AIDS Trestment News
July 17, 1998

Efavirenz (Sustiva™) May Equal or Exceed Protease Inhibitor in Initial Antiretroviral Combination

One of the most important treatment developments at the 12th World AIDS Conference (Geneva, June 28 - July 3) was the report of new phase III data showing that efavirenz (brand name Sustiva, formerly known as DMP-266), used in combination with other treatment, may suppress viral load at least as well as the protease inhibitor indinavir (Crixivan®) in the equivalent combination with nucleoside reverse transcriptase inhibitors. The data was from a head-to-head comparison trial in volunteers with little or no previous antiretroviral treatment. Efavirenz is still experimental; an application for marketing was submitted to the FDA by developer DuPont Pharmaceuticals (formerly DuPont Merck) on June 11, 1998, and to the European Union on June 29; a Canadian application is also being submitted.

Of course much remains to be learned about the benefits and drawbacks of each antiretroviral treatment, but a widespread consensus at the conference seemed to accept efavirenz combinations as now "on the table" for consideration among other major treatment options, which until now have mostly been built around protease inhibitors. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), like nevirapine or delavirdine.

The following research reports were presented at Geneva:

• The most noteworthy result was a comparison of viral load reduction with efavirenz plus AZT plus 3TC, vs. a standard-of-care control group treated with indinavir plus AZT plus 3TC; data were available for up to 24 weeks of treatment. This study assigned 150 patients to each arm, all of them treatment naive to NNRTIs, protease inhibitors, and 3TC. Volunteers had to have viral load over 10,000 copies, and CD4 count over 50.

  The efavirenz combination suppressed viral load to below 400 copies in a significantly higher proportion of the volunteers than the control arm, at all time points between week 2 and week 24. And fewer patients dropped out of the efavirenz study arm due to adverse events, suggesting that the side effects may have been less of a problem than with the standard-of-care treatment.

• While longer-term followup is not yet available from this study, there are 72-week results from a different trial, which tested efavirenz in combination with indinavir. The proportion of volunteers with viral load below 400 copies peaked at week 16 but was still very good at week 72 (the exact percentages depend greatly on how one accounts for missing data -- an issue we will cover separately in AIDS Treatment News). These volunteers were also NNRTI and protease inhibitor naive when they started the trial; their baseline viral load was over 20,000 copies, and their baseline CD4 count was 100 to 500. This 72-week report was based on over 40 study volunteers who have been on the treatment that long.

• Much less information is available for patients who are more heavily pre-treated. But in two studies presented at Geneva, either efavirenz plus indinavir, or efavirenz plus nelfinavir, vs. the protease inhibitor alone, was added to ongoing antiretroviral therapy with two nucleoside analogs. All these volunteers had received the nucleoside analogs for at least eight weeks before they added the new drugs. An analysis of the first 184 patients in this trial showed a statistically significant advantage of the four drugs over the three drugs, in the proportion of persons whose viral load was suppressed to below 50 copies, the cutoff for the test which was used.

• Several other efavirenz studies were presented in Geneva -- including combinations with other drugs, and also including a small study showing that efavirenz plus other antiretrovirals successfully reduced HIV levels in cerebrospinal fluid to below 400 copies, the limit of quantification of the test used, in all eight patients tested.

• According to DuPont Pharmaceuticals, common side effects of efavirenz include rash, nausea, dizziness, diarrhea, headache, and insomnia -- with the incidence of severe skin rash under one percent. Due to birth defects in an animal study, the drug should only be used in pregnancy if the benefit to the mother outweighs the risk to the fetus. In the trial comparing efavirenz plus AZT plus 3TC, vs. indinavir plus AZT plus 3TC, dizziness was significantly more common in the efavirenz arm (9% vs. 1%); significantly less common were nausea (10% vs. 22%) and vomiting. Most side effects were moderate and lasted less than two weeks.

Comment

One concern about efavirenz is that it may be unlikely to work in patients who have already developed resistance to either nevirapine or delavirdine, the two NNRTI drugs currently approved in the U.S. The three drugs of this class appear to be cross resistant, due to a few mutations, especially K103N. It is particularly important to use any NNRTI correctly, and in a maximally suppressive regimen, to minimize the chance of developing resistant HIV. (In the future it might be possible to extend the usefulness of this class of drugs, by developing an antiretroviral which is particularly effective against virus with the K103N mutation. But no such drug is available yet.)

