The Arsenal Files 8/The Arsenal Files Collection #8 (Arsenal Computer) (1996).ISO/health/ain150.txt

Text File | 1996-12-01 | 18KB | 324 lines

                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     [phone] ext 3305
                        November 22, 1996

                Antiretroviral Therapy (Part III)

Editor's Note:  In Part II (8 November 1996) part of the
information following question number nine was lost during
transmission. The question with the corrected response should be:

9.  Okay! What drugs are available to me?

     The number of drugs available to people with HIV has increased
dramatically over the past year. Nine drugs are now FDA-approved
for the treatment of HIV, with several others in the pipeline. Five
of these nine belong to a class of drugs called nucleoside analogue
reverse transcriptase inhibitors, AZT, ddI, ddC, d4t, and 3TC.
Three others belong to a class of drugs called protease inhibitors,
saquinavir, ritonavir, indinavir; the most recently approved drug,
nevirapine, belongs to a third class called non-nucleoside reverse
transcriptase inhibitors (NNRTIs).

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

      Nucleoside Analogs - Reverse Transcriptase Inhibitors

           AZT (Zidovudine, Azidothymidine, Retrovir)
                      Approved March, 1987

                     Descriptive Information

1.   Wilde MI and Langtry HD. Zidovudine: An Update of its
     Pharmacodynamic and Pharmacokinetics Properties, and
     Therapeutic Efficacy. Drugs. 1993;46(3):515-578.

Abstract:
     Zidovudine remains the mainstay in the treatment of patients
infected with human immunodeficiency virus (HIV). The drug delays
disease progression to acquired immunodeficiency syndrome (AIDS)
and to AIDS-related complex (ARC), reduces opportunistic
infections, and increases survival in patients with advanced HIV
infection. There is evidence to suggest that zidovudine also delays
disease progression in patients with mild symptomatic disease.
Although one study has shown zidovudine to have no significant
beneficial effects on survival or disease progression in patients
with asymptomatic HIV infection, several other studies have shown
zidovudine to delay disease progression in this patient group.
Results from related ongoing studies are awaited with interest.
     Zidovudine reduces the incidence of AIDS dementia complex
(ADC) and appears to prolong survival in these patients, and
improves other neurological complications of HIV infection. The
drug also appears to enhance the efficacy of interferon-alpha in
patients with Kaposi's sarcoma. Although zidovudine is widely used
as postexposure prophylaxis following accidental exposure to HIV,
its efficacy in preventing seroconversion is unclear. Whether
zidovudine prevents vertical transmission also remains to be
determined. The overall efficacy of zidovudine in the treatment of
children with HIV infection appears similar to that in adults
despite more rapid disease progression in younger patients.
     Zidovudine-resistant isolates can emerge as early as after 2
months' therapy, and primary infection with zidovudine-resistant
strains has been documented. Both zidovudine resistance and the
syncytium-inducing HIV phenotype appear to be associated with poor
clinical outcome. However, zidovudine resistance may revert on drug
withdrawal or switching to an alternative therapy.
     Zidovudine-associated haematotoxicity may be dose-limiting.
Nonhaematological adverse events associated with zidovudine therapy
are generally mild and usually resolve spontaneously.
     Dosages of approximately 500 to 600 mg/day appear to be at
least as effective as dosages of 1200 to 1500 mg/day and are better
tolerated in patients with less advanced disease. However, optimal
dosage are unclear.
     Despite beneficial effects, zidovudine monotherapy is not
curative. There is evidence to suggest that the concomitant
administration of zidovudine with didanosine or zalcitabine is
effective in patients with HIV disease progression despite
receiving zidovudine monotherapy, and there is some evidence that
concomitant zidovudine plus didanosine therapy is more effective
than alternating monotherapy. However, results from studies of
combination therapy in asymptomatic patients, and from comparative
combination therapy studies are awaited. Cotherapy with agents that
augment haematopoiesis allows the continuation of therapeutic
zidovudine dosages.
     Therefore, at present, zidovudine remains the cornerstone in
the treatment of HIV infection. In the near future, however,
multiple agent zidovudine-containing combination therapy is likely
to be the optimal treatment strategy.


