Important note: Information in this article was accurate in February 2001. The state of the art may have changed since the publication date. The AIDS epidemic is now in its twentieth year; I especially remember being reminded this past June that high school seniors about to graduate had never known a world without AIDS.
As I sat down to compile this annual summary of major strides of the past year, I immediately came upon what may be the ultimately irony of the year, if not the epidemic: Entries number 1 and 2 below involve, respectively, the desperate need for treatments in places where they are barely anywhere to be found, and the increasing impetus to discontinue therapies where they are available with the touch of a pen.
No matter how you say it -- any of the above statements or countless others that could be truthfully uttered can only begin to describe the decimation. For whatever reasons -- probably a combination of reflections at the millennium, the Durban meeting in July (see item 3), and a continuation of reasonably good results with current therapies in the US -- consciousness was elevated this year to a critical level.
Five pharmaceutical companies (Boehringer-Ingelheim [Roxane], Bristol-Myers Squibb, Glaxo-Wellcome, Merck & Co., and Roche) announced in May that they would chop the prices of antiretrovirals for developing nations by as much as 90%.
Meanwhile, reports of record-breaking rates of new HIV transmission come from the Russian Federation: The number of new infections reported in 2000 is more than the total number of all recorded infections in the previous years through 1999. (Injection drug use is believed to be the major factor here.)
Want more? A dear colleague-friend of mine from Delhi reported at a California conference in which more than 100 HIV-treating physicians were in attendance that in all of northern India -- an area with roughly the population of the entire US -- there are seven physicians devoting their time to care of persons with HIV.
For those who didn't see it before 2000, this past year gave ample time, and good reason, to get it at last: This epidemic belongs to all of us.
Beginning with more widespread clinical reports on treatment interruptions at last February's National Retroviral Conference, this year saw an explosion of interest, an explosion which may have exceeded our actual data set on this controversial but fascinating topic.
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 4 cycles of 8 weeks on HAART, followed by 2 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 persons 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 three 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, 2001.
The Durban Declaration, published in Nature magazine just as the Conference started, was a statement signed by more than 5,000 HIV-involved scientists and clinicians, from more than 70 nations, restating the obvious (to most, not to all): HIV causes AIDS.
Dr. David Ho received a standing ovation when he pointed to a slide of HIV virus during a lecture at the meeting, and said, "This, ladies and gentlemen, is the cause of AIDS. Failure to address the modern plague of HIV/AIDS would be an act of criminal irresponsibility which will be judged harshly by history."
We've come a long way since 1,200 treating physicians and researchers -- mostly white men in suits -- met in Atlanta in 1985 to discuss the ways in which the world could meet this new challenge.
The only new drug (as opposed to new formulations of existing drugs) to appear on the market in 2000 was the sixth protease inhibitor, Abbott's long-awaited lopinavir/ritonavir combination, formerly known as ABT-378.
Bar graphs shown at conferences all over the country and throughout the year implied unprecedented levels of anti-HIV activity to be achieved with the use of Kaletra. Abbott's Dr. Dale Kempf -- who contributed to much of the original pi resistance data (circa 1995?96) -- also reported that the drug seems to work well even in patients who have several pre-existing pi-associated mutations. The hope here is that the continuously high antiviral levels achieved will serve to diminish the likelihood of acquiring resistance.
At year's end, there had been little reported on resistance to Kaletra -- seen by supporters as a testament to the drug's touted potency, and by critics as a disappointment-waiting-to-happen. It has been generally well-tolerated, with diarrhea being the major, and not usually a treatment-limiting, side effect.
And, since medicine is filled with anecdotes, I must say that the first patient in whom I used the drug, when it was available via expanded access, had started it with a viral load of 179,000 copies/mL and a CD4 count of 3 cells/mm?. He had been on every drug available. Nine months later his viral load sat at a very comfortable undetectable (<50 copies/mL), and his CD4 count had risen to 67. For one very happy EL (the patient's initials), the promise of Kaletra was fulfilled.
After several years of acquiring data about lipodystrophy (fat redistribution as well as potential changes in blood lipids and/or glucose), this year the lexicon expanded to terms such as mitochondrial toxicity and avascular necrosis.
With the sense of irony so pervasive throughout the history of the epidemic, following years of protease inhibitors and even (although to a lesser extent) NNRTIs being slammed for their potential to cause unwanted buffalo humps or high cholesterol levels, this year saw more widespread reporting of a nucleoside-based problem: Mitochondrial toxicity refers to a breakdown of intracellular organelles involved in normal metabolism -- and, spurred on by long-standing reverse transcriptor therapy, could play a role in effects as far ranging as neuropathy, kidney disease, a serious accumulation of a certain metabolic byproduct (a condition known as lactic acidosis), and a host of others.
But, back to the PIs, several reports this year looked at the likelihood that treatment with PIs, or perhaps other HIV treatments as well, may result in thinning of the bones (osteoporosis) and even a specific condition which results in the need for a hip replacement (avascular necrosis).
The verdict is still out on the association of heart disease with HIV. Is there really a connection? Does it relate to the potential for elevated lipids in persons on HIV treatment? Are persons with HIV getting cardiovascular disease at an earlier age than they otherwise would? Answers to these questions may be forthcoming in 2001, or 2002, or...
Glaxo-Wellcome saw the approval in November of its triple nuke combination, Trizivir. Each pill contains standard dosages of AZT, 3TC, and abacavir. Thus, an entire antiretroviral regimen can be obtained for one pill twice daily. This marks the culmination of a tremendous stride in promoting treatment adherence, although some are skeptical of using this as an entire regimen (concerns about overall potency, potential for abacavir hypersensitivity, etc.).
