dmcanzi@watserv1.waterloo.edu (David Canzi) (02/09/91)
Medical News Briefs for January 21, 1991 to February 3, 1991
Copyright 1990: USA TODAY/Gannett National Information Network
Reproduced with Permission
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Jan. 24, 1991
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MYSTERY PNEUMONIA APPEARS:
A rare pneumonia seen in AIDS patients and others with severely damaged
immune systems is showing up in some elderly patients with no apparent risk
factors, says the Thursday New England Journal of Medicine. The report
concerns only five patients, but investigators say physicians should be on the
lookout for cases of pneumocystis carinii pneumonia (PCP) among their elderly
patients.
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Jan. 25, 1991
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AIDS DEATH TOLL RISES:
The U.S. death toll from AIDS has topped 100,000 and is escalating, the
Centers for Disease Control said Thursday. Of 161,073 people reported to have
AIDS since June 1981, 100,777 had died as of the end of December. About one-
third died during 1990. CDC researchers project that as many as 215,000 more
Americans will die of AIDS during the next three years.
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Articles
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AIDS CLINICAL TRIALS ALERT
National Institute of Child Health and Human Development
January 16,1991
Prepared by:
Pediatric, Adolescent & Materanl AIDS Branch
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda Maryland
Facsimile transmitted by:
National Library of Medicine
National Institutes of Health
Bethesda, Maryland
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RESULTS OF THE NICHD CLINICAL TRIAL
OF THE EFFICACY OF INTRAVENOUS
IMMUNOGLOBULIN (IVIG) FOR THE PROPHYLAXIS OF
SERIOUS BACTERIAL INFECTIONS IN
SYMPTOMATIC HIV-INFECTED CHILDREN.
[NOTE: "<=" = "less than or equal to" ; ">=" = "greater than or equal
to" ; "_Pneumocystis carnii_" = italicized in original document."]
This advisory contains preliminary information for pediatric health care
providers on the findings of the NICHD "Clinical Trial of the Efficacy of IVIG
in the Treatment of Symptomatic Children Infected with human immunodeficiency
virus (HIV)." while no recomendations for clinical practice are being made at
the current time, the NIH wishes health-care providers to have additional
information on this study while publication is being readied for submission to
peer-reviewed medical journals.
STUDY DESCRIPTION
The study was a randomized, double-blind controlled comparison of IVIG, 400
mg/kg infused every 28 days, versus albumin placebo for the prophylaxis of
serious bacterial infections in immunologically or clinically symptomatic HIV-
infected children less than 13 years of age. All study patients were
permitted to receive the prevailing medical standard of care, including
prophylaxis for _Pneumocystis carnii_ pneumonia and Zidovudine (AZT) therapy.
Study patients were randomized to IVIG or albumin placebo within two groups on
the basis of entry CD4 lymphocyte count and previous infection history. Group
I included children with entry CD4 <200/mm3 or a history of AIDS-defining
opportunistic infections (CDC class P2D1) or recurrent serious bacterial
infections (CDC class P2D2). Group II included children with entry CD4
>=200/mm3 and CDC classification of P1B (immunologic abnormalities only), or
other P2 categories (excluding those in Group I or children with malignancies,
class P2E).
This trial enrolled 372 symptomatic HIV-infected children from 28 medical
centers in the mainland United States and Puerto Rico between March 1, 1988
and October 31, 1990. Median follow-up was 17 months. Ninety-one percent of
enrolled children had perinatally-acquired HIV infection; HIV-infected
hemophiliac children were not included in the study population. The mean age
of children at enrollment was 40 months, ranging from 2 months to 11 years;
78% of children were under the age of 5 years at entry. At entry, 12% of
children had immunologic symptoms only (CDC class P1B), with the remainder of
children being clinically symptomatic (CDC class P2). Prophylaxis for
_Pneumocystis carnii_ pneumonia (48% overall) and treatment with AZT (39%
overall), was similar in both placebo and treatment groups. Overall mortality
in the study group as a whole was 17%.
