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Being Alive
The Top Ten HIV/AIDS Stories of 1993
Mark Katz, M.D.
January 5, 1994
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 complications.

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 cycle? 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 infected cells.

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 to.

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 increased.

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 infection!)

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