TP-5: Thymus Hormone Trial Suggests Benefit

Evidence that the thymus gland suffers extensive damage
during HIV infection has led to research on using thymus hormone
replacement therapy as a means to counteract the damage. Thymus
hormones are proteins that affect the development of immune
system T-cells in the thymus gland. They also enhance immune
function in mature T-cells in the blood and lymph. While their
exact role in AIDS therapy is unclear, various experiments
suggest that injecting thymus hormones can increase the numbers
of the various T-cell subpopulations. By enhancing the activity
of the immune system's killer cells, they may increase these
cells' ability to seek out and destroy cells infected by HIV.

Three injectable thymus hormone derivatives are now in
formal trials as AIDS therapies -- TP-5 (thymopentin), THF-g2
(thymic humoral factor) and thymosin-alpha1. No toxic effects
have been noted for any of them.

Despite years of interest in using thymus hormones for AIDS,
hard data has been lacking. Now, investigators claim they have
data showing that injecting TP-5 three times a week confers some
protection against progression of HIV disease.

"In my mind, there is very strong evidence that the drug
prevents progression to AIDS-related conditions," said Marcus
Conant, M. D., a San Francisco AIDS physician and researcher.

The latest TP-5 study, conducted by Dr. Conant and others,
compared the drug against a placebo for 48 weeks in 354
asymptomatic HIV-positive persons. This study was double blind
-- no one knew who was getting TP-5 and who the placebo. All the
study participants took AZT, and they started out with T-helper
cell counts of between 200 and 500.

A close review of the data by AIDS TREATMENT NEWS verified
that something useful does seem to be happening: For those study
volunteers who had been on AZT for longer than six months,
protection against early symptoms of HIV infection was apparent,
though hard to quantify exactly. In this 235- person subgroup,
14 volunteers on placebo developed symptoms versus only four of
those on TP-5.

But major questions persist as to the extent of TP-5's
beneficial action. An attempt by Johnson & Johnson, TP-5's
sponsor, to accelerate FDA approval of the substance was rebuffed
when the company sat down with agency officials in December.

The corporate push began when the study was terminated four
months early by an independent, ad hoc Data and Safety Monitoring
Board (DSMB) reviewing the interim figures. Early termination by
a DSMB usually occurs because a study has already yielded
decisive results. The DSMB's decision on TP-5 sparked loose talk
of an impending step forward in AIDS care, similar to the
introduction of AZT for early HIV infection.

But no dramatic statistical observations underlie the DSMB's
reasoning. The board simply noted that the TP-5 trial was
dragging on for no reason. It would take another four months to
collect the final five percent of the data without any chance
that the study's conclusions could be significantly altered.

The DSMB noted that the data could be considered unreliable
in several respects:

% The drop-out rate was rather high, 20 percent in both the
placebo and treatment arms. High drop-out rates distort
study findings because the volunteers who are doing poorly
or who suffer adverse effects from the experimental drug are
most likely to be the ones who quit. One of the FDA's
requests to Johnson & Johnson was to perform an "intent to
treat analysis" on the data. Using this statistical method,
the company will have to include the drop outs' experience
over the 48 weeks as if they actually continued with the
study. We will then have a better picture of how well TP-5
would perform under real conditions, in which patients
frequently fail to follow prescribed treatments.

% The clinical symptoms used to judge progression of HIV
disease were limited and subjective. The criteria required
two of the following: 10 percent weight loss, temperature
of 38!C for five consecutive days or any 10 days out of any
30, unexplained diarrhea for seven out of any 30 days, just
one episode of oral candidiasis, a single localized eruption
of herpes zoster, or oral hairy leukoplakia. Confirmation
of symptoms was by clinical examination and patient report
only; it is possible that some signs of immune decline were
misdiagnosed or missed entirely. And other disease episodes
not on the trial's list would not be counted, even if they
were severe.

% There was also a T-helper cell criterion for progression
of HIV disease -- to be counted as progressing, an
individual's count had to drop below 200. However, there
was no difference at all in T-helper cell trends between the
study arms. Even in those with more than six months' use of
AZT, T-helper cell counts held steady on average throughout
the 48 weeks, no matter whether volunteers were on TP-5 or
not. Such a finding is at odds with the previous study of
TP-5 as an AIDS therapy (published in AIDS, November 1992,
pages 1335-1339). That small study did find indications of
T-helper cell protection using TP-5, but its volunteers did
not use AZT or any other antiviral medication. It may be
that the effect of AZT in the current trial overwhelmed and
hid any direct support TP-5 gives to T-helper cells.

When looking at a summary of the symptoms volunteers
developed, we were struck by how much TP-5's observed benefit
depends on differences in the rate of occurrence of thrush and
oral hairy leukoplakia. This limited difference has led to some
criticism in the AIDS activist community that TP-5 merely
represents an unnecessary alternative to simpler treatments for
these two diseases of the mouth. But there is no reason to
believe that TP-5 has any direct activity against these
conditions; therefore, if it reduced their incidence, it probably
did so by strengthening the immune system, implying that the drug
did work as intended. TP-5 seemed to make the biggest difference
for people who had used AZT for more than six months.

Howard Grossman, M. D., a New York City physician who
participated in the TP-5 trial, commented, "Even if TP-5 only
does a little, everybody with HIV will be on it if the price is
low." (Pricing is an issue because the effective dose of TP-5
costs about $100 per week in Italy, where the substance is
legally sold.)

According to Robert Kniffen, a Johnson & Johnson
spokesperson, the company is now putting together an expanded
access program (which will probably be free for those eligible).
Dr. Grossman noted that there really is no reason why anyone
eligible shouldn't participate since TP-5 has no record of
adverse side effects.

While the expanded access program is in operation, a
confirmatory study involving up to 1,000 people taking
antiretroviral therapy together with TP-5 or a placebo will be
carried out. Two years will go by before TP-5 can be approved.

Robert Kniffen summarized TP-5's current status in this
manner: "Details of the confirmatory study and an interim
expanded access program are being worked out in consultation with
the FDA and the principal investigators. The status of the drug
reflects the study data, which are unclear. The trick is to get
clear-cut, definitive data."

Another Thymus Derivative

Trials of other thymus hormone derivatives will also need to
show clear data on clinical improvement or viral load, since
these substances' effect on T-helper cell counts may not reflect
their total activity. At Stanford University, Thomas Merigan, M.
D., is conducting a federally-sponsored (ACTG) trial combining
thymosin-alpha1 (a thymus hormone derivative), IL-2 (a substance
used by the body to stimulate T-cell growth), and the anti-viral
drug AZT. Dr. Merigan will use his quantitative polymerase chain
reaction (PCR) technique to detect changes in volunteers' HIV
levels.

Thymosin-alpha1 attracted Dr. Merigan's interest because one
preliminary trial in people with chronic hepatitis B provided
evidence that thymosin cleared that virus from the body.

"Both thymosin and IL-2 affect lymphocyte maturation, but
thymosin works at an earlier point, so it may potentiate IL- 2's
action," Dr. Merigan explained.

Dr. Merigan's study raises the possibility that thymus
hormone derivatives may work better in combination with other
immune modulators.