Posted by Ah, another day, another paper for the anti-HIV establishment to glom onto and misrepresent.
Last week’s issue of the Journal of the American Medical Association published this paper examining the relationship between HIV load and CD4 T-cell decline:
Context Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized.
Main Outcome Measures The extent to which presenting plasma HIV RNA level could explain the rate of model-derived yearly CD4 cell loss, as estimated by the coefficient of determination (R2).
Results In both cohorts, higher presenting HIV RNA levels were associated with greater subsequent CD4 cell decline. In the study cohort, median model-estimated CD4 cell decrease among participants with HIV RNA levels of 500 or less, 501 to 2000, 2001 to 10 000, 10 001 to 40 000, and more than 40 000 copies/mL were 20, 39, 48, 56, and 78 cells/µL, respectively. Despite this trend across broad categories of HIV RNA levels, only a small proportion of CD4 cell loss variability (4%-6%) could be explained by presenting plasma HIV RNA level. Analyses using multiple HIV RNA measurements or restricting to participants with high HIV RNA levels improved this correlation minimally (R2, 0.09), and measurement error was estimated to attenuate these associations only marginally (deattenuated R2 in the 2 cohorts, 0.05 and 0.08, respectively).
Conclusions Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection. These findings have implications for treatment decisions in HIV infection and for understanding the pathogenesis of progressive immune deficiency.
The deniers, of course, have taken that last portion, twisted it, and used it like they used the Padian paper: to somehow suggest that the HIV–>AIDS paradigm isn’t true, and experts are just “bunglers.” More on what the actual research shows–and what the study authors say about their paper–below.
I’m not going to extensively review the paper, as that’s already been done here:
It’s well known (at least among those who bother to read and understand the literature) that those people with higher viral loads tend to progress faster, as was shown by John Mellors back in the mid 1990s using the large Multicenter AIDS cohort study (MACS).
This study took things one step further. They replicated the original findings of Mellors by showing again that viral load roughly predicted how fast AIDS occurred in another large cohort composed of people from 3 seperate study sites. For example, in this new paper people with viral loads less than 500 had an average loss of CD4 cells of 20 per year whereas those with viral loads over 40,000 had an average loss of 78 a year (with a smooth change for values inbetween). Basically this data proved that viral load was a reasonable predictor of rate of progression! They compared this analysis with the original MACS cohort and it looks practically identical!
But then they tried to look at the individual rate of progression of each member of the cohort. Unsurprisingly they found that the rough-and-ready estimates of progression rate within a subgroup varied from one individual to another. When they ran complex statistical analysis on the effects of viral load on THIS data they found that only about 5-6% of the inter-individual variation can be explained by the initial viral load. In another words, while viral load predicts that you WILL lose CD4 count, and you can give an AVERAGE loss of CD4 cells per year based on that count, you can’t say for sure what the ACTUAL loss will be for any one person very accurately.
As Nick mentions, these new findings nicely replicate the earlier research correlating a higher viral load with decreased CD-4 T cell count–confirming its use as a surrogate marker for disease progression. So what we’ve got here is a new paper that agrees with the older literature–how and why are the deniers spinning this? They’re focusing on the last paragraph Nick describes, and using it to suggest that because it’s much more difficult to predict at the individual level exactly how much CD4 loss will correlate with viral load, well, the whole thing must just be bunk! What they apparently don’t realize is that again, this is common in most studies looking at predictive criteria such as these. For example, on average, elevated blood cholesterol levels correlate with an increased risk of cardiovascular disease (CVD). But, one person may have very high blood cholesterol level and show no signs of disease, while another may have fairly low cholesterol and still have CVD. It’s always tougher to apply these population-based measurements at the individual level, since population-based data by their nature average out these individual variations.
What the deniers are also crowing about is the number cited: that “about 5-6% of the inter-individual variation can be explained by the initial viral load.” This, indeed, has clinical implications, as the paper notes in the discussion:
The clinical implications are that in the majority of cases, an individual patient’s plasma HIV RNA level at the time of presentation for clinical care cannot predict, to a significant extent, the rate of CD4 cell decline that he or she will experience over the subsequent years and is therefore of limited clinical value in shaping the decision to initiate antiretroviral therapy. This is despite the fact that a group of individuals with an approximately similar level of plasma viremia will, on average, tend to lose CD4 cells at a faster rate than another group with a lower level of viremia, a previously reported finding that stands uncontested by our results.
Again, this also emphasizes the need for more research on other factors that drive CD4 cell decline in order to have a more robust picture of disease pathogenesis and progression (something certainly not unique to HIV by any means; we don’t have a full understanding of this in any disease I can think of). However, for deniers, these “gaps” in the research are somehow a sign of a failed paradigm, rather than a typical result of novel studies into the area. As Darin Brown over at Barnesville (now “Hank’s ‘You Bet Your Life’” and apparently a group effort by a number of deniers) sneers regarding the new paper:
Now, after 25 years of very expensive research, ‘they’ have arrived at the conclusion that 90% of what we always thought was the most important factor (loss of CD4 cells) can’t be accounted for by the amount of HIV (assuming the viral load test is even accurate in the first place).
Nevermind, the fundamental assumption cannot be wrong. We just need billions and billions more dollars to figure out the ever more enigmatic mechanisms by which HIV is responsible for CD4 loss while only 10% is accountable for by viral load. Just give us more money, and we’ll produce as many “mysteries” as we please, and you pay for.
Nick addresses the actual ramifications of this paper, and the type of thinking espoused by Brown and others:
It should also be mentioned that viral load isn’t used as a clinical criteria for starting treatment unless the load is very high and the CD4 counts are equivocal. Viral load is almost exclusively used for monitoring response to therapy on the individual level, so inter-individual variability isn’t an issue anyway.
This result is very important in that it highlights the need to investigate other factors important in triggering or controlling rate of progression to AIDS, but it won’t really change the current paradigm in terms of understanding AIDS pathogenesis, nor will it change current treatment guidelines, because neither depends on the idea that HIV viral load is the be-all and end-all of AIDS.
Except of course, that it is in the minds of the dissidents.
Finally, as with the aforementioned Padian paper (that we discussed ad nauseum here), the PI of this study, Michael Ledermen of Case Western Reserve University, has words for those deniers who’d use this research as some kind of blow against the HIV –> AIDS paradigm:
The idea that our findings published today in JAMA can be taken to support the concept that HIV is not the cause of AIDS is ludicrous. The role of HIV as the cause of AIDS has been proven over and over again. Clearly the people who are misrepresenting our work are not only incapable of clear thinking, they are also apparently unable to read.
Not that being unable to read or follow the logic of a study has stopped them before, and it’s certainly not stopping them this time either. Expect to hear more “HIV load doesn’t have anything to do with AIDS!” in the future.
References
Rodriguez et al. 2006. Predictive Value of Plasma HIV RNA Level on Rate of CD4 T-Cell Decline in Untreated HIV Infection. JAMA. 296:1498-1506. Link.
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