Date: Mon, 6 Jan 1992 14:21:49 -0500 (EST)
From: SEOVE@MARS.LERC.NASA.gov (ERIC OVERTON)
Message-Id: <920106142149.20401eb3@MARS.LERC.NASA.GOV>
Subject: AZT
To: drum@concert.net

                 ACTG 106: AZT/ddC Combination Shows Benefits
                    for Patients with Advanced HIV Disease
                             
             National Institute of Allergy and Infectious Diseases
 
                                  U P D A T E
                          Tuesday, December 31, 1991
                                 Greg Folkers
                                (301) 496-5717
 
      Combination therapy with zidovudine (AZT) and the experimental drug  ddC 
is well-tolerated and appears to increase the number of certain crucial immune 
system cells in persons with advanced HIV disease,  according to a pilot study 
of 56 patients supported by the National Institute of Allergy  and  Infectious 
Diseases.  
      However, Anthony S.  Fauci, M.D., Director of NIAID, cautioned, "This is 
a pilot study that awaits confirmation in a  larger  group  of  patients.  The 
data  presented  are  too  preliminary  to  make  a final conclusion about the 
toxicities of the two drugs,  or to recommend treatment  using  a  combination 
regimen of ddC and AZT." 
      The research report and an accompanying editorial by Dr. Fauci appear in 
the January 1, 1992 edition of the Annals of Internal Medicine.  
      Based  on the data from this study,  a much larger NIAID-supported trial 
(ACTG 155)  with  more  than  1000  patients  is  now  under  way  to  compare 
combination therapy (ddC and AZT) with monotherapy with either drug alone.  
      "Data  from  ACTG  155  should provide a clear answer to the question of 
whether and AZT/ddC combination is superior  to  single  drug  therapy,"  said 
Daniel F. Hoth, M.D., Director of the Division of AIDS at NIAID.  
      The  current study,  known as ACTG 106,  was carried out at two sites of 
the AIDS Clinical  Trials  Group,  a  network  of  clinical  research  centers 
supported  by  NIAID.  Volunteers  enrolled  in the study at the University of 
Miami and the University of California,  San Diego,  between July 1989 and May 
1990.  
      The  investigators report that combinations of AZT and ddC increased the 
count of CD4+ lymphocytes--white blood cells crucial to the immune  response--
to  higher  levels  for a longer period of time than has previously been shown 
with either drug taken alone by persons with advanced HIV disease.  
      Combination therapy also decreased the levels of  p24  antigen,  an  HIV 
protein,  suggesting  the  suppression of HIV replication.  In addition,  side 
effects of the combinations were no  more  severe,  in  this  small  group  of 
patients, that those of the two drugs taken alone.  
      Although ACTG 106 was not specifically designed to determine the optimal 
dose  of  AZT,  the  researchers  found  that  a  low  daily  dose of AZT--150 
milligrams--was less effective that the currently recommended dose of AZT, and 
was no less toxic.  

      "This observation suggests that doctors should not use the loser dose of 
AZT either alone or in combination with other agents,  except in cases of AZT-
related toxicity," Dr. Fauci said. "The currently recommended dose of AZT, 500 
to  600  milligrams  daily,  remains the first-line antiretroviral therapy for 
patients with advanced HIV disease." 
      For HIV-infected patients who cannot tolerate or do not respond to  AZT, 
the  recently approved drug didanosin (ddI) is a reasonable course of therapy, 
Dr. Fauci writes in his editorial.  
      Upon enrollment, the study subjects in ACTG 106 all had AIDS or advanced 
AIDS-related complex and CD4+ lymphocyte counts of 200 cells/mm3 or less; none 
of them had previously been treated with an antiretroviral drug.  All  of  the 
patients  received  inhaled  pentamidine  for  the  prevention of Pneumocystis 
carinii pneumonia (PCP).  
      The patients were divided into six groups.  One group received  the  low 
(150 mg.) daily dose of AZT; the other five groups received various dosages of 
AZT  (150-600  mg./day) in conjunction with one of two doses of ddC (0.015 mg. 
or 0.030 mg. per kilogram of body weight/day).  
      The mean number of CD4+ lymphocytes  increased  with  all  regimens  and 
increases  were  sustained  beyond  one  year  with  three  of the combination 
regimens.  The levels of p24 antigen decreased with five of the  six  regimens 
by week two and this decrease persisted throughout the study.  With the lowest 
dose  combination  regimen,  the suppression of p24 levels was not noted until 
week eight.  
      In test tube studies, AZT and ddC together have been shown to complement 
each  other's  antiviral  activity.   In  the  current  study,  "The  apparent 
increased  benefit  with combination therapy may be related to the additive or 
synergistic activity of the two drugs that has been seen previously in vitro," 
said study collaborator Margaret A.  Fischl, M.D.,  of the University of Miami 
School of Medicine.  "Also, the emergence of drug-resistant strains of HIV may 
have been diminished by the use of AZT and ddC together." 
      DdC,  like AZT,  inhibits an HIV enzyme  called  reverse  transcriptase, 
which allows the virus to transcribe RNA and DNA.  
      However, the two drugs have different side effects, which holds out hope 
the  two  might be effective together because their toxicities do not overlap.  
 
The most common side effect of ddC is sensory peripheral neuropathy,  a  nerve 
degeneration  that results in pain in the feet and toes.  AZT can cause severe 
anemia and a reduction in certain white blood cells in patients with  advanced 
disease.  
      In the study, 14 patients had 16 episodes of serious adverse experiences 
that may have been attributable to study medication.  No differences among the 
various regimens were noted in the frequency of adverse experiences.  
      Collaborators  on  ACTG 106 included Tze-Chiang Meng,  M.D.,  Stephen A. 
Spector,  M.D.,  Brian Wright,  and Douglas D.  Richman,  M.D.,  University of 
California,  San Diego;  Margaret A.  Fischl, M.D., Ahmad M.  Boota, M.D., and 
Shenghan Lai, Ph.D.,  University of Miami School of Medicine;  Donald Bennett, 