Important note: Information in this article was accurate in February 2002. The state of the art may have changed since the publication date. | 1990 Story #1: Prophylaxis for Opportunistic Infections Aerosolized pentamidine is already yielding its throne to oral trimethoprim-sulfamethoxazole (Bactrim, Septra), as there has been an increasing, steady shift in favor of the latter for PCP prophylaxis. As reported at the December Medical Update, Bactrim is more clearly than ever superior in reducing the incidence of primary or secondary PCP. Plus, it's much cheaper, easier to take, and may serve against toxoplasmosis as well. Data presented at the October ICAAC were compelling, especially the Kaiser Sunset study in which 116 people treated with Bactrim one double-strength pill three times weekly, for a median of 18–24 months, showed zero incidence of PCP! There was also a lower incidence of frank intolerance than previously indicated. Closely related to this is the additional issue of prophylaxis of other OIs. While none have been FDA-approved, nor even widely studied for that matter, medication exists which may reduce the incidence of fungal and atypical mycobacterial (MAI) infections, and we hope a stride against CMV is not too far away. 1991 Story #2: Record Number of New Drugs Approved None of these are cures, but no one can deny the improvement in sheer number of treatment modalities. 1992 should certainly see the approval of DDC, and (may we be so lucky!), the possibility exists for approving peptide T, hypericin, and interleukin (either IL-2 or IL-4), and perhaps a KS drug. 1992 Story #5: Women and HIV Just in case there were any left who were in doubt, the World Health Organization released this past summer the rather sobering statistic that a majority of new HIV infections acquired worldwide in 1992 have been in women. Locally and nationally, all reports point towards increasing percentages of HIV-infected and PWAs being women. 1993 Story #3: Anabolic Steroids 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. 1994 Story #5: Protease Promises Roche is expected to file for accelerated approval of the drug, and while the limited number of slots currently available have activists (and numerous advocates) vocally upset, an expanded access program is soon to be underway. When FDA approval of Invirase (the brand name of saquinavir) does occur, and it may well be in 1995 [It was in December. -- Ed. 2002], this will mark a major change in treatment approach. This will be the first new class of therapy we have seen since the first reverse transcriptase inhibitor was approved 8 years ago. It is likely that protease inhibitors will be used in combination with already-approved RT inhibitors, and much excitement swirls around the other pharmaceutical companies (Abbott, Merck) who are likewise developing drugs in this class. If they work as well in vivo as they do in theory and in vitro, a major extension of health may be underway. As several pharmaceutical companies have raced to the protease competition, so Chiron and Hoffmann-LaRoche have been attempting to push their respective BDNA and RNA PCR tests towards FDA approval. The first half of 1996 will likely see approval of at least one of these diagnostic tests, but many clinicians and patients have already begun to utilize the data which have been gleaned from several retrospective looks at already-completed studies. The simple equation is: Higher viral load should indicate faster progression... but in reality this remains to be prospectively validated. Viral quantification data may explain one of the perennial issues of HIV tracking -- why do some patients with 400 CD4 cells remain stable and asymptomatic, while others progress rapidly? So far, it's just about everyone's best guess that a new therapy should induce a drop in the viral load (of hopefully 0.5–1.0 log or greater) at about two weeks after the change is made. Insurance companies and public sector health care have been understandably reluctant to pay for an expensive test ($100–$200) whose prospective validity remains to be proven... and then what does one do with data such as the August study in Blood in which influenza vaccinations were shown to increase the HIV viral load up to 20-fold in HIV+ volunteers? 1996 Story #1: The "E" Word -- Eradication At a plenary session on antiretroviral therapy at the same Conference, Dr. Scott Hammer of Harvard Medical School poetically stated that, "Eradication of the virus has become an acceptable hypothesis to be tested. Just six months ago this statement would have been dismissed as ludicrous." (At press time, the 4th National Human Retroviral Conference was to be held; at this Conference, Ho and Markowitz were due to present their findings on the plasma viral load as well as lymph node biopsies of these patients at one year of triple therapy.) 1997 Story #7: The Pipeline Lengthens Already available via expanded access programs are abacavir (Glaxo-Wellcome's new RT inhibitor); efavirenz (Sustiva, Merck's NNRTI); and the first representative of a new subdivision of reverse transcriptase inhibitors known as the nucleotide analogs -- Gilead's adefovir (Preveon) [Preveon was rejected by the FDA in 1999 because of unacceptable kidney toxicity. -- Ed. 2002] Further down the road-in-development are new protease inhibitors by Glaxo-Wellcome (amprenavir, formerly 141W94) and Abbott (ABT-378) and another nucleotide analog known currently as PMPA [PMPA, also known as tenofovir, was FDA-approved last year as Viread. -- Ed. 2002]. New target sites for anti-HIV activity are also being sought out with HIV binding inhibitors (e.g. TP-20) and the ongoing development of integrase inhibitors (e.g. zintevir) [TP-20 is likely to be FDA-approved this year; zintevir development has been halted. -- Ed. 2002] 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 group from Australia detailed the largest series yet described at the Geneva Conference. They found that close to 80% of their more than