AIDS TREATMENT NEWS Issue #393, July 25, 2003
phone 800-TREAT-1-2, or 215-546-3776

CONTENTS:

** Failure of Combination Abacavir + Tenofovir + Lamivudine
(3TC)
An antiretroviral combination worked much less well than
expected in controlling HIV. Patients using all three of these
drugs together should talk with their doctor and consider
changing treatment.

** FTC (Emtriva) Approved
A new antiretroviral was approved July 2 -- the 19th now
approved in the U.S. It is chemically related to 3TC.

** New HIV Treatment Guidelines Give More Advice
New U.S. treatment guidelines give doctors and patients more
guidance -- especially on what antiretrovirals to start with.
Advice on when to start has not changed. While the new
guidelines are more useful than previous editions, it remains
critically important to have a physician with extensive
experience in treating HIV.

** HIV Drugs Approved as of August 2003
Here is a list of the 19 antiretrovirals currently approved in
the U.S., listed alphabetically by generic name within each of
the four drug classes. Brand names and other common names are
also included.

** Major HIV Treatment Conference in Paris -- Finding Reports
Online
Several Web sites have excellent coverage of the 2nd IAS
(International AIDS Society) Conference on HIV Pathogenesis and
Treatment, July 13-16 in Paris. Usually readers can look through
a list of titles and click to read the reports important to
them. We also comment on how software advances could greatly
improve medical conferences over the next several years.

** Nelson Mandela on Treatment Access
"If we discard the people who are dying from AIDS, then we can
no longer call ourselves decent people."



***** Failure of Combination Abacavir + Tenofovir + Lamivudine
(3TC)

In late July 2003 GlaxoSmithKline warned physicians that a
three-drug combination of lamivudine (Epivir(R)), abacavir
(Ziagen(R)) and tenofovir (Viread(TM)) had failed to control HIV
effectively in about half the treatment-naive patients in a
clinical trial. The cause of the reduced response to this
particular regimen is not known, but it may involve mutations
causing cross-resistance to the drugs; Glaxo is also checking
for chemical interactions inside the cell. The problem is not
due to any one of the drugs; rather, for some reason this
particular combination turned out not to work well.

The company advised:

"Abacavir and lamivudine in combination with tenofovir should
not be used as a triple antiretroviral therapy when considering
a new treatment regimen for naive or pre-treated patients;

"Any patient currently controlled on therapy with this
combination should be closely monitored and considered for
modification of therapy; and

"Any usage of this triple combination with other antiretroviral
agents should be closely monitored for signs of treatment
failure."


***** FTC (Emtriva) Approved

by John S. James

The U.S. FDA announced the approval of FTC (brand name
Emtriva(TM), generic name emtricitabine, former brand name
Coviracil(TM)) on July 2, 2003.

FTC is chemically related to 3TC. It was approved primarily on
the basis of two clinical trials: one comparing FTC with d4T,
and the other comparing it with 3TC. FTC is taken once per day
with or without food. Special dosing is needed for patients with
kidney problems.

Shortly before approval, a clinical trial comparing FTC and d4T
was stopped early by its Data Safety Monitoring Board (a
somewhat unusual occurrence) because the patients in that trial
who were randomly assigned to FTC were clearly doing better than
those randomly assigned to d4T. (Note that all patients in this
trial were also taking ddI [Videx(R)] and efavirenz
[Sustiva(R)]; combining d4T and ddI is no longer recommended
because of side effects, a problem that probably contributed to
the superiority of FTC in this study.)

European approval is likely by late 2003.

FTC was approved mainly on the basis of two trials: the
comparison with d4T above, and a trial in which patients who
were on treatment including 3TC were randomly assigned to either
stay on their current regimen or switch the 3TC to FTC. The
patients in both groups did comparably well. Four percent of
those on FTC discontinued it due to adverse events, vs. none who
stayed on 3TC -- but this difference is hard to interpret since
those who could not tolerate 3TC would have stopped that
treatment earlier and could never have entered this particular
trial.

FTC has had a long development history involving several
companies, but now will be marketed worldwide by Gilead
Sciences, Inc. (The drug has been shown to be active against HIV
clades A, C, D, E, F, and G, --as well as against clade B, which
causes almost all AIDS cases in the U.S.) In the U.S., Gilead
announced that the "wholesaler acquisition cost" is $252.83 for
a bottle of 30 capsules, a one-month supply.