With the protease-inhibitor-containing regimens which are now in common use, physicians have noticed that even when patients "fail" virologically, they often continue to do well clinically; virological failure (rebound of viral load, although usually not all the way to baseline) has not necessarily caused clinical failure. But no one knows if this will also happen with efavirenz. Each different class of drugs forces HIV to develop very different mutations. It is possible that some of the mutations causing viral resistance to protease inhibitors might also cause the virus to become less harmful; but even if this does turn out to be true for protease inhibitors, it might not apply to other drugs.

With protease inhibitors, the first hint of this effect was seen in an early indinavir trial, where patients were given that protease inhibitor alone at a dose which is now known to be too low. At first the median viral load went down, and the median CD4 count rose, as expected. Then resistance developed, and the viral load came back up. However, the CD4 count did not go back down, but remained up. It may be worth asking whether or not CD4 count increases are similarly sustained when HIV develops resistance to efavirenz.

Meanwhile, this question does not argue against efavirenz, since patients who start that drug would presumably switch to a protease-inhibitor regimen anyway if the first treatment failed. They would not be left on a failing efavirenz regimen.

For More Information

Efavirenz is currently available through expanded access programs; for more information, call the Sustiva Expanded Access Program, 800-998-6854 (8 a.m. to 6 p.m. Monday through Friday, from the U.S. or Canada) or in Europe call +44 (0) 1462 488263.

Additional information about the Geneva efavirenz presentations is available on the World Wide Web. See "Geneva Conference: Finding Information on the Web and Elsewhere ," in this issue of AIDS Treatment News.

Viral Resistance Overview

Just before the 12th World AIDS Conference, researchers met at Lake Maggiore, Italy, for the 2nd International Workshop on HIV Drug Resistance and Treatment Strategies, June 24-27, 1998. There were well over 150 presentations, divided into seven workshop sessions:

• New antiretrovirals;
• Mechanisms of antiretroviral resistance;
• Relationship between phenotype, genotype, and clinical response;
• Combination therapy and its failure;
• Pathogenesis, dynamics, and transmission;
• Immune reconstitution; and
• Long-term suppression/eradication strategies.

We did not attend this highly technical meeting, which is limited mainly to those who are giving research presentations. But some of the major themes which emerged were summarized at the much larger Geneva conference by Dr. John W. Mellors. He noted several take-home messages:

• Second-generation protease inhibitors that are active against resistant HIV, in laboratory tests at least, are also active against wild-type virus, and are headed for phase III studies (large clinical trials).

• New resistance mutations have been reported -- including a new kind of resistance mutation, a triple serine (S-S-S) around position 69 in the RT (reverse transcriptase) gene, caused by a doubling or insertion of codons in the gene, not by a substitution as is the case with the resistance mutations known so far. This S-S-S mutation, when combined with certain others, causes high-level resistance to AZT, d4T, and 3TC, and some increase in resistance to abacavir (1592), but it does not have much effect on ddI or ddC.

• In several retrospective studies in treatment-experienced patients, baseline phenotypic or genotypic resistance testing predicted response to new therapy -- an important step toward validating the usefulness of these tests, although prospective studies are still needed.

• Viral rebound can occur even with wild-type virus (with no known resistance mutations). Apparently this means that drug failure often happens for reasons other than drug resistance.

• An important public-health concern is that drug-resistant HIV -- including viruses which are resistant to many drugs -- is being transmitted.

We will provide additional information on resistance in our ongoing coverage.

Meanwhile, you can hear Dr. Mellors' presentation on the Webcast or on audio tape (see "Geneva Conference: Finding Information on the Web and Elsewhere ," in this issue).

Fusion Inhibitors, T-20; Chemokine Variants; Tat and Interferon Antibodies: Gallo Describes Three New Treatment Approaches

On July 2 virologist Robert C. Gallo, M.D., told a plenary session of the 12th World AIDS Conference how growing knowledge of the life cycle of HIV has led to three antiretroviral approaches entirely different from treatments in use today.

I. Fusion inhibitors. The CD4 molecule on the surface of certain cells (such as the T-helper cell) is often thought of as the receptor which allows HIV to enter the cell. But Dr. Gallo views the chemokine receptors (CCR5, CXCR4, and some others) as the real target of the virus. The CD4 receptor is usually necessary as well; it interacts with gp-120, a protein on HIV, to expose gp-41, another HIV protein, allowing a small part of gp-41 to penetrate the cell wall and cause fusion of the cell and viral membranes. Dr. Gallo cited recent publication of X-ray crystallography research which has given the most detailed picture yet of the of the virus-cell interaction (for a non-technical description, see "Scientists Take First Picture of AIDS Virus Attacking Cell" by Nicholas Wade, The New York Times June 18, 1998, page 1 of the national edition).

