MNSMITH@ECS.UMASS.EDU (Michael Smith) (06/02/89)
[GMHC ISSUE302 has been added to the AIDSNEWS library at RUTVM1]
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TREATMENT ISSUES -- The GMHC Newsletter
of Experimental AIDS Therapies
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Volume 3 Number 2 March 30, 1989
In this issue:
Erythropoietin
Mycobacterial Infections
Choosing a Nebulizer
New Studies
In Brief
Erythropoietin
While AIDS is characterized by depletion of certain white
blood cells which are crucial components of the immune system,
many PWAs also become deficient in red blood cell ("RBC") counts.
Frequently, reduced RBC counts are caused by bone marrow suppres-
sion due to drugs such as AZT or decreased production of a
naturally occurring hormone called Erythropoietin (EPO). A syn-
thetic form of EPO is now being evaluated as a treatment for
anemia, allowing patients to overcome a shortage of RBCs without
receiving transfusions. First tested in patients on dialysis,
trials are now underway to examine EPO's potential role in clini-
cal management of anemia in people with HIV-related disease.
Components of Blood and Anemia
RBCs develop from precursor cells in bone marrow. As these
cells mature, they are released into circulating blood. The main
function of RBCs is to transport oxygen throughout the body. Oxy-
gen binds to the main component of the cell, hemoglobin. Hemoglo-
bin is an iron-containing protein that holds the oxygen until it
is released.
There is an interdependent relationship between RBC count,
the level of oxygen in the blood and production of EPO. Reduced
oxygen levels can be caused by the destruction or loss of RBCs.
Lowered levels of oxygen stimulate production of EPO, which in
turn spurs production of RBCs (1). The link between oxygen and
RBC production has been suspected since the late 1800s, when peo-
ple living at high altitudes were found to have higher than nor-
mal levels of RBCs (1).
Measuring RBCs in circulating blood is done by taking a sam-
ple of blood, placing it in a small tube and separating it into
its various components. The column of red blood cells that col-
lects is then measured. This measurement is known as the hemato-
crit. Normal hematocrit values are about 40-45% of total red
cells. A lower hematocrit indicates fewer RBCs and less hemoglo-
bin. Anemia is not always due to lowered levels of EPO in the
blood. Patients who are anemic for other reasons, such as damaged
bone marrow, seemingly would not respond to treatment with syn-
thetic EPO. Yet PWAs with AZT-related anemia seem to benefit
from EPO therapy, according to researchers working with the drug
(2).
Background
Although EPO was discovered in the early 20th century (3),
only limited quantities have ever been available for research.
Recently, the gene sequence for EPO has been cloned and a geneti-
cally engineered synthetic product is now available for clinical
testing. Indications are that the gene product and naturally
occurring EPO act identically.
We do not completely understand how EPO stimulates increased
production of and faster development of RBCs (3). One benefit of
EPO therapy is that it may eventually allow anemic PWAs who
choose to continue AZT treatment to do so without being regularly
transfused. This use of EPO would alleviate some of the consid-
erable strain that AZT-induced anemia puts on the nation's blood
supply. Finally, EPO would eliminate the risk of transmission of
certain infections from being transfused, particularly non-A,
non-B hepatitis.
Administration
EPO can be measured in blood plasma and in urine by a method
called radioimmunoassay. This method is reliable, sensitive and
requires only a small amount of body fluid (4).
EPO has been administered in two fashions: subcutaneous and
intraperitoneal injections or intravenously. Three reports in
Lancet, a British medical journal, argue that subcutaneous injec-
tions are a superior route. Researchers reported that when given
through subcutaneous injections, EPO had a longer half-life (i.e.
was present in the blood stream longer) than when given
intravenously (5). The longer half-life prompted these research-
ers to reduce the dose, an important consideration given the high
cost of the drug. It was argued that more frequent injections
(the same total dosage in 3 injections per week rather than 1 or
2) were more effective. Representatives of Ortho Pharmaceuti-
cals, the company that is conducting research on EPO in AIDS,
agreed with these general conclusions, but reserved final judg-
ment pending the availability of data on more patients (6).
Finally, another study reported in Lancet compared subcu-
taneous, intraperitoneal (into the gut) injections and
intravenous administration of EPO to kidney patients (7).
Researchers concluded that subcutaneous EPO represents the most
satisfactory route for patients with kidney disease. Since the
question of the best administration technique has not yet been
resolved, we will keep readers apprised of new information on
this subject.
Clinical Trials Experience
EPO is produced primarily in the kidneys. For this reason,
the synthetic form was first envisioned as treatment for patients
with End Stage Renal Disease on dialysis machines. Most clinical
evidence to date is from this patient population. EPO has also
been administered through clinical trials to healthy subjects, to
patients with severe rheumatoid arthritis, and to a small number
of PWAs. Overall, the response has been encouraging.
Two pilot studies of EPO in patients with kidney disease
showed that the drug enhanced RBC formation with minimal toxi-
city. In one dose-escalation study of 10 patients, all partici-
pants benefited from the drug (8). Four transfusion-dependent
patients no longer required transfusions after one week of
therapy. A larger, dose-ranging trial of 25 patients found that
three-fourths of those who were transfusion-dependent were able
to forego further blood replacement therapy (9). This trial
administered doses from 1.5 International Units (IU)/kg of body
weight to 500 IU/kg. The lowest doses, 1.5 and 5 IU/kg, were
found not to be always effective. Patients also reported general
improvement in appetite, food intake and well-being. These data
are encouraging, but it is important to remember that these kid-
ney patients were anemic due to low levels of natural EPO, not
always the case with PWAs.
The scant results we do have from trials in AIDS patients
indicate that EPO is a promising therapy. One small community-
based trial has been progressing well. As this article went to
press, no data from this trial had been analyzed, but one
researcher claimed that the drug "works".