The FDA's announcement noted that FTC has only been approved for
adults age 18 and over, as pediatric safety and effectiveness
have not been established. It suggested using resistance testing
with pre-treated patients to check that their virus is likely to
be susceptible to FTC (the mutations M184V or M184I are the most
common cause of viral resistance to FTC). It noted that about 1%
of patients in clinical studies overall have discontinued FTC
due to adverse events. It also recommended that all patients be
tested for the presence of chronic hepatitis B virus before
starting antiretroviral treatment for HIV, and that patients co-
infected with hepatitis B be closely monitored for at least
several months after FTC is discontinued, as there have been
hepatitis B flare-ups when treatment is stopped. As with all
members of this drug class (nucleoside reverse transcriptase
inhibitors), the prescribing information carries a black-box
warning about risk of lactic acidosis and liver toxicity.

The new HIV treatment guidelines (see article in this issue) did
not consider FTC, because it was approved after the guidelines
had been developed. FTC will be discussed in the next version.

Comment

As with any new drug, FTC's place in clinical practice will
develop over time. This antiretroviral may have important
advantages, but other treatments are much better known. Our
guess is that many physicians will be conservative at first, but
will use FTC as more is learned about long-term safety and
effectiveness, and about which patients are most likely to
benefit.


***** New HIV Treatment Guidelines Give More Advice

by John S. James

New HIV treatment guidelines for adults and adolescents,
developed by a panel of experts convened by the U.S. Department
of Human Services, were published July 14, 2003. This standard
differs from previous editions in giving more direction to
physicians, especially in choosing specific drugs. You can
download this and other guidelines documents at
http://AIDSinfo.nih.gov -- click Guidelines, then Adult and
Adolescent Guidelines.

Advice on *when* to start antiretrovirals has not changed. But
instead of the previous system (pick one drug from column A and
two from column B), the new guidelines recommend choosing one of
basically two preferred regimens, with alternates available if
needed. There is also more guidance for doctors on how to deal
with drug failure and choosing a new regimen.

Much of the useful information is contained in the 29 tables at
the end of the 96-page document.

Comment

Guidelines are never the final word in a complicated, fast-
changing, and controversial area of medicine. It is still
critically important to have the advice of a physician with
extensive experience in treating HIV.


***** HIV Drugs Approved as of August 2003

Here are all the antiretroviral drugs approved in the U.S. at
the end of July 2003. We list them by drug class:

* NRTIs (nucleoside reverse transcriptase inhibitor) target
reverse transcriptase (an enzyme of HIV), by providing false
building blocks that the enzyme puts into new copies of the
virus it is building. Occasionally the false building blocks can
be incorporated into human DNA, causing toxicity.

* NNRTIs (non-nucleoside reverse transcriptase inhibitor) target
the same reverse transcriptase enzyme, but do not provide false
building blocks.

* Protease inhibitors target HIV protease, an enzyme necessary
for late steps in the formation of new copies of HIV. Some
protease inhibitors may inhibit certain human proteases as well,
causing toxicity.

* Fusion inhibitors block infection early by preventing HIV from
fusing with and entering a human cell. Only one fusion inhibitor
has been approved so far, and this particular drug is expensive
to manufacture and difficult to use.

None of these drugs can be taken alone to treat an established
HIV infection. They must be used in well-designed combination
regimens.

NRTIs:
Abacavir (Ziagen)
Didanosine - ddI (Videx)
Emtricitabine - FTC (Emtriva -- previous brand name Coviracil)
Lamivudine - 3TC (Epivir)
Stavudine - d4T (Zerit)
Tenofovir DF (Viread)
Zalcitabine - ddC (Hivid,)
Zidovudine - AZT (Retrovir)

NNRTIs
Delavirdine (Rescriptor)
Efavirenz (Sustiva, brand name Stocrin in many countries)
Nevirapine (Viramune)

PROTEASE INHIBITORS:
Amprenavir (Agenerase)
Atazanavir (Reyataz, formerly named Zrivada)
Indinavir (Crixivan)
Lopinavir+ritonavir (Kaletra)
Nelfinavir (Viracept)
Ritonavir (Norvir)
Saquinavir (Fortovase, earlier formulation Invirase)

FUSION INHIBITORS
Enfuvirtide (Fuzeon)

Combination Medications

These brand names are combinations of two or three of the
medicines above in one pill. Combinations reduce the number of
pills patients must take each day. They can also help meet
requirements of health plans that limit the number of
"prescriptions" per month regardless of medical need.
Combivir (AZT + 3TC)
Trizivir (abacavir + AZT + 3TC)


***** Major HIV Treatment Conference in Paris -- Finding Reports
Online

by John S. James

Here are some of the best Web sites for information about the
2nd IAS (International AIDS Society) Conference on HIV
Pathogenesis and Treatment, July 13-16 in Paris. On these sites
you can scan headlines and titles, then click on the articles
you want to read. Keep in mind that new information from the
Paris conference is being added all the time on these sites and
elsewhere -- and that over the next several months much of the
information from this conference will become less current, as
newer findings are reported.

