DNCB Treatment Today

in AIDS TREATMENT NEWS. We publish it not because of any
judgment about the value of DNCB in treatment of HIV disease,
but because a number of people are now making decisions about
whether or not to use this controversial treatment, and they
need information.

Seven years ago AIDS TREATMENT NEWS published an in-depth
article on DNCB (chemical name dinitrochlorobenzene, a
chemical which is painted on a small patch of skin and causes
a reaction much like poison oak -- see issue #14, September
26, 1986). At that time the "guerrilla clinics" that
dispensed DNCB were a national news story, and probably
hundreds -- perhaps thousands -- of people with AIDS or HIV
were using the treatment. Later, almost everyone abandoned
it; for years there seem to have been no more than a few
dozen people (and perhaps fewer) using it anywhere for HIV or
related conditions.

But during the period of early enthusiasm there were
commendable efforts to get DNCB studied scientifically. These
efforts were frustrated by the all-too-familiar obstacles and
delays which have impeded everything that has happened in
AIDS treatment development. But despite the obstacles, and
after much hard work, a small, limited study did get off the
ground. Recently, years later, its results were published.

While scientists see this data as preliminary and suggestive
at best, the published paper has provided a focus for a
handful of activists, mostly in San Francisco, to promote
DNCB with relentless enthusiasm, often suggesting that people
stop other treatments which their physicians have
recommended. Because of the gloom about treatment prevailing
at this time, and because the DNCB advocates have media
access and skills, and because few have put forward opposing
views, these advocates are influencing the treatment
decisions of an increasing number of people. Healing
Alternatives Foundation (the San Francisco AIDS buyer's club)
reports selling 55 DNCB starter kits a week, both directly
and through mail order; some other groups also distribute
DNCB, but we do not know how much.

The following article is based on hundreds of pages of
documentation, interviews with 15 users of DNCB, and
additional interviews with researchers, activists, and
physicians. AIDS writer Dave Gilden started with no
preconceived conclusion about whether or not DNCB is useful.
He finished with no final answer, but with a strong
impression of how thin the evidence is. JSJ]

* * *

Since AIDS TREATMENT NEWS reported on DNCB seven years ago,
public interest had largely disappeared, but now it is on the
rise again. One man, who works in the office of a physician
specializing in HIV and just obtained the substance for his
lover, commented, "My lover's helper T-cells are down to
seven. What we have right now has helped but isn't going
anywhere. We have used everything out there, and we need more
drugs."

Because interest is now high in the community, and DNCB has a
number of enthusiasts who promote it, AIDS TREATMENT NEWS
undertook an extensive investigation to examine the existing
evidence that it might or might not be beneficial. We started
with an open mind and used several different approaches,
interviewing researchers, practicing physicians, and people
with HIV. Despite the reams of documentation issued by DNCB's
supporters, in the end we could find little to substantiate
this chemical's effect in HIV.

But anecdotal reports of long-term stabilization in people
using DNCB, especially in combination with other treatments,
mean that this approach cannot be dismissed out of hand. And
even if DNCB turns out to be ineffective in most people, it
may point the way to other, more broadly beneficial compounds
with similar modes of action.

Background

DNCB is a very powerful stimulator of a skin immune response
known as delayed-type hypersensitivity. When dissolved in
acetone and painted on a small area of the skin, it causes a
rash that peaks a day or so after application. After
penetrating the skin, DNCB combines with cell surface
molecules, causing an immune response as if foreign cells
were present. Virtually everyone with an intact immune system
eventually can be sensitized to DNCB after repeated
applications, and so can most people with AIDS. People react
to DNCB in a very similar manner as they do to poison oak or
poison ivy.

Delayed-type hypersensitivity reactions involve the branch of
the immune system known as cell-mediated immunity. Certain
white blood cells called cytotoxic lymphocytes (as well as
activated macrophages) are the main kinds of cells which
produce this response. (Cytotoxic lymphocytes are among the
cells with CD8 receptors on their surface, as distinguished
from T-helper cells, which have CD4 receptors.) For the
purposes of this article, there is no reason to go too deeply
into the theory behind DNCB. Suffice it to say that it is
used in hopes of increasing the body's systemic cell-mediated
immune defense against HIV.

