From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: AZT and Quality of Life
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6295
Organization: unspecified
Date: Thu, 8 Oct 92 09:53:48 PDT

Info from follow-up of ACTG 016 and ACTG 019, the so-called "gold 
standards" for AZT usage.

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Gelber RD; Lenderking WR; Cotton DJ; Cole BF; Fischl MA; Goldhirsch A; 
Testa MA. 

Quality-of-life evaluation in a clinical trial of zidovudine therapy in 
patients with mildly symptomatic HIV infection. The AIDS Clinical Trials 
Group. 

Annals of Internal Medicine, 1992 Jun 15, 116(12 Pt 1):961-6. 

ABSTRACT:                                                              

OBJECTIVE: To evaluate the effects of zidovudine therapy in patients 
with mildly symptomatic HIV infection using Q-TWiST (quality-adjusted: 
Time Without Symptoms and Toxicity). 

DESIGN: Analysis of a previously reported multicenter, randomized, 
placebo-controlled clinical trial. 

SETTING: Thirty-two AIDS Clinical Trial units. 

PATIENTS: A total of 351 patients with mildly symptomatic HIV infection 
were assigned to placebo, and 360 patients were assigned to zidovudine, 
1200 mg/d. 

MEASUREMENTS: A modified Q-TWiST method for comparing treatments based 
on time spent without severe symptomatic adverse events and without 
disease progression. Zidovudine and placebo were compared in a threshold 
utility analysis considering reduction in quality of life associated 
with adverse events and disease progression. Adverse events defined by 
laboratory findings were distinguished from findings representing 
symptomatic events. 

RESULTS: The incidence of severe symptomatic adverse events was 22.8% 
for the zidovudine group and 15.1% for the placebo group (P = 0.01), 
but, as previously reported, zidovudine improved progression-free 
survival relative to placebo (at 18 months, 91% compared with 81%; P = 
0.001). In an 18-month period, patients receiving zidovudine went an 
average of 14.5 months without disease progression or a event compared 
with 14.7 months for placebo. The zidovudine group gained 0.9 months 
without disease progression but lost 1.1 months due to adverse events. 
Within the 18-month observation period, treatment provided more Q-TWiST 
than placebo if the quality of life after HIV disease progression was 
assumed to be 10% to 20% worse than the quality of life after a severe 
symptomatic adverse event. 

CONCLUSIONS: The Q-TWiST analysis projects that quality-of-life 
reductions due to severe symptomatic adverse events might be balanced by 
the quality-of-life benefits of delayed HIV disease progression for 
patients who received zidovudine for mildly symptomatic HIV infection. 
At currently recommended doses (500 to 600 mg/d, half the dose used in 
this study) zidovudine therapy is likely to yield a more favorable 
result. 

Page 961:

"Infection with human immunodeficiency virus type 1 (HIV) results in a 
progressive deterioration in immune function , subsequent disease 
manifestations, and ultimately death. Controlled clinical trials of 
treatments for HIV infection have focused primarily on delaying disease 
progression to the acquired immunodeficiency syndrome (AIDS) or AIDS-
related complex. Two completed studies, one evaluating zidovudine, 1200 
mg/d in patients with mildly symptomatic HIV infection (AIDS Clinical 
Trials Group [ACTG] 016) and the other evaluating zidovudine, 500 or 
1500 mg daily, in patients with asymptomatic HIV infection (ACTG 019), 
demonstrated that zidovudine significantly delayed the time to advanced 
AIDS-related complex, AIDS, or death, whichever occurred first. Based on 
this evidence, these double-blind studies were terminated, and all 
patients were offered zidovudine therapy. The studies were not designed 
to demonstrate treatment effects on overall survival and focused solely 
on the prevention of disease progression and the evaluation of 
toxicities association with therapy."

Page 963:

"A total of patients who experienced severe or worse adverse events of 
various types is shown according to treatment group in Table 2. A total
of 127 patients (35.3%) in the zidovudine group and 86 patients (24.5%) 
in the placebo group had at least one adverse event. The incidents of 
adverse events was greater in the zidovudine group than in the placebo 
group with respect to both laboratory abnormalities (18.8% compared with 
11.1%) and symptomatic events (22.8% compared with 15.1%)."

"The Q-TWiSt analysis indicated that within the first 18 months of 
study, the average time spent after an adverse event before the 
occurrence of disease progression was 3.1 months in the zidovudine 
group, 1.1 months more than that of the placebo group. In contrast, 
within 18 months after randomization, the average duration after disease 
progression was 0.3 months in the zidovudine group, 1.0 months less than 
that of the placebo group. Thus, zidovudine recipients spent more time 
after adverse events before the occurrence of disease progression but 
less time after disease progression than placebo recipients.

Table 2. Patients Experiencing Severe (Grade 3) or Worse Adverse Events.

------------------------------------------------------------------------

VARIABLE                                     ZIDOVUDINE       PLACEBO   

                                                GROUP           GROUP   

                                              (n =360)        (n = 351) 

                                             ---------------------------

                                                        n (%)           

------------------------------------------------------------------------

LABORATORY FINDINGS                                                     

 Hematologic abnormalities                    31 (8.6)         6 (1.7)  

 Hepatic abnormalities                        19 (5.3)        20 (5.7)  

 Metabolic abnormalities                      22 (6.1)        13 (3.7)  

SYMPTOMATIC EVENTS                                                      

 Gastrointestinal symptoms                    30 (8.3)        14 (4.0)  

 Malaise and fatigues                         24 (6.7)        10 (2.8)  

 Headache                                     14 (3.9)        13 (3.7)  

 Fever                                        12 (3.3)        11 (3.1)  

 Psychiatric problems                         13 (3.6)         9 (2.6)  

 Rheumatologic symptoms                       11 (3.0)        10 (2.8)  

 Constitutional symptoms                       6 (1.7)        11 (3.1)  

 Dermatologic symptoms                         8 (2.2)         4 (1.1)  

 Neurologic symptoms                           7 (1.9)         4 (1.1)  

 Respiratory symptoms                          7 (1.9)         1 (0.3)  

 Cardiac symptoms                              6 (1.7)         1 (0.3)  

 Visual symptoms                               4 (1.1)         3 (0.8)  

 Otorhinolaryngologic symptoms                 2 (0.5)         2 (0.5)  

 Gynecologic symptoms                          1 (0.3)         1 (0.3)  

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