             Journal Articles - Historical Overview
                      (Chronological Order)

1.   Fischl MA et al. The Efficacy of Azidothymidine (AZT) in the
     Treatment of Patients with AIDS and AIDS-Related Complex: A
     Double-Blind, Placebo-Controlled Trial. NEJM. 1987;317(4):185-
     91.

Abstract:
     We conducted a double-blind, placebo-controlled trial of the
efficacy of oral azidothymidine (AZT) in 282 patients with the
acquired immunodeficiency syndrome (AIDS) manifested by
Pneumocystis carinii pneumonia alone, or with advanced AIDS-related
complex. The subjects were stratified according to numbers of T
cells with CD4 surface markers and were randomly assigned to
receive either 250 mg of AZT or placebo by mouth every four hours
for a total of 24 weeks. One hundred forty-five subjects received
AZT, and 137 received placebo. When the study was terminated, 27
subjects had completed 24 weeks of the study, 152 had completed 16
weeks, and the remainder had completed at least 8 weeks. Nineteen
placebo recipients and 1 AZT recipient died during the study (P
less than 0.001). Opportunistic infections developed in 45 subjects
receiving placebo, as compared with 24 receiving AZT. The base-line
Karnofsky performance score and weight increased significantly
among AZT recipients (P less than 0.001). A statistically
significant increase in the number of CD4 cells was noted in
subjects receiving AZT (P less than 0.001). After 12 weeks, the
number of CD4 cells declined to pretreatment values among AZT
recipients with AIDS but not amonG AZT recipients with AIDS-related
complex. Skin-test anergy was partially reversed in 29 percent of
subjects receiving AZT, as compared with 9 percent of those
receiving placebo (P less than 0.001). These data demonstrate that
AZT administration can decrease mortality and the frequency of
opportunistic infections in a selected group of subjects with AIDS
or AIDS-related complex, at least over the 8 to 24 weeks of
observation in this study.

2.   Fischl MA et al. The Safety and Efficacy of Zidovudine (AZT)
     in the Treatment of Subjects with Mildly Symptomatic Human
     Immunodeficiency Virus Type 1 (HIV) Infection: A Double-Blind,
     Placebo-Controlled Trial. The AIDS Clinical Trials Group.
     Annals of Internal Medicine. 1990;112:727-37.

Abstract:
     OBJECTIVE: To evaluate the efficacy and safety of zidovudine
early in the treatment of human immunodeficiency virus type 1 (HIV)
infection. DESIGN: A double-blind, randomized, placebo-controlled
trial with subject stratification by pretreatment CD4 T lymphocyte
counts. SETTING: Multicenter trial at AIDS Clinical Trial units.
SUBJECTS: Seven hundred eleven subjects with mildly symptomatic HIV
infection. INTERVENTION: Three hundred fifty-one subjects were
assigned to placebo and 360 to zidovudine, 200 mg orally every 4
hours. The median duration of follow-up was 11 months. MEASUREMENTS
AND MAIN RESULTS: Fifty-one subjects developed the acquired
immunodeficiency syndrome (AIDS), advanced AIDS-related complex,
or death as a first critical event. For the stratum of subjects
with more than 200 but less than 500 CD4 T lymphocytes/mm3 before
treatment, 34 events occurred in placebo recipients and 12 in
zidovudine recipients (P = 0.0002; relative risk [RR] estimate,
3.23 [95% CI, 1.67 to 6.24]). For the stratum of subjects with 500
to 799 CD4 T lymphocytes/mm3 before treatment, 2 events occurred
in placebo recipients and 3 in zidovudine recipients. Candidiasis
at study entry independently increased the risk for having an event
(P = 0.005; RR estimate, 2.3 [95% CI, 1.29 to 4.12]); HIV
antigenemia at study entry also increased this risk (P = 0.01; RR
estimate, 2.1 [95% CI, 1.2 to 3.8]). Significant differences
between the treatment groups in CD4 T-lymphocyte counts occurred
in subjects with more than 200 but less than 500 CD4 T
lymphocytes/mm3 after 4 weeks of therapy (P = 0.002). Differences
persisted through week 52. Less prominent changes occurred in
subjects with 500 or more CD4 T lymphocytes/mm3. Serum levels of
HIV antigen decreased significantly in zidovudine recipients.
Serious anemia and neutropenia occurred in 5% and 4% of zidovudine
recipients, respectively, and in 0% and 1% of placebo recipients,
respectively. CONCLUSION: Zidovudine delayed progression of HIV
disease and produced little toxicity in subjects with mildly
symptomatic HIV disease and less than 500 CD4 T lymphocytes/mm3.