Two ongoing studies at St. Luke's-Roosevelt also seem to
indicate that EPO has a positive effect for at least some
patients (10). Approximately 20 patients with AZT-induced anemia
have been enrolled in this study. Patients are randomized to EPO
or placebo three times a week for 12 weeks, or until their hema-
tocrit reaches 38-40. After 12 weeks, all patients receive EPO
for an additional six months with doses adjusted to maintain the
hematocrit at 38-40. Only 3 patients have completed the study,
but Dr. Randy Levine, principle investigator, reports that one
patient has had a 50% decreased need for transfusions. The other
two patients now have hematocrit levels in the high 30's -- just
below the normal range. Dr. Levine also stated that some of the
participants had increases in hematocrit levels and others need
fewer transfusions. Although these data are preliminary, Dr.
Levine's impression is that a subgroup of patients in the studies
are responding. At this point, we have no information on the
long-term effects of EPO in PWAs.
Toxicity
Adverse reactions have been reported in kidney patients, but
these appear to be related to their kidney disease, not EPO
treatment. Some of the toxic side effects include hypertension,
heart attacks, strokes, and heart irregularities. Patients with
rheumatoid arthritis, AIDS, and healthy volunteers, treated with
EPO, do not experience these adverse reactions. Some patients
have complained of aches and a cold sensation in their bones 1-2
hours after treatment (11).
Thus far, no patients have produced antibodies which would
neutralize synthetic EPO (12). Producing such antibodies is an
immune system reaction that is sometimes seen when foreign sub-
stances, helpful or otherwise, are introduced in the
bloodstream; such a response would seriously hinder EPO's thera-
peutic potential.
What Next?
At this point, EPO appears to be a safe and potentially
effective treatment for anemia, even when the lowered RBC count
is not due to low EPO levels. The drug is somewhere between
Phases II and III of clinical trials. It is further along the
licensing voyage for kidney patients and will probably first be
approved for that indication. At this point, EPO is a promising
candidate for early release under FDA's Treatment-IND program,
which allows access to certain drugs in late Phase II testing
when a patient has no alternative. Anemic PWAs who cannot con-
tinue AZT or other drugs that are bone marrow suppressive, but
wish to do so should be allowed access to EPO. Treatment Issues
will provide information as it becomes available on this promis-
ing drug.
[Ed. note: We appreciate the assistance of Dr. Arlene Bensam in
researching and writing this article.]
Mycobacterial Infections
by Jeffrey Roth, Ph.D.
Mycobacterium denotes a group of bacterial infections that
are seen much more frequently in PWAs than in the general public.
The major Mycobacterial infections worldwide are caused by
Mycobacteria Tuberculosis ("MTB"). Its incidence is increased in
HIV disease, especially among IV drug users and in those from
poor areas where MTB is epidemic (13). Another frequently seen
infection in PWAs is Mycobacterium Avium Intracellulare. This is
actually a complex of diseases caused by Mycobacterium Avium and
Mycobacterium Intracellulare, two bacteria which cannot be
clearly differentiated. Therefore, they are usually grouped
together and referred to as "MAI". MTB classically causes
disease in the lungs, but can affect other organs. MAI can be
limited to the lungs or any other one organ, but is more commonly
systemic, i.e. causes disease throughout the body. MAI is one of
the most common systemic bacterial infections seen in AIDS (14).
Mycobacterial diseases, once considered extremely rare in
humans, are increasingly recognized as significant contributors
to AIDS-related illness and death. One study of 151 HIV-infected
patients demonstrated that 66 (44%) were infected with some form
of mycobacteria (15). While clinicians were once likely to
regard mycobacterial infections as untreatable, many are now more
aggressive, utilizing a variety of often experimental therapies
in an attempt to control the infections. Considerable work
remains to be done to develop effective anti-MAI drugs.
Symptoms
People with AIDS are thought to acquire mycobacterial infec-
tions with a higher incidence than people with an intact immune
system, presumably because the body's defense to mycobacteria
primarily involves T4-cells, which are severly depleted in AIDS
patients. Pulmonary TB, which can occur in anyone, is acquired by
inhaling airborn droplets which have been coughed by an infected
individual. The increased incidence of TB in HIV seropositives
has been ascribed to reactivation of latent infection from an
earlier period in the patient's life or new exposure to the
mycobacterium or both.
Prior to the AIDS epidemic, MAI was only rarely reported as
causing human disease. In HIV-infected individuals, MAI causes
more gastrointestinal, liver and bone marrow disease than pul-
monary disease. MAI is commonly found in soil and water, and
evidence suggests that it is acquired by ingestion. The clinical
presentations of MTB and MAI are similar: fevers (often
chronic), chills, malaise, weakness, weight loss, drenching night
sweats (often requiring changes of bedclothes and sheets);
cramping and diarrhea more commonly in MAI, and cough more com-
monly in MTB. These symptoms are chronic, and may be dismissed
by the sufferer as insufficiently severe in the initial stages to
warrant treatment. As in all diseases, however, early diagnosis
and treatment are likely to improve prognosis.