one hundred 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 item 3), 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. Well, this year saw the release of several studies all of which indicated that the HAART-induced rise in T-cells (i.e., the (at least partial) restoration of the immune system) diminishes the risk of OIs to the point where prophylaxis -- for PCP as well as MAC (the latter had a CD4 count of 50–75 as the threshold for use of preventative medication) -- can safely be discontinued. (It is recommended that if your T-cells have risen, that you not stop prophylaxis on your own -- but discuss it with your provider. There may be cases in which continuation is advised.) A related amazingly-good-news item was published by Scott Whitcup, MD and group in JAMA in November -- 14 patients with CMV retinitis who had been treated with presumably lifelong maintenance (remember PICC lines?) and whose CD4 counts had risen in the face of HAART, had their CMV medication held. And after a mean of 16.4 months of follow-up, no patient had reactivation of his CMV. 2000 Story #2: Is Treatment Interruptus Safe? Dr. Anthony Fauci of the National Institutes of Health presented data at the Durban Conference, concurrent with a warning about drawing preliminary conclusions. His recommendation, which remains the official one at this time, is that therapy not be interrupted except as part of a controlled clinical trial. In addition to data presented in Durban on the NIH cohorts, the Swiss Cohort's Dr. Bernard Hirschel reported on the largest pool to date -- 56 patients who had completed four cycles of eight weeks on HAART followed by two weeks off were assessed for what happened to their viral loads in successive interruptions: Some had the desirable result of no rebounds at all (14%), some had rebounds which were essentially unchanged from interval to interval (28%), some had rebounds which became higher each time (28%), and some had the other potentially desirable result of rebounds which became lower each time (20%). In other words, anything could happen. Nevertheless, infected people from all over those countries where treatments are available -- perhaps tired from drug-related side effects, bored with adherence lectures, frustrated with body fat changes, fearful of broken bones, or just simply craving empowerment -- took the opportunity to perform, usually with their provider's knowledge if not active endorsement, their own interruption "experiments." The continuing saga of this story, a mere 3 years after the first report of the Berlin patient's successful treatment interruption, should reach headline status again at the 8th National Retroviral Conference, slated to be held in Chicago the first week of February, 2002. |
Even before September 11, 2001 seemed like a year with fewer major HIV stories than in previous years.
I used to sit down each December and make a list of what might be 15—20 stories, each of which somehow had significance -- by changing the way we think about things, or do things. In 1994, we had ACTG 076, which would forever change the way we dealt with HIV+ pregnant women. In 1996, there was the Vancouver International Conference, with the optimism of HAART, viral load testing, and even the elusive "E-word" (eradication, for you students of HIV history, an idea whose time may have been premature). In 1999, we were optimistic about resistance testing, and, simultaneously, anxiously concerned about reports of newly infected people already showing the presence of resistance mutations.
This is not to say that 2001 was a year without news -- just that the news was mostly a refinement, if you will, of what we already knew. (The image of kneading dough comes to mind -- you poke and roll and prod, and then turn the whole thing over to work it some more -- with the hope of a better finished product.) I decided to write on six stories for the year, and then publish a review of some of the headliners in previous years. After all, 2001 is the year that...
Not exactly a cause for celebration, and some grimaced even to call it "an anniversary." (For me, peace came with "commemoration.") But June 5, 2001 marked the 20th anniversary of the first report, in Morbidity and Mortality Weekly Report (MMWR), of a cluster of Pneumocystis carinii pneumonia in five homosexual men in Los Angeles. A few weeks later a report from New York City cited a rare type of cancer occurring in gay men. (I recalled then learning about Kaposi's sarcoma in medical school in 1972 -- and went back to my notes from second-year pathology, and indeed, had written in the margin: "Rohner [pathology professor] says: may see one case in a lifetime of practice..."
The term Acquired Immune Deficiency Syndrome was actually not born until some 15 months later, in the September 24, 1982 issue of MMWR.
On June 5 of this year, some attended special memorial services, others gathered to tell stories and view quilts, while others lived their lives as normally as on any other day. For indeed, part of the legacy of this epidemic is that of self-empowerment -- you get to do and be whatever works best for you.
The year started with Chicago's 8th National Conference on Retroviruses and Opportunistic Infections, a conference usually packed with hard clinical and research news. But this year, opening night featured talks by well-known Kenyan epidemiologist Kevin DeCock and Harvard economist Jeffrey Sachs.
DeCock called for something to be done about the more than 12 million African AIDS orphans, calling the HIV epidemic "Africa's biggest issue since slavery," while Sachs called prevention efforts to date, "a dismal failure." Both lectures, back to back, signified for me a message that an attunement to the global holocaust was no longer something to "consider." It simply was. From that moment on, every conversation about the success of treatments in developing nations would be laced with a pause, and then either a stated or implicit comment about the rest of the world.
