Being Alive - February, 2000
Mark Katz, M.D
Honorable mention must go to chip technology, to the way in which obtaining information has changed within the span of only a few years. While preparing this article, I recalled a moment from the Dark Ages of AIDS -- 1993 (the year the Concorde Trial was publicized), when a former beau tried to explain to me what the Internet was. "Soon you'll be able to have access to virtually any information out there in the world by just turning on your computer."
"But where will all this information be stored?"
"In cyberspace," he added assuringly.
"Where's that?" My left brain was grappling.
"Don't worry if you don't get it. By the end of this decade, we'll all be there every day."
Maybe it was the at first startling-and to many, unanticipated-findings of trial dmp-006 (showing superiority of an efavirenz-containing triple regimen in suppressing viral load when compared to a protease inhibitor (PI) counterpart). Maybe people wanted fewer pills. Or just more options. Or a response to the anxiety over long-term possible side effects of the regimens we had been celebrating since early 1996-the regimens which have changed the entire course of the epidemic in this country (see item 3).
1999 saw a marked increase in the use of so-called "protease-sparing regimens," with efavirenz or nevirapine, both NNRTIs, or abacavir, as the third drug. The ongoing Atlantic Study has demonstrated that at one year (albeit in a reasonably healthy population-average viral load around 15,000), viral suppression is comparable with an NNRTI or PI-containing combination, and perhaps slightly less potent in a regimen consisting of three NARTIs ("nukes").
Although a majority of polled physicians at November's Infectious Diseases Society of America (IDSA) meeting indicated they would choose a pi-sparing regimen for persons with no prior therapy, and viral load of <100,000, the key questions-Is there a best initial regimen? Is there a best second (or later salvage) regimen?-remain to be answered.
Is the reign of protease over? Hardly, I think most of us would agree. NNRTIs sport a variety of possible side effects-rash in any of them, and for efavirenz in particular, a disturbingly high incidence of possible central nervous system alterations (anything from insomnia to nightmares to hallucinations). Another key consideration is the cross-resistance issue; if you become resistant to any of the three available NNRTIs, you are likely resistant to all of them. This factor in part has inspired many providers to endorse their use in subsequent, or salvage, regimens, rather than in first-line.
Bottom line issues: The uncertainties surrounding the best initial regimen underscore more than ever the importance of a mutual consent between patient and provider as to when to start, and what to use.
Yes, it's a new test and it costs at least several hundred dollars to run. Yes, outcomes rely on expert interpretation-the human, not microchip, kind. But this year saw a marked acceptance of genotypic antiretroviral resistance testing (GART), the first major diagnostic stride since viral load testing made its way into the HIV arena during the pivotal years of 1995-96.
Several studies released at the January 6th National Retroviral Conference (one of them often referred to as "the Baxter study" from the name of the first author, the other as the Viradapt study) demonstrated that, despite the above and other limitations, knowing which resistance mutations have been accumulated enable a more rational decision as to which antiviral drugs are more likely to work in a given patient. We soon may be able to say farewell to the years-old practice of changing all of the drugs in a failing regimen, and thus spare the use of medications which until now we have somewhat blindly stopped.
Insurance companies and public sector funding sources are increasingly paying for GART testing, but the issue of what is the proper time to run the test (three possible options together cover just about everyone being followed for HIV -- before any treatment begins, after a first regimen fails, or after multiple regimens have failed) remains to be elucidated and validated by controlled trials.
Coming closely down the road (prediction: it will be on the Top Ten list for 2000 or 2001) is phenotypic testing (will it be known affectionately as part, or PHART?) -- which can yield even more exact information as to a specific drug's potency against a given person's virus. Stay tuned.
I can still remember the huge led continuously ticking at summer 1998's International AIDS Conference in Geneva, informing us that there had been more than 36 million HIV infections in the world since the beginning of the epidemic.
In late 1999, that number stands at 50 million. From the hardest hit countries such as Zimbabwe come statistics almost impossible to comprehend -- 25% of the adult population harbors HIV-and barely a protease inhibitor in sight! Tensions mounted in nations such as South Africa-where there are 1600 new infections a day (and where the International AIDS Conference will be held this coming July)-due to the government's role in preventing access to treatments. The rate of new infections in the former Soviet Union (nations such as Russia and Belarus) -- sparked by the rise in injecting drug use-makes it the world's fastest pool of HIV transmission right now.
From our own nation came discouraging news as well-the CDC in August indicated that while deaths from AIDS were still well below their peak of earlier this decade, the rate of decline of the death rate has slowed (it had been 42% from 1995 to 1997, and was only 20% from 1997 to 1998). One possible explanation: Is the first "generation" of HAART-treated patients becoming exhausted, i.e. are the regimens failing after an "era of good feelings"?