DNCB's use as an AIDS treatment was first proposed by L.
Bruce Mills, M.D., a dermatologist and researcher who learned
of its use for treating certain warts in children, while he
had been working at Stanford University. Treating just a
small patch of skin could cause the warts to disappear all
over the body -- clearly by provoking a systemic immune
response, not only the local rash caused by DNCB in the area
being treated. Dr. Mills published his experience treating 26
people with AIDS or ARC in 1986.(1) Ensuing articles in the
Advocate and other publications helped spread the news. But
after months of publicity and widespread use of DNCB,
community interest almost disappeared for several years.

The Revival, the Data, and the Doubts

Interest in DNCB has revived this spring, largely due to the
efforts of journalist Charles Caulfield; his articles in the
gay newspaper San Francisco Sentinel and his presentations
around the country described an apparent reversal in his
disease progression after using DNCB since July 1992.
Caulfield reports that his T-helper cell count continued to
decline (after he started DNCB), then went back up within
months from a low 140 to 490; and, correspondingly, his
absolute CD8 count went from 400 to 1190 during the same
period. Clinical symptoms, such as thrush and diarrhea,
disappeared. Caulfield for years had been taking oral
acemannan (an aloe vera plant extract that is a purported
immune stimulant), which he credited with keeping him
disease-free after seven major opportunistic illnesses five
to ten years ago. For the first six months on DNCB, Caulfield
also self-administered injectable acemannan; we will discuss
combination therapies below.

Although Caulfield has been quoted as saying that DNCB (plus
acemannan) has virtually eliminated his AIDS,(2) in an
interview with us he confined himself to terming DNCB, "a
permanent general prophylaxis."

Most of Caulfield's documentation of his personal success
with DNCB comes from a lymph node removal performed last
February, as part of the well-known series of biopsies to
investigate HIV pathogenesis at NIH's Laboratory of
Immunoregulation (directed by Anthony Fauci, M.D.).(3) Our
examination of those biopsy results, which Caulfield has
distributed, indicates a picture that is not so optimistic.
It is clear that the lymph node architecture is seriously
eroded, as is typical of people with lengthy HIV infection,
and there continues to be a large number of HIV-infected
cells in the nodes and bloodstream. On the other hand, the
lymph nodes retain their ability to trap considerable amounts
of HIV particles with their follicular dendritic cells, even
though these cells no longer exist in an organized tissue.
Cells that take part in cell-mediated immunity also still
exist in large numbers, but their capacity to mount a
response to foreign protein is diminished. At our press time,
Caulfield had returned to the NIH for a second biopsy, which
should give an indication of the trend in his disease process
-- whether he is improving, worsening or stable. It will also
indicate how representative the first lymph node was.

The NIH has also examined a lymph node from two other DNCB
users. Results are not yet available for the second of these
biopsies, but the first reveals a picture similar to
Caulfield's, although better. Immune cell counts were higher
and HIV levels lower. Once again, a large number of
follicular dendritic cells remained, although the structure
of the node was considerably degenerated.

This result came from one of the founders of the DNCB
"guerrilla clinic" movement in the 1980s, who is once again
active in distributing the chemical. He told us that his T-
helper cell count had fallen to 70 three years ago. He then
resumed using DNCB after several years hiatus during which he
was on AZT. At the time of the lymph node biopsy his T-helper
cell count was up to 779. "They told me at the NIH that this
is the closest thing to a cure they've seen," he happily
related.

Dr. Fauci mentioned DNCB as a treatment strategy worth
investigating at this June's International Conference on AIDS
in Berlin. We talked on the telephone with him to get a
better sense of his interest in DNCB as well as his appraisal
of his lab's results so far. Dr. Fauci stated that he
understood he was being misquoted in the community. Fauci,
who also oversees AIDS research for the entire NIH, told AIDS
TREATMENT NEWS, "We did lymph node biopsies on people without
immune modulation, and now we want to study patients who are
taking immune stimulants. DNCB is one among many such
substances. One of our patients was on DNCB and said it
turned him around. He told us about other people taking it,
so now we're looking at them. When people have a positive
experience, it makes a drug interesting, although such
experiences happen with many drugs that ultimately don't pan
out."

