In-depth studies of immune function in people with moderately advanced HIV disease who were treated for three months with an antiretroviral drug cocktail show that immunity can be partially restored, according to preliminary results from AIDS Clinical Trials Group (ACTG) 315, supported by the National Institute of Allergy and Infectious Diseases (NIAID). The drug combination being tested consists of zidovudine (AZT), lamivudine (3TC) and the protease inhibitor ritonavir.
Protocol chair Michael M. Lederman, M.D., plans to discuss these interim results in a late-breaker session at the Fourth Conference on Retroviruses and Opportunistic Infections in Washington, D.C., on Sunday, January 26 at 9:30 a.m. Dr. Lederman is director of the AIDS Clinical Trials Unit (ACTU) at University Hospitals of Cleveland and Case Western Reserve University.
Recent studies indicate that people who respond to highly active antiretroviral therapy (HAART) -- drug combinations that include protease inhibitors -- can experience decreased plasma levels of HIV, increased circulating CD4+ T cell counts, decreased risk of opportunistic infections and decreased short-term mortality.
However, ACTG 315 is the first study to probe the immunologic consequences of such therapy. This became possible last spring after the recompetition for ACTG funding included an award to establish the ACTG Immunology Advanced Technology Laboratories. This network of 16 immunology laboratories has since set up standardized immunologic assays and now serves the ACTUs that comprise the ACTG. "ACTG 315 is the first field-test of this new scientific capability within the ACTG," comments NIAID's Lawrence Fox, M.D., Ph.D., medical officer in the Division of AIDS HIV Medical Research Branch.
The significance of this study," says Dr. Lederman, "is that it will give us real clues to how the immune response recovers after therapy."
ACTG 315 enrolled 53 men and women with CD4+ T-cell counts between 100 and 300 cells per cubic millimeter (mm3) of blood. To be eligible for the trial, they previously must have tolerated at least three consecutive months of AZT therapy but never have received 3TC or a protease inhibitor. ACTG 315 enrolled 53 men and women with CD4+ T-cell counts between 100 and 300 cells per cubic millimeter (mm3) of blood. To be eligible for the trial, they previously must have tolerated at least three consecutive months of AZT therapy but never have received 3TC or a protease inhibitor.
After a 35-day washout period during which they took no antivirals, the study participants began taking ritonavir (Abbott Laboratories) alone, gradually escalating the dose to 600 mg twice a day. Ten days after starting ritonavir, they added three daily doses of 200 mg AZT (Glaxo Wellcome) and twice-daily doses of 150 mg 3TC (Glaxo Wellcome) to the regimen, and will remain on this treatment for 48 weeks. Dr. Lederman presented the analysis of data from 33 patients after 12 weeks of treatment.
The data show that the dramatic rise in CD4 counts and fall in plasma levels of virus seen early after starting HAART are accompanied by partial restoration of the immune response. It remains to be seen after further treatment, says Dr. Lederman, if prolonged virus suppression results in greater restoration of immune function.
ACTG 315 indicates the value of initiating potent antiretroviral therapy early before significant loss of immune function has occurred," Dr. Lederman concludes. "Our findings also suggest that physicians should be cautious about backing off from OI prophylaxis once it is indicated, despite early increases in CD4 counts."
In the three-month analysis, Dr. Lederman's group found that the increase in CD4+ T cells could be attributed to both more memory cells (those that have encountered HIV before) and more naive cells (those not exposed to HIV or another antigen before), while naive cells are primarily responsible for the rise in CD8+ T cells. Meanwhile, the percentage of activated CD4 and CD8 T cells fell, and average plasma levels of TNF- (tumor necrosis factor alpha, a protein that is usually very high in people with HIV) dropped, as the median plasma HIV RNA burden fell by more than 700-fold.
The investigators also analyzed the repertoire of T-cells according to a variable region on its receptor, V, which can exist in 24 different varieties in humans. Patients with dramatic but restricted patterns of V expansion experience more rapid progression of HIV disease than other patients. In ACTG 315, V repertoires were highly perturbed at baseline and remained so at 12 weeks. Functional immune response, as measured by delayed-type hypersensitivity (a skin test used to assess cellular immune function) and lymphocyte proliferation assays (to assess immune memory), was only partially restored.
The team is still evaluating the virologic effects of HAART on lymphoid tissue. Follow-up studies also will examine immunologic function after longer term HAART, and after changes in therapy for participants who fail to respond. Data are being analyzed to ascertain the mechanism underlying restoration of circulating T cells in patients receiving HAART.
"ACTG 315 is the first of a series of studies developed by the new ACTG Immunology/Immune-Based Therapies Research Agenda Committee," comments Dr. Fox, "that takes full advantage of the capabilities of the Immunology Advanced Technology Laboratories. This resource will greatly expand our understanding of HIV immunopathogenesis, opening up exciting horizons for understanding what happens in the course of disease itself in terms of response to therapy."
Other related ACTG studies include ACTG 328, which is evaluating interleukin-2 plus HAART directed at restoring the immune response, and ACTG 334, cyclosporin plus antiviral therapies, aimed at blocking the immune activation that may potentiate viral replication.
NIAID, a component of the National Institutes of Health, conducts and supports research aimed at preventing, diagnosing and treating illnesses such as AIDS and other sexually transmitted disease, tuberculosis, asthma and allergies.
NIH is an agency of the U.S Department of Health and Human Services.
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