CD4 lymphocyte count testing for decades has been a staple for monitoring the immune status of HIV patients. However, many physicians today rely more on viral load testing, a measure of viral suppression, to assess patients’ disease progression and response to antiretroviral therapy. This led researchers to explore how likely HIV patients with evidence of viral suppression would be to maintain durable CD4 cell counts above the threshold for opportunistic infection risk. Their findings are the subject of this issue of Strategies.
Since the early days of the HIV/AIDS epidemic, CD4 cell counts have been a key measure of immune function in HIV patients, and that has remained the case even with widespread adoption of plasma HIV RNA viral load testing as the primary indicator of viral suppression.
“Going back to the 1980s, the CD4 cell count was the only number for patients and clinicians to grasp on to,” explained Howard Gale, MD, MT(ASCP). “It was the only number that told them something about what was going to happen to the patients. Until viral load testing came along that was all people had, and so both clinicians and patients became very reliant on this number.” Gale is infectious diseases laboratory supervisor at the Veterans Affairs Medical Center in Washington, DC.
Reflecting the CD4 cell count test’s established place in HIV care, guidelines for managing HIV and even classifications of the disease still rely on CD4 cell counts. For example, U.S. Department of Health and Human Services guidelines recommend CD4 cell count testing at several points in HIV-related care, including patients’ entry into care, before they start antiretroviral therapy (ART), and every 3–6 months to assess their immunological response to ART and the need to start or discontinue prophylaxis for opportunistic infections. However, these guidelines also suggest that patients with CD4 cell counts well above the threshold for opportunistic infection risk, 200 cells/µL, might have their counts measured less frequently, every 6–12 months.
Some experts, including Paul Sax, MD, have argued that the latter proviso is an acknowledgement of the test’s declining importance in HIV care. “I look at this ‘every 6 to 12 months’ frequency as a gentle way of trying to wean us off a monitoring strategy we have had now since the 1980s,” he contended in an editorial. “Both patients and providers are so accustomed to regular CD4 monitoring that it seems too difficult to stop doing it cold turkey. But if the data are looked at critically, one could easily make the argument that among these stable HIV patients on treatment, the CD4 cell count need not be measured at all.” Sax is a professor of medicine at Harvard Medical School and medical director of the infectious diseases division and HIV program at Brigham and Women’s Hospital in Boston.
Gale and his colleagues at the Veterans Affairs Medical Center recently undertook the type of critical evaluation of CD4 cell count data that Sax described, retrospectively analyzing 25,463 paired viral load and CD4 cell count test results returned over a 13-year timeframe for 1,820 patients (Clin Infect Dis 2013;56:1340–3).
The researchers started with a password-protected log of CD4 cell count and viral load testing data, which the infectious diseases lab maintains for public health reporting and other purposes. From this, they developed a statistical program to analyze the results.
The authors defined a patient sequence as a period of continuous HIV suppression. Criteria for the start of a patient sequence included at least two pairs of viral load-CD4 cell count tests with a viral load <200 copies/mL, CD4 ≥200 cells/µL, CD4 percentage ≥14%, ≤390 days between the tests, and a subsequent viral load-CD4 cell count pair within 390 days. A patient sequence ended when any one of four conditions occurred: a CD4 count <200 cells/µL; viral load rebounded to ≥200 copies/mL; a >390-day gap in testing; or the end of the study’s observation period. The authors defined a CD4 dip as when a patient experienced a CD4 count <200 cells/µL during a patient sequence.
After excluding patients who did not meet sequence requirements, the final analysis included results from 832 patients, of which 537 had one sequence, and 295 had two-to-six sequences. Overall, 93% of patients included in the final analysis maintained CD4 cell counts of at least 200 cells/µL. The researchers conducted chart reviews for the 61 patients who experienced 84 CD4 dips, and found non-HIV-related causes in 39%. Dips tended to occur soon after ART treatment started, and no one experienced a dip after 2.2 years of ART. The authors found that for patients with an initial CD4 cell count of 300–349 cells/µL, the probability of having maintained a CD4 count ≥200 cells/µL during 4 years was 95.3%. This probability rose to 97.5% when the initial CD4 count was ≥350 cells/µL.
With patients who maintained viral loads <200 copies/mL and CD4 cell counts ≥300 cells/µL “highly unlikely” to experience a CD4 count <200 cells/µL, the authors concluded that routine CD4 monitoring in clinically stable, virally suppressed patients might be unnecessary. “We found only five patients who had CD4 counts above 300 cells/µL who ever went below 200 cells/µL,” explained Gale. “Our study basically shows that individuals who have CD4 counts above 300 cells/µL and who remain virally suppressed and clinically stable are not going to go below 200 cells/µL, so they don’t need CD4 counts to assess their risk of developing opportunistic infections.”
Sax found the study a convincing demonstration of the lack of clinical utility of CD4 cell count monitoring. “The results are striking,” he said. “The most important reason for not measuring CD4 counts routinely in a stable patient is that the results will not influence care, since patients with high CD4 cell counts so rarely dip below clinically‐meaningful thresholds.”
Sax was not alone in hailing the findings. “This is an interesting study, with interesting implications and a potentially significant impact on the distribution of limited budget resources,” said Eugene Martin, PhD, professor of pathology and laboratory medicine at the University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School in Somerset. While he accepted the authors’ findings and agreed with their conclusions, he emphasized that this study reflected only the patient population at one organization.
Gale urged other laboratorians to conduct similar studies in their own institutions. The SAS macro the authors used to determine patient sequences was published as a supplement to their article. “CD4 cell count test patterns and results could be different from institution-to-institution if patients and physicians behave differently or if the CD4 counts or viral load measurements vary. But I would expect they’re all pretty standardized and it would be pretty easy to reproduce our numbers,” he said.
Gale cautioned, however, that merely presenting data to physicians would not lead to a change in ordering practices for this test. “There’s no logical reason to have routine CD4 cell count testing once HIV suppression and higher CD4 counts have been established, but there’s a big emotional reason for it. Patients have gotten used to seeing their CD4 counts, and some will worry when they don’t,” he observed. “It’s up to doctors to counsel patients as they would for any test that’s fallen out of favor at some point in time. You just have to be honest with people and say ‘this is not a useful test anymore. With the limited resources, maybe this is a test we can stop doing.’”
Sax outlined a three-step process to curtail unnecessary CD4 cell count monitoring, which he called a “wasteful addiction.” First, he suggested that HIV treatment guidelines eliminate recommendations for regular CD4 monitoring in clinically stable patients. He then proposed that quality improvement initiatives “acknowledge the primacy of HIV RNA as the definitive (and only) marker of the efficacy of current antiretroviral therapy.” Finally Sax called for physicians to have further dialogue with patients. “The message should be simple,” he said. “We no longer need this test to make decisions about your treatment.”