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Past Issues
Volume 15, number 1
January 2001
Contents
Women, Men and Viramune
Are there gender differences in nevirapine toxicity?
Get Out The Dictionaries
A brief lesson in medical terminology
Salvation in Your Medicine Cabinet
Recycle those excess drugs and help the world
Pipeline Preview
On the eve of the Retrovirus Conference, new drug news
Sex Differences in Nevirapine
Rash and Hepatitis
By Bob Huff
Last year, the AIDS world was rocked when news came that the South
African Medicines Control Commission had halted a study of an experimental
HIV drug after two women in the trial died and several others developed
severe liver disease. Coming in the months leading up to the International
AIDS Conference in Durban, this episode catapulted the problems
of bringing HIV treatments to South Africa into the international
spotlight.
The experimental drug in the trial was FTC, a compound in the same
therapeutic class as AZT and ddI. But blame for the women's deaths
came to rest on one of the other drugs the women received in their
combination cocktail: Nevirapine, an approved, non-nucleoside reverse
transcriptase inhibitor already at the center of another raging
controversy about access to treatment in South Africa.
A Breakthrough for Treatment in Africa?
A widely hailed study (HIVNET 012) reported in 1999 that, for only
four US dollars, a single dose of nevirapine (Viramune) given to
a pregnant woman about to give birth and another dose to her baby
could dramatically reduce the chances that the infant would be infected
during labor and delivery. For the first time it seemed a grip had
been gained on the intractable problem of treating HIV in poor countries.
Nevirapine for prevention of mother-to-child HIV transmission was
effective, it was practical and it was relatively affordable. But
was it safe? South African government officials, reluctant to spend
scarce resources on saving the babies of HIV-infected mothers, claimed
there was too little known about the side effects of nevirapine
to make it widely available. Ominously, the FTC trial deaths seemed
to back them up.
A close look at the experience with single-dose nevirapine finds
little cause for concern. In the HIVNET 012 study, 310 pregnant
women received single-dose nevirapine and another 308 women received
AZT just before giving birth. The rates of adverse events and drug-related
toxicity were observed to be similar in the groups. The incidence
of laboratory abnormalities was also similar in each group. Mild
to moderate rash was reported for four mothers in the nevirapine
group and five in the AZT group. Among the babies, nine in each
group had a mild or moderate rash. No serious rashes were reported
for any participants.1 In another large trial of nevirapine
involving 652 pregnant mothers in South Africa who each received
two doses of the drug, there were no episodes of liver toxicity
or serious rash reported.2
Because no placebos were used in these trials, one cannot conclude
that the risks of adverse events are any greater or lesser for mothers
who do not receive antiretroviral drugs just before birth. And the
long-term effect upon the development of treated children can only
be determined by years of follow-up. But the low rates of serious
adverse events observed suggest that these treatment regimens are
safe, at least in the short term. So safe, in fact, that the HIVNET
authors proposed that presumptive treatment of all pregnant women
with single-dose nevirapine may be justified in settings where HIV
testing and pre-test counseling are not affordable.
But what caused the deaths and liver disease in the FTC trial and
was nevirapine responsible? In a complicated stratified trial design,
participants received FTC or lamivudine (3TC, Epivir) plus, depending
on their baseline viral load, either nevirapine or efavirenz (Sustiva/Stocrin,
another drug in the same class as nevirapine). Participants also
received stavudine (d4T, Zerit) as a background nucleoside analog
to round out the cocktail. All participants were monitored for elevated
liver enzyme levels, the standard laboratory markers for the development
of hepatitis. There were no reported differences in the incidence
of severe (Grade 4) liver enzyme elevations between those who received
3TC and those who received FTC. Nor were any differences observed
in these enzyme levels between blacks and non-blacks in the study.
But of 385 patients receiving nevirapine in the trial, 36 (9%) had
Grade 4 liver enzyme elevations while no such liver enzyme abnormalities
were observed in 83 patients receiving efavirenz. This clearly pointed
the finger at nevirapine. And, as we later learned from a report
at the Fifth International Congress on Drug Therapy in HIV Infection
in Glasgow, Scotland last November, women in the trial were twice
as likely as men to experience a Grade 4 elevation of liver enzymes
during the first four weeks of taking nevirapine. This is compelling
evidence from a randomized trial that there may be a sex difference
in the likelihood of liver disease for those who receive nevirapine.3
PEP Tragedies
About the same time as the nevirapine crisis was developing in
South Africa, in the United States an HIV-negative African-American
healthcare worker suffered a needle-stick accident as she was drawing
blood from an HIV-infected patient. She was placed on a post-exposure
prophylaxis (PEP) protocol containing AZT, 3TC and nevirapine. Fourteen
days after starting the drugs, she developed malaise, fatigue, fever
and chills. At 20 days, the HIV drugs were halted after her liver
enzyme levels increased dramatically above the normal range. A week
later she developed liver failure and went into a coma. She subsequently
received a liver transplant, recovered and remained HIV-negative
six months after the accident.4
Two more tragic case reports involving post- exposure prophylaxis
were presented at the Glasgow conference. Two women who had been
raped were treated with a PEP regimen containing nevirapine. Both
women required liver transplants after liver disease developed within
a month on the regimen.5 And in yet another needle-stick
accident, a female health-care worker in Chicago complained of nausea
and anorexia eight days after starting a PEP regimen containing
nevirapine. She subsequently developed a severe rash despite discontinuing
the drug after the first symptoms occurred.6 Due to these
and other cases, the U.S. Centers for Disease Control (CDC) in January
2001 warned against the routine use of nevirapine in post-exposure
prophylaxis regimens.7
Background to the Warnings
January 2001 marked the tenth anniversary of the first use of nevirapine
in humans. The problems with skin rash and liver enzyme abnormalities
were detected during the earliest trials of the drug. These eventually
led to manufacturer recommendations that patients start nevirapine
treatment at a lower dose for two weeks until it was clear the full
dose could be safely tolerated. After several years of clinical
experience with nevirapine and a mounting number of serious adverse
reactions, culminating in the South African deaths, the European
Medicines Evaluation Agency (EMEA) issued a strong public statement
in April of 2000 drawing sharp attention to the risk of liver disease.