Nevertheless, from the company whose predecessor 13 years ago gave us the very first antiretroviral, which as a single drug was twelve pills per day, dosed every 4 hours around the clock, this is, to say the least, an extraordinary way to mark the progress of treatment!
Also, the days of ddI (Videx) packets, or large dissolvable, or chewable, pills may be over. Towards year's end, Bristol-Myers Squibb received approval for a single capsule, smaller than most of the other antiretroviral drugs around, as its once-a-day Videx-EC formulation. It still must be taken on an empty stomach, but each capsule contains small beadlets of drug which resist degradation and are slowly released to work their reverse transcriptase inhibition "magic."
The same company is working on an extended release version of d4T (Zerit) -- which might be available in 2002 -- and would be a once daily dosing. They also have a once daily protease inhibitor, BMS 232,632, in the not-too-far-away pipeline.
A once-daily triple regimen, of ddI + efavirenz (Sustiva) + FTC (a not-yet-approved reverse trancriptase inhibitor) looked promising in the ANRS 091 trial presented in February. A mean drop in viral load of more than 3 logs was seen, with 39 out of 40 subjects achieving undetectable viral loads (<400 copies/mL) at 12 weeks.
Whatever can be done to simplify regimens and promote patient adherence is a worthwhile endeavor: Two different studies also presented at Durban each showed that lack of adherence correlates to greater mortality from HIV. In other words, Adherence = Life!
The debate between PI-inclusive and PI-sparing regimens continued full force in 2000, with community debates all over Los Angeles (and likely elsewhere) running in tandem with the presidential election debates.
The degree of decisiveness of the outcome of such debates may be comparable to that of the national election: Some insist: Use a PI-sparing up front. Why? Fewer pills. Therefore better adherence. More patient-friendly. Less lipodystrophy. Less potential for bone problems.
With equal fervor others say: Use the pi first. More clinical/survival outcome data available on it. More potent. NNRTIs are better for salvage. If/when you become resistant to one NNRTI, you've lost the usefulness of the entire class.
LA County reported last spring on a resurgence of syphilis in men who have sex with men. Some were surprised, others saw it as a validation of the failure of prevention efforts (see item 10).
In all of 1999, there had been only 120 cases of syphilis in LA County, none of them recorded as being in gay men. Then beginning in March of this past year, a crop came up in West Hollywood, Silver Lake, Hollywood, and Long Beach. In a 2-week period that month, there were 51 cases of this infection reported in gay men -- more than half of whom were already known to be HIV+.
Our county, with its superb health surveillance system, immediately called for a step-up of screening for syphilis at regular intervals (with the commonly used blood test, the RPR, or VDRL). HIV-related and other community-based organizations stepped up prevention and education efforts, and while the caseload increased for the next month or more, the fervor diminished as this mini-epidemic seemed to.
Still, you should be aware that acquiring syphilis is painlessly easy -- and that any act of unprotected sex leaves one, HIV+ or not, vulnerable. It can be treated effectively, especially when discovered in the primary stage, and thus people who are sexually active should be involved in an ongoing std surveillance program, and do whatever they can to diminish the risk.
This year the myriad of considerations surrounding HIV-related medications took a protean (that's not protease!) leap:
Stepped up warnings of side effects even more dangerous than initially discerned, for the antivirals abacavir (Ziagen) and nevirapine (Viramune), led to FDA-sponsored letters going to all US physicians, and of course, an increase in community-focused dissemination of information.
At least two studies presented in Durban revealed greater-than-previously-seen side effects (especially neuropathy) with the use of hydroxyurea. The use of this "enhancer" of ddI, and potentially other nucleosides as well, had rapidly dropped off by year's end.
A UNAIDS-sponsored study in June, 2000, revealed that the commonly used microbicide nonoxynol-9 -- having been talked about in prevention lectures for close to a decade now -- might actually lead to increased HIV transmission (perhaps by causing irritation of the membranes and thus increasing the portal for HIV entry). Its use is no longer recommended.
We learned that the commonly used herb St. John's wort (hypericin), long touted as having anti-HIV effects, can interact with indinavir, and likely with other PIs as well, so as to decrease serum levels. St. John's wort is now contraindicated in the presence of PIs.
We learned that two of the most commonly used drugs used to lower cholesterol (lovastatin/Mevacor? and simvastatin/Zocor?) have their levels raised dramatically in the presence of PIs, due to extensive metabolism by the CYP3A4 system, thus increasing the potential for toxicity from these so-called "dyslipidemic" medications.
Having been at the helm of national surveillance of the epidemic from its onset, the Centers for Disease Control took a new stride this year. In September, they published a draft (you can see it, too, at http://www.cdc.gov/nchstp/od/news/draft.plan.pdf) of a Prevention Strategic Plan which contains four major targets to be achieved by 2005:
Public opinion and input was invited on the entire 74-page document, and the revised, finalized version will be available on the CDC's web site (www.cdc.gov).
While some have criticized the report for being either "too much, too little, or too late," I find the formalizing of goals, and the implementation of strategies to achieve these -- all enhanced by the accessibility of information via the Internet -- remind us all once again how each of us can be an activist!
Also this year The Institute of Medicine published No Time to Lose: The AIDS Crisis Is Not Over, another document which formalizes and inspires personal as well as collective activism.
Mark Katz, MD is the Regional HIV/AIDS Physician Coordinator for Kaiser Permanente of Southern California.
010101
BA20010201
Copyright © 2001 - Being Alive. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used. Subscription lists are kept confidential. Being Alive, 621 N. San Vicente Blvd., West Hollywood, CA 90069 TEL: 310.289.2551; FAX: 310.289.9866; Email: BeiAlive@aol.com http://www.beingalivela.org/
ÆGiS is made possible through unrestricted grants from Roxane Laboratories, Inc., iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.
ÆGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2001. ÆGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on ÆGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of ÆGIS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.
