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The Clinical Edge

Adieu CD4 Monitoring?

Dr. Diane Havlir examines the practice of routine CD4 monitoring and its role in the management of HIV infection.

How often should we be monitoring CD4 cell counts? The transformation of HIV treatment calls into question this stalwart practice--in place for over 30 years! Just last month the DHHS Guidelines (1) weighed in on this question and recommended a dramatic change, ie, after 2 years of suppressive ART, CD4 counts should be monitored every 12 months for patients with counts of 300-500 cells/µL, and possibly never (optional) for those with counts >500 cells/µL.

No more routine CD4 monitoring for all patients! I would argue this change in national guideline was long overdue and perhaps not extreme enough.

No more routine CD4 monitoring for all patients! I would argue this change in national guideline was long overdue and perhaps not extreme enough.

HIV medicine has had a CD4 "culture," one that involves both providers and patients. An abnormally low CD4 count and CD4/CD8 ratio was one of the hallmarks of AIDS when the very first cases were recognized. We enthusiastically incorporated this rather exotic test into our standard HIV monitoring. We used CD4 counts to guide the initiation of prophylaxis for opportunistic infections and to target our diagnostic workups. We relied upon it heavily in prognosis discussions with our patients. With the advent of effective antiretroviral combinations, we used the CD4 count as a guide for when to start therapy and as a yardstick of response. We used it to stop prophylaxis. We even used it to stop ART, back when we thought that might be a good idea.

CD4 counts also have been important to our patients. Even our patients with very little education or an aversion to anything technical would quote their CD4 cell counts with authority. When CD4 cell counts plunged into the single digits, I recall patients naming each cell and mourning each cell loss. I remember virtual toasts with patients whose CD4 cell counts rose beyond an important medical and sentimental threshold. The CD4 was an extraordinarily valuable tool for us as providers, and it was an unintended source of drama among our patients.

We still rely on CD4 cell counts, particularly in patients with low values, to guide start and stop of prophylaxis and direct our workups. But times have changed in HIV medicine, and so has the role of the CD4 count. We don't use the CD4 count to tell us when to start ART--we start ART on all our patients. When patients have viral suppression and counts above 350 cells/µL, we don't really use it at all in management--our metric for assessing ART efficacy is HIV RNA. So why should we check CD4 in stable patients on ART? Gale, et al recently published a nice analysis showing little likelihood of a benefit for CD4 monitoring among patients with viral suppression and counts over 300 cells/µL.(2)

What this translates to, as reflected in the new Guidelines, is that we do not need to monitor CD4 in stable patients with viral suppression and high CD4 cell counts. In 2010, our HIV clinic at San Francisco General Hospital changed our own internal policy and adapted a standard that patients on a stable ART regimen with viral suppression and CD4 counts >500 cells/µL would not have CD4 monitoring and those with counts of 201-500 cells/µL would have it done only annually. This policy was a bit controversial at the time. Initially, many providers could not accept that CD4 monitoring was not helping in management. Even some patients were upset--"Why are you not checking my CD4?" In my own practice, patients begged me, they even tried to bribe me in their own way to check a CD4 cell count. I gently refocused them to viral suppression and other important measures of preventive medicine. Now most patients doing well are no longer as focused on CD4 cell count, particularly those who are relatively new in HIV care.

Nevertheless, sometimes we are forced to check CD4 counts in stable patients because some funding agencies and quality improvement programs withhold services or ding us if our patients do not have regular CD4 cell counts. Ironically, the very people who control funds sometimes threaten to withhold funds for a practice that is actually compliant with our guideline, and is saving money. Hopefully, this will change now that DHHS has put this CD4 cell monitoring recommendation into a national guideline.

As you ponder changing your clinic or personal practice based on these guidelines, don't underestimate the need for education, dialogue, and discussion with patients and providers. That is of course the case for any change, but this one is a bit more complicated because we have spent decades telling our patients, the funders, and the public that CD4 cell counts are critical for patient management. A shift in the CD4 "culture" is needed, and is under way. It can be done, and it should be done, to meet our responsibility for medically and fiscally responsible practice. We also will need to work with our funders and local agencies to encourage them to align with these new guidelines.

Well, now that I've made the argument for changing our practice of CD4 monitoring, I have to end this piece with a recent twist in the CD4 story. At CROI this year, Seranno-Villar presented data showing that the CD4/CD8 ratio was a strong predictor of unfavorable outcomes in the broadest sense, even among patients with viral suppression and high CD4.(3) I am not going to restart ordering CD4. But I would say that the final chapter on the CD4 story in HIV has not been written and we eagerly await more data to see if there is any relevance to clinical practice.

So, it is not adieu to CD4, but a dethroning of a kingpin of monitoring. That, like many changes in HIV, is emblematic of progress in managing a disease that continues to evolve.

References

  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services.
  2. Gale HB, Gitterman SR, Hoffman HJ, et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts ≥300 cells/L and HIV-1 suppression? Clin Infect Dis. 2013 May;56(9):1340-3.
  3. Serrano-Villar S, Sainz T, Lee SA, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T-cell subsets, heightened CD8+ T-cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014 May 15;10(5):e1004078.