The statement stressed the importance of following the two-week
lead-in period, intensive monitoring during the first eight weeks
of therapy and immediate discontinuation of nevirapine if certain
symptoms occur. Of particular concern are symptoms of severe rash,
hypersensitivity reaction or hepatitis, including elevated liver
enzymes.8
These warnings were strengthened six months later when the manufacturer
sent a letter to U.S. health care professionals extending the critical
initial period of close monitoring to 12 weeks. Yet, as noted in
that warning, approximately one-third of adverse events have been
reported to occur after 12 weeks.9
Despite the strength of these warnings to the medical community,
despite the doubled rate of hepatitis among women in the FTC trial,
and despite an apparent preponderance of case reports about severe
and fatal adverse events involving women, there have been no official
cautions about any particular danger for women starting nevirapine.
Sex Differences in Nevirapine Rash
Recently, additional evidence was published that says women may
have more frequent skin-related adverse events when starting nevirapine.
An article in Clinical Infectious Diseases (January 2001)
reports on a retrospective cohort study that finds likely significant
differences in the incidence of nevirapine-associated rash between
men and women.10
The researchers examined the medical records of all patients from
three large U.S. HIV clinics who received nevirapine for at least
30 days during the period from 1993 through September 1998. Patients
who discontinued nevirapine due to severe skin rash prior to 30
days on treatment were also included. The patients studied had been
treated in clinics at Washington University in St. Louis, the University
of North Carolina in Chapel Hill and at UCSF in San Francisco. The
primary outcome of interest was a report of severe (Grade 3 or 4)
rash during the first 90 days of nevirapine treatment. A secondary
outcome was discontinuation of nevirapine due to any degree of rash.
The search of medical records found 358 individuals (95 women;
263 men) from the three sites that met the entry criteria for nevirapine
use. The overall incidence of severe rash during the first 90 days
after starting nevirapine was 3.4 percent. But women were eight
times more likely to have had severe rash than men, with an incidence
of 9.5 percent compared to 1.1 percent for the men. Also, women
were five times more likely to have discontinued nevirapine due
to any degree of rash than were men.
When any rash (from mild to severe) was counted, about 16 percent
of women and 8 percent of men were affected. Two women and two men
experienced Stevens-Johnson syndrome, a life-threatening form of
severe rash in which large sheets of skin die and peel off. Because
of the smaller number of women treated with nevirapine, the two
cases represent a larger proportion of women with Stevens-Johnson
syndrome than men. There were apparently no deaths reported due
to nevirapine in this sample. The incidences of elevated liver enzymes
and liver disease were not collected.
While the sex of the patient was strongly associated with the development
of severe rash in this study, other possible factors were also identified.
Individuals with higher CD4 counts when starting nevirapine tended
to have more episodes of severe rash and had to stop therapy due
to rash more often. Patients younger than 35 years tended to discontinue
nevirapine more often than older patients but did not have significantly
more cases of severe rash. Of 23 women who took birth control hormones,
4 (17%) experienced severe rash compared to 5 of 72 (7%) women not
taking contraceptive hormones. In this population, 76 percent of
the women were African-American compared with 43 percent of the
men. The authors report, however, that no association was observed
between race and the incidence of rash in the study.
Rash Decisions
Although the key clinical trials that led to the approval of nevirapine
uncovered a risk of having skin reactions when starting the drug,
none of those studies examined the differential risk between men
and women. One company-sponsored report also presented at the Glasgow
conference last year described an early, large (2,249 patient) trial
comparing nevirapine with placebo. The authors reported an equal
incidence of elevated liver enzymes in each comparison arm and a
greater number of liver-related deaths in the placebo arm. Overall,
women comprised 20 percent of that study population although, once
again, the adverse event rates for men and women were not reported
separately.11
There is a small amount of provocative evidence that women may
experience more adverse reactions to medications in general. Though
not HIV-specific, two surveys of hospital inpatients performed in
the 1970s and 1980s found a generally increased risk of drug-related
skin reactions among women, reporting an incidence in women 35 to
50 percent higher than in men.12,13 But the authors of
the nevirapine sex differences study caution that, while the differences
they found in the incidence of severe rash between men and women
are statistically significant, the overall number of episodes of
rash in their study are small and could possibly be due to other,
unexamined, factors. Another limitation of the study is that the
observations were not pre-planned but were collected from medical
records after the fact. Retrospective studies of this sort can contain
undetected biases if, for example, different staging systems for
rash were used at different times or at different sites. One limitation
in particular is a lack of information about any additional medications
patients may have been taking while they were receiving nevirapine.
Despite these caveats, the authors conclude, it is at least safe
to say that the risk of nevirapine rash cannot simply be extrapolated
between sexes, as is commonly done. This is a particular problem
since our knowledge of adverse reaction rates is drawn from study
populations with small proportions of women. As demonstrated by
the sex-differences study, overall incidence rates of rash may be
similar to the rates for men, but rates for women may appear dramatically
higher when they are isolated. Since no previously published study
of nevirapine has differentiated adverse reaction rates by sex,
clinicians and patients have no choice but to judge expected rash
episodes by published overall incidence rates or by anecdotal experience.