Notes:

(1) If a Web link in this article does not work, the site may
have been reorganized. In that case go to the home page (usually
the first part of the Web address, through the .com or .org) and
look for the IAS (International AIDS Society) conference reports
from there.

(2) It is best to read or skim through all the titles on the Web
pages shown below. If there are many titles, a shortcut is to
use the search (find) command in your browser. But this browser
search will miss relevant articles if the titles do not happen
to use the same words you specify.

** Best Organized Site: Clinical Care Options,
http://clinicaloptions.com/go/ias2003

This site, written primarily for medical professionals, may
become the best Web presentation, and perhaps the most useful
coverage of this conference overall.

Its IAS conference coverage is organized as seven tracks:
* Daily news
* First-line antiretroviral therapy
* Antiretroviral resistance & salvage therapy
* Clinical implications of studies of HIV pathogenesis
* Pharmacology & adverse effects of therapy
* Metabolic complications and lipodystrophy
* Opportunistic infections and coinfections

The daily news stories include protease inhibitors and
cardiovascular disease, sex differences in fat redistribution
(including noting that lipoatrophy is much more common in people
with HIV than had been expected), new T-20 information, high
drug resistance in newly diagnosed people with HIV in Europe,
and a number of reports on particular protease inhibitors and
other antiretrovirals.

The other six sections include over 50 "capsule summaries" that
present major clinical trials or other important conference
presentations in a standardized table format. (For example, in
the "Metabolic Complications and Lipodystrophy" track, the
capsule summary on cardiovascular disease in a large cohort
receiving antiretroviral therapy has outline-type presentations
divided into these categories: Summary and key conclusions;
Background; Summary of study design; Baseline characteristics of
study population; and Main findings. Other capsule summaries can
have different section titles, and narrative is allowed when
needed.) This kind of presentation may seem strange at first,
but we found it effective for presenting key information
quickly. In August, Clinical Care Options expects to add
analysis of the same information by three experts in each of the
six areas covered in these tracks -- hopefully building on the
capsule summaries, and providing more scrutiny and debate on the
clinical implications than a single author's comments.

You need to register on the site to read the articles -- a free,
one-time process that takes five to ten minutes. Most Web
browsers can keep track of your user name and password, avoiding
the need to log on every time you use the site.

** Quick Summaries for Patients: The Body,
http://www.thebody.com/confs/ias2003/complete.html

This page has titles and links to more than 50 short reports,
divided into 25 topic areas (as of July 25, 2003). Readers can
scan the titles, or search for a particular word in any of the
titles, using the search function provided by most browsers. For
example, we searched for "lipoatrophy" (which means fat wasting
-- lipoatrophy can cause a sunken-face appearance, and often means that
one's antiretroviral regimen needs to be changed). We
found a topic area with five reports on lipoatrophy, and an
additional report outside that topic area.

Some of the other topic areas involve:
* Drug resistance
* Antiretroviral therapy
* Complications of antiretroviral therapy
* Clinical trial results

While The Body is designed for patients, the IAS conference was
held for medical professionals; some medical terms are
unavoidable. If you want to search for a drug, the generic name
is usually the best -- although you might want to try other
names as well. For example, Fuzeon (the brand name of the drug
also known as T-20) appears in a title as the generic name,
enfuvirtide. More importantly, be aware that different research
can be confusing and contradictory, and some will be found to be
wrong. Science is normally that way near the leading edge; only
in schoolbooks are there usually clear lines between right and
wrong ideas.

** Reports for physicians: Medscape,
http://www.medscape.com/viewprogram/2536

The Medscape HIV site reviews important late-breaker
presentations (results too late to be submitted for regular
consideration for the conference, but allowed in by a special
procedure because of their value and timeliness). Late breaker
session #1 includes the high rate of resistance found in Europe
that was widely reported in the general press, the failure of
week-on-week-off antiretroviral treatment, and the very
important study showing that HIV transmission by breastfeeding
could be prevented by treating the infant with either 3TC or
nevirapine. Late breaker session #2 included a Canadian study on
factors associated with resistance development (chiefly high
viral load -- and intermediate adherence between 60% and 90%),
good results from atazanavir in avoiding metabolic toxicities,
and promising results from two new drugs active against many
resistant viruses --SPD754, a nucleoside analog, and TMC114, a
protease inhibitor.

Outside the late breakers, some of the reports currently on the
site include:
* Treatment access initiatives in developing countries;
* 48-week data for enfuvirtide (Fuzeon, T-20);
* Update on treatment interruption (15 abstracts were presented
at the conference);
* Viral dynamics and fitness;
* Drug resistance update;
* New approaches to antiretroviral therapy;
* Complications of antiretroviral therapy;

Note: this site requires free registration. Also, early news
reports now on the site may be replaced later by CME (continuing
medical information) modules.

