Consequently, until ART is started, the risk of AIDS is almost certainly greater in those who defer ART than in those who start immediately. The absolute magnitude of this difference will depend on the initial AIDS risk, being higher in those at higher risk. Even after initiation of ART in those who initially defer, the risk of AIDS in this group is unlikely to fall, in a time span of a few years, below that in those who started ART immediately i.e., the line in Fig. 1, for the deferred group initially remains above that for the immediate group even after ART is started because the former started ART at a lower baseline CD4 cell count. The recently reported results from the ART Cohort Collaboration compared AIDS rates according to the baseline CD4 cell count group. The higher AIDS rate in those initiating ART at a lower CD4 cell count remained after a follow-up of 3 years (Fig. 2; ).
Therefore, existing available evidence strongly suggests that the risk of AIDS and death over the subsequent 3 years is lower, albeit by only a small amount if the CD4 cell count is high, if ART is initiated immediately rather than deferred. So, if the dominant concern is to avoid AIDS and death over the next 3 years, then the better strategy for the person with CD4 cell count 350 × 106 cells/l is to start ART immediately. A recent analysis from the Swiss HIV Cohort, in which people starting ART were matched with people who appeared similar except that they were not initiating ART, reached this same conclusion . This was the case even when follow-up experience in those who did not start ART was right censored when the CD4 cell count declined to < 200 × 106 cells/l if ART had not been initiated by this point. It is important to emphasize that the absolute reduction in risk when therapy is initiated is much greater in those with lower CD4 cell count, so while there is a clear reduction even in those with CD4 cell count > 350 × 106 cells/l, the absolute risk was very low even before this reduction (Fig. 2).
So why are the above findings not considered to provide conclusive evidence that ART should be initiated immediately, rather than deferred, in people with relatively high CD4 cell count? The reason is that ART is now so effective that it actually provides hope of avoiding AIDS for an entire natural lifespan. It is this perspective – rather than just 3 years – that many people will take. Even if untreated, the cumulative risk of AIDS over 3 years in a person with a viral load of 10 000–29 900 copies/ml and CD4 cell count of 200–350 × 106 cells/l is < 10% . Over 5 years, the cumulative risk is around 15%. The great majority of people with a CD4 cell count of 350 × 106 cells/l will remain AIDS-free 5 years later whether they initiate ART immediately or defer until their short-term risk has become unacceptably high. Therefore, the more important question is where the risk line (in Fig. 1) will be from 3 years onwards (perhaps up to 50 years or more), rather than in the next 3 years. This is considered in the next section.
Before this, other analyses assessing short-term AIDS risk have been presented as part of the ‘when to start’ debate and these should be put in context. Some studies have presented analyses showing the risk of AIDS and/or death after starting highly active antiretroviral therapy (HAART) according to the CD4 cell count and, in some cases, the viral load at the pre-HAART baseline [4,27,28]. Such data are useful for assessing prognosis in people starting ART but they do not directly address the question of exactly what CD4 cell count should be chosen for the start of ART as they do not account for the risk of AIDS and death before starting ART if it is delayed. Further, higher risk of AIDS after starting ART in those with lower CD4 cell count at initiation cannot be used to conclude that the effect of ART is less in those with lower CD4 cell count at initiation, because the AIDS risk during ART reflects the AIDS prognosis at the time of initiation as well as the effect of ART. Cole et al.  have attempted to address this lead-time bias issue by jointly modelling the three processes operating in a person who defers ART: the probability of getting AIDS or dying before starting ART, the probability of starting ART, and the probability of developing AIDS and/or dying after starting ART. This essentially formalizes the approach we have used above in our interpretation of data from studies of HIV natural history and people on HAART (illustrated in Fig. 1, before 5 years). Based on data from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study, they concluded that deferring ART until the CD4 cell count was < 200 × 106 cells/l resulted in a greater 3-year AIDS risk (although adjustment for lead-time bias indicated that the effect of deferral to < 200 × 106 cells/l was of substantially lesser magnitude than was suggested by the crude analysis of time since ART initiation referred to above) but that deferral of ART in those with CD4 cell count 350–500 × 106 cells/l until < 350 × 106 cells/l was reached (but not < 200 × 106 cells/l) did not result in any greater AIDS risk (although confidence intervals for the relative hazards were relatively wide) . Therefore, these findings are consistent with the points made above.
