Being Alive 1994 Jan 5: 1
This year the epidemic entered its thirteenth year; perhaps the much
sought-after luck is long overdue! For the fourth consecutive year, I
take this opportunity to record one observer's impressions of the major
stories of 1993.
1. The Concorde Study
The Concorde was clearly the most talked about study at this year's
International AIDS Conference, and both patients and providers are
still reeling on a daily basis from its effects. Opponents of antiviral
therapy could now say, "You see, AZT doesn't make a difference, and we
don't even understand what CD4 count means!" But proponents of therapy
feel that this study yields an important piece of data that had
previously been talked about, but not quite understood antiretroviral
therapy might have a finite period of usefulness for each patient and
we had been naive indeed to think that the benefits of AZT or any of
its relatives would last forever!
The study also revealed that while the AZT-immediately-treated group
ultimately looked clinically the same after three years, in comparison
to a group who was treated only when or if symptoms developed, the CD4
count of the immediately-treated patients remained higher throughout
the period of study. Indeed, the question now becomes, how reliable a
surrogate marker of clinical course is the CD4 count?
Proponents of antiviral therapy, and early intervention at that, also
had to their side of the column this year the publication in July of
the European Australian Collaborative Group (EACG) 020 study. This
study of 994 patients treated with 1000 mg AZT daily for almost 2 years
did show a statistically significant slowdown of fall in CD4 count or
development of AIDS in comparison to a placebo group.
To a greater extent than ever before, this year has seen the
polarization of opinion as to the timing and potential benefit of
antiviral therapy. We have a range of opinions, from those who would
take two drugs from the moment infection occurs or is diagnosed to
those who would never swallow a single AZT, ddI, or ddC pill, believing
that it would add nothing to quality or length of life!
2. Boosting the Immune System
Almost as a fitting complement to the above difference of opinion comes
this year's cataclysmic leap of faith and hope that the "money" may lie
in immune boosting therapies.
From interleukin-2 to autologous CD8 expansion to vaccine
immunotherapies, data is being gathered in this area which had been too
long ignored. Two important caveats underlie the use of immune
boosters. First of all, so as to not simply give the virus additional
targets to infect, most agree that antiviral therapy should be used in
conjunction with therapies which make more CD4 cells. Second,
researchers point out that while the promise of more CD4 cells may
possibly lead to fewer infections and ultimately greater longevity,
this fact has yet to be proven in a rational, scientific manner.
Martin Delaney of Project Inform reported in October that there is a
tissue bank in San Francisco which will soon begin accepting autologous
CD4 donations from HIV-infected individuals. So one has the possibility
of saving one's T-cells when there are plenty of them, for use at a
later time when there are not!
3. Anabolic Steroids
Although their across-the-board use is yet unproved, many hours of
discussion and some degree of controversy erupted this year over the
use of anabolic steroids such as testosterone to treat HIV and its
Donald Kotler, MD, of New York City and one of the "deans" of nutrition
and HIV, was quoted (I heard it myself!) as saying, "I am convinced
that within several years steroids will be an important part of
treating HIV patients." In Los Angeles, with or without proper
indications, several providers have been doing so for years.
While their use may reverse symptoms of wasting, increase libido and
reduce fatigue, we have yet to see a published scientific
placebo-controlled study which addresses these issues. Fortunately,
several well-respected local providers are beginning to gather such
data, and 1994 should give us more of an answer.
4. The AIDS Czar
Like her or not, Kristine Gebbie has stepped into a long-sought-after
pair of shoes; her appointment can be perceived as a statement that we
do at last have an Administration which cares about people with HIV.
Or, to others, she is seen as ineffectual and many years too late.
Sometimes, as I lay awake at night, I think about what would I be
asking if I were in her position. Here is one example: given a finite
number of dollars and researchers and subjects, should we have another
study to compare two or three antiretrovirals which work by reverse
transcriptase inhibition, or should we develop therapies which work at
some other of the fifteen or so defined steps in the virus's life
5. CDC Redefinition
The CDC first officially used the term and defined "AIDS" in September
of 1982. There were redefinitions, usually additions to the list of
surveillance conditions, in 1985 and 1987. As of January 1 of 1993,
four more conditions were added, bringing the total to 27.
