Document 0193
 DOCN  M9590193
 TI    Combination antiretroviral chemotherapy: an interim analysis.
 DT    9509
 AU    Schooley RT; University of Colorado, Denver, USA.
 SO    Annu Conf Australas Soc HIV Med. 1994 Nov 3-6;6:82 (unnumbered
       abstract). Unique Identifier : AIDSLINE ASHM6/95291906
 AB    Monotherapy with nucleoside analog reverse transcriptase inhibitors is
       associated with suppression of viral replication, an increase in CD4
       cell counts, and, in most studies, a decrease in HIV-1 related morbidity
       and/or mortality. It is clear, however, that these benefits are limited
       in magnitude and duration. Several factors have been posited to
       contribute to this incomplete response to antiretroviral chemotherapy.
       These include the incomplete control of viral replication, the emergence
       of viral species with reduced susceptibility to antiviral agents, and,
       perhaps, differential effects of antiviral agents on virus sequestered
       in certain cell types or anatomic locations. Several novel approaches
       are currently under development in an effort to address each of these
       problems. While these investigations are under way, combination therapy
       with currently available agents has received increasing attention as a
       possible approach to the limitations associated with monotherapy. In
       vitro studies have demonstrated that combinations of nucleoside analogs,
       NNRTIs, protease inhibitors, and interferons result in a more pronounced
       and sustained suppression of viral replication in most systems
       investigated to date. Clinical trials with combinations of these agents
       have been under way for the past four years. The completed studies have
       generally been pilot studies in which safety and surrogate endpoints
       have been the primary focus. These studies have, in general,
       demonstrated that combination nucleoside analog therapy is associated
       with more pronounced antiviral and immunologic effects with little
       additional toxicity. Maximal benefits are, in general, observed when
       combinations are chosen that emphasize agents with which treated
       individuals have not had extensive prior experience. In the studies
       completed to date, combination therapy has not yet, however, been
       demonstrated to result in decreases in HIV-1 related morbidity and/or
       mortality. This presentation will focus on the results of two recently
       completed combination therapy trials. In the first of these trials the
       emphasis involved the initial use of combination therapy in individuals
       with advanced immunologic status. This study (BW-34, 225) demonstrated
       that the initial use of ddI or ddC in combination with zidovudine
       resulted in a substantially greater and more prolonged rise in CD4 cells
       than in the group receiving zidovudine monotherapy. This effect appeared
       to be associated with a more pronounced antiviral effect, rather than a
       suppression of the onset of resistance to antiviral agents. The second
       trial (ACTG 229) is the largest completed combination therapy trial in
       which HIV-1 protease inhibitors have been utilized. This trial compared
       zidovudine + ddC, ddC + sequinavir, and the combination of zidovudine +
       ddC + sequinavir. Recipients of the triple combination tolerated the
       combination well, and demonstrated more significant suppression of viral
       replication, and a larger, more sustained rise in CD4 cells. The area of
       combination therapy will remain under intense investigation for the next
       several years. The most critical questions to be addressed include the
       need to establish whether more pronounced antiviral activity can be
       demonstrated to result in a reduction in HIV-1 associated morbidity and
       mortality. If this can be established, the development of combination
       regimens should be relatively straightforward following a paradigm that
       has been in use in the area of antihypertensive therapy for the past
       several decades.
 DE    Antiviral Agents/*THERAPEUTIC USE  Clinical Trials  CD4 Lymphocyte
       Count/DRUG EFFECTS  Didanosine/THERAPEUTIC USE  Drug Therapy,
       Combination  Human  HIV Infections/*DRUG THERAPY/IMMUNOLOGY/MORTALITY
       HIV-1/*DRUG EFFECTS/IMMUNOLOGY  Survival Rate  Zalcitabine/THERAPEUTIC
       USE  Zidovudine/THERAPEUTIC USE  MEETING ABSTRACT

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