Purpose: This is a randomized trial of combination antiretroviral therapy alone or in combination with thymus transplantation. The primary purposes of this trial are to assess the safety and tolerance of these interventions, their relative effects on HIV dynamics in peripheral blood and lymphoid tissue, and their relative effects on immune reconstitution as measured by absolute CD4 lymphocyte number. Background and Significance: Current efforts to treat HIV-infected patients utilize antiretroviral agents which inhibit reverse transcription or the HIV protease-catalyzed cleavage of large precursor proteins. The use of these agents alone or in combination has succeeded in suppressing virus replication and produced a small rise in absolute CD4 lymphocytes accompanied by clinical impact on the natural history of HIV disease. Published data thus far have shown the activity and clinical benefit of these agents to be transient and relatively modest. It appears that the impact of treatment is limited in part by the development of antiretroviral resistance and the impaired regenerative capacity of the immune system in HIV-infected hosts. Critical to the pathogenesis of antiretroviral resistance and this impaired regenerative capacity is the widespread dissemination of HIV to lymphoid tissue early in the course of infection, an event which creates a large reservoir of virus, which may foster the emergence of resistant isolates and damage the potential for immunologic recovery. Recent observations on the kinetics of HIV disappearance from the plasma and the increases in absolute CD4 lymphocytes of patients receiving antiretroviral therapy suggest a dynamic state of continuing virus production (109 viral particles per day), viral turnover (viral half life in plasma of 2 days), and CD4 lymphocyte production and destruction (109 CD4 lymphocytes produced and destroyed each day). The existence of this large dynamic reservoir presents a formidable obstacle to effective antiretroviral therapy. Within this protocol we propose to assess the interventions of aggressive antiretroviral therapy and thymus transplantation to reduce HIV burden and facilitate immunologic reconstitution in HIV-infected subjects. Methods: Sixteen study subjects will be HIV seropositive adults with absolute CD4 lymphocytes between 200 and 500/mm3 and no history of CDC- defined B or C clinical conditions. Prior antiretroviral therapy must involve monotherapy only, totaling less than 6 months, and no prior lamivudine or protease inhibitor use is allowed. Half the patients will be randomized to receive transplanted thymus tissue. All study subjects will receive standardized antiretroviral treatment consisting of ritonavir 600mg po BID, zidovudine 200mg po TID and lamivudine 150mg po BID for the duration of the study. Because of the potential for intolerance with the simultaneous initiation of all three agents, the drugs will be started at half doses initially with gradual increase to full doses over a period of two weeks.
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