3.   Volberding PA et al. Zidovudine in Asymptomatic Human
     Immunodeficiency Virus Infection: A Controlled Trial in
     Persons with Fewer than 500 CD4-Positive Cells per Cubic
     Millimeter. NEJM. 1990;;322(14):941-49.

Abstract:
     Zidovudine (AZT) is a potent inhibitor of the replication of
the human immunodeficiency virus (HIV), and it has been shown to
improve survival in advanced HIV disease. We conducted a
randomized, double-blind trial in adults with asymptomatic HIV
infection who had CD4+ cell counts of fewer than 500 per cubic
millimeter on entry into the study. The subjects (92 percent male)
were randomly assigned to one of three treatment groups: placebo
(428 subjects); zidovudine, 500 mg per day (453); or zidovudine,
1500 mg per day (457). After a mean follow-up of 55 weeks (range,
19 to 107), 33 of the subjects assigned to placebo had the acquired
immunodeficiency syndrome (AIDS), as compared with 11 of those
assigned to receive 500 mg of zidovudine (P = 0.002; relative risk,
2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those
assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk,
1.9; 95 percent confidence interval, 1.0 to 3.5). In the three
treatment groups, the rates of progression (per 100 person-years)
to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and
4.3, respectively. As compared with those assigned to placebo, the
subjects in the zidovudine groups had significant increases in the
number of CD4+ cells and significant declines in p24 antigen
levels. In the 1500-mg zidovudine group, severe hematologic
toxicity (anemia or neutropenia) was more frequent than in the
other groups (P less than 0.0001). In the 500-mg zidovudine group,
nausea was the only toxicity that was significantly more frequent
(in 3.3 percent) than in the placebo group (P = 0.001). We conclude
that zidovudine is safe and effective in persons with asymptomatic
HIV infection and fewer than 500 CD4+ cells per cubic millimeter.
Additional study will be required to determine whether such
treatment will ultimately improve survival for persons infected
with HIV.

4.   Collier AC et al. A Pilot Study of Low-Dose Zidovudine in
     Human Immunodeficiency Virus Infection. NEJM.
     1990;323(15):1015-21.

Abstract:
     BACKGROUND. Zidovudine delays the progression of human
immunodeficiency virus (HIV) infection but is associated with
hematologic toxicity at high doses. Regimens are needed that
preserve or enhance efficacy and reduce toxicity. Acyclovir has
been reported to potentiate the effect of zidovudine on HIV in
vitro. METHODS. We conducted a Phase II open-label, dose-escalating
trial to evaluate the clinical and antiviral effects of zidovudine
at low (300 mg daily, 28 subjects), medium (600 mg, 24 subjects),
and high (1500 mg, 15 subjects) doses, either with or without
acyclovir (4.8 g) by random assignment. The subjects had the
acquired immunodeficiency syndrome (AIDS)-related complex, but not
AIDS. All of them had either HIV p24 antigenemia or plasma viremia
and CD4-lymphocyte counts of 200 to 500 per cubic millimeter when
they began treatment. RESULTS. Performance scores and fatigue
improved the most in the low- and medium-dose zidovudine groups
(both P less than or equal to 0.025). Those assigned to low-dose
zidovudine gained the most weight and had the greatest improvement
in the mean CD4-lymphocyte count (from 321 per cubic millimeter at
base line to 412 per cubic millimeter after 12 weeks, P = 0.01).
The proportion of subjects in whom HIV antigenemia resolved, the
decrease in the level of antigenemia, and the reduction in the
plasma virus titers were similar at all three doses. Subjects
assigned to receive the low or medium dose who subsequently crossed
over to the 1500-mg dose (n = 19) did not have an increase in
CD4-cell counts or a decline in levels of HIV antigen, but they did
have dose-related toxicity. The addition of acyclovir to zidovudine
was well tolerated, but it did not enhance any of zidovudine's
antiretroviral effects. CONCLUSIONS. In this pilot study a very low
dose of zidovudine (300 mg) had clinical and virologic effects
similar to those of higher daily doses (600 and 1500 mg). The
minimal effective dose of zidovudine for the treatment of HIV
infection has yet to be determined, and further studies of very low
daily doses are warranted.