Although most nevirapine-associated deaths have been liver-related,
the sex-differences study only reported on the relative incidence
of rash. Yet, mild to moderate rash may be one of the warning symptoms
of liver disease. In the South African FTC trial, rash was temporally
associated with Grade 4 liver enzyme elevation in 25 percent of
cases. If this association is common, then an increased incidence
of rash may possibly warn of an increased risk for liver disease
among women starting nevirapine. Compounding the risk for black
women, it's been suggested that the appearance of rash on darker
skin may be more difficult to diagnose than on lighter skin.14
Add to this an increasing trend among physicians to "treat through"
mild nevirapine rash when initiating therapy, and the need for close
clinical management and frequent monitoring of liver enzymes becomes
crucial.
The evidence of sex differences in the incidence of drug-associated
rash and liver disease suggests that women, with whom most U.S.
clinicians probably have less overall experience, need vigilant
monitoring and extra counseling about possible treatment-associated
adverse events — including rash — when initiating an antiretroviral
regimen containing nevirapine.
Footnotes:
1. Guay LA, et al. Intrapartum and neonatal single-dose nevirapine
compared with zidovudine for prevention of mother-to-child transmission
of HIV-1 in Kampala, Uganda: HIVNET 012 randomized trial. The
Lancet. 1999 254:795–802.
2. Moodley D, et al. Evaluation of safety and efficacy of two simple
regimens for the prevention of mother to child transmission (MTCT)
of HIV infection: nevirapine vs lamivudine and zidovudine used in
a randomised clinical trial (the SAINT study). (Abstract TuOrB356)
XIII International AIDS Conference, Durban, South Africa, July 9–14,
2000.
3. Sanne I, et al. Severe liver toxicity in patients receiving
two nucleoside analogues and a non-nucleoside reverse transcriptase
inhibitor. (Abstract) Fifth International Congress on Drug Therapy
in HIV Infection, Glasgow, UK. AIDS. 2000;14(supplement):PL
9.3.
4. Sha BE, et al. Adverse effects associated with use of nevirapine
in HIV postexposure prophylaxis for 2 health care workers. (Research
Letter) JAMA. 2000;284:21.
5 . Henderson D. Post-exposure prophylaxis. (Abstract) Fifth International
Congress on Drug Therapy in HIV Infection, Glasgow, UK. AIDS.
2000;14(supplement):PL 6.1.
6. Johnson S, et al. Adverse effects associated with use of nevirapine
in HIV postexposure prophylaxis for 2 health care workers. (Research
Letter) JAMA. 2000;284:21.
7. Centers for Disease Control and Prevention (CDC). Serious adverse
events attributed to nevirapine regimens for postexposure prophylaxis
after HIV exposures — Worldwide, 1997–2000. MMWR.
2001 Jan 5.
8. European Agency for the Evaluation of Medicinal Products. EMEA
Public Statement on Viramune. April 2000; EMEA/11260/00.
9. Roxane Laboratories. Important Drug Warning Re: Severe, life-threatening
and fatal cases of hepatotoxicity with Viramune. November 2000.
10. Bersoff-Matcha SJ, et al. Sex Differences in Nevirapine Rash.
Clinical Infectious Diseases. 2001;32:124–9. (This study was
first presented as a poster at the 6th Conference on Retroviruses
and Opportunistic Infections in 1999).
11. Cahn P, et al. Hepatic safety with nevirapine (NVP) and two
nucleosides in patients with advanced HIV infection, from a placebo
(PBO) controlled clinical endpoint trial (1090). (Abstract) Fifth
International Congress on Drug Therapy in HIV Infection, Glasgow,
UK. AIDS. 2000;14(supplement):PL 8.6
12. Arndt KA, Jick H. Rates of cutaneous reactions to drugs: a
report from the Boston Collaborative Drug Surveillance Program.
JAMA. 1976;235:918–22.
13. Bugby M, et al. Drug induced cutaneous reactions: a report
from the Boston Collaborative Drug Surveillance Program on 15,438
consecutive inpatients. JAMA. 1986;256:3358–63.
14. Gilden D. Liver Failures Spark Nevirapine Warning. (Statement
by Franck Rosseau, V.P. for Medical Affairs, Triangle Pharmaceuticals,
sponsor of the FTC trial). The amfAR Treatment Insider. August
2000;1(4).
But is it really, really safe?
Although no severe rashes or liver problems have been reported
for single-dose nevirapine given to pregnant women, the original
Phase I study of nevirapine in pregnant women may be worth taking
a closer look at. In a trial conducted at seven hospitals in the
United States and Puerto Rico, seventeen women in active labor were
given single doses of nevirapine (either 100 mg or 200 mg) when
they arrived at the hospital. The women had previously been enrolled
in the study and were receiving a standard course of zidovudine
to prevent HIV transmission to their infants. Blood samples were
drawn at frequent intervals after the nevirapine dose and daily
after delivery. The levels of nevirapine in the blood samples were
charted to find the peak concentration and the rate of clearance
from the body.
Nevirapine has a relatively long life in the blood (ideal for preventing
mother-to-child transmission) but the amount of time nevirapine
remained in the bodies of these pregnant women varied dramatically
— both between the women on the study and from historical data
in men and non-pregnant women. One woman, who received a 100 mg
dose, still had more than half the nevirapine in her blood after
seven days. Considering that one of the needle-stick victims who
started prophylactic nevirapine (see 'PEP Tragedies') developed
symptoms within 8 days, it's not unimaginable that there may eventually
be a rare adverse event resulting from single-dose nevirapine. Yet,
this scenario is highly unlikely because, as in the needle-stick
case, symptoms have only developed after several consecutive days
of daily dosing.