** NATAP,
http://www.natap.org/2003/IAS/ndxIAS.htm

The National AIDS Treatment Advocacy Project now has more than
15 articles, on subjects including antiretroviral regimens, drug
resistance, hepatitis C treatment, human growth hormone, and
methadone interactions.

** HIVandHepatitis.com,
http://www.hivandhepatitis.com/2003icr/2ndias/main.html

This site has over 40 articles on clinical trials, new
experimental antiretrovirals, viral resistance, dosing,
complications of antiretroviral therapy (over 15 articles),
salvage therapy, pharmacology, drug supply, treatment
interruption, preventing transmission, immune reconstitution,
and vaccines.

** IAPAC AIDScan,
http://www.iapac.org

The International Association of Physicians in AIDS Care
published the daily newsletter AIDScan on the four days of the
conference, with short articles on over a dozen major topics.

** Kaiser -- Video Webcasts, and Transcripts,
http://www.kiasernetwork.org/paris2003

This site has video "webcasts" and also transcripts of selected
sessions. But there are serious limitations:
* The slides, central to most of the presentations, are not
available.
* Only a small fraction of the talks have webcasts or
transcripts -- mostly the large, general lectures and debates
with important background information, but little new data (as
that might be proprietary).
* The video images are often poor quality -- and the transcripts
include many errors, so they must be read cautiously. (The
alternative would have been major delays, if all the speakers in
each session had to edit and return the transcripts of their
remarks before the session could go online.)

** Official IAS Conference Site,
http://www.ias2003.org/

The conference abstracts -- given to participants as a book, and
also as a CDROM -- are not online as of the end of July, but are
expected to be on this site in a few weeks. The Final Programme
-- a 3-megabyte PDF file of the 350-page program book given to
participants -- is currently available (except that the Late
Breakers section has been omitted).

** Official IAS Site,
http://www.ias.se/

This is the official site of the International AIDS Society
organization (as opposed to the official site for the Paris
conference of this organization). It has a 26-page article by
AIDS writer Mark Mascolini on clinical studies at the 2nd IAS
Conference on HIV Pathogenesis and Treatment.

[Also note Mark's review of a different conference, the XII
International HIV Drug Resistance Workshop, June 10-14, 2003 in
Los Cabos, Mexico. The links to both articles are currently on
the IAS home page, http://www.ias.se/ ]


Comment on Webcast and Future Conference Technology

The Present: For now we have found that the best way to present
conference information for those who were not in the meeting is
through expert reviews, like those on most of the sites
mentioned above. When webcasts are used, they should show good-
quality reproduction of the speaker's slides, not poor-quality
video of the speaker. Often the talks are useless without the
slides.

Many conferences provide abstracts online before the meeting,
but this one did not. When people travel from around the world
to spend a few days together, they need to study and plan in
advance so they can best use their time for meeting and working
with others. Not having the abstracts ahead of time hurts
participants, as well as those who need the information but were
not at the conference.

Some of the Web sites and articles above could be better
organized and written, to avoid unnecessary difficulties for
readers.

The Future: We believe the next big improvement will be speakers
creating presentations designed primarily for viewing online.
These will allow flexible arrangements of charts, animated
charts, sound, text, and video -- and allow interactive pathways
through the material if desired, including intelligent searches
based on authors' marks or annotations. Templates will allow
easy learning and setup for simple presentations, such as a
series of slides with a recorded voice lecture for each.

Then anyone could view the presentation in its original quality
at any time, either before, during, or after the meeting, and
from anywhere in the world. At the conference, speakers could
take a few minutes to explain an abbreviated view of their
presentation, then open the session to discussion; listeners
could take few notes because they would know they could review
the full information any time, and search for exactly what they
needed. Audience comments and/or group decisions could be added
to the permanent online record if the author desired. These
presentation modules would replace the abstract, slides,
pointer, lecture, webcast, transcript, and more, all in perfect
technical quality.

Then conferences could shift focus from hundreds of people
sitting in auditoriums for lectures, to working groups that come
together to build relationships and get things done. And the
other six billion people who could not get to the meeting could
still participate in that work.


***** Nelson Mandela on Treatment Access

"The world must do more, much more on every front in the fight
against AIDS. Of course, it means dramatically expanding our
prevention efforts, but the most striking inequity is our
failure to provide the lifesaving treatment to the millions of
people who need it most. The single most important step we must
now take is to provide access to treatment throughout the
developing world. There is no excuse for delay. We must start
now. If we discard the people who are dying from AIDS, then we
can no longer call ourselves decent people."

Nelson Mandela, July 15, 2003, at the International AIDS Society
conference in Paris -- quoted by Stephen Lewis, United Nations
Special Envoy on HIV/AIDS in Africa, speaking in Durban, South
Africa, August 3.


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AIDS Treatment News
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