The use of CD4 count less than 200 as qualifying for a diagnosis of
AIDS has led to a marked increase in cases locally and nationally, and
also statistically has made for a greater percentage increase in cases
among women than men.
6. "Designer" Antivirals
Antisense and other novel therapies began to make more sense,
especially with the increasing awareness that reverse transcriptase
inhibition by itself will not be enough. These feats of molecular
engineering pose some formidable problems, such as how to get them into
the cells where we want them without them first being degraded by the
body's own enzymes. Nevertheless, their specificities may enable them
to masterfully perform the tasks for which they are designed, and
unlike the already FDA-approved drugs, they work on chronically
GEM-91 is the first antisense compound to (soon) go into clinical
trials, and already a new improved GEM-92 has been formulated.
Ribozymes, also called "molecular scissors," are a related class of
compounds which have been developed to interrupt viral translation.
7. Genetics as Cofactor?
Studies presented at the International Conference in Berlin involved
subjects who were likely exposed to HIV but did not become infected.
These included African sex workers, as well as some members of the San
Francisco City Clinic Cohort who were infected but have not progressed
toward clinical illness (so-called long-term nonprogressors, which may
represent 8-9% of the total infected population).
These two populations the exposed but uninfected and the infected but
non-progressing may each have certain genetic correlations as seen in
the HLA antigens which are inherited from parents. A definitive
cause-and-effect has not yet been proven, but it is enticing to suppose
that such does exist. And it is rewarding to many to see that these
populations are at last being studied!
8. Liposomal Therapies
This recently developed technology has already made therapies of
certain HIV-related conditions much better tolerated. The encapsulation
of the drug-to-be-delivered enables it to better reach the target and
thus guards against the systemic side effects we have become so used
Liposomal forms of doxorubicin (Doxil) and daunorubicin (DaunoXome)
have been in clinical trials, and the results, especially with Doxil,
may be ushering in a new era of therapy for Kaposi's sarcoma.
Speaking of KS, the list of therapies in trial is staggering
pentoxifylline (Trental), antiangiogenesis compounds, trans-retinoic
acid, paclitaxel (Taxol), interleukin 4... in addition to the already
used systemic (alpha-interferon, Adriamycin/bleomycin/vinblastine,
etoposide) and intralesional therapies.
9. Cytokines Are In
Once belonging to the category of "technical jargon" understood by few,
cytokines have been better understood and have important roles in both
pathogenesis and treatment issues. These chemicals elaborated by cells
include interferons, interleukins and substances such as tumor-necrosis
factor (TNF) and platelet release factor (PRF).
Indeed, a prevalent theory of pathogenesis holds that in early HIV
infection the more benevolent cytokines, e.g. interleukin-2,
predominate, but that in later stages chemicals such as TNF-alpha are
10. Prophylaxis of OIs Widen
Rifabutin had been FDA-approved in the last week of 1992 to be used as
prophylaxis against MAC infection. We understand that it reduces
perhaps by 50% the number of new cases of MAC but, unlike TMP-SMX for
pneumocystis, does not bring these down to near zero.
An ACTG-sponsored trial (196) is currently comparing rifabutin as
prophylaxis to clarithromycin to the combination of the two.
CMV remains a major opportunistic infection without approved
prophylaxis; several small series of high-dose acyclovir show it to be
insufficient. Currently there are multi-center trials for each of two
substances, oral ganciclovir and an acyclovir prodrug (valaciclovir).
(And this year's list almost made it to its conclusion without the very
mention of the importance of pneumocystis prophylaxis, preferably with
TMP-SMX (Bactrim/Septra), for anyone with fewer than 200 CD4 cells, one
of the few unarguable tenets of treatment in the course of HIV