Perspectives

CD4 Count/Viral Load in HIVRichard Hengel*

Georgetown University, Washington, D.C.

What a gratifying five years it’s been working in HIVcare. Potent new generation anti-retroviral medicines re-duced HIV related morbidity and mortality upwards of75% in clinical settings where patients were lucky enoughto have access to these drugs (1). Such success againstdeadly pathogens has only been observed with the likes ofvaccines for diseases such as small pox, or newly curativedrugs for diseases such as tuberculosis and malaria. Ofcourse, new anti-retroviral drugs, even in combination, donot cure HIV, and we anxiously await proof that theirspectacular positive effects are durable. Furthermore,troubling side effects have been reported, and treatment-related declines in HIV RNA to levels below conventionallimits of detection occur only about 50% of the time inreal-world clinical settings. Yet, for patients taking thesemedications, morbidity and mortality gains appear to beholding, and we have yet to see increases in deaths orhospitalizations to remind us of the bad old days.

Changes in drugs are not the whole story. About thesame time as the new effective medications became li-censed in the United States, HIV RNA polymerase chainreaction (HIV PCR or “viral load”) technology becamewidely available to evaluate viral burden and monitor theeffects of treatment. Like Yang to Yin, adding understand-ing of virology to understanding of immunology contrib-uted immensely to better understanding the whole of HIVdisease. Viral burden, as measured by HIV PCR, drivesimmune deterioration, as measured by CD4 T cell loss. Inuntreated patients, combined analysis of viral burden andimmune deterioration are powerful tools for prognosis, asis likely the case for treated patients (2).

In the midst of all this good news is the bad. With theexplosion of therapeutics and diagnostics comes a similarexplosion in complexity and cost. Choosing clinical man-agement options that maximize quality while minimizingcost requires considerable finesse, and even HIV special-ists can disagree on the specifics of therapy. But severalgeneralizations can be made: at a minimum, a potentcombination of anti-HIV drugs, appropriate prophylacticdrugs and immunizations, and HIV PCR testing with CD4T-cell enumeration form the bedrock of quality-care forpatients with HIV disease.

Several publications exist to help the physician keepabreast of rapid changes in standards of care. In 1996, theDepartment of Health and Human Services and the HenryJ. Kaiser Family Foundation convened the Panel on Clini-cal Practices for the Treatment of HIV to develop guide-lines for the clinical management of HIV infected adultsand adolescents. These welcome, evidence-based, recom-

mendations first appeared in 1998 and are updated regu-larly on the world-wide-web. In essence, they recommendtreating patients with moderate viraemia and immunedeterioration with either a protease inhibitor or the non-nucleoside reverse transcriptase inhibitor efavirenz, alongwith at least two other additional drugs, typically nucleo-side reverse transcriptase inhibitors. Ongoing treatmentefficacy is judged by CD4 T-cell enumeration two to fourtimes per year and viral load testing three to four times peryear (3).

Recently, the United States Public Health Service andthe Infectious Diseases Society of America updated evi-denced-based Guidelines for the Prevention of Opportu-nistic Infections in Persons Infected with Human Immu-nodeficiency Virus. Significant changes to these guidelinesaccommodate immune reconstitution in the face of effec-tive anti-HIV treatment regimens, at least as judged byCD4 T cell criteria. They allow for stopping primary pro-phylaxis (preventing a disease from occurring in the firstplace) when evidence of sufficient increases in CD4 T cellcounts exist. However, in the absence of published expe-rience the guidelines are cautious about stopping second-ary prophylaxis (preventing a disease from recurring afterit has already occurred) (4).

Rightly or wrongly, advances in HIV care often maketheir way into the clinic before definitive phase III clinicaltrial results are obtained. This puts HIV care dangerouslynear the crest of the technology wave. Obvious and com-pelling evidence for any single approach to clinical man-agement does not yet exist. This is precisely why consen-sus guidelines are useful. An additional benefit,increasingly important in today’s super-charged health-care marketplace, are the counterweights providedagainst any shortsighted cost containment strategies.

How are HIV PCR and CD4 T cell results used to max-imum benefit? CD4 T cell enumeration measures immu-nological reserve, while HIV PCR measures the force de-pleting that reserve. The variable of time addsconsiderable power to these tests, creating a sort of cal-culus for HIV infection. Baseline values in untreated pa-tients help to determine the need for adjunctive prophy-lactic therapy and to identify the patient in whomwatchful waiting, rather than treatment, is the appropriatecourse. Most patients require therapy, but there are pa-

*Correspondence to: Dr. Richard Hengel, Department of Medicine,3800 Resevoir Rd., Washington, DC 20007.