This complex process of cell fusion may offer many potential targets for drugs. Dr. Gallo cited T-20, being developed by Trimeris, Inc., as a potential treatment based on this approach which is already in clinical trials, and noted that viral load drops faster than with most other antiretrovirals. [Note: For background on T-20, see AIDS Treatment News #293, April 17, 1998.]

II. Chemokines. Dr. Gallo discussed three chemokines (rantes, MIP-1 alpha, and MIP-1 beta) which interact with the receptors CCR5 or CXCR4. There are both theoretical and epidemiological reasons to believe that these chemokines have antiretroviral effects; for an example of the latter, persons who have been exposed to HIV many times but remain uninfected have been found to have unusually high levels of these substances. But using the chemokines themselves as therapy could be problematic, due to their normal function of cell signaling; they usually provide a pro-inflammatory signal, which may not be wanted, and which might stimulate increased HIV production. For this reason some researchers have discounted chemokines as potential therapy. But Dr. Gallo pointed out that the cell signaling and the antiretroviral action are two different effects -- and chemical variants of the natural chemokines can inhibit HIV infection without causing the cell signaling. These chemokine variants could potentially provide a new class of antiretroviral treatments.

III. Antibodies against tat and alpha interferon. Dr. Gallo believes (as do most HIV researchers) that HIV kills some T-cells directly -- but that the larger loss is because even the uninfected T-cells do not proliferate properly. Dr. Gallo believes that part of the problem with the uninfected cells is caused by overproduction of alpha interferon (a natural inhibitor of cell proliferation) in HIV disease. Another cause of the abnormal lack of proliferation of uninfected cells may be the tat protein, which is produced by HIV and may have various harmful effects; Dr. Gallo cited recent evidence that high levels of antibodies against tat correlate with patients doing better. Also, in laboratory tests, removing tat and excessive alpha interferon from cell cultures can restore T-cell proliferation to normal.

A way to develop a treatment based on this mechanism would be to make a vaccine which would cause the body to produce antibodies against tat and against alpha interferon (to reduce the alpha interferon level to normal -- and to reduce the level of tat as much as possible, since it has no normal function in the body). The vaccine would contain chemical variants of tat and of alpha interferon, designed to cause antibody production. Such a vaccine might be given several times a year -- perhaps also with HIV antigen (to stimulate an HIV-specific T-helper response) to keep the virus under control. Dr. Gallo noted that the cost of such a treatment could be low enough to allow widespread use in developing countries.

Note: Dr. Gallo's talk will be available through 1999 at http://www.webcast.aids98.org. The talk, titled "How HIV Functions, Multiplies, and Causes Disease: Possible New Approaches to Therapy," is within the plenary, "Biomedical Advances in HIV Research," Thursday July 2. For those who prefer to purchase an audio tape, the tape number for this plenary is PL4. See "Geneva Conference: Finding Information on the Web and Elsewhere," in this issue.

Geneva Conference: Finding Information on the Web and Elsewhere

If you want more detailed information from the Geneva conference than you can get by reading newsletters or going to lectures, panel discussions, or teleconferences that may be available in your area, the best source by far at this time is the World Wide Web (often available today in public libraries, if you do not have other access). The four main kinds of conference information on the Web are: Searchable abstracts; Webcast audio lectures; Online summaries by reporters (some of them book length), and Miscellaneous (information available through various official and unofficial sites, including extended abstracts for selected presentations, and email discussion lists on certain conference topics). All of these resources are available without charge.

Later there will also be another Geneva conference information resource -- a CD-ROM with abstracts, text of some plenary talks, updated extended summaries, and several thousand slides. These disks will be expensive, 250 Swiss franks (about $175) -- probably necessary to cover the cost of preparing a labor-intensive document which will have a limited market. (You can order the 12th World AIDS Conference Update CD-ROM from Congrex Sweden AB, fax 011-46-8-661-8155.)

Also note that the abstracts as submitted will almost certainly be added to AIDSLINE, and show up in future searches of that database.

In addition, audio tapes of about 130 oral sessions are available for purchase, at $11 each (with quantity discounts); call Convention Cassettes Unlimited, 800-776-5454 (U.S., toll-free), or 760-773-4498, between 8 a.m. and 5 p.m. Pacific time Monday through Friday; ask for an order form for tapes of the 12th World AIDS Conference.