Diagnosis
The diagnosis of mycobacterial disease can be made in
several ways: if cough is present, sputum should be examined and
X-rays obtained; stool specimens should also be examined. Occa-
sionally, the clinical presentation will suggest a tissue biopsy,
such as a lymph node, liver or bone marrow biopsy. These tissue
samples are stained with certain dyes that detect the presence of
mycobacteria. Bronchoscopy and gastrointestinal endoscopy speci-
mens are examined for the presence of mycobacteria. The absence
of organisms on tissue or specimen examination, however, does not
rule out the presence of mycobacterial infection. Blood culture,
or the incubation of blood samples in the laboratory, has a good
diagnostic yield, and is often the test upon which a diagnosis
relies. Even the most modern laboratory methods, however, fail
to give a preliminary result in less than a week, with a defini-
tive diagnosis (including a distinction between MTB and MAI, the
treatments for which are very different). This lag is due to
the length of time it takes to grow mycobacteria in culture
(approx. 6 weeks for MAI, 4 weeks for MTB). Because of the
imperfect ability of any single test to isolate and identify
mycobacteria, several tests may need to be done. Bone marrow
biopsy is highly accurate, although this procedure can be uncom-
fortable. One study of 47 patients found the predictive value of
staining bone marrow samples to be 86.1% (16). Given certain
clinical situations where other possibilities have been elim-
inated, some clinicians may choose to treat presumptively
although this approach carries obvious risks.
Treatment
Disease caused by mycobacteria is treated differently from
most other bacterial infections. Some biological features of
mycobacterial infections help explain why this is so. First, the
treatment period is generally very long. In immunocompromised
patients, maintenance therapy is often lifelong. Mycobacteria,
unlike most bacteria, can remain dormant for long periods and
they are unaffected by antibiotics during this dormancy period.
Treatment must therefore continue through the period during which
the mycobacteria are actively reproducing. Second, mycobacteria
are frequently resistant to available antibiotics. This explains
why several drugs are used concurrently to treat mycobacterial
infections. The number of drugs used can be as high as seven or
more for the treatment of MAI in AIDS patients.
MTB. Tuberculosis is usually a treatable disease and will be
discussed only briefly. All the major antituberculosis drugs are
taken orally. The most commonly used drugs include isoniazid
(INH), rifampin, ethambutol, streptomycin, and pyrizinamide
(PZA). The CDC recommends beginning therapy in HIV seropositives
with tuberculosis with at least three concurrent medications
(almost always including INH) (17). The course of treatment is
recommended for at least 9 months (or six months following nega-
tive tests for mycobacteria), with lifetime close surveillance
for recurrence of disease. In practice, however, many clinicians
advocate lifelong maintenance therapy with INH after a full
course of treatment.
MAI. Unlike MTB, there is no standard, or generally effective
therapy for MAI complex disease. Since MAI has been only
recently considered to be important, there has not been similar
time, as is the case with MTB, to develop more effective drugs
and consensus regarding use. Still, there are many agents which
have been developed and tried with some success. Many variables
influence the ultimate efficacy of MAI treatment, including the
underlying clinical status of the patient, the strain of MAI and
its susceptibility to antimicrobials (drugs to treat bacteria),
and the ability of the patient to tolerate the multidrug regimen.
Following is a synopsis of the drugs used to treat MAI.
Since these drugs are almost never used alone, an appraisal of
their individual effectiveness is difficult. A word about toxi-
city: multidrug regimens, such as those used in treating MAI, are
more likely to cause problems for individual patients because of
the number of agents involved and their possible additive
effects. Moreover, since side effects are often idiosyncratic, it
can be difficult to predict in advance who can tolerate a regi-
men. The first name listed is the generic name of the drug; the
name in parentheses is the market name assigned by the drug's
manufacturer.
1. INH. This oral drug is the oldest modern anti-TB medica-
tion. Its principal role in AIDS patients is where diagnoses
of both MTB and MAI are being considered, and good anti-TB
coverage is desired without detracting from an anti-MAI
regimen.
2. Rifampin (Rifadin). This anti-MTB drug has been used
frequently in combination with other agents, and is gen-
erally felt to be efficacious. Taken orally, the major tox-
icity is to liver function, which must be monitored during
therapy.
3. Rifabutin (Ansamycin). This newer agent, a derivative of
rifampin, is felt by some to be more effective against some
non-MAI mycobacteria (such as MTB and the mycobacterium
which causes leprosy) than Rifampin; it may also be better
tolerated in some individuals. While still investigational,
it is freqently used in protocols.
4. Ethambutol (Myambutol). This oral drug, also used
against MTB, is common in multidrug regimens. Among its
major side effects has been reversible decreases in visual
perception and color blindness.
5. Amikacin (Amikin). Given intravenously, it has been
more traditionally used in certain resistant bacterial
infections. It can cause progressive kidney failure and
hearing loss, both of which must be monitored during
therapy.
6. Imipenem (with cilastin, Primaxin). This newer agent is
an intravenous anti-bacterial used for many bacterial infec-
tions. Along with amikacin, many clinicians feel it to be
among the more effective agents when used in combination
with other drugs.
7. Ethionamide (Trecator-sc) is an oral agent, also used for
MTB. Its side effects are generally gastrointestinal upset
and psychiatric disturbances, such as depression.
8. Clofazimine (Lamprene), an oral agent, is considered by
some to be especially effective. Its traditional use has
been in the treatment of leprosy and is generally well-
tolerated. Long periods are required for clofazimine levels
to accumulate in tissues. Following prolonged therapy,
clofazimine, which is a phenazine dye, will tint the skin a
bluish grey.
9. The quinolone antibiotics, notably ciprofloxacin (Cipro)
and ofloxacin, have been described as having in vitro anti-
MAI effect. Higher blood levels seem to be achievable with
ofloxacin, which is not yet available in the US. Ciproflox-
acin, an oral agent, will soon be available in intravenous
form. It is more commonly included in anti-MAI regimens.
10. Cycloserine (Seromycin) has a high side effect profile,
including neurological and psychiatric effects, which makes
its use less attractive than other drugs.
11. Erythromycin, an oral drug, and a new drug of its class,
azithromycin, are being evaluated in the treatment of MAI.