If nevirapine is slower to clear from women's bodies, whether pregnant
or not, then the increased incidence of rash and liver problems
among women on daily-dosing regimens may be due to a gradual accumulation
of the drug to toxic levels. The wide variability of drug concentrations
seen in pregnant women and reports of slower clearance of nevirapine
from non-pregnant women point to the need for additional pharmacokinetic
studies of nevirapine in women.
Footnotes:
Mirochnick M, et al. Pharmacokinetics of Nevirapine in Human Immnodeficiency
Virus Type 1-Infected Pregnant Women and Their Neonates. Journal
of Infectious Diseases. 1998;178:368–74.
Lamson MJ, et al. Effects of gender on the single and multiple
dose pharmacokinetics of nevirapine. Pharm Res. 1995; 12:S-101.
| Representation
of Women in Key Clinical Trials of Nevirapine |
|
Clinical Trial
Investigator, Journal, Year |
Total NVP Enrollment |
Number of Women Enrolled |
| De Jong, JID 1994 |
10 |
0 |
| Havlir, JID 1995 |
21 |
0 |
| Havlir, JID 1995 |
21 |
5 |
| Cheeseman, JAIDS 1995 |
62 |
2 |
| D'Aquila, Annals 1996 |
199 |
34 |
| De Jong, JID 1997 |
20 |
0 |
| Henry, JAIDS 1998 |
330 |
41 |
| Montaner, JAMA 1998 |
98 |
8 |
| Floridia, JAIDS 1999 |
27 |
5 |
| Barreiro, AIDS 2000 |
104 |
14 |
| Podzamczer, 7th Retro 2000 |
~72 |
~19 |
| Cahn, Glasgow 2000 |
~1125 |
~234 |
|
| ~ denotes estimation |
Basic Tips on Understanding Medical Terminology
By Cathy Elliott-Lopez — Women Alive, Los Angeles
Living with HIV is a constant learning process. Not only are we
forced to learn about the disease itself, but in many instances
we must learn the medical jargon that is associated with it.
For those of us who lack a formal medical education, this is often
a difficult process. I remember learning during early childhood
that there were usually two, and sometimes three, different names
for the same part of the human body. There was the common term,
which we all learned, like head, arm, etc.; there might be a "kid's"
term like "pinkie," and then there was the obscure "medical term."
How many of us remember having this one pulled on us in the third
or fourth grade? "Psst! Hey, your epidermis is showing!" Mortified,
we invariably glanced toward our genital region assuming we had
left something unzipped — only to have the other kids laugh
and shout, "Epidermis means skin!"
For the majority of us (unless we actually chose to pursue a career
in the medical field) our vocabulary of medical terminology stopped
growing after high school health class. I recall during the first
few years after my diagnosis when I was striving to learn as much
as I could about the disease. I attended countless medical updates
and conferences only to come out feeling more ignorant than when
I went in. It seemed like things that could have been said very
simply using good old-fashioned English got twisted around with
medical jargon.
But before we criticize the researchers, doctors, and medical professionals
in general, we must realize that these powerful, and in many cases,
brilliant people to whom we entrust our lives have spent years and
years in school to learn this stuff. We really can't expect them
to flip back and forth between their world and ours just like that.
That's why we need to meet them halfway. It wasn't until I got a
grasp of the lingo the docs were using that I started to understand
what they were talking about, and in so doing, I began to take charge
of my own care.
The Basics
To begin, it must be understood that most medical terminology derives
from Latin or Greek. If you didn't study these in school, or even
if you did, I suggest you visit the local library and check out
a medical dictionary (or perhaps your doctor will let you borrow
one). Dorland's Medical Dictionary is a handy one to start with.
By no means will you become an expert overnight — remember,
it takes years for that. But at least if you can understand some
of the words and how they're formed, you'll be well on your way
toward making sense of what you read and hear at treatment updates
regarding new medications and research data.
Start by looking at the whole word in question. For example "pancytopenia."
Then break it down into its various parts. Pan-cyto-penia. In this
example, pan means all or total, cyto refers to cells,
and penia indicates a deficiency. So the definition of pancytopenia
is a deficiency of all blood cells. Got it? O.K.
Let's try another one. How about "lipodystrophy" (I know that's
a favorite). Let's break it down. Lipo refers to fat; trophy
is talking about growth or development. And anything with the word
dys in it has an abnormality. So there it is! Lipodystrophy:
An abnormal development of fat. Anyone for liposuction?
Here's an even simpler one, "leukocyte." We've already learned
that cyto refers to cells. If you look up the definition
of leuko, you'll see that it means white. So a leukocyte
would be a white blood cell. Ta-Da! It should now be easy to figure
out what leukocytopenia means. And if you knew that erythro
means red, how would you say "deficiency of red blood cells" in
medical-ese?
All right, so you're not as enthusiastic about this as I am. That's
O.K. I'm sure as you gradually learn this stuff you will eventually
come across some word (one that you hear all the time but never
understand) and you'll be able to use this system to figure it out.
I can hear you now, "Aha! So that's what perianal pruritis means.
