December 1, 2011
That HIV is bad for you is indisputable. But how bad is the virus itself? What harm does it do as it endlessly replicates? Until recently, we were generally comfortable allowing HIV to go unmolested among patients with high CD4+ cell counts. Now, as we begin to appreciate the axis of evil among viremia, immune activation and inflammation, and we move toward expanding the HIV-treatment net, it is reasonable to ask how harmful it is to have circulating virus over time.
Researchers from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS), a network of clinical sites across the U.S., have devised an interesting method of examining the viral load not at a single, cross-sectional time point, but over time to arrive at a cumulative burden of HIV.7 Called viremia copy-years, this technique provides an area-under-the-curve of HIV exposure that can be examined against a variety of outcomes. The concept is similar to that of pack-years of cigarette smoking.
In this paper, data from 2,027 patients initiating ART from 2000 to 2008 were used to calculate viremia copy-years and then evaluate the association between this and mortality. The median CD4+ cell count at treatment initiation was just over 200 cells/µL and, after a median follow-up of 2.7 years, patients each contributed a median of eight viral load determinations. Most (81 percent) were virologically suppressed by six months after ART was started, but 4 percent of the cohort had died (after a median of two years).
Median viremia copy-years was 5.3 log10 copy X years/mL. The unadjusted hazard ratio (HR) for log10 viremia copy X years/mL was 1.81 (95% CI: 1.51-2.18), indicating that for each log10 increase in viremia copy-years, the hazard of death increased nearly two-fold. In adjusted and weighted analyses, viremia copy-years was independently associated with mortality (HR 1.65; 95% CI: 1.32, 2.06). In analyses that included demographic and clinical covariates, the cross-sectional viral load measures were no longer associated with mortality. In addition to viremia copy-years, having a lower most recent CD4+ cell count and older age were each also independently associated with an increased mortality risk.
The cross-sectional viral load is useful in a clinical setting, but it fails to capture the longitudinal exposure of the patient to HIV -- plus, it is so 2010. Instead, viremia copy-years provided a Cassandra-like power to determine the risk of all-cause mortality in this large sample of patients initiating therapy. An independent 44-percent increase in mortality risk was observed per 1 unit increase in log10 copy X year/mL of cumulative viral load burden. Thus, viremia copy-year was up there with age (life's greatest risk factor for death) and recent low CD4+ cell count as a harbinger of doom.
Importantly, greater exposure to HIV over time was predictive of death independent of the most recent CD4+ cell count. This supports the idea that viremia is harmful even when CD4+ cell counts have not been decimated. Further, this work dovetails nicely with observational cohort data, including a pooled analysis of over 40,000 patients from Europe and North America who were not receiving ART and had at least a single CD4+ cell count above 350 cells/µL, that found higher rates of death even at higher CD4+ cell counts compared to the general public.7
It has been assumed that the excess risk of illness and death at higher CD4+ cell counts comes at the hands of immune activation and the inflammatory responses it provokes. In the CNICS study, markers of inflammation and immune activation were not included as this was a retrospective analysis, but such data would help close the loop of association between viremia and death.
Nevertheless, these findings provide important additional evidence of the deleterious effects of ongoing viremia on health and have introduced us to a new concept of continued viral replication.
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