Recommendations for treatment protocols vary and many are
unpublished. Individual regimens will vary enormously depending
on the underlying medical status of the patient and which drugs
can be tolerated. Additional factors may be more subtle. For
example, a patient with extensive gastrointestinal MAI may
receive five oral agents, but may absorb very little from the GI
tract; in such a case, if treatment were to proceed, many clini-
cians would consider intravenous therapy to be superior. On the
other hand, chronic intravenous therapy presents the burden of
home nursing care, the risk of catheter infection, and other
problems.
Specific protocols have included the CDC's suggestion of
ansamycin, INH, ethambutol, and clofazimine (18). Young et al
evaluated a regimen of amikacin, ciprofloxacin, and imipenem-
cilastin with promising results (19). Young, in a subsequent
paper (20) recommends amikacin, clofazimine, ethambutol, rifam-
pin, plus any fifth drug. An abstract presented at last year's
Stockholm AIDS conference reports on experience in two patients
with INH, rifampin, cycloserine, and amikacin. In each of two
cases, cycloserine proved too toxic, and was substituted by nor-
floxacin, which is absorbed less efficiently than ciprofloxacin
or ofloxacin (2121). Another abstract from the Stockholm confer-
ence recommends ansamycin, clofazimine, ethambutol, and INH after
a study with 8 patients (22).
Anti-MAI regimens are commonly continued for many months,
especially in the presence of real clinical improvement. This
can be difficult to guage, however, since PWAs often have other
medical problems which contribute to their distress. Most pub-
lished recommendations suggest discontinuing therapy in the ab-
sence of clinical improvement after 4-6 weeks of therapy. Indivi-
dual clinicians may be more or less aggressive, depending on per-
sonal experience and other factors specific to individual cases,
including the wishes of the patient.
Prevention
Unfortunately, no prophylactic treatment is available for
these infections; the drugs used to treat them are too toxic.
Prevention, to the extent possible, is important because of the
difficulty in treating mycobacterial infections and the debili-
tation they cause.
MAI has recently been found in (tap) hot water systems,
including those in hospitals (23). However, since it is felt
that most individuals have already been exposed to MAI, the bene-
fit of avoiding ingestion of hot tap water is uncertain. Factors
such as individual host susceptibility, time of initial exposure
to MAI, and clinical status may be important indicators in deter-
mining who may eventually develop MAI.
Avoidance of MTB is in some ways easier, because the mechan-
ism of transmission by airborn droplets is known. In large urban
centers (New York, for example), the incidence of pulmonary
tuberculosis is sharply on the rise, especially among the indi-
gent and those living under crowded conditions such as homeless
shelters. Some physicians recommend that HIV positive individu-
als avoid raw foods, especially those grown in the ground to
minimize mycobacterial exposure. However, there is no proof that
this strategy is helpful. Finally, it might be advisable for
PWAs to be careful around patients with MTB when those patients
are coughing a great deal. However, after one week of treatment,
risk of transmission to others is greatly reduced. This precau-
tion is much less important around patients with MAI outside of
the lungs and before completion of one week of treatment.
While mycobacterial infections are difficult to treat, phy-
sicians should not consider treatment hopeless. No established
treatment protocol exists, but there has been some success in
controlling these infections with a combination of the drugs
detailed in this article. Treatment Issues will be reporting on
any developments in this important area of clinical management of
AIDS, which is so elusive at this point.
Choosing a Nebulizer
by Stephen Gum, M.D.
One of the greatest advances in the management of AIDS since
the advent of AZT is the recent early release by the FDA of aero-
solized pentamidine for the prevention of pneumocystis carinii
pneumonia (PCP). This event marks the FDA's recognition that
aerosolized pentamidine is probably effective in reducing the
incidence of PCP.
PCP
There are other investigational drugs for PCP prevention.
Bactrim (also known as Septra) has been used with effectiveness.
This drug also has the advantage of preventing toxoplasmosis and
other infections. Dapsone and Fansidar have also been used. All
these drugs are thought to be effective and many physicians have
used them as their drugs of first choice for PCP prevention.
These drugs are significantly less expensive than aerosolized
pentamidine and easier to take. Unfortunately, there have been
few clinical trials comparing the effectiveness of these various
drugs. In addition, these medications are sulfa-based and up to
50% of patients with AIDS do not tolerate them. An additional
20% of patients will develop an intolerance to them over time.
Pentamidine intramuscularly & intravenously has been approved
since 1984 for episodes of PCP (24). These administration tech-
niques carry the risk of toxicity to the liver and kidneys. Thus
aerosolized pentamidine has become the most widely used experi-
mental drug for PCP.
Treatment Issues (vol. 2, no. 6), previously discussed what
is known of the pathophysiology of PCP and provided an update on
the use of aerosolized pentamidine. Since then (Aug. '88), the
FDA's Treatment-IND approval makes the drug more available to a
greater number of patients. Aerosolized pentamidine is not yet
fully licensed. But private insurance carriers will more likely
pay for the therapy now that it has been conditionally approved.
This article deals with the choice of a nebulizer for the
administration of pentamidine.
Aerosol Therapy: Background
A nebulizer is a mechanical device that takes a liquid medi-
cation and converts it to an aerosol mist which can then be
inhaled into the patient's lungs to treat a specific condition,
in this case PCP. The organism causing this pneumonia lives in
the alveoli, a difficult area to reach with aerosolized medica-
tion. Droplets tend to land on the upper airways, i.e. the tra-
chea and bronchi. The many incidents of PCP in spite of prophy-
laxis that we saw with early aerosolized pentamidine therapy
have been attributed to the mechanics of the "green machine",
which produced droplets that are considered too large. Most dro-
plets produced by this machine land in the mouth and throat, and
never make it to the lungs at all.