Before retrieving detailed conference information, it helps to know a little about how this meeting was organized, and how the abstracts and sessions were numbered. The major official conference presentations were divided into four tracks: Track A, Basic Science; Track B, Clinical Science and Care; Track C, Epidemiology, Prevention and Public Health; and Track D, Social and Behavioral Science. (While officially equal, in practice Track B usually gets the most emphasis at the World AIDS Conference, and Track D the least.)

The abstracts are referenced with 5-digit numbers. The first number is the day of presentation ("1" is Monday June 29, "5" is Friday July 3, and "6" means that the abstract was accepted for publication only but not given an oral or poster presentation slot. Many oral talks also appear as posters, sometimes on a different day; where appropriate, a reference may include both the oral session number and the abstract number. The important Late Breaker talks, and Late Breaker publication-only abstracts, are numbered like other abstracts, with the talks also identified as "LB 1" through "LB 24;" all were presented in two simultaneous sessions on the last day of the conference, while their abstracts were presented on earlier days. In addition, there were community symposia and other talks outside of the four major tracks; these do not have abstracts, but many of them are available on the Webcast or by audio tape.

Here are the major Geneva conference resources available today on the Web:

Searchable Abstracts

All 6,000 abstracts accepted by the conference are online at the official Web site, http://www.aids98.ch. You can search by any word or words in the abstracts, and read or print all or some of the abstracts you find. The search software works quite well. But there are some problems users should know about.

Note: The following instructions apply at this time (July 14). The site may be changed later.

The main problem now is the difficulty in finding the abstract search function on the official Conference Web site; you have to know where to look. After going to http://www.aids98.ch, select "Build your own Programme" (a bar on the left side of the screen). That will take you to another page from which you can select "Online Search Programme." [Note: This link may be difficult to see. It is just below the heading, "Build your own Programme based on the Abstracts."]

If this is your first time, you will need to follow the instructions and create a user name and password in order to reach the abstracts; for later searches, it will be faster if you remember your name and password -- but if not, you can make up another. If the system says that your user name and password are unacceptable, try another; the name is probably already in use by somebody else. (The ostensible reason for having a password is that this system was set up primarily for use before and during the conference, to prepare an itinerary of presentations to see at the meeting. The system keeps the itinerary for each user, allowing you to come back later and add more items to it.)

There are instructions for doing the search, but you may not need them. Just select "Standard Search," and you can type one word which will be searched anywhere in the abstracts. Then select "View All Titles" or "View Full Abstracts," depending on which you want to see. It is often useful to look at the titles first.

Unfortunately you can only print 10 titles or abstracts at a time -- unless you put them into your itinerary, which then allows printing of up to 200 at a time. This is the only use we ever had for the itinerary function.

Be aware that the abstracts were submitted on paper forms and then read by an optical scanner -- a machine which never works perfectly. Many typographical errors were introduced by the scanning process. Apparently there was not time or money to hire technical editors to read through all of the originals and scanned copies to make corrections; a spelling checker would have been problematic, since it is probably better to leave all the errors than to correct just the obvious (and less serious) ones which a spelling checker could find.

The online abstract search is supported by an unrestricted educational grant from Abbott Laboratories.

Comment

A way to reduce the scanning-error problem at future conferences is to give presenters the option of submitting their abstracts by email. Of course paper abstracts must still be accepted, as many will not have computer access, and others will have graphics or formulas not well suited to the computer formats provided. It would also help greatly if computer printouts of all accepted abstracts could be returned to the authors for optional corrections -- allowing them to update their content and data as well, weeks or months after the original submission deadline, making the entire conference record that much more current.

While thanking the pharmaceutical sponsors who make this information distribution possible, we also note that valuable data is being generated -- potentially exclusive access to detailed information about what everyone in the world is searching for in the online World AIDS Conference abstracts. (The same searches can be done using a CD-ROM which was given without additional charge to attendees who requested it, and then no central data is generated.) The password system makes the data collection cleaner, since most people will use the same name each time and the records of their searches can be linked together. Since the individuals are not identified, privacy issues are minimal. The main practical concern is that the requirement to go through a "front door" and use a password makes the process less convenient for users. [Note: the 12th World AIDS Conference is not collecting information about user searches of the abstracts. But the password system which is in place as we go to press does make access more difficult than otherwise necessary.]

