Use of Hematopoietic Hormones for Bone Marrow Defects in AIDS

Aboulafia provides an extensive review of the occurrence of and treatments for bone marrow disorders that complicate HIV infection and AIDS. Understanding of the pathogenesis of these disorders is increasing, and the availability of recombinant colony-stimulating factors (CSFs) has, in many ways, facilitated the treatment of HIV-1 infection and its complications. Nonetheless, numerous critical questions remain regarding the optimal use of these expensive and powerful reagents.

When Should CSF Therapy Be Inititated?

In patients with neutropenia, when should CSF administration be initiated? Recent data from a controlled trial of granulocyte CSF (G-CSF, filgrastim [Neupogen] in HIV-1-infected persons with absolute neutrophil counts (ANCs) from 750 to 1,000 cells/mL demonstrated a decreased incidence of bacterial infections among persons assigned to G-CSF.[1] In this trial, all persons were treated with G-CSF if their ANC fell below 500 cells/mL. These results notwithstanding, many clincians would be loathe to treat all patients with an ANC less than 1,000 cells/mLwith G-CSF.

Better predictors of the risk for bacterial infection are needed. In this regard, the results of an AIDS Clinical Trial Group trial (ACTG 815) indicate, not surprisingly, that both macrolide and trimethoprim-sulfamethoxazole prophylaxis decreases the risk of serious bacterial infections and that lower performance status is associated with a higher risk for such infections.[2] Surprisingly, persons under 40 years of age and women tended to be at greater risk. Perhaps for now, routine administration of G-CSF should be offered to persons with an ANC less than 500 cells/mL (a point below which the risk for serious bacterial infections increases dramatically[3]) and to those with an ANC less than 1,000 cells/mL and a history of recurrent bacterial infections.

Other Critical Questions

In patients who receive G-CSF therapy, if both the degree and duration of neutropenia predict the risk of infection, how high must the ANC climb to prevent morbidity and for how long must the ANC remain in “the safe range”? Could strategies that promote weekly and brief neutrophil increases provide clinical benefit with fewer injections and lower cost?

Tantalizing data suggest that granulocyte-macrophage CSF (GM-CSF, sargramostim [Leukine, Prokine]) administration may increase the antifungal and antimycobacterial activities of mononuclear phagocytes,[4,5] and a brief anecdotal report suggests that administration of GM-CSF may help clear mucosal infection with Candida species in persons with AIDS.[6]

Can GM-CSF enhancement of monocyte function compensate, in part, for the profound T-cell deficiency associated with advanced AIDS? Can monocyte activation decrease the risk of opportunistic infections in this population, and what is the effect of this strategy on the pro-inflammatory cytokine network and on HIV-1 RNA?

Although most patients experience a brisk neutrophil response to administration of GM-CSF or G-CSF, will patients who fail to respond to G-CSF respond to GM-CSF, and vice versa?

Anemia, Transfusion, and Prognosis in AIDS Patients

As Dr. Aboulafia reminds us, the anemia of AIDS may have many etiologies, although drug- and infection-related causes are most common. Interestingly, in several older studies, anemia appeared to be an independent predictor of mortality in persons with AIDS with or without Mycobacterium avium intracellulare infection.[7-9] Whether anemia was an indirect marker of severity of disease or was related to other predictors of poor outcome, such as plasma HIV-1 RNA levels, is not known. Yet, transfused patients with HIV-related anemia also tended to have a particularly poor prognosis.[10]

A greater transfusion requirement also may be reflective of more advanced disease. However, in vitro data suggest that allogeneic leukocytes contained within packed red blood cell units used for transfusion may activate HIV expression through a mixed lymphocyte reaction,[11] and a preliminary report indicates that transfusion of packed red blood cells to persons with HIV-1 infection is associated with small but significant rises in plasma HIV-1 RNA levels.[12]

Whether leukocyte reduction strategies will affect HIV-1 RNA levels or long-term outcome among transfused HIV-1 infected patients may be answered by the results of the National Heart, Lung and Blood Institute’s Viral Activation by Transfusion Study (VATS)[13] now ongoing in 11 US medical centers. Also needed and targeted by this study is an examination of the potential mechanisms whereby anemia and transfusion as a treatment for anemia may affect long-term outcome and risk for opportunistic infections in patients with advanced HIV-1 infection.