In any aerosol therapy, the amount of medication getting to
the lungs is determined by a several factors. Previous history
of lung disease will make certain parts of the lung less accessi-
ble to aerosol therapy. Breath holding is not thought to be
beneficial (25). The most important factor in making a choice
among nebulizers is to determine which machine maximizes the dis-
tribution of the drug to the alveoli (the areas where PCP
resides) and minimizes the side effects.
There is some evidence that the position of the patient dur-
ing therapy may be a factor in determining distribution. An
unpublished study looking at this factor showed that distribution
to the top of the lungs was improved when the patient was lying
down (26). This study is now complete and the results will be
released in May. If it is found that some of the PCP recurrences
were in the top portions of the lungs, the improved distribution
to this area while lying down would be beneficial. There is an
added problem in that most nebulizers are difficult to use when
in this position. Nebulizers can be adapted with the use of
extension tubing but this addition may affect the efficiency and
droplet size.
The dose of medication placed in the nebulizer is also
important. A higher dose may increase the short term or long term
side effects. With IV medication, we know how much medication
the patient is getting. With oral medication, we know in most
cases how much is absorbed. With aerosolized medication, the
dose reaching the alveoli is more affected by outside factors,
mentioned above, and the choice of nebulizers discussed below.
Particle Size
The size of particles produced by the nebulizer is one of
the main determinants of where the aerosol medication goes. Yet
measurement of particle size is an inexact science. If one
author is measuring them using one method, another author using a
different method will get different results. The numbers are
always approximate in any case.
Aerosolized particles are measured in microns. The optimal
particle size for delivery of medication to the alveoli is
smaller than 4 microns. Some studies recommend 1-2 microns.
Large droplets greater than 12 microns end up never getting to
the lungs at all. They precipitate out in the mouth and throat.
Smaller droplets (5-10 microns) probably land in the trachea and
bronchial tubes and are eventually swallowed into the stomach.
Droplets of 1-4 microns probably do make it to the alveolar
spaces. This is where we want pentamidine to land since this is
where the microbe that causes PCP lives.
There is a theoretical possibility that a droplet could be
too small. The studies that suggest this have been done with dry
particles in a dry environment. The lungs, however, are an
environment of 100% humidity. Anything hygroscopic (water
absorbing) will expand in 100% humidity. So smaller hygroscopic
particles will get larger. What is critical is the deposition
pattern--where these particles lodge in the lungs. The potential
disadvantage of small particles (around 0.25 microns) is that
they may move around randomly and deposit on airways before they
can expand or they may be exhaled, and therefore be of no use in
preventing PCP. But with a hygroscopic aerosol, the amount
exhaled is lower than the studies done with dry particles would
suggest. Therefore droplets that may theoretically be considered
too small may in fact be useful. In any case, the size of the
particle the nebulizer produces is critical in choosing among
nebulizers.
Efficiency
Only a small fraction of the dose of any medication put in a
nebulizer gets to the lungs. Few studies have looked at the
efficiency of nebulizers, but a number of studies are in pro-
gress. O'Doherty, et al. in Lancet, reported on a small study
comparing the Respirgard II with the Pulmosonic and two other
nebulizers not available in this country (27). The authors used
two doses of pentamidine and looked at reductions in pulmonary
function and other factors. Throat and stomach deposition were
least with the Respirgard II, which also caused the fewest
adverse effects. The adverse effects were greatest with the Pul-
mosonic and the higher pentamidine dose, which also caused signi-
ficant reductions in pulmonary function. The authors found the
Respirgard II delivered drug more evenly throughout the lungs,
but this machine also deposited most of the drug in its tubing
and filter.
Jet vs. Ultrasonic
In addition to nebulizer efficiency and droplet size, there
are several other factors to consider in the choice of a nebu-
lizer. Reliability may be important. Of the two types of nebu-
lizers available, ultrasonic ones have the potential disadvantage
of ceasing to function optimally after a certain point, if the
crystal becomes damaged. There is also the potential that fungi
or algae may grow in an improperly cleaned ultrasonic nebulizer,
and thereby increase the risk of infection in already immuno-
compromised patients. Ultrasonic nebulizers are, however, more
convenient than jet nebulizers. They are usually smaller and
easily transportable. Jet nebulizers require a compressor or a
tank of oxygen (or air). For most people, convenience would be
lower on the priority list compared to effectiveness. Ultrasonic
nebulizers produce more particles per unit time, but the amount
of drug getting to the lungs is not determined just by the number
of particles or the size of the particles, or the choice of nebu-
lizer. Smalldone, et al, used a Harvard pump to study dry parti-
cles in a dry experimental environment (28,29). But wet aerosols
in 100% humidity (in the lungs) may behave differently; it is
important to keep this difference in mind when judging nebulizers
based on his data. Ultimately, the amount deposited in the
alveoli is what is important.
In addition, all nebulizers are set up to operate optimally
with certain tubing attachments, gas flow rates and sometimes
with particular compressors. Changes in these factors may have
an effect on droplet size and/or efficiency.
The FDA's Treatment-IND protocol is very specific in recom-
mending a particular nebulizer, the Respirgard II. This is the
nebulizer used in the recent multicenter trial which compared
three doses of aerosolized pentamidine. The study compared 60 mg
biweekly, 150 mg biweekly and 300 mg monthly. Researchers found
that the 300 mg dose given once monthly was the most effective,
noting a "significant difference" between the highest and the
lowest dosage (30).
Because of the differences between nebulizers, the choice of
nebulizer determines the dosage that will be required. It has
been found that 300 mg once a month with the Respirgard II is
effective. We may find that higher or lower doses may be
required with other nebulizers to have the same effectiveness.
Comparisons of Nebulizers
The data presented in the following chart looks at droplet
size and efficiency in comparing currently available nebulizers
in this country.
All of the nebulizers produce droplets of varying size. The
size reported here is the average size (31). The asterisk(s)
following each value for droplet size and efficiency measurements
corresponds to the ensuing discussion of the study or review from
which the data was taken.