Cool."
| Here is a
list of commonly used medical terms to start you on your way: |
|
| Prefix/Suffix |
Example |
| a = an absence of |
a/vir/emia
(no virus in the blood) |
| alg(ia) = pain |
neur/algia
(nerve pain) |
| anti = attacks |
anti/retroviral
(attacks retroviruses) |
| contra = against |
contra/ceptive
(against conception) |
| cyt(e,o) = cell(s) |
macro/cyte
(big cell) |
| dys = abnormal |
dys/plasia
(abnormal growth) |
| emia = in the blood |
tox/emia
(toxins in the blood) |
| endo = inside |
endo/scopy
(examining the inside) |
| erythr(o) = red |
erythro/cyte
(red blood cell) |
| gastr(o) = stomach |
gastr/itis
(stomach inflammation) |
| gen(esis) = origin, new |
osteo/genesis
(formation of new bone) |
| glyc(o) = glucose (sugar) |
hyper/glyc/emia
(high blood sugar) |
| hem(ato) = blood |
hemato/logy
(study of the blood) |
| hepat(o) = liver |
hepat/itis
(liver inflammation) |
| hyper = high, elevated |
hyper/lipid/emia
(high blood lipid levels) |
| intra = within |
intra/muscular
(in the muscle) |
| itis = inflammation |
pancreat/itis
(inflammation of the pancreas) |
| leuk(o) = white |
leuko/penia
(deficiency of white blood cells) |
| lip(o) = fat |
lipo/dys/trophy
(abnormal fat development) |
| lysis = break up |
cyto/lysis
(breaking up cells) |
| mal = bad, poor |
mal/nutrition
(poor nutrition) |
| mega(lo) = large |
mega/dose
(large dose) |
| my(o) = muscle |
my/algia
(muscle pain) |
| osteo = bone |
osteo/pathy
(bone disease) |
| penia = deficiency |
osteo/penia
(deficiency in the bones) |
| peri = around |
peri/oral
(around the mouth) |
Recycling HIV Drugs:
Exporting Medicine, Experience and Hope
By Bob Huff
This article is about a program started by HIV-positive people
in New York to send surplus HIV medicines to people who need them
in Latin America.
Despite the desperate need for HIV treatment in parts of the developing
world with soaring rates of death due to AIDS, pharmaceutical companies
have been reluctant to either reduce prices or to set up meaningful
drug donation programs. The companies have claimed that drugs sent
to regions without an infrastructure for monitoring and educating
patients will be wasted and may even contribute to an epidemic of
drug resistance that will sabotage treatment efforts down the line.
But by focusing on the problems of providing HIV treatment on a
mass scale, these arguments have shifted attention away from effective
actions that can be taken immediately. Fortunately, networks of
individuals have emerged in Europe and the United States willing
to send HIV drugs to developing regions by recycling and redirecting
the excess supply of rich countries.
AID for AIDS — A Case Study
AID for AIDS (AfA) was begun in 1996 in a New York City East Village
apartment. Gay men from Venezuela living in New York collected unused
HIV medications and started sending them to their HIV-positive friends
back home. During the first year they provided 20 people with drugs.
Most of those first clients are still alive, many of them now staffing
local offices of AfA in their home countries. Last year, AfA served
248 clients and shipped over $3 million worth of HIV drugs from
New York to people in Latin America and around the world. AfA has
done this with no significant help from pharmaceutical companies,
relying instead on donations of drugs and money from individuals
in the States and abroad.
AfA now has regional offices in Venezuela, Peru, Chile and the
Dominican Republic. AfA regional offices are part of the fabric
of AIDS service organizations in the home country and AfA staffs
are all members of the local AIDS communities. AfA also maintains
liaisons with local government agencies and social security programs.
Since each country served has different resources and needs, local
representation helps ensure AfA's responsiveness. For example, in
Venezuela, individuals who are employed are eligible for local Social
Security, which will pay for HIV medicines. But the government AIDS
drug program is not always reliable and sometimes AfA has to step
in if supplies are interrupted. Although there is a Public Health
Service available to unemployed Venezuelans, it has no money to
buy AIDS drugs. It's not uncommon for Public Health social workers
to send clients in need to AfA. Virtually no private insurance system
in Latin America pays for HIV drugs.
AfA has served about 500 individuals since its operations began;
250 clients are actively enrolled in the program, and there are
currently about 150 people who have qualified and are waiting for
drugs. Only six children are currently receiving medicines, but
AfA is developing a "Kids Project" to increase the amount of pediatric
formulations of HIV drugs that are donated.
Capacity Building
Besides providing drugs and assistance to people living with HIV
in Latin America, AfA considers it an important part of its mission
to improve the local professional capacity to prescribe and manage
antiretroviral therapy. Doctors are informed about drugs, their
side effects and interactions. International treatment guidelines
(from the U.S. and the local country, if any) are distributed and
AfA's client qualification policies are explained. Doctors gain
experience using the drugs and adjusting regimens with results of
CD4 assays and, increasingly, HIV RNA and genotype testing. More
importantly, physicians, patients, families and the community see
evidence that AIDS does not need to be fatal and that treatment
is effective.
Theorists of economic development refer to this process of distributing
knowledge and experience as "capacity building." Hans Binswanger,
an HIV-positive man and Director of the Environmental, Rural, and
Social Development Department for Africa at the World Bank, is a
proponent of immediately extending treatment to developing countries
without waiting for organized improvements in infrastructure. Binswanger
believes that drug recycling efforts are a positive move. He maintains
that as drugs are imported and used, local infrastructure will spontaneously
begin to develop. Medical labs will upgrade their equipment as the
demand for CD4+ counts increase and viral load assays will soon
follow. If and when large-scale donation programs begin to operate,
there will already be in place a network of doctors experienced
with using the drugs and managing patients. As the thin end of the
wedge, the recycling programs may have an impact that extends far
beyond the lives directly saved.