Over this past year, pharmaceutical companies (led by Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, and Roche) helped to pave the way for bringing some of this to fruition. And yet at year's end, within hard hit South Africa, a mini-epidemic raged within the greater one -- a political battle over the government's refusal to provide HIV medications via that country's public health system.
Another stride in global acknowledgment came in late June, when the UN Special Assembly on HIV/AIDS (with its slogan "Global Crisis -- Global Action" and tagline "Together we can") convened in New York. More than 300 organizations were represented, and out of the several days of discussion came the promise of an even stronger bridge between the developed and developing nations. (For more information, see the comprehensive reviews at www.UNAIDS.org)
For the sixth time since April 1998 (when Department of Health & Human Services guidelines were first posted online), revised guidelines were released. An important undercurrent of "relaxation" of treatment parameters was seen -- e.g., for the asymptomatic patient, antiviral treatment was now recommended if the CD4 went below 350 (not 500), or the viral load by BDNA went above 30,000 copies/ml (not 10,000), or by PCR went above 55,000 (not 20,000). Concerns about chronic side effects coupled with the awareness that HAART therapy does improve clinical course -- even when started late -- went into the decision of a panel which consisted, as always, of clinicians and researchers, as well as people living with HIV.
Not since the beginning of this advisory service had there been such a huge wave of public sentiment: Critics of drug therapy hailed this as their victory, patients with concerns about longer-term toxicity felt freer to ask for treatment interruptions, and for most of us, it led us once more to realize that anything we say about HIV and its treatment today may be "history" by next week.
Beginning once again with the Retrovirus Conference, a theme running through the year's work was that people already living with HIV could, and should, still play an important role in prevention. (The "duh..." factor here is that to create a new infection, one has to start with someone already infected, along with someone who isn't!) For many years, prevention efforts seemed to focus on the dichotomous "we" and "them," leading those who were already positive to feel like damaged goods, pushed into dealing with issues of drug treatment and, in earlier days, planning for an untimely demise.
With all we know about how HIV is, and is not transmitted, and with a stable number of new infections each year in the US (around 40,000) most epidemiologists termed prevention efforts a failure. Most everyone agreed, with the rising numbers globally, that this was indeed "dismal."
Kevin DeCock emphasized that HIV+ people must be taught prevention. Nationally and locally, AIDS service organizations created programs to improve self-esteem and reduce intercurrent substance use in the HIV+ population (e.g., LA Shanti's Prevention for HIV Positives (PHP)).
Early in 2002, however, an announcement came which might further undercut such programs -- an article in The Los Angeles Times the first week of January was entitled, "Explicit Ads Prompt Review of US AIDS Prevention Grants." The prevention camp may be left with a more overwhelming burden than ever: how to prevent a disease which is spread by sex and drug use without addressing sex and drug use...
("Balm" refers to a soothing substance. This line is one of those asked of the Raven in Edgar Allen Poe's famous poem.)
Despite the 1999 FDA rejection of its prior compound adefovir (Preveon), Gilead forged ahead with the clinical development of its tenofovir (Viread). In November it became the sixteenth FDA-approved drug for the treatment of HIV, and the first in the subclass of reverse transcriptase inhibitors (RTIs) known as the nucleotides.
It fits many of the desirable criteria in a drug to be marketed today -- simple dosing (one 300 mg pill once daily), no known dose adjustments to be made to it or other accompanying HIV meds, an almost unheard-of low incidence of serious side effects, and an additional feature (not formally FDA-approved as of this writing) which may enhance its marketability -- activity against hepatitis B as well.
The FDA approved a once-weekly formulation of interferon, which has for several years been a common therapy for this form of hepatitis, which accompanies HIV in a significant number of HIV+ people. Schering-Plough Pharmaceuticals' Peg-Intron represents the interferon chemically packaged in such a way (pegylation, which means the molecule is attached to a chemical called polyethlyene glycol (peg)) that it takes much longer for the drug to break down in the body. Thus, instead of three times weekly dosing of interferon, this can be given once a week. Data showed comparable efficacy of this new formulation to the older ones -- at least a third of people on it sustain an undetectable hepatitis C viral load.
In addition, until this year, performing liver transplants (usually a lifesaving procedure for people with advanced hepatitis C) in those CO-infected was virtually unheard of. At the Transplant 2001 Conference held in May, University of Pittsburgh researchers reported on six people CO-infected, all of whom had liver transplants since 1997. Two of the six had died -- one from organ rejection, the other from an infection not related to HIV -- but the other four were alive and, essentially, well.
And, shortly before year's end, perhaps the world's most famous "CO-infected" person, Larry Kramer, received his transplant.
This story illustrates what happens so often with HIV: What is unthinkable one year (e.g., imagine in 1997 being told you were HIV+ but might not need lifelong therapy!) becomes a popular standard the next.
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