*Review Article
Respiratory Care reported data collected from a number of
studies. The article reviewed particle size for 5 jet and 4
ultrasonic nebulizers (32). Among the jet nebulizers, the
average particle size was found to be 2.0 microns for the
Cadema Aerotech II system; 0.93 for the Respirgard II; 0.25
for the Ultravent; 4.3 for the Fanjet and 1.1 for the Cen-
timist. Ultrasonic nebulizers generally had larger parti-
cles. The Fisoneb was found to have average particles of
5.0 microns; DeVilbiss Pulmosonic, 4.2; DeVilbiss Porta-
sonic, 1.6 and the Siemens "Green Machine", greater than 12.
**Study 1
One small study reported in Chest, looked at two DeVilbiss
machines, one jet and one ultrasonic (33). The jet nebu-
lizer, DeVilbiss 646, was examined at two flow rates: 6
liters per minute and 12 l/m. Particle size for this
machine was measured to be 6.0 microns at 6 l/m and 3.7 at
12 l/m. The Pulmosonic, which is an ultrasonic nebulizer,
produced particles of 4.2 microns on the average.
***Study 2
A study by Smalldone et al, compared particle size and effi-
ciency for three nebulizers (34). All three were found to
have acceptable particle sizes: Cadema Aerotech II, 1.0;
Respirgard II, .76 (both are jet nebulizers); Fisoneb, 2.5
(ultrasonic). Efficiency measurements showed dramatic
differences, however. The Cadema delivered 21% of the pen-
tamidine to the lungs, the Fisoneb, 16% and the Respirgard,
4.6%.
****Report to DeVilbiss
Finally, Smalldone et al prepared a report to DeVilbiss Co.
which examined the Pulmosonic and the newer Portasonic, both
ultrasonic nebulizers (35). Average droplet size for the
Pulmosonic was found to be 3.6 microns; for the Portasonic,
3.5. Average efficiency was measured at 22% for the Pulmo-
sonic and 25% for the Portasonic.
Using droplet size of less than 4 microns as the criterion,
most of the jet nebulizers above meet the standard. There are
differences in average particle size when looking at the same
nebulizer in different studies. In addition, the difference in
flow rates (6 liters/min vs. 12 l/m) for the DeVilbiss 646 causes
the droplet size to vary from acceptable to unacceptable levels,
pointing out the importance of setting up the equipment according
to recommendations. Of the ultrasonic nebulizers, only the
DeVilbiss Portasonic consistently produced droplet sizes that
would be within the range of acceptability (1-4 microns). DeVil-
biss Pulmosonic had virtually no droplets less than 2 microns and
may be unsuitable for applications requiring high yields of fine
particles for delivery to the peripheral lung regions (36). Two
jet and three ultrasonic nebulizers were examined from the stand-
point of efficiency, i.e. how much drug makes it to the lungs.
Efficiency ranged from a low 4.6% with the Respirgard to approxi-
mately 25% with Portasonic. With the Respirgard II, patients
reported little nausea and no unpleasant taste but less pentami-
dine was deposited in the lungs. The lower frequency of adverse
effects is probably due to the small amount deposited in the
mouth and stomach with this device. This nebulizer also achieved
more uniform peripheral deposition, which may be an important
factor in preventing PCP (37).
Respirgard II has the smallest droplet size, approximately
.8 micron, but it delivers only a small amount of drug to the
alveoli. It had the least side effects for the dose given. This
may be a nebulizer for those who have trouble with side effects
but it may take higher doses of pentamidine to have the same
effective dose compared to other nebulizers.
Summary
New studies comparing efficiency would be useful. Perhaps
they would show that we could use less drug, (reducing the cost),
while being equally effective. Or perhaps the same amount of
drug would be more effective. These are studies that could pos-
sibly be conducted outside of a traditional clinical trial. The
choice of a nebulizer for the administration of aerosolized pen-
tamidine is not yet an easy one because of the paucity of data.
What happens in theory may not happen in a clinical situation.
Probably critical is droplet size, which should be less than 4
microns. This spring we will have new data obtained from a com-
parison study looking at various nebulizers in terms of droplet
size, efficiency and dispersion.
Since the FDA-chosen Respirgard II is one of the least effi-
cient nebulizers, the choice of a dose of 300 mg once a month
suggests that more of the dose will get to the lung when using a
more efficient nebulizer. But this, again, is theory.
Choosing one nebulizer and one dose was the only thing FDA
apparently felt safe doing for the standardization of their IND
study. The choice serves to reduce the variability for the study
protocol and uses an equipment and dose combination that has been
proven effective in a large trial (38). It does not mean that
other methods won't later be proven to be more effective. In New
York, at present, Medicaid will provide reimbursement for aero-
solized pentamidine only if used following the IND protocol which
is specific for Respirgard II. Since many clinicians have long
been using aerosolized pentamidine successfully in their prac-
tices with different machines and doses, perhaps it is unduly
restrictive to require all PWAs on Medicaid to conform to the IND
regimen. Other large trials of this drug are underway, and prel-
iminary results have shown doses lower than 300 mg monthly to be
effective prevention (39). New York Medicaid will only provide
the nebulizer itself to homebound patients or to doctors for
office use, a restriction that may end up costing Medicaid more
money in the long run when the cost of additional office visits
is included.
Many variables should be considered when choosing a nebu-
lizer for personal use. Unfortunately, we don't have all the
answers to some of the questions here. Hopefully, this article
has shed some light on the many issues surrounding prevention of
PCP with aerosolized pentamidine. We will continue to cover this
important topic and will report any significant developments.
New Studies
The Community Research Initiative (CRI), a group of physi-
cians who have come together to conduct humane clinical trials
for AIDS drugs, will soon begin recruiting for 3 new trials.
