Being Alive, Los Angeles; March 1998
Mark Katz, MD

Several stories from the Conference made newspaper headlines throughout the country, but for a thorough in-person "experience" of the Conference, you can go to its website (www.retroconference.org) and actually (with the appropriate computer equipment) see slides from and hear the key lectures. Also, an excellent daily conference summary appears at www.healthcg.com.

John Mellors, M.D. summarized the tone of the Conference as one of "cautious optimism." Just two years ago, at the same Conference, the world heard the first reports of significant viral load suppression because of the use of protease inhibitors (PIs) in combination with two nucleoside analogues.

Opportunistic Infections: Not Quite Dinosaurs, But The impact of triple combination therapy on the course of the epidemic in the U.S. was again borne out by the many reports of the decline in new cases of AIDS, in incidence of opportunistic infections, and in deaths from AIDS-related causes. The year 1997 saw a 40-50% decrease in AIDS mortality in many U.S. cities. From 1994-97, the University of California, San Francisco, saw a 71% drop in PCP cases and a 93% drop in CMV infections. San Francisco General Hospital reported they had one case of CMV retinitis during the first half of 1997, a 94% decline from 1994 levels!

Antivirals: Whatever You Use, Get the Viral Load Down and Keep It Down! Despite a common hope that we will be told one day that drugs A1B1C do a far better job of enhancing quality of life and survival than drugs X1Y1Z, the bottom line message remains: Use a powerful enough regimen to suppress the virus. Keep in mind what researcher Dale Kempf demonstrated: Duration of HIV suppression is proportional to the nadir (low point) of the initial drop, i.e. the lower you can initially bring your viral load the longer the drug regimen will be effective. Use a powerful regimen up front!

Although there is still divergence of opinion on exactly when to start antiretroviral therapy, the data from many trials remain consistent. When the decision is made to initiate drug therapy, a highly potent regimen should be used, rather than using a less potent regimen and sequentially adding drugs as needed.

The Merck 035 trial compared initial (24-week) regimens of indinavir alone versus AZT/3TC versus all three drugs in AZT-experienced patients. At 24 weeks, all groups were offered the triple regimen. With data out to two years, we see that 80-85% of patients in the initial triple-drug group remains undetectable (less than 500 copies/mL). The groups who took either of the other two regimens, even though they have been receiving all three drugs for over one and a half years now, have not "caught up" (in terms of viral load suppression or T-cell rise) to the group which received triple therapy from the beginning.

"In the long term, I have already shifted over half of my research effort to vaccine development. In the long run, I think AIDS will become, in this country and Europe, a more manageable disease. And so, consequently, the real, huge problem will be in the developing countries. And the only way we know how to tackle that is through vaccines." Dr. David Ho, Aaron Diamond AIDS Research Center New York

Don't Forget the Non-Nukes!

Some excitement was generated over the upcoming non-nucleoside reverse transcriptase inhibitor (NNRTI, or "non-nuke") known as efavirenz (brand name Sustiva). This new drug joins the class which includes the already-approved drugs nevirapine (Viramune) and delavirdine (Rescriptor). A study indicated that while there is some cross-resistance between efavirenz and the other NNRTIs, the newest drug may have a more favorable resistance profile. (It may be true, but didn't we hear that with nelfinavir and the other PIs at first?) An efavirenz/indinavir combination was shown to suppress viral load significantly and with good duration of suppression (91% undetectable at less than 400 copies/mL at 60 weeks!).

Data on the long-term INCAS trial were also presented, with a follow-up of as long as two and a half years in people who had been placed on triple combination of AZT/ddI/nevirapine. Although the number of patients was small, the viral load of 69% (9 out of 13) remained undetectable for this period of time.

Although NNRTIs are not as potent as PIs, their efficacy and long-term safety continue to be documented. This class of drugs may have an expanding role in intensifying treatment regimens where some further viral load suppression is desired. They may also have "up front" use in regimens where viral load is high enough to merit treatment, but not high enough to necessarily warrant a PI (e.g. viral load of 15,000 copies/mL). Finally, these drugs provide another choice for those people who have been failed by the standard nucleoside/PI regimens.

Abacavir Caution

Last month, the Newsletter raised this issue, but it should be said again. Glaxo-Wellcome's new reverse transcriptase inhibitor, abacavir, currently in clinical trials and most likely to be approved later this year, may have a significant side effect associated with its use. Approximately 3% of people taking this drug develop a reaction (usually marked by fever, rash, and nausea, but any of these symptoms may be absent-and a person may experience diarrhea and muscle aches instead). If the medication is stopped, the symptoms subside within a few days. However, the medication must not be restarted or a life-threatening allergic reaction may occur! (There has already been at least one death reported from this, and I personally believe it could seriously impact abacavir's use if this reaction occurs in more individuals.)

Twice Daily Protease Regimens

Perhaps the biggest news about protease inhibitors came from reports that both nelfinavir (Viracept) and indinavir (Crixivan) can be used twice daily and still achieve blood levels comparable to the current three times daily dosing. The twice daily dosing requires that the drugs be taken at higher dosages than when at three times daily.

