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Being Alive

Medical Update: April 28, 1997




 

Being Alive 1997 Jun 5: 4

Overall AIDS Deaths in U.S. Decline for the First Time The Centers for Disease Control (CDC) announced recently that overall deaths from aids declined 12% when comparing the first half of 1995 to the first half of 1996. This is the first time that there has been a decline in the number of deaths from aids since the epidemic began. You should be aware, however, that not all populations were equally represented in this statistic. When broken out by gender, the decline for men was 15% from year to year, while women were dying from aids at a rate 3% higher in 1996 than the comparable period in 1995. Racial breakdowns also showed disparities. Deaths for African Americans declined only 2%, while the death rate for whites was 21% lower in 1996 than in 1995.

Delavirdine Approved by the FDA In April, the U.S. Food and Drug Administration (FDA) approved the use of a second non-nucleoside reverse transcriptase inhibitor (NNRTI). Approval of delavirdine (brand name Rescriptor) follows closely the approval of the first NNRTI, nevirapine. Both these drugs work at the same point of the viral life cycle as AZT, 3TC and the "d" drugs, but have a mechanism different from nucleoside analogs (AZT and the like or more familiarly "nukes").

Like nevirapine, delavirdine is approved for use in combination with other antivirals. All studies submitted for the drug's approval involved delavirdine in combination with either ddI or AZT or both these nucleoside analogs. The combination of delavirdine and AZT proved superior to AZT alone when looking at the viral load reduction for one year. When delavirdine was combined with ddI, however, there was no statistical difference in markers for disease progression from the use of ddI alone. Thus, there is some ambiguity about the efficacy of delavirdine and its place in the standard of care is far from clear.

The major side effect of delavirdine is skin rash, seen in about 20% of the participants in early studies. Only 5% of all the people in the studies had to discontinue use because of side effects. Those who might choose to use this drug need to be aware of how it interacts with protease inhibitors. Delavirdine tends to increase the level of indinavir (Crixivan) in the blood. Thus if one is taking indinavir in combination with delavirdine, one should reduce the standard indinavir dosage. Exactly what that dosage reduction should be is a topic for discussion with your physician.

Triple Combination Study Comes to Early Halt In late February, the aids Clinical Trials Group (ACTG) announced that they were halting prematurely their study of triple combination antivirals. The study (ACTG 320) had been comparing the use of AZT plus 3TC to AZT plus 3TC plus indinavir. Over one thousand people had enrolled in this study that began early in 1996. At the start of the study, all participants had less than 200 T-cells, had been on AZT for longer than three months, and had never used either 3TC or a protease inhibitor. The study participants were equally divided into two arms that received either two or three drug combinations.

In January of this year, researchers reviewed the preliminary data and realized that the triple combination was clearly superior in efficacy to the double combination. They found that the death rate among those on two drugs was 5%, while the rate for those on the triple combination was only 2%. The study was halted and all participants on two drugs were offered the third.

There are a couple of observations to be made here. First, this study confirms with some hard evidence what we have been saying for some time: three drugs are better than two. Until ACTG 320 we did not have this data, but now we do. If your CD4 count is less than 200, you should be on a triple antiviral combination; two drugs just won't do. All other things being equal, you will live longer and progress more slowly on triple rather than double combination therapy. The other observation is that the era of double combination studies may be over, at least for those with low CD4 count. Even though this study provides valuable data, it really doesn't tell us something we didn't already suspect. Given the superiority of triple combinations, one has to question the ethics of continuing to study two drug combinations in people with less than 200 T-cells.

Compassionate Use Program for Abacavir (1592U89) Glaxo Wellcome's newest antiviral, abacavir (previously referred to as 1592U89), has shown great promise in early trials. Abacavir is the most powerful reverse transcriptase inhibitor that we have seen so far. With reports of almost 2 log reductions in viral load among study participants, this drug appears to be at least as potent as the protease inhibitors.

Abacavir has shown better penetration of the central nervous system (CNS) than AZT and thus may be especially useful for those experiencing aids-related dementia. Animal studies have shown a greater than 26% penetration of the blood-brain barrier, while AZT's penetration is estimated to be from 20-25%. Viral resistance to abacavir occurs with a single specific mutation of the virus; in this regard, it resembles the resistance pattern of 3TC. However, unlike 3TC, even with the development of resistance, abacavir appears to retain some antiviral activity. Current studies show excellent bioavailability. The most common side effects reported to date are headache and nausea.

Studies of abacavir are ongoing and FDA approval of the drug is seen as likely early in 1998. Meanwhile, Glaxo Wellcome has announced the formation of a three-armed compassionate use program. The program will be limited to a total of 2,500 participants in the U.S., Europe and Australia.

The first arm of the program is for children with a viral load of greater than 100,000 and a CD4 percentage of less than 15%. In addition to these criteria, the child must have tried one reverse transcriptase inhibitor and failed on that drug. This pediatric program is expected to begin in June. For the aids dementia complex program, participants must have severe dementia diagnosed by a neurologist and must have had prior treatment with AZT.

Current expectations are that about 500 people will participate in the first two arms of the program. That leaves 2,000 slots in the entire U.S., Australia, and the whole continent of Europe for the third, general adult arm of this compassionate use program. Preliminary entry criteria are a viral load of greater than 50,000 copies, a CD4 count of less than 100, and failure on two nucleoside reverse transcriptase inhibitors and one protease inhibitor. This arm of the program is expected to begin sometime in July. Glaxo Wellcome is said to be considering a broader, more expansive access program for early 1998. Meanwhile, we do not have information yet on how to apply for any of the above programs. Once Glaxo provides this information, we will pass it along.

Cidofovir for Peripheral CMV Retinitis Cidofovir is the latest drug to become available for treating CMV retinitis. This drug may have an advantage over ganciclovir and foscarnet because it eliminates the need for a permanent catheter line. Maintenance dosing is one infusion every other week. On the other hand, the drug has been associated with severe kidney problems in some patients.

A recent issue of the Annals of Internal Medicine reported on a small study of cidofovir for treating peripheral CMV retinitis (which, it should be noted, is not immediately sight threatening). Forty-eight patients were randomized to be treated with cidofovir or deferred until the condition began to progress. Researchers found that the median time to progression for the deferred group was only 22 days, while those who were immediately treated showed a median time to progression of some 120 days.

The obvious conclusion is that all cases of CMV retinitis should be treated immediately so as to forestall progression of the disease. This study shows that cidofovir is a viable treatment that may be more attractive to the patient because of the dosing schedule. Thus, the patient may be willing to begin immediate treatment of the condition.



 




Information in this article was accurate in June 5, 1997. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.