E-mail: rhengel@niaid.nih.govReceived 1 November 1999; Accepted 1 December 1999

Cytometry (Communications in Clinical Cytometry) 42:79–80 (2000)

© 2000 Wiley-Liss, Inc.

tients with very slow disease progression in whom therisks and inconvenience of treatment, at least in the shortterm, outweigh any possible benefits. For the majorityrequiring treatment, dynamic responses of HIV PCR andCD4 T cells to therapy distinguish responders from non-responders. Such distinctions are made based on the pres-ence or absence respectively of decreases in HIV PCR andincreases in CD4 T cell count. Non-response, or transientresponse, may frequently be due to adherence issues,judging from the differences between reported clinicaltrial data and real-world experience.

Not infrequently however, patients may have a goodresponse to one test but poor response to the other. These“off-quadrant” scenarios are troubling and controversial(5,6). Declining HIV RNA but a flat CD4 T cell responsemay represent immune exhaustion or be a harbinger oftreatment failure. Such a patient might benefit from adju-vant immunomodulatory therapy, such as IL-2 treatment(assuming IL-2 proves beneficial in current phase III clin-ical trials). Recrudescent HIV PCR with durable increasesin CD4 T cell count might represent a happier state ofaffairs if differences in pathogenesis exist between wildtype HIV and drug-resistant mutants. In this case, thedisconnection between HIV RNA and CD4 might suggestless compulsive pursuit of HIV RNA suppression. Giventhe emotional roller-coaster ride of “success” and “failure”for patients, proof of this controversial hypothesis is im-perative. Measurement of immune activation might sortout such problems, but the current candidate, CD38 ex-pression on CD8 T cells, needs further standardization andvalidation.

Until there is a cure for HIV disease it is unavoidablethat HIV care will continue to become more complex, notless. With the advent of HIV PCR the time of a singlelaboratory test to monitor the course of HIV infection isover. Whereas b-2 microglobulin or neopterin offered nocompelling advantage over CD4 T cell enumeration inmeasuring immune deterioration, HIV PCR analysis opens

a whole new dimension on HIV disease by quantifying theforce driving immune deterioration. But it is important toremember that viral RNA measurements do not replace orsupplant CD4 T cell counts, as published guidelines makeclear. To do so would merely substitute Yang for Yin,once again leaving us with a less complete picture of HIVdisease. If anything, tests giving a greater understanding ofHIV pathogenesis are on the horizon, such as measure-ments of immune activation, intra-cellular cytokine pro-duction or viral drug resistance tests.

Ten years ago, few would have predicted the successseen in HIV care during the latter half of the decade. Ahappy confluence of advances and technologies bestoweddramatic improvements for treated patients living withHIV. Of course, we await a preventative vaccine, espe-cially in the developing world where costs presumablypreclude drug treatment strategies. Meanwhile, physi-cians and patients with access to recent advances willhave to accommodate increasing levels of sophisticationin clinical management as parallel advances in drugs andtechnology become available.

LITERATURE CITED1. Palella FJ Jr, et al. Declining morbidity and mortality among patients

with advanced human immunodeficiency virus infection. HIV Outpa-tient Study Investigators. N Engl J Med 1998;338:853–860.

2. Mellors JW, et al. Plasma viral load and CD41 lymphocytes as prog-nostic markers of HIV-1 infection. Ann Intern Med 1997;126:946–954.

3. Department of Health and Human Services and Henry J. Kaiser FamilyFoundation. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR, 47(No. RR-5):1–91 1998.(updated at http://www.hivatis.org).

4. CDC. 1997 USPHS/IDSA Guidelines for the prevention of opportunisticinfections in persons infected with human immunodeficiency virus.MMWR 1999;48:1–59.

5. Kaufmann D, et al. CD4-cell count in HIV-1-infected individuals remain-ing viraemic with highly active antiretroviral therapy (HAART). SwissHIV Cohort Study. Lancet 1998;351:723–724.

6. Deeks SG, Barbour JM, Swanson M, Hecht FM, Grant RM. Responseafter virologic failure of protease inhibitor based regimens: correlationbetween CD4 and viral load response after two years of therapy. SixthConference on Retroviruses and Opportunistic Infections. 1999. Chi-cago, IL. [abstract #494].

80 PERSPECTIVES