10 Big AIDS Stories (Plus One Tribute)
Mark Katz, M.D. looks at 1998
1. Is "The Gap" bridgeable?
No matter which statistic you read -- 10 million new infections since the 1996 Vancouver conference, 25 percent of sexually active adults in Zimbabwe infected, India having more HIV-positives than any other nation in the world -- the global message this year was indeed a dismal one.
For me, it overshadowed much of the continuing good news (see item 4 below) at home. And, by the way, you don't have to journey to a developing nation to witness "the gap" in access to education and treatment -- just visit any inner city in the U.S.
The theme of this past year's International AIDS Conference in Geneva was "Bridging the Gap." Delegates from Romania and Guatemala, nations which have perhaps yet to see a protease inhibitor (P.I.), wandered through aisles of pharmaceutical-sponsored booths and were able to fill up on Swiss chocolates or ice cream (or both), water bottles, and an assortment of totebags.
A lighted electronic counter sat at the front of the assembly on closing day and ticked off the number of people living with HIV in the world. I came into the arena that morning and it read 33,529,972. Next to it a printed sign of the International AIDS Society proclaimed, "Reasons to Be Here." By the time I left that morning's summary session, it had exceeded 33,533,000.
Next year's International Conference, which will be held in Durban, South Africa, will be the first ever to be held in a developing nation.
The American obsession with fat and body image took an ironic turn in the HIV world in 1998 as clinicians and researchers scrambled to find out what was happening, and why tens of thousands of persons living with HIV were developing buffalo humps, increased abdominal girths and enlarged breasts, all while fat was being pulled from now-more-spindly extremities.
Fat redistribution patterns had been observed for a while before 1998 began, but this year gave a more detailed description of the syndrome, seen mostly -- but not exclusively -- in people on protease inhibitors.
A detailed hypothesis of the syndrome was published in The Lancet (Volume 351, Issue 9119), and Andrew Carr and his group from Australia detailed the largest series yet described at the Geneva Conference. They found that close to 80 percent of their more than 100 patients on PIs reported some degree of alteration of body appearance by year two of therapy (AIDS 1998; 12:F51-58).
The most appropriate treatment of fat redistribution has yet to be determined and documented. Many were tried in 1998 -- protease-sparing regimens (see next item), use of a different PI, liposuction, growth hormone, etc. -- but the year closed without clear insight on what "it" is and what to really do about it.
The additional finding of elevated blood lipids in protease-treated patients may be part of this syndrome, but were important enough to me to merit a separate entry (see item 5).
3. Spare the protease?
One year ago, the term "protease-sparing regimen" had not yet made its way into the inventive and rapidly changing HIV lexicon.
The past year saw the release of several studies which touted potentially comparable benefits of triple combination regimens which contained no protease inhibitor, to the standard since 1996 of two reverse transcriptase inhibitors plus one PI. DuPont Pharmaceutical Company scored a coup at the Geneva Conference in releasing their DMP-006 data, which indicated that a regimen of AZT, 3TC and efavirenz (their soon-to-be-released non-nucleoside RT inhibitor, Sustiva) was comparably potent -- perhaps more so -- than a regimen of AZT, 3TC and indinavir (Crixivan). (The study was criticized by some in that the efavirenz used was "open-label"; subjects knew they were receiving it, and not a placebo.)
Meanwhile Glaxo Wellcome released its data on AZT, 3TC and abacavir-triple nucleoside reverse transcriptase inhibitors (thus "sparing" the use of two classes of antiretrovirals both the PIs and the NNRTIs) -- in comparison to AZT and 3TC alone. This data led to the late-year approval of abacavir (Ziagen), a drug whose ultimate place in the HIV treatment armamentarium is being sorted out as I write.
A split in opinion pervades the HIV-treating world, here as in many cases. Some see protease-sparing regimens as an effective way to avoid drug-related complications, resistance, and interfered-with lifestyles; others note that we have less of a track record (in time used) with PI-sparing regimens, and they say, simply, "Aren't PIs more powerful?"
So proclaimed the banner headline of an August issue of San Francisco's Bay Area Reporter, when, for the first time in the 17-year history of the epidemic, a week passed without an AIDS-related obituary.
Similar data was publicized elsewhere this past year: We had already been witness to plummeting hospitalization rates, increases in survival, and pervasive closure of AIDS units/hospices, but in March, F.J. Palella and group published it as the lead article in the prestigious New England Journal of Medicine, thus describing formally and conclusively to the entire world "Declining Morbidity and Mortality Among Patients With Advanced Human Immunodeficiency Virus Infection" (N Engl J Med 1998; 338:853-60).
Their now-famous graphs are shaped just like the letter "X": two intersecting lines, one rising (representing use of PIs) and one falling (representing death from AIDS). When was the last time you saw a case of cryptosporidiosis?