DHEA: A Phase I dose-ranging trial of this drug, which may
have immunomodulatory and/or antiviral activity will be recruit-
ing PWAs with T4 counts under 200 who are intolerant to or unwil-
ling to take AZT. Participants may not be on other experimental
HIV treatments. The study will have two arms: 1000 mg DHEA and
2000 mg.
Lentinan: This immunomodulator has been used as a cancer
treatment. It will be assessed in a Phase I-II trial for its
antiviral and immunomodulatory activity in 50 HIV-positive indi-
viduals with T4 counts between 200-450. Candidates must not have
had an AIDS-defining infection, lymphoma or other malignancy.
The study will be placebo controlled. Patients may not have
taken any other immunomodulators for one month before beginning
the trial.
Megace: This drug is an experimental appetite stiumlant
that will be tested in PWAs with anorexia or cachexia (wasting
syndrome). The goal of this Phase II-III trial is to promote
weight gain and an improved sense of well-being. The trial will
recruit 50 PWAs, and will be double-blind, placebo-controlled.
One in seven participants will be randomly assigned to placebo.
If, in any group, additional weight loss occurs, that participant
will be enrolled directly into an open-label trial (i.e. they
will definitely get drug).
For further information about these or other trials,
interested individuals should have their physicians contact CRI.
In Brief
CD4 Update: This promising antiviral does not seem to be
sailing through clinical trials. Researchers working with the
drug have informed Treatment Issues that safety trials are
proceeding and that CD4 is well tolerated both locally and sys-
temically. One Phase I study has completed the dose escalation
portion of the trial, which means that patients have received the
highest dose being considered for treatment. No serious adverse
side effects have been seen yet. Another Phase I trial sponsored
by Genentech at the San Francisco General Hospital is at a
standstill. Researchers expect to proceed with a Phase II trial,
but a company representative told us that there are no definite
plans for studies measuring the drug's efficacy. The decision to
proceed will be made "sometime in 1989". This seems like a dis-
tressingly apathetic approach to testing a promising drug. Genen-
tech also informed us that the dose seen to be effective in
animals has been administered to people with no adverse side
effects.
Meanwhile, the long promised CD4 trial at NYU is also
stalled; the study is being redesigned. When the NIH restruc-
tured their clinical trials bureacracy last year, promises were
made about speeding the development of protocols. Indeed, a new
position was created: "Protocol Specialists" were hired to facil-
itate writing of these documents, which are the blueprints for
studies of experimental drugs. Where are the specialists now
that we need them? Given the excellent test tube evidence for
this drug, it is amazing that CD4 is not moving faster through
clinical trials. With no Phase II trial on the horizon, we seem
to be facing that maddening yet familiar situation where promis-
ing drugs are imprisoned in committee meetings.
Dextran Sulfate Absorption: Researchers at Johns Hopkins,
in conjunction with the NIH, have determined that Dextran sulfate
is minimally absorbed when taken orally. The method used to
obtain this information involved measuring Dextran's blood thin-
ning effect in 6 patients who took one oral dose of the drug, a
crude way to detect Dextran in the blood. (A test which directly
measures Dextran is now available, and will be used to verify
these findings.) Very little blood thinning activity was
observed, considered an indication that only minute amounts of
the drug were absorbed. In contrast, patients who received an
intravenous dose displayed "dramatic inhibition of blood clot-
ting". One researcher who has been working with Dextran disputes
these results, faulting the sensitivity of the test and the small
amount of drug patients received.
Although these findings are disappointing, it should be
emphasized that we know little about Dextran's efficacy as an
antiviral in people. Poor absorption could be one explanation
for the lackluster clinical results seen with this drug to date.
The original test tube data which generated interest in this drug
has not been repudiated. But now clinical trials should be
designed to deliver the drug directly to the bloodstream. This
information in no way represents the last chapter on Dextran sul-
fate. A word of caution: no one should attempt to inject Dextran
sulfate; it can completely block the blood's ability to clot, and
lead to serious or fatal bleeding. Treatment Issues will report
any data on other administration techniques for Dextran as soon
as it is available.
Free AZT: Burroughs Wellcome, manufacturer of AZT, funds a
program to distribute this expensive drug free of charge to qua-
lifying PWA's as part of its Patient Temporary Assistance Pro-
gram. Available on a three-month renewable basis, the program
stipulates that PWA's who may qualify should ask their physicians
to write to Burroughs Wellcome requesting an application. Pending
approval, free AZT is then shipped monthly to the patient for
three months. If the patient's financial situation is unchanged
after 90 days, he may continue in the program, but must re-apply.
The reapplication procedure is a simpler process. Interested
persons are encouraged to contact Lisa Behrens at 1-800-722-9292
x3633.
AIDSWalk 1989: Join 20,000 other New Yorkers on Sunday, May
21, 1989 as they walk to raise money for GMHC. Now in its fourth
year, AIDS Walk New York is the single largest fund-raising event
for GMHC. Last year it generated a substantial portion of the
agency's annual operating budget. Pre-registration is required.
Interested walkers should contact AIDS Walk New York at (212)
727-7840.
Treatment Issues is GMHC's newsletter devoted to providing reli-
able information on experimental AIDS therapies. Describing an
experimental therapy should not be construed as recommending it.
All new treatments should be done under a physician's care.
Treatment Issues is published ten times yearly. Copyright 1989
Gay Men's Health Crisis, Inc. All rights reserved.
Non-commercial reproduction is encouraged. Subscription lists
are kept confidential.
Editor: Barry Gingell, M.D.
Managing Editor: Kevin Armington
GMHC, Department of Medical Information, 129 West 20th Street,
New York, NY 10011.