Some critics say recycling programs are futile since drug donations
provide a mere "drop in the bucket"compared to what is needed in
developing countries. But to any of the 250 people served by AfA
last year, it's a life-giving drop. And because many of AfA's clients
are involved in HIV advocacy and prevention, the lives saved stay
engaged in the work of saving other lives. A cadre of committed
activists serve as walking advertisements for the power of HIV treatment
as they help organize community pressure on government and non-governmental
agencies to expand treatment opportunities further.
AfA is committed to documenting the impact of their efforts so
others can learn from their experience. AfA-sponsored research was
presented in a poster session at the International AIDS Conference
at Durban, South Africa, in 2000. AfA also has partnered with researchers
at the University of Rio in Brazil to obtain free HIV genotype testing
for their clients.
Making it Work
AID for AIDS has established a set of procedures to ensure that
scarce resources are used to the greatest effect. These procedures
include standards for accepting clients, insuring the quality of
the drugs, protecting the confidentiality of clients, and following
up to see that drug regimens are effective. Just as important are
procedures that provide education for professional development and
a system for medical review of cases and outcomes.
Who is Eligible?
To qualify for AfA drugs, patients must document that they meet
the medical criteria.
- Patients must have fewer than 300 CD4+ T cells/mm3,
documented with a T-cell count within the past three months. If
CD4+ counts are not locally available, blood can be shipped to
a lab that will perform the test. AfA staff routinely telephones
the medical laboratories to confirm CD4+ count results.
- Clients with higher CD4+ counts may also be eligible if they
can document viral load greater than 50,000 copies/mL within the
past three months. However, viral load assays are not currently
as available in Latin America as CD4+ counts and are not required.
- Any patient with one or more documented opportunistic infections
may qualify without immediate CD4+ counts. CD4+ counts must subsequently
be submitted, however.
Additionally:
- Clients must also furnish a medical history, copies of lab reports
for liver enzymes, renal function, pancreatic enzymes, lipid profiles,
and complete blood count. Results of a syphilis test, a tuberculin
skin test, toxoplasma serology, and, for women, a Pap test are
also requested.
- Potential clients must provide a copy of a doctor's prescription
for each medicine requested.
- Clients must have no other way to receive medication such as
through private funds, social security or another drug recycling
program.
- Clients must agree to have a CD4+ count performed every six
months after starting the program. This is essential to demonstrate
that the current regimen is working for the patient and also to
provide data for ongoing AfA follow-up and research. If CD4+ counts
remain low despite treatment, AfA medical staff contacts the client's
doctor to consult about changing regimens. If clients live in
a city with an AfA office, they will be evaluated and counseled
about adherence. Persistently non-adherent clients will be terminated.
If a client is unable to pay for the six-month CD4+ count, AfA
will help find someone to pay for the test (about US $30.00).
If a client fails to provide a CD4+ count when requested at the
end of each six-month period, his or her drug supply will be terminated.
- There is always a waiting list for the service, but AfA gives
preferential priority to AIDS activists and prevention workers.
This is to ensure that people who are trained and committed to
fighting HIV are able to keep working. AfA sees this as an investment
that multiplies the benefit of the medicines.
- The final condition for receiving drugs is that a sufficient
and sustainable supply is available. If a requested drug is scarce,
AfA medical reviewers may suggest substitutes to the client's
doctor. If an alternate drug cannot be arranged, individuals will
continue on the waiting list until a secure source develops.
Client Screening
AID for AIDS has its headquarters in New York City and currently
has regional offices in Santiago, Caracas, Lima, and Santo Domingo.
Clients who enter the program through the regional AfA offices are
counseled and screened by local AfA medical staff. The local offices
collect the application documentation and fax it to New York, where
it is evaluated and the client is qualified. Clients who live in
remote areas of countries with AfA offices will apply to and receive
their drugs through the local office. Clients from countries without
a local office must apply to and receive drug shipments from the
New York office directly.
When a new client is accepted into the program, the New York medical
officer assigns a confidential client code number. Thereafter, all
cases are processed and prescriptions filled by code number only.
Names are linked only to client numbers when the sealed cartons
of drugs are actually shipped.
In New York, inventories are maintained on a real-time basis and
the local offices are updated weekly about what is in stock. If
requested drugs are not available or if the AfA medical staff thinks
the prescribing doctor has made a mistake or has prescribed an ineffective
regimen, the doctor is contacted. If supplies are short, the client's
doctor is informed of which drugs are available and given the option
to change the prescription. If the doctor has constructed an inappropriate
combination, educational materials are provided that explain current
treatment guidelines. If the AfA medical officer is still not satisfied
with the prescription, a case review is conducted.
Case presentations are made to a panel of five AfA-associated doctors
who reside in the various countries served. The panel is presented
with the patient's clinical history, a recent CD4+ cell count and
a viral load result, if available. Case presentations are confidential.
Reviewers give their individual opinions about the best drug combination
for the patient, with a written explanation for their choice. These
opinions are summarized and are sent to the client's doctor. The
review process is intended to be a learning opportunity for all
involved and is a critical part of the AfA mission to educate providers
about HIV treatment and clinical management. If a client's doctor
continues to prescribe inappropriate combinations, the client is
counseled to select a doctor with experience in the accepted use
of HIV medications.
If AfA learns that a client has stopped taking the supplied drugs
or is selling them on the black market, the client is terminated
from the program. So far, most clients have been highly motivated
and adherent.
The Role of Local Offices
The regional offices, in addition to screening clients and distributing
drugs, provide support groups, education and adherence education.