For now, limiting transfusions to HIV-infected persons with symptomatic anemia is prudent. Administration of recombinant human erythropoietin (rHuEPO [Epogen, Procrit]) may decrease transfusion requirements without affecting plasma HIV levels.[14] However, it is not clear that a target hematocrit level in the mid-30s is either necessary or justifiable. Rather, the hematocrit should be maintained at a level that is compatible with patient comfort.

References:

1. Kuritzkes D, Parenti D, Ward D, et al: Filgrastim (r-met-HuG-CSF) for prevention of severe neutropenia and associated clinical sequelae in HIV-infected patients: Results of a 24-week, prospective, randomized, controlled trial (abstract 365). Fourth Conference on Retroviruses and Opportunistic Infections, 1997.

2. Currier JS, Williams P, Feinberd J, et al: ACTG 815: A prospective study of bacterial infections in advanced HIV disease (abstract 364). Fourth Conference on Retroviruses and Opportunistic Infections, 1997.

3. Jacobson MA, Cohen PT, Liu RC,et al: Risk of hospitalization for serious bacterial infection (SBI) associated with neutrpoenia severity in patients with HIV. XI International Conference on AIDS, Vancouver, 1996.

4. Wang M, Friedman H, Djeu JY: Enhancement of human monocyte function against Candida albicans by the colony stimulating factors (CSF): IL-3, granulocyte macrophage CSF and macrophage CSF. J Immunol 143:671-677, 1989.

5. Bermudez LE, Young LS: Recombinant granulocyte-macrophage colony stimulating factor activates human macrophages to inhibit the growth or kill Mycobacterium avium complex. J Leukocyte Biol 48:67-73, 1990.

6. Bonfanti P, Capetti A, DeMicheli A,et al: HuGM-CSF employment for resistant candida infections in HIV disease. XI International Conference on AIDS,Vancouver, 1996.

7. Chaisson RE, Moore RD, Richman DD,et al: Incidence and natural history of Mycobacterium avium-complex: Infections in patients with advanced human immunodeficiency virus disease treated with zidovudine. Am Rev Resp Dis 146:285-289, 1992.

8. Sathe SS, Gascone P, Lo W,et al: Severe anemia is an important negative predictor for survival with disseminated Mycobacterium avium-intracelulare in acquired immunodeficiency syndrome. Am Rev Resp Dis 132:1306-1312, 1990.

9. Wenger JA, CC Whalen, MM Lederman, et al: Prognostic factors in patients with the acquired immunodeficiency syndrome. J Gen Int Med 3:464-470, 1988.

10. Vamvakas E, Kaplan HS: Early transfusion and length of survival in acquired immunodeficiency syndrome: Experience with a population receiving medical care at a public hospital. Transfusion 33:111-118, 1993.

11. Busch MP,Lee TH, Heitman J: Allogeneic leukocytes but not therapeutic blood elements induce reactivation and dissemination of latent human immunodeficiency virus type 1 infection: Implications for transfusion support of infected patients. Blood 80:2128-2135,1992.

12. Mudido P, Georges D, Dorazio D,et al: HIV-1 activation after transfusion Transfusion 36:860-865, 1996.

13. Busch MP, Collier A, Gernsheimer JD,et al: The Viral Activation Transfusion Study (VATS): Rationale, objectives, and design overview. Transfusion 36:854-859,1996.

14. Carey JT, Jackson B, Lederman MM,et al: The effect of r-hu erythropoietin on HIV p24 antigen expression in anemic zidovudine-treated AIDS patients (abstract SB 437). International Conference on AIDS, June 20-23, 1990.