"Webcast" Audio Lectures and Slides

About 30 to 50 lectures a day were videotaped and are being placed on the World Wide Web, where they will remain until the end of 1999. Free telephone technical support is available (but only for one month after the conference) if you need help in setting up the software; call 404-836-2186 between 4 a.m. and 5 p.m. Eastern time. This important "Webcast" system is supported by Gilead Sciences.

Whoever selected the lectures for this broadcast has done a good job in picking some of the medically important ones. But Track D (Social and Behavioral Science) was not recorded on some days, due to technical limitations. While some lectures were placed online locally within hours of presentation, others which were recorded are not yet online, apparently because of the wait for the master videotapes to clear U.S. customs.

This system allows users to receive audio recordings -- plus still photos of the accompanying slides, which do help in following the lectures. The slides do not reproduce well, however, so fine details and small writing are lost.

We did have some technical hassles setting up our computer to use this system; however, all of them involved standard computer technology, not the Webcast site specifically. Users will not be dependent on the Webcast technical help desk, which is scheduled to close soon. Those who need assistance can ask anyone who knows enough about their computer to download the "Real Player" software package and get it running on their Web browser. Once it is set up, the system is easy to use.

Online Summaries, and Other Information

The online conference summaries provide the most accessible, in-depth reports of the conference -- the easiest to obtain and the easiest to understand. Since this information is still changing rapidly, we have not listed the Web sites here, but are maintaining links at our AIDS Treatment News Internet Directory site, http://www.aidsnews.org (usually "aidsnews.org" is enough to get you there). At this site, select the 12th World AIDS Conference section.

AIDS Diarrhea: Phase III Trial Recruiting in Over 30 U.S. Sites

Persons with AIDS who have diarrhea (from any cause, including side effects of other drugs) which has lasted 14 days or more may be eligible for a study of PROVIR™ (SP-303), an experimental drug derived from a plant long used in South America to treat diarrhea. This drug, being developed by Shaman Pharmaceuticals, is believed to work differently than diarrhea medicines in common use, to directly reduce abnormal flow of water into the intestines.

This study requires six days of inpatient treatment, followed by 21 days of outpatient treatment for those who respond to the drug. Three quarters of the volunteers will receive the active drug in various doses and formulations; one quarter will receive a placebo.

Volunteers must be at least 18, meet the criteria for AIDS and be on a stable antiviral regimen, have a stool weight of at least 300 grams per day, and not be pregnant or lactating. They must not have been in a trial of another experimental drug within 30 days, nor received treatment for an intestinal infection within 14 days. There are some additional medical criteria.

Shaman Pharmaceuticals, Inc., of South San Francisco, works with traditional healers to discover drugs in plants that already are in human use -- giving it a better success rate in drug discovery than other companies which screen plants at random. Unlike some companies, Shaman does not try to patent the plants themselves -- and it takes steps to return value to the communities from which its discoveries are derived. It is also testing an oral drug for systemic fungal infection, and several potential treatments for type II diabetes.

Research sites are located in the following area: Arizona (Phoenix, Scottsdale); California (Los Angeles, Palo Alto, San Francisco, West Hollywood); District of Columbia; Florida (Coral Gables, Maitland, Miami, Orlando, Tampa); Georgia (Atlanta, Decatur); Illinois (Oak Park); Indiana (Indianapolis); Louisiana (Kenner, New Orleans); Massachusetts (Boston); Maryland (Baltimore); Minnesota (Minneapolis, St. Paul); Michigan (Detroit); Missouri (St. Louis); North Carolina (Raleigh); New Jersey (Union); New York (Brooklyn, New York City); Puerto Rico (Ponce, San Juan); Texas (Houston, San Antonio); Washington (Seattle).

For more information about the PROVIR diarrhea trial, call NCGS & Associates, 843-723-9555.

San Francisco: Geneva Conference Review, July 22

On Wednesday, July 22, the University of California AIDS Research Institute will present "The 12th World AIDS Conference in Geneva, A Report Back to the Community." The event lasts from 1 p.m. to 6 p.m., with poster displays from 1-2, presentations from 2-5, and a reception from 5-6. Audience questions are encouraged. This symposium is sponsored in part by Abbott Laboratories.

Presentations will include immunology and virology, clinical care and treatment, prevention and behavioral science, and policy and ethics.

The meeting will take place in Cole Hall, 513 Parnassus Street, San Francisco. Those using public transportation can take the N Judah to the UCSF stop on Irving Avenue -- and can then either walk up a steep hill, or take an elevator in the UCSF building up several stories to the Parnassus level, then cross Parnassus Street and turn right to find number 513.

ISSN # 1052-4207

Copyright 1998 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.