Primary study endpoints were the occurrence of laboratory-proven serious
bacterial infection (meningitis, bacteremia, osteomyelitis, septic arthritis,
actue sinusitis, pneumonia, acute mastoiditis, or abscess of an internal
organ) or death. Secondary endpoints included clinically-diagnosed serious
infections, and hospitalizations.
RESULTS
Data from the study were reviewed January 10, 1991, by an independent Data
Safety and Monitoring Board, which found that in those children with entry CD4
lymphocyte counts of 200/mm3 or greater, IVIG significantly prolonged the time
free from serious laboratory-proven bacterial or clinically-diagnosed
infections (24 month infection-free survival, 68% in IVIG group children
compared to 48% in placebo group children, p=0.005).
As of October 31, 1990, 48 children in the study experienced one or more
laboratory-proven serious bacterial infections. thirty children in the placebo
group developed one or more laboratory-proven serious bacterial infections
compared to 18 IVIG group patients. A similar reduction in serious infections
with IVIG treatment was seen when clinically-diagnosed serious infections
(pneumonia and acute sinusitis) were included (Table 1).
===========================================================================
Table 1: NICHD Clinical Trial of the Efficacy of IVIG in Treatmeny of
Symptomatic HIV-infected Children. 3/1/88-10/31/90.
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Outcomes | IVIG | Placebo
| (N=185) | (N=187)
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Number of Children with >=1 | |
Lab-Proven Serious Bacterial | 18 | 30
infections | |
---------------------------------------------------------------------------
Number of Children with >=1 | |
Lab-Proven Bacterial or | 54 | 77
Clinically-Diagnosed Serious | |
Infections | |
---------------------------------------------------------------------------
Death | 31 | 31
===========================================================================
In Group I children with entry CD4 >=200/mm3 randomized to receive IVIG, the
median time to development of a serious laboratory-proven bacterial of
clinically diagnosed infection was approximately 1 year longer than that
observed for children randomized to the placebo arm (583 days in the IVIG
children versus 221 days in the placebo children). Eighteen of 26 placebo
group patients developed one or more serious laboratory-proven bacterial or
clinically-diagnosed infections, compared to 14 of 34 children receiving IVIG
(p=0.005 for 24 month infection-free survival) (Table 2). However, for Group
I children entering with CD4 count less than 200/mm3, there was no difference
in infection-free survival between the placebo and IVIG groups (282 days in
the IVIG children vesus 255 days in the placebo group).
In Group II, the proportion of children who developed serious laboratory-
proven bacterial and clinically-diagnosed infections was less than observed in
children in Group I. Forty-two children in the placebo group developed one or
more serious laboratory-proven bacterial or clinically-diagnosed infections
compared to 26 IVIG group chaildren (p=0.03 for 24 month infection-free
survival) (Table 2). A 21% difference in infection -free survival at 24
months is observed between children receiving IVIG and those receiving placebo
(75% 24-month infection-free survival in the IVIG group compared to 54% in the
placebo group).
===========================================================================
Table 2: NICHD Clinical Trial of the Efficacy of IVIG in Treatment of
Symptomatic HIV-infected Children. 3/1/88-10/31/90.
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| Group I | Group II |
| N=115# | N=257 |
|------------------------------------------------------|
| CD4 <200/mm3 | CD4 >=200mm3 | | |
|----------------------------------| | |
Outcomes | IVIG | Placebo | IVIG | Placebo | IVIG | Placebo |
| N=23 | N=28 | N=34 | N=26 | N=128 | N=129 |
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Number of Children | | | | | | |
with >=1 Lab-Proven | 8 | 7 | 5* | 9 | 5* | 14 |
Serious Bacterial | | | | | | |
Infections | | | | | | |
-------------------------------------------------------|-------------------|
Number of Children | | | | | | |
with >=1 Lab-Proven | 14 | 15 | 14**| 18 | 26***| 42 |
Bacterial or | | | | | | |
Clinically-Diagnosed| | | | | | |
Serious Infections | | | | | | |
---------------------------------------------------------------------------|
Death | 16 | 18 | 7 | 6 | 8 | 6 |
============================================================================
Group I: Entry CD4 <200 or CDC P2D1 or P2D2
Group II: Entry CD4 >=200 and CDC P1B, P2B, P2C, P2D3, or P2F
# No entry CD4 in 4 Group I patients, all in placebo group, 1 death, 2
clinical infection.
