CD4 T CELL ASSESSMENTS IN EVALUATION OF HIV THERAPEUTICS - Flow Cytometry in Drug Discovery and Development - page 168

most common opportunistic infections, Pneumocystis carinii pneumonia, cytome-
galovirus, andMycobacteriumavium complex (MAC) [14]. They are also susceptible
to develop cancers such as Kaposi's sarcoma and lymphomas [15]. HIV-infected
patients with Kaposi's sarcoma are more likely to develop PCP within 24 months if
their CD4 counts are below 200 cells/mm 3 [14].

8.3 FIRST AZT CLINICAL TRIALS

After the discovery of the HIV virus, there was an urgent need to develop therapeutics
that would either eliminate the virus from the body or keep it from replicating. The
first viable candidate as an HIV therapeutic was zidovudine (AZT), a nucleoside
reverse transcriptase inhibitor (NRTI). AZT is a thymidine analogue that was initially
designed as an anticancer drug, but was found to inhibit the DNA polymerase enzyme
reverse transcriptase, required by HIV to replicate in the host system [16]. After initial
safety evaluations showed that AZT was well tolerated by patients, a double-blind,
placebo-controlled trial of the efficacy was conducted [16, 17]. The trial enrolled
282 patients with AIDS manifested by Pneumocystis carinii pneumonia and patients
with advanced AIDS-related complex, a term used to describe symptoms typically
experienced before the progression to AIDS. The criteria for response were based on
clinical end points such as survival, occurrence and frequency of opportunistic
infections, occurrence of AIDS-associated neoplasms, Karnofsky performance
status, body weight, and the number and severity of symptoms. Patients were
stratified into two groups based on absolute number of CD4 T cells, one group with
<

100 cells/mm 3 and the other group with 101-499 cells/mm 3 . Over the course of
24 weeks, 145 subjects received AZT, while 137 received a placebo. At the end
of 24 weeks, patients who received AZT had increased CD4 counts, while patients
who received the placebo had decreased counts. Patients with AIDS-related complex
who received AZT showed the largest increase in CD4 counts through the end of the
study. This group had median baseline levels of 190 cells/mm 3 that increased to
340 cells/mm 3 after 20 weeks. Patients with AIDS had CD4 counts that initially
increased, but then gradually decreased to below baseline levels after 20 weeks. This
group had baseline levels of 54 cells/mm 3 that initially increased to 133 cells/mm 3
after 4 weeks, but then declined to 49 cells/mm 3 at 20 weeks. This trial first
demonstrated the importance of using CD4 counts to measure the efficacy of
treatment during stage of disease. While clinical end points were the preferred
criteria for response, CD4 counts had vital prognostic value as biomarkers for disease
progression because a higher baseline count correlated with a higher increase in CD4
T cells and a decrease in frequency of opportunistic infections. Patients who were
clinically defined as having AIDS and who had a low baseline CD4 count did not see
the same immunological response from the drug.
After this single clinical trial that demonstrated its efficacy, AZTwas approved by
the FDA on March 19, 1987 with accelerated approval. This fast track approval
system was designed to push viable candidates quickly through FDA approval to
make them accessible to patients. AZT was approved while clinical trials continued