     5.   Fischl MA et al. A Randomized Controlled Trial of a
          Reduced Daily Dose of Zidovudine in Patients with the
          Acquired Immunodeficiency Syndrome. NEJM.
          1990;323(15):1009-14.

Abstract:
     BACKGROUND. The initially tested dose of zidovudine for the
treatment of patients with advanced disease caused by the human
immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose
is effective, it is associated with substantial toxicity. METHODS.
To evaluate the efficacy and safety of a reduced dose, we conducted
a randomized controlled trial in 524 subjects who had a first
episode of Pneumocystis carinii pneumonia. The subjects were
assigned to receive zidovudine in either a dose of 250 mg taken
orally every four hours (the standard-treatment group, n = 262) or
a dose of 200 mg taken orally every four hours for four weeks and
thereafter 100 mg taken every four hours (the low-dose group, n =
262). RESULTS. The median length of follow-up was 25.6 months. At
18 months the estimated survival rates were 52 percent for the
standard-treatment group and 63 percent for the low-dose group (P
= 0.012 by the log-rank test). At 24 months the estimated survival
rates were 27 percent for the standard-treatment group and 34
percent for the low-dose group (P = 0.033). In both groups, 82
percent of the subjects had another opportunistic infection, and
the length of time to that infection was similar in the two groups
(P = 0.56 by the log-rank test). CD4 T-lymphocyte counts improved
transiently in both groups, and serum levels of HIV antigen
decreased in the subjects with antigenemia. The hemoglobin level
declined to less than 5 mml per liter (80 g per liter) in 101
subjects in the standard-treatment group and in 77 in the low-dose
group (39 vs. 29 percent, P = 0.0009 by the log-rank test). The
neutrophil count declined to less than 0.750 x 10(9) per liter in
134 subjects in the standard-treatment group and in 96 in the
low-dose group (51 vs. 37 percent, P = 0.0001). CONCLUSIONS. The
reduced daily dose of zidovudine used in this study was at least
as effective as the standard dose and was less toxic; however, with
the use of a four-week induction period with a high dose followed
by low-dose treatment, severe anemia and neutropenia were common
complications of treatment with zidovudine.

     6.   Hamilton JD et al. A Controlled Trial of Early Versus
          Late Treatment with Zidovudine in Symptomatic Human
          Immunodeficiency Virus Infection. NEJM. 1992;326(7):437-
          43.

Abstract:
     BACKGROUND. Zidovudine is recommended for asymptomatic and
early symptomatic human immunodeficiency virus (HIV) infection. The
best time to initiate zidovudine treatment remains uncertain,
however, and whether early treatment improves survival has not been
established. METHODS. We conducted a multicenter, randomized,
double-blind trial that compared early zidovudine therapy
(beginning at 1500 mg per day) with late therapy in HIV-infected
patients who were symptomatic and had CD4+ counts between 0.2 x
10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic
millimeter) at entry. Those assigned to late therapy initially
received placebo and began zidovudine when their CD4+ counts fell
below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the
acquired immunodeficiency syndrome (AIDS) developed. RESULTS.
During a mean follow-up period of more than two years, there were
23 deaths in the early-therapy group (n = 170) and 20 deaths in the
late-therapy group (n = 168) (P = 0.48; relative risk [late vs.
early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the
early-therapy group, 28 patients progressed to AIDS, as compared
with 48 in the late-therapy group (P = 0.02; relative risk, 1.76;
95 percent confidence interval, 1.1 to 2.8). Early therapy
increased the time until CD4+ counts fell below 0.2 x 10(9) per
liter (200 per cubic millimeter), and it produced more conversions
from positive to negative for serum p24 antigen. Early therapy was
associated with more anemia, leukopenia, nausea, vomiting, and
diarrhea, whereas late therapy was associated with more skin rash.
CONCLUSIONS. In symptomatic patients with HIV infection, early
treatment with zidovudine delays progression to AIDS, but in this
controlled study it did not improve survival, and it was associated
with more side effects.


Note:  This historical overview of AZT will continue with Part IV.