GMHC wishes to acknowledge the generous financial assistance of
the New York State Dept. of Health in publishing this issue of
Treatment Issues.
Footnotes:
1. Erslev AJ. Blood and mountains. In:Wintrobe MM ed. Blood, pure
and eloquent. New York: McGraw Hill, pp 257-80, 1980.
2. R. Levine, Personal communication.
3. Zanjani ED et al. Erythropoietin. Transfusion 29(1):47, 1989.
4. ibid. p. 49.
5. Bommer J et al. Subcutaneous erythropoietin. The Lancet
II(8607):406, 8/13/88.
6. Abels RI et al. Subcutaneous erythropoietin. The Lancet
II(8612):684, 9/17/88.
7. MacDougall IC et al. Pharmacokinetics of rhEPO in patients
with continuous ambulatory peritoneal dialysis. The Lancet
I(8635):425, 2/25/89.
8. Winearls CG et al. Effect of human erythropoietin derived from
recombinant DNA on the anaemia of patients maintained by chronic
heamodialysis. The Lancet II:1175, 1987.
9. Esbach JW et al. Correction of the anemia of end-stage renal
disease with recombinant human erythropoietin. Results of a com-
bined phase I and II clinical trial. N Engl J Med 316:73, 1987.
10. R. Levine, Personal communication.
11. Zanjani ED et al. Erythropoietin. Transfusion 29(1):53, 1989.
12. Egrie JC et al. Characterization and biological effects of
recombinant human eythropoietin. Immunobiology 172:213-24, 1986.
13. Leads from the MMWR: Tuberculosis and the Acquired Immuno-
deficiency Syndrome - New York City. JAMA 259(3):338-339, 1988.
14. Young LS et al. Mycobacterial infections in AIDS patients,
with and emphasis on the Mycobacterium avium complex. Rev of
Infec Dis, 8(6):1024-1033, 1986.
15. Schurmann D et al. Incidence and diagnosis of mycobacteria in
patients with HIV infections: results of a 2 year prospective
study. Poster #7543, IV Intern'l Conf. on AIDS, Stockholm, 1988.
16. Uribe-Botero G et al. Detection of mycobacteria by floures-
cent staining in bone marrow specimens from AIDS/ARC patients.
Poster #7546, IV Intn'l Conf. on AIDS, Stockholm, 1988.
17. American Thoracic Society, Centers for Disease Control.
Mycobaterioses and AIDS. Amer Rev of Resp Dis 136:492-6.
18. Centers for Disease Control. Diagnosis and management of
mycobacterial infection and disease in persons with human immuno-
deficiency virus infection. Ann of Inter Med 106:254-256, 1987.
19. Young LS et al. Mycobacterial infections in AIDS patients,
with an emphasis on the Mycobacterial avium complex. Rev of
Infec Dis 8(6):1024-1033, 1986.
20. Young LS et al. Mycobacterium avium complex infection. Jour
of Infec Dis 157(5):863-967, 1988.
21. Valenti W et al. Treatment of M. avium-intracellulare infec-
tion. IV Intern'l Conf. on AIDS, abstract #7547, Stockholm,
1988.
22. Lucas CR et al. Evidence that drug therapy may be effective
in Mycobacterium avium intracellulare (MAI) bacteraemia. IV
Intern'l Conf. on AIDS, abstract #7534, Stockohlm, 1988.
23. duMoulin GC et al. Concentration of Mycobacterium avium by
hospital hot water systems. JAMA 260(11):1599-1601, 1988.
24. Saver S. American Medical News, Chicago, IL, pp 1; 44-45,
2/17/89.
25. Personal communication.
26. Personal communication.
27. O'Doherty MJ et al. Differences in relative efficiency of
nebulizers for pentamidine administration. The Lancet p. 1283,
12/03/88.
28. Smaldone GC et al. Characteristics of nebulizers used in the
treatment of AIDS-related pneumocystis carinii pneumonia. Jour
Aerosol Med 1(2):113, 1988.
29. Smalldone GC et al. Report to DeVilbiss, 7/14/88.
30. A Treatment-IND for the use of aerosolized pentamidine in
HIV-infected individuals at high risk for PCP. Sponsored by:
Lyphomed, Rosemont, IL, protocol chairman: David W. Feigal, MD,
MPH.
31. Newman SP et al. In vitro comparison of DeVilbiss jet and
ultrasonic nebulizers. Chest 92(6):991-4, Dec. 1987.
32. Corkery KJ et al. Aerosolized pentamidine for treatment and
prophylaxis of pneumocystis carinii pneumonia: an update.
Respiratory Care 33(8):676-85, Aug. 1988.
33. Newman SP et al. In vitro comparison of DeVilbiss jet and
ultrasonic nebulizers. Chest 92(6):991-4, Dec. 1987.
34. Smaldone GC et al. Characteristics of nebulizers used in the
treatment of AIDS-related pneumocystis carinii pneumonia. Jour
Aerosol Med 1(2):113, 1988.
35. Smalldone GC et al. Report to DeVilbiss, 7/14/88.
36. Corkery KJ et al. Aerosolized pentamidine for treatment and
prophylaxis of pneumocystis carinii pneumonia: an update.
Respiratory Care 33(8):676-85, Aug. 1988.
37. O'Doherty, MJ et al. Differences in relative efficiency of
nebulizers for pentamidine administration. The Lancet p. 1283,
12/03/88.
38. A Treatment-IND for the use of aerosolized pentamidine in
HIV-infected individuals at high risk for PCP. Sponsored by:
Lyphomed, Rosemont, IL, protocol chairman: David W. Feigal, MD,
MPH.
39. Bernard EM et al. Prevention of PCP with aerosol pentamidine.
IV Intern'l Conf. on AIDS, abstract #7169, Stockholm, 1988.