On the subject of the lymph nodes, Fauci, as well as Giuseppe
Pantaleo, M.D., another major figure at the Laboratory of
Immunoregulation, were adamant that you cannot tell anything,
good or bad, from one or two lymph node biopsies. Said Fauci
about the results of the two biopsies, "I can't comment until
I have a firm scientific finding, which may take another ten
to thirty biopsies, depending on the magnitude of DNCB's
effect. But I want to make it clear that I'm not damning
DNCB, nor am I endorsing it."

More new data on DNCB was published this spring by Raphael
Stricker, M.D., and colleagues in three presentations(4,5,6).
The first was a report on a 20-person "pilot study" sponsored
by the California Pacific Medical Center (where Dr. Stricker
was working), Project Inform, and the Elizabeth Reed Taylor
Foundation.(4) One of the report's co-authors is William
Epstein, M.D., an expert on contact dermatitis who has worked
with DNCB since the nineteen fifties. Dr. Epstein advised the
study investigators on safe, proper application of the
chemical.

Almost two years ago Dr. Epstein told this writer, "I can't
say whether DNCB is having any effect in AIDS. If so, it's
not an obvious effect." Now he thinks, "The study results
look interesting. It looks like there is some value, and we
know DNCB won't make the disease worse. But it is very hard
to show an immune modulator's benefit. We need to follow up
with many more subjects and more time."

AIDS TREATMENT NEWS at this point has contacted five of the
paper's co-authors. Strangely, only Drs. Stricker and Epstein
wished to associate themselves with the results; two of the
others refused to comment on the record at all. Dobri Kiprov,
M.D., a co-author and Dr. Stricker's superior at California
Pacific, told us, "I personally feel that the results do not
justify any excitement or further workI The study was
published against my judgment." (Project Inform, a principal
sponsor of the study, states that it was not given the
opportunity to review the data prior to publication.)

A glance at the data shows good reason for doubt. Although 20
people started the trial, two do not appear in the published
data for unstated reasons. Another two volunteers dropped
out. Other than the fact that volunteers had not been
diagnosed with AIDS, and had T-helper cell counts of from 100
to 500 (average: 347), no information is presented as to the
study participants' health. There is no control population
for comparison. Average values for "pre-DNCB" and "post-DNCB"
data were presented for the sixteen continuing participants,
who were observed for a period of three to twenty months.
Since the two averages are calculated from measurements taken
at greatly different points in treatment, they are even
harder to interpret than usual.

In any case, there was no noticeable increase in CD4 (T-
helper) cells. While there was a modest 20 percent average
gain in CD8 counts, none of that increase occurred among
cytotoxic lymphocytes, which remained stable. (There was,
though, no indication that DNCB negatively affected anyone's
counts.)

In the words of a statistician of our acquaintance, "You're
down to the anecdotal level here. Unless there was a dramatic
difference, you probably need more people to achieve anything
that has real significance."

As Dr. Epstein pointed out, trials of immune modulators for
treating HIV/AIDS are notoriously hard to evaluate. Measuring
subpopulations of immune system cells is difficult because
the tests are inaccurate. And even if you can get accurate
counts, their meaning is hard to analyze because they tell
little about functional improvement in the immune system. Is
any of the new activity aimed against HIV?

Dr. Stricker tried to resolve this issue by using a new test,
known as quantitative PCR, to measure how HIV levels in the
blood changed after DNCB treatment began. Unfortunately, the
company doing the testing, which was using its own private
version of quantitative PCR, pulled out of the project after
analyzing only a few early samples from just 11 of the
volunteers, including the two dropouts. The paucity in the
PCR data was not mentioned in the published article.

The company involved, HRI Research of Concord, California,
would not even let its name be associated with the data. When
contacted, an official of the company refused to comment on
the reasons for this rupture, except to say that the company
had other, more pressing work to do and that the DNCB
situation had become intensely "political."

Quantitative PCR data right now is still more controversial
than cell subset measurements. There is first of all the
question of whether the test is accurate; even if it is, the
reason for fluctuations in viral load is hard to understand.
And even if you tested many subjects many times, it is not
clear how much of a change in viral load is needed to make a
difference in symptoms.