Local staff can refer people with HIV to other agencies and government
assistance programs. Some offices also offer supportive services
such as massage and advice about herbs and alternative therapies.
Clients in countries with no local office receive long-distance
telephone counseling and educational materials from New York.
Local offices also provide services to people on the waiting list
and to people who do not yet qualify for treatment. Secondary prevention
counseling is crucial to reduce transmission from healthy but virally
unsuppressed individuals. Treatment and adherence education in advance
helps prepare people for a successful outcome when they eventually
qualify for therapy.
Regional offices also maintain on hand a small stock of locally
donated drugs to cover emergencies or to temporarily supply patients
until a government program takes over. If an individual's government-provided
medications are interrupted due to bureaucracy or error, the local
drug bank can offer an interim supply. The local drug banks also
occasionally send emergency supplies to AfA sister offices when
needed. However, no drugs are shipped to the New York office.
Dispensing the Drugs
All full-time clients of the program are served and dispensed from
the New York office. Computer-generated fill-sheets detail the client
code number and monthly medication count for that client. Orders
are filled on an individual basis and sent in their original bottles.
An individual's entire order is packaged together in a single bag
coded with the client number.
Monthly supplies destined for clients in a country with a local
office are packed together in a carton and shipped to that office.
The local office receives the shipment and checks-in each order,
matching the prescriptions to the drugs received. Individual supplies
are then picked up by clients at the office or are mailed within
the country to the client. Clients in countries without a local
office receive individual packages directly from the New York office
each month.
Shipping from New York is by FedEx, by courier (usually friends
of AfA who are traveling to the country) or is otherwise sponsored
by individuals who donate shipping fees. Drugs are shipped only
out of the country. There have been no unsolvable customs or regulatory
problems encountered to date. Newer formulations of drugs such as
Norvir that can survive brief periods without refrigeration have
made overnight shipping of all HIV drugs feasible.
Finding the Drugs
When donated drugs arrive in the New York AfA office, any previous
patient's name labels are removed. If a bottle has been opened,
each individual pill is visually checked for damage. Drugs will
be distributed up to six months past their date of expiration. The
drugs are inventoried and placed in an air-conditioned drug storage
room. Medicines that require cold storage are placed in refrigerators.
Inventories are updated daily and low supplies trigger a search
for new donations of that drug.
Drugs donations come from a variety of sources. Most donors are
people with HIV in the U.S. who have accumulated an excess supply
after a change of regimen or have collected unused drugs from friends.
Social workers and clinics have been reliable sources for recycled
drugs. AfA currently is supplied by about thirty different organizations
that routinely collect excess drugs.
What Does it Take to be Effective?
Jesus Aguais, the director of AID for AIDS, is outspoken about
the need for new drug recycling programs to take on this work and
for existing ones to increase their activity. However, he is adamant
that recycling programs should be prepared to implement operating
procedures as stringent as AfA's if they expect to be effective.
Starting a drug-recycling program might seem like an attractive
way to provide direct aid to those who need help. But it takes more
than a good heart to establish and run a program, says Aguais. The
consequences of an interrupted supply in terms of resistance or
for the possibility of misdirected resale of drug demands a carefully
structured system of client validation and follow-up. At the very
least, having close ties with local AIDS service organizations and
PWA groups are crucial. Aguais stresses that programs need to be
"fact-based," with a direct connection to clients and their needs.
Building upon an established network of support for PWA's is a good
start.
An easier initiative for concerned individuals and groups in the
U.S. to set up is a collection-point operation. On the supply side,
well-established connections with clinics and social workers are
important to ensure a steady flow of donations. AfA has developed
a "Starter Kit" for individuals and groups who would like to collect
excess medicines for recycling programs. The essence of this effort
is to make local contacts with AIDS agencies, social workers and
doctors to solicit drug donations and to collect funds that will
support shipping costs. AfA provides guidelines and a sample flyer
in the Starter Kit.
Ultimately, a committed medical and support staff that is willing
to work long hours for next-to-nothing is at the heart of the program's
success. Says Aguais: "If we run out of money it's not a disaster,
as long as we have the drugs to send. We have some angels we call
on to pay the FedEx bill."
Money is a constant struggle, but so far AfA has survived and grown
on individual contributions. A fundraiser sponsored by POZ Magazine
has been the latest lifeline. Aguais says the next step is to start
seeking grant money to help them expand their service. Pharmaceutical
company contributions have been minimal. Regional offices are funded
primarily by individuals in these countries. There are four full-time
workers in Venezuela, three in Peru, one in Chile, and one in the
Dominican Republic. Six full-time workers, including a physician,
staff the New York office along with the help of volunteers and
unpaid staff. Promises of funding for new offices in Colombia, Honduras
and Brazil have been received.
AID for AIDS Immigrant Program
As an offshoot of their drug-recycling work, AfA uncovered an unmet
need among immigrants to the New York region that they decided to
address. HIV-positive immigrants to the United States, regardless
of legal status, have few support services to help them obtain HIV
medications. AfA supports one case manager to serve 240 immigrant
clients with education, counseling and referral for care. AfA helps
this underserved population to enroll into Medicaid and state ADAP
programs that pay for HIV drugs.
Immigrants may lack a stable address or privacy at home, and they
may face stigma if HIV drugs are mailed to them directly. As a service,
AfA offers its address to receive medications mailed from pharmacies
and drug assistance programs, then holds the packages for pickup
by the client. This program does not involve recycled drugs and
is only for individuals who have a source of prescription drug assistance.
Most Common Drugs
The drugs most commonly shipped by AfA are ddI (Videx), nelfinavir
(Viracept), d4T (Zerit) and nevirapine (Viramune).