And on the early end of the epidemic in this country-transmission of new infection-the term barebacking become part of many a household vocabulary this year. Persons who know they have HIV engage in high-risk activity-sometimes the partner knows, sometimes not. To remind myself every day what I think about it, I carry around in my briefcase an article from Frontiers in which a barebacker reveled in the delights of the activity, cautioning anyone who would pass judgment on him. (I carry it around to remind myself that there has been a swelling of sentiment, if not a tacit community approval, by some, for having unprotected sex in 1999.)
In case you have any doubt about the success of treatments of the last four years, consider this: If your doctor had told you in 1995 that a new class of drugs was coming along which would cause the death rate to plummet, cause AIDS units in US hospitals to become virtually obsolete, cause many physicians to not be able to remember the last time they saw a case of cryptosporidiosis or toxoplasmosis, and even enable people on PCP prophylaxis to discontinue it after their T-cells rose back above the threshold recommended for treatment (usually a CD4 count of 200)-might you not have considered your physician to be a bit "touched"?
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.
In addition to the good news for NNRTIs noted in item 1, several studies this year pointed towards the benefits of antiviral therapies in pregnancy-even simplified regimens started very late in the course. This culminated in the September release of the data from a study known as HIVNET, in which more than 800 pregnant Ugandan women who did not receive antiviral medications prior to labor were randomized to two groups: One group received the previously validated "short-course" AZT regimen-AZT at the onset of labor, continuing through delivery, and given to the infants for the first week of life-and the other half received a single dose of the drug nevirapine at labor, and the neonate received a single dose within the first few days of life.
By 14-16 weeks of age, 13.1% of the nevirapine-treated children were HIV+, vs. 25.1% of the AZT-treated. In other words, a regimen costing around four dollars and exemplifying simplicity to the extreme still resulted in a significant reduction of vertical transmission.
The implications of HIVNET are staggeringly good for the developing world, where the epidemic is still exploding, and where many women do not have access to prenatal care. It also speaks to the likelihood of nevirapine becomingly increasingly used as part of a pregnancy regimen in the US. (I personally feel that, given the irony of history-nevirapine's June 1996 FDA-approval was severely eclipsed by the roll-out of the first three PIs over the preceding six months-now it may take the more prominent, and deserved, place in HIV therapy.)
Indeed, HIV treatment was easier in 1990, the year I first wrote this year-end wrap-up column. You treated with AZT-the only antiretroviral available at the beginning of this decade-until someone became ill (either from the AZT or the disease progression as a result of its failure), and then you obtained ddI through the nation's new and inventive expanded access program (ddI would not be FDA-approved until October 1991)-and eventually HIV illness usually became the victor.
Now there are 14 approved drugs, consensus guidelines posted on the Internet, and if it wasn't enough just to learn their names (did you know that 3TC, lamivudine, and Epivir are all the same thing-and that this is half of what Combivir contains?), there are terms and acronyms virtually unknown a year or two ago.
When we start treatment, will we see manifestations of IRD (immune restoration disease)?
When should we consider intensification of the regimen?
How concerned should we be over a CD4-viral load disconnect?
Can you get GART done?
Is mega-HAART worth a shot?
And should we precede it with an STI (structured treatment interruption)?
And when is it okay to take a drug holiday?
I have long been a proponent of people with HIV learning all they can about their condition, as a tool for self-empowerment, in order to be a partner with one's provider. But let me put out another idea: If all of this overwhelms you, and you'd rather just go to the movies, or surf the web for other more "enjoyable" sites (...?!), consider finding yourself a provider who is accessible and whom you trust. Remember, it's our job to learn this stuff, and point you in the best direction possible...
Although lipodystrophy wasn't new to the HIV world in 1999, we did achieve clarification on certain aspects: Although two of the commonest components of the still formally-undefined syndrome (body-fat distribution changes and elevations in blood lipids, cholesterol and/or triglycerides) seem to occur more commonly in persons on PIs, these changes may also occur in persons who have never seen a drug from this class (and have been reported even in some HIV+ persons still naïve to therapy). Terms such as "Crix belly" should go the way of the mini-mall.
The best way to deal with the lipid changes for now, should they occur, is to treat the elevations in the same way we would in an HIV-negative person (there are dozens of drugs which can be used for this purpose).
How to deal with fat redistribution is more of an enigma: Several studies released and/or published this year have pointed towards improvement-with or without statistical significance-in persons switched to a pi-sparing combination, while still maintaining adequate viral suppression. Results of a placebo-controlled randomized trial of growth hormone are still pending. Often, patients are reassured that the sunken cheeks appearance which may appear is not really wasting syndrome (as we used to see in the pre-HAART era), given the stability of total body weight.
