We Order Too Many CD4 Cell Counts, but Should We Really Stop? A Top HIV Clinical Development of 2017
"What's my count, doc?" It's a frequent question my patients ask, followed by whether the number I report is good, or not. Even in an era when most of our patients have plasma HIV RNA levels below the limits of detection of sensitive assays, we have trained our patients to know and follow their CD4 cell counts to encourage adherence to medication and increase health literacy.
However, the value of frequent CD4 cell count measurement for those with suppressed virus levels has been questioned. Guidelines are all over the place. The U.S. Department of Health and Human Services (DHHS) antiretroviral treatment guidelines recommend that patients with controlled viremia and CD4 cell counts between 300 and 500 cells/mm3 have annual CD4 cell count testing; those with counts above 500 cells/mm3 for at least two years can consider the CD4 cell count to be optional. Informed by data from the ARTEMIS trial, where CD4 monitoring had no clinical benefit for patients who had suppressed viral loads and CD4 counts above 200 cells/mm3 after 48 weeks of therapy, European guidelines call for lower thresholds for letting up on CD4 monitoring. The European AIDS Clinical Society recommends that the frequency of CD4 cell monitoring be decreased when CD4 counts are more than 350 cells/mm3, while the British HIV Association drops CD4 monitoring frequency at counts more than 200 cells/mm3.
To determine the clinical impact of these different thresholds for reduced CD4 cell count monitoring to every 9-12 months from the typical 3-4 months, a team of investigators looked at data collected in several large HIV clinical cohorts being conducted in Europe and Brazil, plus the U.S. Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. The thresholds for reduced CD4 cell count determination examined were 500, 350, and 200 cells/mm3 for people in the cohorts who were treatment-naïve, free of AIDS at the start of therapy, and achieved viral suppression with a plasma HIV RNA less than 200 copies/mL. Using inverse probability weighting to adjust for baseline and time-varying confounders, the team estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count.
Over 47,000 people met the criteria for inclusion in this analysis, and there were 464 deaths and 1,091 AIDS or death events. Overall, there was no significantly increased mortality risk with a reduction in CD4 cell count monitoring to annual at a threshold of 200 cells/mm3 or 350 cells/mm3 compared with 500 cells/mm3 -- HR was 1.05 (95% confidence interval [CI] 0.86-1.29) and 1.02 (0.91-1.14), respectively. Similarly, there was no detected harm associated with the lower thresholds for the combined AIDS/death endpoint. However, compared with the threshold of 500 cells/mm3, the 24-month risk ratios of virological failure (viral load more than 200 copies/mL) were significantly higher (2.01 [1.17-3.43]) for thresholds of 200 cells/mm3 and 350 cells/mm3 (1.24 [0.89-1.73]).
The Bottom Line
We love our data and our patients even more so. They cling to their CD4 cell counts and cautiously inquire whether they are still "undetectable." That is why although this and prior, less robust, analyses are reassuring about reduced CD4 cell count monitoring, it is a hard sell. The study found no greater harm in less frequent CD4 cell counts for all but those with counts below 200 cells/mm3, but it was not designed to look for any benefits from more regular monitoring. For many patients, there is a psychological need for a metric indicating steady progress. As a bicyclist, I know that my rides are frustrating when my handlebar speedometer is on the blink: I have no real idea how well I am doing for all my hard work, and I suspect I am a bit slower in such instances. It is the same with those taking daily antiretrovirals. They need to know, and when the numbers are happy, they are happy.
Clearly, there are economic considerations. CD4 cell counts do not grow on trees. However, that there was a greater risk of virologic failure at the lower CD4 threshold might be telling. I suspect that, for many people, the CD4 cell count is like the crowd I imagine on the sidelines during my rides over the rolling hills (small mountains) of the North Carolina countryside: waving banners; shouting, "Allez!"; and keeping me on track.
David Alain Wohl, M.D., is a professor of medicine in the Division of Infectious Diseases at the University of North Carolina (UNC). He is site leader of the UNC AIDS Clinical Trials Unit at Chapel Hill, director of the North Carolina AIDS Education and Training Center (AETC), and co-directs HIV services for the North Carolina state prison system. In 2014, he became co-director of the UNC-Duke Clinical RM Ebola Response Consortium.