Researchers report that early clinical response in terms of degree of viral load suppression appears to be the same for the two dosing schedules. It is likely that the FDA will eventually re-label these drugs with alternative dosing regimens. Some patients and providers may have already changed dosing. Protease/Protease Combinations

A follow-up of the widely-reported study of 141 PI-na ve patients placed on ritonavir/saquinavir-initially with no nucleoside analogues (although these have since been added to a significant number of subjects)-revealed that at 48 weeks, 73% maintained a viral load level of less than 50 copies/mL. Also, a study that I personally found intriguing measured viral load suppression when amprenavir (the new Glaxo-Wellcome PI-in-development) was given alone or combined with another PI. Of the 27 initial subjects, those who had amprenavir alone had viral load reduction of 1.74 logs at four weeks. These results are certainly not impressive, and the researchers were criticized for having a single drug arm in their study. The viral suppression with amprenavir, combined with indinavir, saquinavir or nelfinavir, however, measured at least 2.5 logs and as high as 3.2 logs (with amprenavir/nelfinavir). This report of viral load reductions of more than 3 logs suggests wider potential for combination PI therapy "up front" if the viral load is considered high enough to warrant it.

Cross-Resistance: As Expected, More Than Expected

We know that many patients who are failed by one or two PIs don't seem to respond to any of the other protease inhibitors. Research evidence backs up this observation. There is indeed significant cross-resistance between all four of the currently available PIs.

Using a phenotypic test, 483 isolates were tested, of which 365 were resistant to at least one PI. The chance of isolates resistant to any single PI also being resistant to any of the other three was always greater than 50%. Geno or Pheno: What's Your Type?

As many had predicted, there are a number of problems with the current genotypic assays for drug resistance, none of which have been FDA-approved. Current research in this area is heading towards a different method for determining which drug combination works best against a given virus. These are phenotypic assays, and are being rapidly developed. Genotypic analyses, which have been "pushed" largely by the companies who have developed them, can give false positive or negative information.

Rescue With Hydroxyurea?

Contrary to what many would have hoped for, there was no definitive regimen to recommend for people who have exhausted available treatment options. (Some would call this a "salvage regimen," but I prefer "alternative regimen.") The potential use of an already FDA-approved anti-leukemia drug, hydroxyurea (brand name Hydrea), received significant media attention and even made the front page of the Los Angeles Times. The information presented at the Conference was actually rather sparse (see page 10 for more information). The good news is that, since hydroxyurea doesn't work on an HIV-specific enzyme, but rather on a human cellular enzyme, the possibility of HIV resistance developing is indeed minimal. Several studies showed good viral load suppression when the drug is taken twice daily, along with one or two nucleoside analogues-usually ddI and/or d4T-and its use will probably continue to increase. However, watch for possible declines in white blood counts when this drug is used.

Ultra Sensitive May Become Ultra Important

Several studies validated the use of viral load as an important marker. There were also reports of the so-called "ultra sensitive assays." These tests detect viral load lower than 500 copies/mL, the limit of detection of most of the present tests used, and can return values as low as 20-40 copies/mL. Reports from both France and Norway, in a total of several hundred patients, confirmed that an individual with a test result between 50 and 500, for example, is more likely to have a higher viral load on a successive reading than someone whose viral load stays less than 50.

Several ultra sensitive assays have already been developed, but an important question remains. Even if we presume that a viral load of 15 copies/mL, for example, is superior to a value of 300 in predicting lack of imminent development of resistance/progression, does this mean that it makes clinical sense to switch drug regimens at such a value?

Today there are only eleven approved anti-HIV drugs. Does a viral load well below 500 but above the limit of detection of the ultra sensitive assay mean that a regimen of three drugs needs to be replaced by another regimen of three? I doubt that clinicians will do so in the near future.

Pathogenetic Insights

Evidence was presented to support the evolving notion that the earlier HIV is detected and treated, the better the prospect for long years of reasonable health. Bruce Walker of Massachusetts General Hospital reported on the documentation of an HIV-specific T-cell response which can ultimately help rid the body of HIV-infected cells. He also indicated that this immune-response capacity appears to be permanently diminished if treatment is started "later" rather than "earlier." How late is too late remains to be discovered. (This does not mean that treatment won't help considerably even if instituted later. It just means that this particular function of the immune system may never be restored.)

PEP Becomes PET

There was some discussion (but no consensus reached for lack of data on the cost-benefit outcome) on the increasing use of post-exposure treatment (once called PEP for "post-exposure prophylaxis" and now dubbed PET for "post-exposure therapy"). This therapy would be available for individuals who sustain a possible exposure through high-risk activity, such as unprotected sex (as in condom breakage) or needle-sharing with someone who has HIV. A working group, consisting of representation from the CDC, NIH, FDA, HRSA and DHHS, anticipate releasing a preliminary statement on PEP this spring. For now, although no formal guidelines exist, in many health care settings, individuals potentially exposed to HIV-containing fluids are asking for HAART and receiving it. Good News for the Central Nervous System

There appears to be a good correlation between suppressed viral load in the blood and viral load in the central nervous system (CNS). In other words, reducing HIV in the blood also reduces HIV in the CNS. HAART was shown to be associated with decreased incidence of neurocognitive impairment. There is also evidence of markedly improved survival rates from PML, an opportunistic brain infection, just from placing patients on triple therapy.

980301
BA98030

Copyright © 1998 - 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, 3626 Sunset Blvd., Los Angeles, CA 90026 TEL: (213) 667-3262; TTD: (213) 661-7837; FAX: (213) 667-2735; Email: BeiAlive@aol.com  http://www.mbay.net/~bngalive/index2.html