AIDS, T cells, chemotherapy: HAART-breaking?

Chemotherapy depletes T cells in AIDS patients on HAART, but preexisting lymphopenia limits the scale compared with non-AIDS patients. Thus T-cell recovery time to baseline may be rapid, but the risk of additional AIDS-related complications persists.

Treatment advances for AIDS-related lymphoma (ARL) have largely been predicated on highly active antiretroviral therapy (HAART).¹  Before HAART, the combined immune injury of AIDS and chemotherapy made effective cancer treatment unfeasible. Chemotherapy is now more well-tolerated secondary to immune preservation with HAART. Conventional wisdom stresses that successful administration of anticancer therapy is dependent on concomitant HAART. This inference is challenged by data indicating favorable outcomes in patients who stopped HAART until completion of cancer therapy.²  A study of 105 ARL patients reported by Bower and colleagues in this issue of Blood does not resolve this debate, but the authors do detail virological and immunological changes seen in a subset of 68 patients treated concomitantly with HAART and chemotherapy who survived 3 months or longer.

Importantly, the fact that analysis of lymphoid recovery was restricted to survivors favors selection of subjects with a higher number of CD4⁺ cells. However, this selection bias is justified because it reduces spurious results that may occur when subjects with low numbers of CD4⁺ cells die disproportionately early in the study timeline, shifting the mature dataset to represent the remaining subjects—mainly those with higher numbers of CD4⁺ cells. In such a scenario, the appearance of later CD4⁺ cell increases could be unrelated to any actual changes in individual patient counts. The analysis by Bower and colleagues likely has avoided this confounding element. Consequently, the data they present inform important concepts regarding AIDS, T cells, and chemotherapy.

To better appreciate the issue at hand, recall that lymphocytoxic chemotherapy is a more potent T-cell destroyer than is HIV by several orders of magnitude. HIV-seronegative adults typically lose approximately 600 cells/mL within 2 treatment cycles, reaching a nadir at 150 to 600 cells.³  Recovery from this degree of depletion usually takes well over 12 months. Importantly, most patients with ARL have far fewer than 600 CD4⁺ cells/mL at the time of lymphoma diagnosis—a consequence of years, not weeks, of ongoing HIV replication. In this study, the survivors' median baseline CD4⁺cell count was 178 cells/mL, and ranged from 8 cells/mL to 636 cells/mL. Thus, when starting with a damaged immune system, even minor additional CD4⁺ cell loss can be life-threatening. Conversely, small, rapid CD4⁺ cell increases can substantially reduce morbidity. As with febrile neutropenia, opportunistic illness (OI) risk is, in part, dependent on the depth and duration of T-cell depletion. The study survivors had a median CD4⁺ cell loss during chemotherapy of 51 cells/mL, which they recovered within 3 months after treatment. An increase of 50 CD4⁺ cells is an important event in AIDS therapy. The more rapidly the CD4⁺ cells increase above specific risk-stratified levels, the less likely it is that a given OI will develop.

Because HAART can rescue some patients quickly from chemotherapy-induced T-cell nadirs, these data support the choice of ARL therapeutics being based on effectiveness against the specific ARL tumor subtype. Concern for immune injury should not unduly dissuade this approach. However, the work by Bower and colleagues also confirms that chemotherapy-induced CD4⁺ cell depletion occurs even with concomitant HAART. Furthermore, complete immunologic health remains elusive: in this study, there were 15 late OIs (including 2 AIDS-related and 5 non–AIDS-associated cancers). Although supporting concomitant HAART and chemotherapy, the real message here relates to posttreatment CD4⁺ cell recovery. As for the 35% of patients who did not survive the 3-month mark, the role of concomitant HAART is indeterminate. An important caveat to remember is that HAART is not one regimen, but rather a strategy combining multiple anti-HIV drugs in various cocktails, each with distinct pharmacologic properties. The real heartbreaker nowadays is lymphoma treatment failure and the lost opportunity to manage chronic HIV.