However, in case the world receives the good news and infers the wrong message, a simple mathematical reality exists: fewer deaths from AIDS = more people living with HIV. Activism in classrooms and dinner parties and on the streets must not let "AIDS reductionism" (as Project Inform's Martin Delaney coined the term several years ago) take over the collective consciousness.
A different lead article in the New England Journal of Medicine in 1998 reported on a higher incidence (8 percent) of heart failure in 952 HIV-infected people than would presumably be found in an uninfected group (Barbaro et al, New Engl J Med 1998; 339:1093-9). The clinical significance of this remains unclear, since the term "heart failure" is often more ominous-sounding than the actual condition.
However, another aspect of the lipodystrophy syndrome (see item 2) may have important implications on the heart: the association of elevated levels of blood lipids, cholesterol and triglycerides in people on HIV treatment regimens. The mechanism of such is still not well worked out, but this year also saw the first reports of possible premature coronary artery disease with HIV. Is it really happening (reports have been anecdotal, i.e., small in numbers)? If so, is it a side effect of medications? Or a consequence of living longer with HIV, which is known to accelerate cellular aging?
For now, anyone on antiviral therapy -- particularly PI-containing regimens -- should have lipid levels monitored. Levels which are high, via criteria already well formulated by the National Cholesterol Intervention Program, merit treatment with lipid-lowering medications.
6. It's still called "immunodeficiency"
The immune system -- its role in pathogenesis and in treatment -- had several "jump starts" and was further clarified in 1998.
It began with Dr. Bruce Walker's announcement in January at the 5th National Conference on Retroviruses in Chicago that treatment of new or acute HIV infection (i.e., present for less than six months) could result in maintenance of virtually all immune system functioning. Treatment later in the course of HIV, as is usually done, can still restore a considerable amount of immune potency -- but the best chance is to diagnose, and to treat, early!
Although there is not yet an FDA-approved immune-boosting therapy for use in HIV, two candidates have emerged as the front runners.
Data presented at the International Conference in July showed that monthly injections of the so-called "Salk immunogen" (an inactive substance that looks like actual HIV to the immune system) can help restore some immune system responsiveness. This therapy is being tested further, and should it come to approval, may be marketed eventually as Remune).
The use of interleukin-2, already approved for use in kidney cancer (Proleukin), continued to increase, as did the CD4 counts of people taking it. It is given by subcutaneous injection or intravenous infusion -- and an ongoing Phase III trial should help answer questions which have now been asked for years: Is the increase in CD4 count associated with reduced infections and hence increased survival? Also, given the moderate-to-severe side effects experienced by many takers (fever, aches, nausea and other flu-like symptoms), can it be administered safely and effectively?
7. Speaking of "It's not over..."
Although the Centers for Disease Control and Prevention reported on a decline in sexual activity among teen-agers in the U.S. (summarized in a Sept. 21 editorial in the Los Angeles Times, "At Last, Good News on Sex"), a session at the November meeting of the American Public Health Association (Catania, et al) reported epidemiological data on HIV prevalence in four large American cities.
The UCSF Urban Men's Health Study of 2,800 men who have sex with men (MSM) indicated, among other things:
Locally, Project Open Window, Los Angeles' epidemiological study of new HIV infections, also reported on the high rate of substance use (specifically methamphetamine) associated with contraction of the virus.
8. Treatment and salvage options: are they innumerable?
Two new antivirals came onto the scene formally in 1998 -- the NNRTI efavirenz (Sustiva) and nucleoside RTI abacavir (Ziagen). With 13 approved antivirals, formulating combinations of two or three drugs gives a rather formidable number of potential regimens. Michael Saag, M.D., of the University of Alabama, noted that his medical center's HIV clinic reported 189 different combinations of antivirals being used last year! (Will we ever know which one, if any, is best?)
A major international study which started last year is seeking to gauge the relative efficacy of three different types of initial therapeutic regimens: The Atlantic study will compare, in treatment-naïve patients, three nucleoside RTIs, vs. two nucleosides plus an NNRTI, vs. two nucleosides plus a PI. (Preliminary data on this important study is due to be presented early in 1999.)
For salvage regimens (and sometimes for "up-front" use as well) protease inhibitor combinations stepped out further into the treatment option list this year. In addition to the most widely studied and used ritonavir-saquinavir, other combinations include: ritonavir-indinavir, indinavir-nelfinavir, and ritonavir-nelfinavir.
9. Short course therapy for pregnant women
The now clearly validated use of AZT in HIV-positive pregnant women, after the first trimester -- resulting in a more than 70-percent decline in transmission to offspring -- was joined this year by several related strides:
An increasing number of pregnant HIV-positive women are being offered two drugs, and sometimes a triple, PI-containing regimen as well. So far, retrospective data indicates no major problems with the combination therapies. The anticipated (although not yet proven) decline in vertical transmission may exceed 80 to 90 percent.
