Biomedical Engineering Reference
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In another trial that tested whether stage of disease affected CD4 counts, patients
were enrolled as late-stage participants with CD4 counts
200 cells/mm 3 and the
patients enrolled as early-stage participants had few symptoms and CD4 counts > 200
cells/mm 3 [20]. The study found that 89% of patients given AZT during the late stage
of the disease developed drug resistance, while 31% of patients given AZT during the
early stage of the disease developed drug resistance. This study found that a low CD4
count was predictive of increased probability of resistance. The findings that AZT had
a greater impact on patients with early-stage HIVinfection led the U.S. Department of
Health and Human Services to revise their guidelines regarding the initiation of
treatment with AZT [20].
The AZT trials first demonstrated the prognostic value of CD4 as a biomarker to
evaluate the efficacy of antiretroviral drugs based on the strong correlation between
CD4 T cell counts and disease staging [21-23]. These studies showed that CD4 clearly
has value as an indicator of immune dysfunction and disease progression in HIV-
infected patients. The recommendation that CD4 counts be used to monitor patients
with normal counts underlines CD4's significance in patient management as demon-
strated by the Center for Disease Control's 1993 Revised Classification System and
Expanded Surveillance Case Definition [13]. In 1997, the FDA changed approval
guidelines of antiretroviral drugs to use CD4 count and HIV-RNA levels in clinical
trials assessing the efficacy of new candidates [24, 25]. Prior to1997, traditional
approval relied on clinical end points in trials of ARV drugs as seen in the first AZT
trials. Studies continued to show that CD4 levels and plasma HIV-RNA levels
correlated with the onset of certain clinical conditions and, subsequently, an increase
inCD4 count and a decrease inviral load indicated that the risk for AIDS-related illness
and death declined. Based on these findings, the FDA's Division of Antiviral Drug
Products convened a meeting of the Antivirals Advisory Committee in July 1997. The
committee concluded that HIV-RNA is a suitable end point for both accelerated
approval and traditional approval and recommended that increases in CD4 counts must
also be consistent with changes in viral load. Based on the finding that CD4 was a
suitable surrogate marker, clinical end points were no longer necessary, but remained
an option. While studies have shown that CD4 counts are appropriate surrogate end
points in clinical trials, there is conflicting evidence that other factors may contribute to
the clinical benefit of the drug independent of the CD4 count [26].
Since 1992, there have been 32 different drugs developed to attack the HIV virus
utilizing a variety of different mechanisms, which have shown to enhance CD4 levels
and decrease HIV-RNA (Table 8.1). The classes of drugs are as follows:
<
. Multiclass combination products
. Nucleoside reverse transcriptase inhibitors
. Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
. Protease inhibitors (PIs)
. Fusion inhibitors
. Entry inhibitors - CCR5 coreceptor antagonist
. HIV integrase strand transfer inhibitors
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