Currently there is a shortage of nelfinavir (Viracept) and efavirenz
(Sustiva, Stocrin). AfA has a surplus of amprenavir (Agenerase),
ritonavir (Norvir), saquinavir (Invirase) and delavirdine (Rescriptor).
A wide range of antifungal and other anti-infective drugs to treat
and prevent HIV opportunistic infections are also routinely shipped,
with TMP/SMX (Bactrim) the most requested drug. No narcotics are
accepted.
How You Can Help
Individuals in New York who wish to donate can call the AfA office
and arrange to have someone pick up the drugs. Those outside of
New York can mail their donations to the office. AfA will provide
FedEx shipping for large donations.
AID for AIDS
515 Greenwich Street, #506
New York, NY 10013
212/337-8043
aid4aids@aol.com
Other drug recycling programs
HIV Medicines for Guatemala
http://www.macaw.com/hivmeds/
Dr. Matt Anderson
Montefiore Family Health Center
360 East 193rd Street
Bronx, NY 10458
African AIDS Network
Lee Wildes
415/440-3722
lwildes@aidseti.org
Also, see the December 2000 issue of POZ Magazine's POZ
Partner for more about AID for AIDS and other HIV drug recycling
programs.
New Targets, New Drugs
The 8th Conference on Retroviruses and Opportunistic Infections
is being held in Chicago, IL during the first week of February this
year. As we went to press, a Monday morning session on antiretroviral
chemotherapy offered an update on the progress of several "new generation"
drugs in the development pipeline. Here's an overview:
New Targets — Fusion inhibitors
Attachment, fusion, and entry inhibitors were hot topics at the
conference with news about CCR5 inhibitors, a gp120-CD4 attachment
inhibitor, a gp120-coreceptor inhibitor and the gp41 fusion inhibitors,
T-20 and T-1249. Combinations of some of these agents in pre-clinical
testing have been reported to have synergistic anti-HIV activity.
Now a few are reporting results from early human testing.
T-1249 is a younger sibling to T-20 and is said to have a non-overlapping
resistance profile. Both drugs are given as daily injections under
the skin. Seventy-two drug-experienced patients were enrolled to
receive T-1249 injections as their only therapy for 14 days. Doses
ranged from 6.25 mg per day to 50 mg per day on a once or twice
daily schedule. Median decreases of HIV RNA from baseline at the
end of 14 days were correlated with dosage — down –1.40
copies/mL at the highest dose. An improvement over T-20, once-a-day
injections of T-1249 seem to provide adequate blood levels. One
case of hypersensitivity reaction and one case of severe (Grade
4) neutropenia were reported. As with T-20, mild pain at the site
of injection occurred in nearly half of the participants.
T-20 and is said to have a non-overlapping resistance profile.
Both drugs are given as daily injections under the skin. Seventy-two
drug-experienced patients were enrolled to receive T-1249 injections
as their only therapy for 14 days. Doses ranged from 6.25 mg per
day to 50 mg per day on a once or twice daily schedule. Median decreases
of HIV RNA from baseline at the end of 14 days were correlated with
dosage — down –1.40 copies/mL at the highest dose. An
improvement over T-20, once-a-day injections of T-1249 seem to provide
adequate blood levels. One case of hypersensitivity reaction and
one case of severe (Grade 4) neutropenia were reported. As with
T-20, mild pain at the site of injection occurred in nearly half
of the participants.
New Protease Inhibitors (PI)
BMS-232632 is a new protease inhibitor that has efficacy in line
with that of the competition but gets bonus points for once-a-day
dosing. The quality that may distinguish this newcomer is a remarkable
lack of blood lipid abnormalities compared to other protease inhibitors.
Lest anyone rejoice that this is the first non-toxic HIV drug, blood
lipid levels have not been definitively associated with certain
treatment-related toxicities, such as lipodystrophy. BMS-232632
also has one striking peculiarity: Mild to moderate elevation of
unconjugated bilirubin has been observed in nearly all patients
to receive the drug. Although these bilirubin elevations have been
asymptomatic and no other liver laboratory markers have been affected,
larger Phase III trials lay ahead and long-term follow up will determine
the drug's safety.
DPC 681 and DPC 684, billed as "second generation" protease inhibitors,
have entered Phase I safety trials. Pre-clinical studies report
inhibitory activity at attainable plasma levels against several
subtypes of HIV-1 as well as clinical HIV-1 isolates with multiple
mutations known to reduce susceptibility to current generation protease
inhibitors.
And a pre-clinical report on what some will surely choose to call
a "third generation" protease inhibitor, a drug yet to be tested
in people, called TMC126 shows activity against multi-drug resistant
viral isolates at extremely small concentrations and atypical mutation
patterns when resistance does emerge.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI):
TMC120 is a new orally available NNRTI from the Belgian laboratory
bringing us TMC126. Its first use in people was reported at the
conference. The drug is said to be active against HIV strains that
are less susceptible to current generation NNRTI, such as efavirenz.
In a Phase I study design similar to that reported for T-1249 above,
43 treatment-naive patients (34 men, 9 women) were randomized to
receive either 50 mg or 100 mg of TMC120 or placebo, twice daily
for 7 days as their only therapy. On the eighth day, median decreases
in HIV RNA from baseline were correlated with dosage, with drops
of –1.44 log copies/mL for the 50 mg dose; –1.51 log copies/mL
for the 100 mg dose; and –0.17 log copies/mL for placebo. Mild
sleep abnormalities were noted.
Treatment Issues will have more from the 8th Retrovirus Conference
in our next issue.
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