Of key importance for the developing world, where prenatal care as well as drug therapies are all too scarce, is a Thai report released last spring indicating that women given AZT as late as 36 weeks into pregnancy (i.e., shortly before term) still showed a 50-percent reduction in transmission to their offspring. The cost of this seemingly late but still effective intervention is around $50, vs. the earlier use of AZT, costing more than $800.
10. New diagnostics: clarifying or confusing?
Ultrasensitive viral loads, described in 1997 and covered in the '97 wrap-up, came into more widespread usage in 1998. With sensitivity levels down to less than 40 to 50 copies/mL, the medical community is being faced with what Cedars Sinai HIV/AIDS specialist Eric Daar, M.D., has called "the paradox of HIV treatment": If we say that 50 is better than 500, in terms of preventing HIV progression, should a patient who was formerly at, let's say, under 50 and now is at 300, have his or her regimen switched? Does this really represent "failure"? Will the ultimate survival of such people be lengthened by switching, or by not switching?
Similarly, tests for genotypic and phenotypic analyses of a person's viruses -- although not yet FDA-approved -- are much further along in development than they were a year ago. But many questions remain unanswered as of now. For example:
Does the cost justify their use (e.g., $800 for a phenotypic analysis)? (If you said "yes," consider how many infected Americans are not on medications due to lack of funds. . . .)
How reliable is the information obtained? What will treating clinicians do with it?
Tribute: the death of one who bridged the gap
Jonathan Mann spoke of AIDS more eloquently, more consistently and more vigorously than anyone else I ever knew.
Standing-room only crowds would come to hear his words of inspiration. He exuded that rare combination of mastery with humility. He spoke of AIDS more eloquently, more consistently and more vigorously than anyone else I ever knew.
Indeed, he may have done more to bridge the gap than anyone else in the public limelight.
Jonathan Mann, one of my personal life heroes, was perhaps as close to the soul of the epidemic as a mortal could be. Last September's Swissair crash marked the end of his all-too-short 51 years of life, as well as that of his beloved wife, Mary Lou Clements-Mann.
In grieving the loss of a man I had sat in front of and smiled warmly at (the smile, of course, had been returned) just eight weeks earlier at the International Conference, I found myself recently sorting through old papers and articles -- as if to validate that, indeed, he had lived.
I found a Dec. 30, 1986 Los Angeles Times article entitled, "Despite Predictions of Tests In 1987, Safe Vaccine Is Years Away." At the time, Mann was director of the World Health Organization's AIDS program -- which he had founded -- and in the article, was quoted as saying: "Under the best of circumstances, large trials to determine whether an AIDS vaccine works are several years away. But we might be able to significantly accelerate vaccine development if we start planning now for these trials."
As part of a perhaps ironic tribute to Mann's life and work, the year of his death, also saw large-scale international vaccine trials under way. It may be three years before we know if the recombinant gp120 preparation truly protects from infection.
Ominously, Mann also stated in the 1986 interview, "The most complex and difficult questions will arise after full-scale vaccine trials begin."
I wish he could be around to help us deal with them.
I met him personally only once. At the first International AIDS Conference I ever attended, the world's Third, in Washington, D.C., June of 1987, I found myself escaping from the weight of information one muggy afternoon and walking from the Washington Hilton to a Dupont Circle coffee house (years before Starbucks ground its first beans in that neighborhood). I sat down, and while enjoying a refreshment, opened a "fun reading" book I had just purchased, my huge red conference manual at my side.
A well-dressed man walked in and sat down at the next table; he toted the same conference manual. He smiled at me. I thought his gesture might be what it was not (I was ultimately to surmise), and I wasn't interested, anyway: I knew I had to get back to the conference within the hour, as there was to be a late afternoon speech by a reputedly fantastic speaker I had only heard of, Dr. Jonathan Mann.
I became visibly nervous when the man at the next table said to me, "How are you doing?"
"Fine, thanks," I noted. "I just came down here to get away from the clamor of the Conference for a bit." I pointed to his, and then my, conference manual. "It's so easy to get overloaded."
"I know just what you mean," he smiled again. His voice was somehow reassuring. "I think it's important to learn how to take care of yourself. If everyone in the world acted that way, we'd be victorious over this darned virus already . . ."
After a few more notes of conversation were exchanged, I began to excuse myself. "I have to get back -- I want to go hear this Jonathan Mann from the World Health Organization speak. I hear he's terrific; ever hear of him?"
"Oh, yes," he acknowledged. "I hope you find him enriching. Good luck."
(Postscript: If you are an average reader, in the time it took you to read this article, several dozen, perhaps more than a hundred, additional people have been infected with HIV. Perhaps it was an injecting drug user in Kiev, or a sex worker in Kinshasa, or a high school student in Pocatello, Idaho, or your best friend. . . .)
This article has been reprinted at The Body with the permission of AIDS Project Los Angeles (APLA).
This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.