHS guidelines but expressed more extremely by the 2012 IAS-USA guidelines. Both panels believe that the complications of current treatment are sufficiently manageable for the difference of an average of 40 rather than 35 lifetime years of treatment to be negligible, and that public health will benefit from reductions in population viral load. While data from randomised studies are not available for people with higher CD4 counts, Saag argued that cohort data suggests that earlier treatment, at the least in the short-term, does not indicate significant harm. Also, for some doctors, the increasing concern of the long-term implications from uncontrolled HIV viral replication prior to starting treatment, and to a lesser extent, even residual viraemia on treatment, has become such a convincing concern that they see withholding treatment, even from people with the highest CD4 counts, as approaching medical negligence.
To counter this interpretation of the current evidence, Jens Lundgren, fromthe University of Copenhagen, (a member of the EACS guideline panel and co-chair of the START study) argued that a move to universal treatment was a sufficiently important public health policy for this to need to be driven by rigorous evidence that personal benefits outweigh the risks for patients with CD4 counts higher than 350 and especially when higher than 500.2 The need for this to come from randomised studies is important because so far, large cohort studies have reported contradictory results for these patients. The lack of evidence from studies that were designed to look at the potential harm from earlier treatment (this not a strength of cohort studies) has lead to a reliance for this aspect of the guidelines, on expert opinion, which is universally accepted as the least reliable evidence base for treatment recommendations.
One caution that should temper any rush to universal treatment at higher CD4 counts, comes from data showing that outside the context of clinical studies, 10-30% of patients do not achieve optimal viral suppression on their first combinaton, increasing the likelihood of drug resistance, potentially years before there was a clinical need for treatment. Also, while tolerability with todays treatment has steadily improved, potential toxicity may be reduced further in future treatments.
This raises a reasonable caution against everyone starting treatment at CD4 >350 when the absolute risk of HIV related events is already very low, especially given that historically, earlier treatment based on expert opinion has invariably proven to be wrong. The equipoise supported by the current data is especially important to emphasise for people currently in the START study.
This large international study will enroll the last of its 4000 proposed participants earlier in 2013, all with CD4 counts higher than 500 cells/mm3 at baseline. Following randomisation to either immediate ART or deferring until CD4 counts reach 350, results are expected by 2016, or earlier if the differences between the two arms are strikingly different.
Participants currently in the deferred arm of the START study, should remain confident and supported by data from large European cohorts showing that the absolute risk for events occurring while their CD4 count is between 350 and 500, is unlikely to very be different from if they started at 500.
Similarly, participants in the immediate arm of START should be reassured that cohort data support the low risk of complications from earlier ART, but that this is dependent on maintaining an undetectable viral load, itself related to careful adherence. Also, that a lower quality of life should not become the price for reducing community viral load, though both are challenging to measure: treatment is easy to modify or switch if the first combination is difficult to tolerate.
Until the START study produces results, individuals with high CD4 counts should be supported if their preference is to start treatment, whether they are doing this for their own or their partner's health. HIV treatment is highly individual though and this decision will be right for some but not for others.
For patients outside the START study, the drive for treatment as prevention is only likely to increase between now and 2016 -- irrespective of the clinical impact of earlier treatment -- it is important to keep a clear distinction between population level benefits and personal health benefits when individualising the decision to start treatment.
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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