* p = 0.04, 24-month infection-free survival, IVIG vs. placebo
** p = 0.005, 24-month infection-free survival, IVIG vs. placebo
*** p = 0.03, 24-month infection-free survival, IVIG vs. placebo
Mortality in the study group as a whole was 17% (median follow-up 17 months).
There was no difference in mortality between the placebo and IVIG treatment
groups, with 31 deaths in each arm.
Bacteremias accounted for the majority (75%) of laboratory-proven serious
bacterial infections. The most common bacterial isolate was _Streptococcus
pneumoniae_, accounting for 19 episodes of bacteremia. Fourteen episodes of
pneumonococcal bacteremia were noted in 12 children in the placebo group,
compared to 5 episodes in 4 children receiving IVIG. The most striking effect
of IVIG treatment on the incidence of pneumonococcal bacteremia was noted in
Group II children, where 10 episodes occured in placebo patients, compared to
0 in children receiving IVIG.
Pneumonia accounted for the majority (65%) of clinically-diagnosed serious
infections. All reported pneumonia and sinusitis episodes underwent
independent review by two physicians blinded to the child's treatment status
for classification as acute or not-acute episodes for study purposes.
Children randomized to placebo were 1.5 times more likely to develop acute
pneumonia than children receiving IVIG (66 episodes in 51 of 187 placebo group
children compared to 43 episodes in 29 of 185 IVIG group children.)
When all reported presumed bacterial infections, serious and minor and
laboratory-proven as well as clinically-diagnosed, are included, a reduction
in all infections is observed in IVIG group children. Children reandomized to
the placebo group experienced 1.4 times more presumed bacterial infections of
any nature than did children who received IVIG (646 infections observed in
placebo group children compared to 473 infections in IVIG group children,
p=0.02).
IVIG treatment was associated with a reduction in the number of
hospitalizations (excluding social and short-term [one day or less]
hospitalizations) for children with entry CD4 count >= 200/mm3. Overall,
there were approximately 45 excess hospitalizations observed per year for
every 100 HIV-infected children with CD4 count 200/mm3 or above in the placebo
group when compared to the IVIG group.
Adverse reactions to study drug infusions were minimal and similar between
albumin placebo and IVIG groups, noted in 0.6% of 3,203 placebo infusions and
0.5% of 3,199 IVIG infusions.
CONCLUSIONS
The results of this study indicate that IVIG was effective in prolonging
infection-free time in immunologically or clinically symptomatic HIV-infected
children with CD4 counts 200/mm3 or above. In children with CD4 counts
<200/mm3, efficacy was not demonstrated and other interventions may be needed
to prevent serious bacterial infections. The study population did not include
hemophiliac children, and while a significant proportion of children were five
years old or older, 78% of children enrolled in this study were under 5 years
of age, and the vast majority of children (91%) had perinatally-acquired HIV
infection. Therefore, the possible efficacy of IVIG in hemophiliac children
was not addressed by this study. Further evaluation of this and other ongoing
studies may delineate further a subgroup of symptomatic HIV-infected children
that would be most likely to benefit from the initiation of IVIG therapy.
This study supports the importance of indentification of HIV-infected children
to permit appropriate immunologic evaluation by their physician, and the
initiation of appropriate adjunctive therapy (such as IVIG therapy and PCP
prophylaxis) and, when appropriate, antiretroviral therapy.
FOR ADDITIONAL INFORMATION, PLEASE CALL 1-800-TRIALS-A.
Re-keyed into ASCII format by:
Steve Clancy, M.L.S.
Reference Dept.
Biomedical Library
University of California
Irvine, California
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Volume 4, Number 1 February 5, 1991
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--
David Canzi "Silencing the racists protects free speech"
Kitchener-Waterloo Record, editorial, Dec. 18, 1990