On the surface, the published PCR data looked at least
promising: The overall average viral load decreased by 38
percent among the nine in the study who both continued on
DNCB and had blood samples tested. But because of all the
questions surrounding these figures, AIDS TREATMENT NEWS
obtained the charts for all the individual study participants
in whom virus load was measured by PCR. It turns out that the
figures for two people, whose initial PCR results showed
exceptionally high blood levels of HIV, seriously skewed the
published overall averages. These two were only evaluated
once by PCR after the original, pre-treatment measurement.
The only post-treatment measurements were carried out on
samples taken just two months after the original ones, and
the results were two- and four-fold less than the first time
around. Without more data points to establish a trend, the
reasons for these two larger drops can only be speculated.
The observed declines could merely reflect faulty test
results, or something else in the volunteer's lives besides
DNCB. Whatever the reason for the two anomalous cases,
eliminating them from the DNCB data seriously weakens the
quantitative PCR results.

Dr. Stricker admits that the study data is weak. "We have
lots of frozen samples waiting for PCR testing," he lamented,
"This was just a pilot study with no controls, but the data
looks good, especially when you compare the compliant and
noncompliant participants. DNCB is an attempt to boost the
immune system to control HIV. It is a very crude technique,
but it is the only thing we have."

In a poster at the Berlin AIDS Conference,(5) Dr. Stricker
presented "follow-up" data on 24 volunteers (some of them
apparently new people) involved in the DNCB trial. The
average length of observation is longer, but the results are
similar to the original paper in Immunology Letters. So are
the problems. This time there is no quantitative PCR data to
sort out. On the other hand, seven "noncompliant" subjects,
really those who chose to drop out of the study, were sorted
out and contrasted with the volunteers continuing with DNCB.

The problem here is the classic one of self-selection. Those
who happen to do worse tend to quit a therapy, while those
who are doing better, for whatever reason, tend to continue.
One indicative sign is that the "noncompliants" started the
trial with considerably fewer cytotoxic lymphocytes than the
continuing participants. Considering the noncompliants apart
from the compliants is not a fair way to judge a therapy's
efficacy. (Note that the published abstract of the poster
presentation -- the poster was presented at the Berlin
conference, but has not yet been published -- does not
separate the compliant and non-compliant. It shows that the
average CD4 count dropped from 353 to 251 -- hardly a
positive result for DNCB.)

More Personal Experience

Billi Goldberg, a San Francisco DNCB treatment activist who
assisted in analyzing the trial results, replies to
criticisms of Dr. Stricker's study by saying, "We ran the
trial on a shoestring and we got published. I just want to
know whether people on DNCB lived, and I let other people
argue about trials."

Dr. Stricker himself says, "The study participants are all
doing very well after three years. [Actually, the average
follow up time at this point is only about 18 months,
Stricker later conceded.] The poster at Berlin received a lot
of attention from NIH scientists like Fauci and Pantaleo as
well as from Jonas Salk. I would like to continue the study
for five years." Unfortunately, Dr. Stricker and California
Pacific Medical Center recently came to a parting of ways,
reportedly at least partly due to the DNCB trial, and the
study is in limbo. Be that as it may, Stricker continues, "I
know 30 people around the country who have used DNCB for up
to seven years and are doing very well. Some of them were
diagnosed with AIDS four years ago."

To be fair, other groups also have had trouble demonstrating
the efficacy of their proposed immune modulators (see, for
example, AIDS TREATMENT NEWS #168 on thymopentin, a thymus
hormone derivative). Given the lack of any accepted way of
proving such substances, perhaps, for the present, we can
only look at personal experiences with DNCB to see how
individuals are faring on the treatment. If some people feel
DNCB has helped them, then DNCB may be promising for at least
a certain subgroup.

Indeed, Dr. Stricker followed this method last spring, in a
brief article(6) which presented a table on "clinical and
laboratory features of ten long-time DNCB users." Six of the
ten became infected with HIV in 1984 and 1985, and three in
1982; one was reportedly infected in 1979. (Several of these
dates were established by testing frozen blood samples.) The
ten started on DNCB between 1986 and 1989.

