Document 0956
 DOCN  M9650956
 TI    Failure of antiretroviral therapy: role of viral and cellular factors.
 DT    9505
 AU    Cinatl J Jr; Cinatl J; Rabenau H; Doerr HW; Weber B; Institut fur
       Medizinische Virologie, Universitatskliniken; Frankfurt, Deutschland.
 SO    Intervirology. 1994;37(6):307-14. Unique Identifier : AIDSLINE
       MED/96022717
 AB    Effective therapy of human immunodeficiency virus (HIV) infection is
       mainly based on inhibition of reverse transcriptase by nucleoside
       analogues such as zidovudine (azidothymidine; AZT), didanosine, and
       zalcitabine. A major problem associated with long-term AZT therapy is
       the waning efficacy ('clinical resistance') over time. Clinical isolates
       of HIV-1 with reduced susceptibility to AZT can be recovered from
       HIV-infected individuals under prolonged treatment. However, the
       clinical importance of AZT resistance is uncertain. Other factors such
       as increased virus burden, increased virulence, and AZT toxicity could
       contribute, singly or in combination, to the loss of therapeutic
       benefit. Recent observations based on experimental models and clinical
       trials suggest that cellular mechanisms ('cellular resistance') may
       account for clinical resistance to antiviral agents. In vitro
       experiments demonstrated that in analogy to antitumoral therapy, the
       acquisition of multidrug resistance, i.e., resistance of cells to
       multiple, structurally unrelated chemotherapeutic agents, may play a
       role in the failure of long-term antiretroviral therapy. The 'cellular
       resistance' may contribute directly to the failure of antiviral therapy
       by the generation of subtherapeutic levels of antiviral compounds and/or
       their active forms. Indirectly, such subtherapeutic concentrations of
       active substances which permit limited replication of virus may
       represent a selective pressure for emergence and development of a
       resistant virus population. Hence it is of great importance to
       investigate the role of cellular factors in 'clinical resistance' to AZT
       and other anti-HIV agents. More detailed knowledge of cellular
       interactions and antiviral agents could help to improve or develop new
       strategies for antiviral therapy regimens.
 DE    Antiviral Agents/*THERAPEUTIC USE  Clinical Trials  Drug Resistance,
       Microbial  Drug Resistance, Multiple  Human  HIV Infections/*DRUG
       THERAPY/VIROLOGY  HIV-1/*DRUG EFFECTS/PATHOGENICITY  Reverse
       Transcriptase Inhibitors/*THERAPEUTIC USE  Treatment Failure  JOURNAL
       ARTICLE  REVIEW  REVIEW, TUTORIAL

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).