I predict we'll be hearing even more in 2000 about mitochondrial toxicity-another term not brand new (an excellent review was published by Kees Brinkman et. al. in AIDS, December 1998) but increasingly talked about. This refers to a potentially huge array of symptoms and conditions which can come about from the use of nucleoside analogues (NARTIs). Over time, they may interfere with the human cells' normal metabolic processes, and reduce their capacity to generate energy-resulting in conditions as seemingly diverse but perhaps ultimately tied together as myopathy (most often connected to AZT), pancreatitis (most often seen with ddI, ddC, or d4T), kidney dysfunction (such as that seen with the antiviral adefovir, rejected in November by the FDA Advisory Committee on the basis of toxicity), and even a serious, potentially fatal syndrome known as lactic acidosis.
If you become more anxious reading this, I suggest you re-read the first paragraph of item 4...Remember, these therapies are not benign-neither is the virus which they often succeed in suppressing. A trusting relationship with the providers of your health care team-including a chance for you to voice your concerns and to hear a balanced perspective-became more vital than ever in 1999.
We used to call it non-A, non-B hepatitis, but thanks to the inexorable march of scientific progress, we learned a decade ago about this specific virus-which probably accounts for a good proportion of liver cirrhosis and cancer seen all over the world. We figured out a way of diagnosing it-the antibody test has been available for around seven years-and now the issue of treatment has galvanized global attention.
A study published in August in the New England Journal of Medicine spoke to a prevalence of HCV (hepatitis C virus) of 1.8% in the American population, corresponding to an estimated 3.9 million infected. The issue of HIV/HCV co-infection is, not surprisingly, staggering as well, since both viruses can be transmitted through the same route-injecting drugs.
Estimates of HCV incidence in the PWAs who acquired their virus via injection drug use have often surpassed the 30-50% range. Since HCV may slowly erode the liver's ability to process medications-including antiretrovirals-many experts recommend treating the HCV first, so as to make the body, specifically the liver, more receptive to anti-HIV therapy. Co-infected persons are known to progress more rapidly to cirrhosis-and also have an increased likelihood of HIV transmission: In one study, 16.3% of babies were born HIV+ to mothers who had HIV but not HCV, compared to 26.1% vertical HIV transmission for babies of co-infected women.
The consensus of when and with what to treat is evolving, but most often interferon and ribavirin are considered. The latter marks the ironic return of a drug frequently obtained outside the US and used for its alleged anti-HIV properties in the mid-1980s. (Studies failed to validate its efficacy and it was never FDA-approved for HIV therapy).
The most recent revision of the DHHS guidelines (see http://www.hivatis.org) recommend that all HIV+ persons be screened for HCV, and that those who are co-infected should avoid alcohol.
(On another hepatitis-related note, the guidelines also recommend that HIV+ persons who are hepatitis A-negative, i.e. have no evidence of prior infection, be vaccinated with hepatitis A vaccine.)
Last winter's National Retroviral Conference included the startling news of an anonymous German-forever dubbed "the Berlin patient" -- who was treated shortly after becoming HIV-infected, and after stopping his antiviral regimen three times (the first two because of the occurrence of coincidental non-HIV-related conditions), had his viral load remain at undetectable levels for several years.
Was he just lucky? Or are there innumerable potential "Berlin patients" all over the world? Does starting and stopping treatment offer some therapeutic advantage (perhaps in the concept of auto-vaccination)? This report inspired the HIV treating community to rethink our notions of whether or not lifelong potent treatment is always necessary-answer far from known. (For most people, another lesson to be emphasized from this anecdote is the commonly held importance of treatment as early as possible when the infection is acute, i.e. newly-acquired.)
And, as if to balance some of the optimism as well as underscore the treatment question, September's ICAAC conference included the release of data from the "NoHRT" study. This report, presented by the National Institute of Health, involved 18 patients with suppressed viral loads on therapy (12 of them had also received the immune booster interleukin-2). Therapy was stopped and they were closely followed for possible return of the virus-and in all 18, the viral loads became detectable again (average time to levels over 50 was 11 days, to over 500 was 18 days).
This is the story you get to choose. Send us your ideas for an important development in 1999 which was not covered in the items above. We will publish results in an upcoming Being Alive Newsletter. In this way, the top stories will really be composed as a collective effort.
Send your suggestion to Kevin Kurth at Being Alive, 621 N. San Vicente Blvd., West Hollywood, CA 90069, or send an e-mail to ProgVolDir@aol.com
Mark Katz, MD, is the Regional HIV/AIDS Physician Coordinator for Kaiser Permanente of Southern California.
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