Using DNCB or not, there are a large number of people who
survive HIV, even with an AIDS diagnosis. This writer has met
dozens of people who have been stable for three years or more
with low T-helper cell counts, and hardly any are on DNCB. As
for statistics, Susan Buchbinder, M.D., who is Chief of
Research at the AIDS Office of the San Francisco Health
Department, reports that in an HIV-positive group she is
following (the San Francisco City Clinic Cohort), eight
percent of the members have lived for ten years or more with
HIV while retaining normal or near normal T-helper counts.(7)
And only half the group members experience an AIDS-defining
illness in their first decade with HIV. (See AIDS TREATMENT
NEWS # 178, "Berlin: Long-Term Survival Studies Suggest New
Treatment Strategies," for background on possible reasons for
long-term survival.)

With this in mind, the table presented by Dr. Stricker shows
a group of remarkable but not exceptional people. Seven of
the ten have low T-helper (CD4) counts, ranging from 30 to
350. For nine of the ten, CD8 counts were within the usual
range for people with HIV (1,000 or somewhat above except in
late-stage disease.) Of the three stellar performers, one is
listed as also taking isoprinosine and another is on compound
Q.

But one table showing undated post-DNCB immune cell counts
does not say much one way or the other. Perhaps these people
experienced dramatic improvements in their health after
starting DNCB. Maybe their physical condition is much better
than their helper-T cell numbers indicate. Because of these
lingering questions, AIDS TREATMENT NEWS interviewed 15
people currently using DNCB. Eight have been applying the
substance for six months or less, but seven were long-time
users of up to seven years. At least four of these seven were
among the ten included in Dr. Stricker's published note.

Since these were committed users by and large, it was to be
expected that negative impressions would be few. Typical of
these people's sentiment was the statement of one man: "The
further I go from western medicine, the better I feel."
Several people mentioned how empowering the weekly act of
applying DNCB was. A common comment was that DNCB increased
energy levels. Also, many people felt that their symptoms
cleared up faster after starting DNCB, especially those
involving the skin, mouth and vagina.

The most frequent negative effect was scarring and persistent
rashes from the DNCB application. One person said he has
constant welts on all the recent patches of skin where he
painted DNCB. This person further suspected that DNCB was
making him "hyperallergic" to other things as well, such as
chlorinated pools and antibiotics, both of which now give him
hive-like rashes, although they never did before.

This person, who was using DNCB for six months until he
recently stopped, also saw his CD4 and CD8 cell counts, low
to begin with, drop by 60 percent. Most of the newer users
haven't yet seen much change in blood counts, except for one
man whose CD8 count went up from 700 to 1100.

The long-time DNCB users we contacted claimed they were able
to minimize DNCB rashes by learning the concentration and
amount to apply that produced only a small, temporary red
spot. Other than that, their reports were mixed. Four of the
seven have gone for years without severe symptoms, but one is
now seriously ill with cryptosporidium, an intestinal
parasite; and in another, blood counts are dropping. A fifth
man came down with lymphoma in 1990 while on DNCB, but is
generally healthy now. He believes an improved method of
applying DNCB has helped to preserve his health since this
episode. However, he also had a course of chemotherapy and
then was treated with acupuncture for three years. He also
takes megadoses of various vitamins.

This use of multiple treatment strategies is typical. Only
four of those interviewed (two short-time and two long-time
users) are at present on an exclusive DNCB regimen. Chinese
herbs are popular among this group, as are antioxidants (such
as NAC, beta carotene, and vitamin C), megavitamins, and
coenzyme Q. In addition, many are taking co-trimoxazole
(Bactrim, Septra) to prevent pneumocystis pneumonia, plus a
variety of antibiotics to treat lesser infections.

One person who has adopted a multifaceted approach is long-
time DNCB user Thomas Avena. He said, "When I work with my
health, my cell counts go up. I confront my level of fear,
meditate, take walks, and concentrate on my diet. Meditation
is work, but it gives me tremendous benefit. Every illness I
have seems activated by frustration and stress."