Since we have only around 5 years of experience of triple ART regimens, we can only indirectly evaluate the risk of AIDS diseases and death over the longer term, by comparing intermediate endpoints that we believe relate most closely to the long-term risk of AIDS and death. For some years, use has been made of viral load outcomes to assess and compare the effects of antiretroviral drugs [30–34]. It is well established that the effect of ART on viral load is strongly correlated with the effect on the CD4 cell count and risk of AIDS [22,30–36], and it has become widely accepted that the goal of ART is to achieve and maintain a viral load < 50 copies/ml [19,20,37]. So long as such a level of viral suppression is maintained in a person with a CD4 cell count > 200 × 106 cells/l, the risk of AIDS remains very low [36,38]. The need for viral suppression as low as 50 copies/ml is to minimize the risk of emergence of viral strains resistant to drugs [39,40]. Virologic failure – failure of viral load to become, or to stay, at a low level on ART – is often associated with development of drug resistance [41,42]. Since resistance to one drug in a class tends to also reduce susceptibility of virus to other drugs in that class , virological failure and development of drug resistance is a serious problem with long-term consequences for maintaining viral suppression. It seems reasonable, and conservative, to assume that in the future development of new drugs to which the virus of most infected people is sensitive will be limited. In those who achieve viral load < 50 copies/ml within 24 weeks of the start of ART, the risk of virological failure is very low ; this suggests that prevention of development of AIDS for many years to come – perhaps even over a natural lifespan – depends largely on avoiding resistance within the first few months after initiation of ART. Resistance cannot always be detected directly because such tests lack sensitivity . Effectively then, the emphasis is on avoiding virological failure on ART: resistance will probably be present in most such patients, whether it is detected in genotypic or phenotypic resistance tests or not.
As discussed above, the principal means we currently have of trying to examine this issue is to assess whether the risk of virological failure is lower if ART is started immediately or if it is deferred. There are reasons for believing that either could be the case. Consider, on the one hand, a person with a CD4 cell count of 350 × 106 cells/l in 2003 and who might have a CD4 cell count of 200 × 106 cells/l in 2008 if ART is deferred. Immediate ART may carry the lower risk of virological failure if it is the case that the risk of virological failure is lower in people initiating ART at higher CD4 cell counts and/or lower viral loads. We studied almost 3000 people from three large cohort studies who initiated ART after 1996 and found no evidence that the risk of virological failure was lower in those starting ART at CD4 cell counts > 350 × 106 cells/l compared with those initiating ART at CD4 cell counts of 200–350 × 106 cells/l . Those with higher baseline viral loads took a longer time to achieve initial viral suppression than those with lower baseline viral load, but the probability of achieving viral load suppression by 32 weeks was similar, as was the subsequent rate of viral rebound. Other authors have studied this issue  but not on individual patient data . Consider, on the other hand, this same person with a CD4 cell count of 350 × 106 cells/l in 2003 who defers ART until 2008; the risk of virological failure may be reduced because of advances in ART (becoming less toxic, easier to take and more potent) and adherence management that may have occurred during this period. Of course, it is impossible to answer this definitively because we do not know what treatment improvements will occur in the next few years. However, it is informative to look at the changes in early virological failure rates seen since the introduction of HAART in 1996. This is best achieved by looking at complete, open clinic cohorts with no patient selection. Figure 3 shows data from an open clinic on the percentage with virological failure by 1 year from starting ART (with at least three drugs). Failure is defined as having a viral load > 400 copies/ml measured between 24 weeks and 1 year, followed by another value > 400 copies/ml. Those without a viral load available between weeks 24 and 48 are excluded. There has been a decline in the percentage with virological failure between 1996 and 1998, but there has been little change since then, with the value levelling out at approximately 15%. More extensive data are required on this issue, including for rates of virological failure over more than 1 year. However, this preliminary examination suggests that – in so far as future AIDS risk be determined by 1-year rate of virological failure – the durability of reduction in AIDS risk will be no shorter, and perhaps longer, in those who defer ART. As argued above, this indicates that the AIDS risk will be lower over the longer term in the deferrers.
Before concluding, some other issues require consideration. First, the degree to which the patient feels ready to start ART is probably the most important determinant of virological response. There is little point in starting ART in patients who are not ready, unless their short-term risk of disease makes it essential to start. Second, while the data shown take account of drug toxicity in so far as it directly (owing to fatal adverse events [49,50]) or indirectly (owing to an effect on adherence [51,52]) affects risk of virological failure and death, there is also the fact that toxicities can affect quality of life [53,54], and this will be a major consideration for many people when deciding whether to initiate ART at a given time. Our view has been that it is important first to address whether immediate or deferred ART is likely to delay AIDS and death most. Given this information, patients can individually then factor in the quality-of-life issues as they relate to them personally before making their final decision. However, this is not easy as there are insufficient data on quality of life in most trials and cohorts. In addition, treatment interruption is relatively common (although by no means universal) [55,56]. Those who initiated ART with a higher CD4 cell count and lower viral load will probably be able to interrupt safely for longer, if at some point they do interrupt ART. This is another important consideration when deciding whether to start ART at a given time.
We would like to thank Dr Alvaro Muñoz for helpful comments on this manuscript.
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