Larry Janssen, who started DNCB last winter, commented, "I'm
saying that DNCB is part of the portfolio of options, it's
not the answer. Everybody wants to be told what to do, but
you have to figure out what works for you." This seemed to us
to be as succinct a summary of our interviewees' experience
as anything we could say.

DNCB in Real Life

Talk of combination therapies bothers Billi Goldberg, a
retired civil engineer who at the moment is the main popular
theorist of DNCB. (Several of the DNCB users we interviewed
said that they were convinced to start on the chemical
because they were impressed by the writings of Goldberg on
the science behind DNCB.) Goldberg has based a case for DNCB
on the work of Drs. Mario Clerici and Gene Shearer at the
National Cancer Institute and others on the "Th1-Th2 switch"
-- a possible suppression of cell-mediated immunity-- as an
indicator progression to AIDS.(8) They argue that the decline
in cell-mediated immunity, orchestrated by the Th1 subset of
T-helper cells, results from an increase in antibody
production, which is governed by the activity of Th2 T-helper
cells. These two T-helper cell subsets tend to suppress each
other, and a predominantly Th2 defense against HIV seems less
effective than a predominantly Th1, cell-mediated response.

According to Goldberg, "DNCB is not the answer, but a step in
the right direction. It will boost cell-mediated immunity and
control intracellular infections, which are most AIDS
opportunistic infections. The people it works best in are
those who get off all drugs except PCP prophylaxis. They must
be treated for the other diseases should they appear. People
who are asymptomatic and get off herbs, which increase
antibodies, and high-dose vitamin C, which suppresses
lymphocyte proliferation, they do well." Although DNCB is
supposed to counter the immune-suppressing effects of HIV and
help control opportunistic infections, Goldberg thinks that
most major medications used in AIDS have white blood cell
toxicity that can interfere with DNCB's effect -- either by
impeding the cell-mediated immune response directly or by
promoting the Th2 immune mode that discourages cell-mediated
immunity. The only exception, in his view, is temporary use
of acemannan as a complementary salvage therapy in people
whose absolute CD8 counts have fallen below 400.
(Isoprinosine is another possibility.) DNCB, meanwhile, is to
be taken for life.

There is mounting evidence from long-term survivor studies,
and elsewhere, that some kind of cell-mediated immunity is
crucial to maintaining health during HIV infection (again,
see AIDS TREATMENT NEWS # 178 on long-term survivors). But
nearly everybody with HIV (including people with high CD8
counts) also produces anti-HIV antibodies -- that is why they
test positive on the HIV blood test. Shearer and Clerici are
not nearly as rigid on the subject as Goldberg. Dr. Shearer
explained over the telephone, "All we're certain about is
that cell-mediated immunity is important. It's possible to
have both cell-mediated and antibody immunity in HIV. The
distinctions are fuzzy. The question is how to optimize the
immune balance, and we don't know how to extrapolate from our
experiments with in vitro cell clones."

One of the pioneers of lymph node studies in HIV is Cecil
Fox, Ph.D., who is president of Molecular Histology
Laboratories. Dr. Fox is collaborating with the NIH team in
the current lymph node study.

Dr. Fox told AIDS TREATMENT NEWS, "People who think they are
going to meet the challenges of this disease with one drug
are fooling themselves. This is a multifactorial disease
going on for a decade or two of a human's life. One drug is
not going to be effective for all that time. In the future
there will be an HIV treatment armamentarium. Different
treatment combinations for different phases will be
appropriate, with therapy changing from year to year
depending on the person's needs." Fox predicted that an
effective regimen would be available within the next several
years. He did not exclude DNCB as a possible candidate for
his "armamentarium."

A Physician's Experience

The physician today with probably the broadest on-going
experience with DNCB is David Payne, D.O., of Mesa, Arizona.
Dr. Payne started recommending DNCB a year ago and now has
150 HIV patients on it. Echoing Dr. Fox, Dr. Payne is trying
DNCB as part of a combination of medications that evolves
according to disease stage. Among the other treatments Dr.
Payne suggests are hypericin and curcumin as antivirals, and
blood root (sanguinaria), which may work as an immune
stimulant. Some of his patients also are taking nucleoside
analogs such as